Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease.

Science.gov (United States)

Lin, Wei; Zhang, Panpan; Chen, Hua; Chen, Yu; Yang, Hongxian; Zheng, Wenjie; Zhang, Xuan; Zhang, Fengxiao; Zhang, Wen; Lipsky, Peter E

2017-02-10

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19 + CD24 - CD38 hi was increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD). A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19 + CD24 - CD38 hi plasmablasts/plasma cells, CD19 + CD24 + CD38 - memory B cells, CD19 + CD24 int CD38 int naïve B cells, and CD19 + CD24 hi CD38 hi regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19 + CD24 - CD38 hi plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array. In untreated patients with IgG4-RD, the peripheral CD19 + CD24 - CD38 hi plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19 + CD24 - CD38 hi

Plasmablasts During Acute Dengue Infection Represent a Small Subset of a Broader Virus-specific Memory B Cell Pool

Directory of Open Access Journals (Sweden)

Ramapraba Appanna

2016-10-01

Full Text Available Dengue is endemic in tropical countries worldwide and the four dengue virus serotypes often co-circulate. Infection with one serotype results in high titers of cross-reactive antibodies produced by plasmablasts, protecting temporarily against all serotypes, but impairing protective immunity in subsequent infections. To understand the development of these plasmablasts, we analyzed virus-specific B cell properties in patients during acute disease and at convalescence. Plasmablasts were unrelated to classical memory cells expanding in the blood during early recovery. We propose that only a small subset of memory B cells is activated as plasmablasts during repeat infection and that plasmablast responses are not representative of the memory B cell repertoire after dengue infection.

EBV+ HHV-8+ Multicentric Castleman Disease With Plasmablastic Aggregates in an HIV+ Man: An Evolving Clinicopathologic Entity.

Science.gov (United States)

Shivane, Aditya; Pearce, Amy; Khatib, Nadia; Smith, Mark E F

2018-06-01

We report a case of EBV+ and HHV-8+ multicentric Castleman disease with plasmablastic aggregates in an HIV-positive individual. A 41-year-old man presented in early 2015 with fevers, sweats, weight loss, intractable itching, and on subsequent testing was found to be HIV positive. Investigations showed cervical lymphadenopathy and splenomegaly. He was treated for HIV and his symptoms resolved. His symptoms recurred in January 2016, and a provisional diagnosis of multicentric Castleman disease was entertained. The HHV-8 (human herpesvirus-8) and EBV (Epstein-Barr virus) viral load was elevated. A left supraclavicular lymph node core biopsy was performed, which showed features of multicentric Castleman disease with plasmablastic aggregates that are EBV (EBER) and HHV-8 positive. He responded well to rituximab treatment and remains well with no symptoms at recent follow-up.

An Unusual Case of Plasmablastic Lymphoma Presenting as Paravertebral Mass Evaluated by {sup 18}F-FDG PET/CT

Energy Technology Data Exchange (ETDEWEB)

Treglia, Giorgio; Paone, Gaetano; Stathis, Anastasios; Ceriani, Luca; Giovanella, Luca [Oncology Institute of Southern Switzerland, Bellinzona (Switzerland)

2014-03-15

A 60-year-old man underwent radiological investigations due to the onset of back pain. Computed tomography (CT) and magnetic resonance imaging (MRI) showed the presence of a paravertebral mass located ahead the body of the third thoracic vertebra. Based on these findings the patient underwent biopsy of the paravertebral mass, which showed the presence of a plasmablastic lymphoma. Therefore, the patient underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) for staging. Before {sup 18}F-FDG injection, the patient had fasted for at least 6 h; at the time of the radiopharmaceutical injection he presented glucose blood levels corresponding to 98 mg/dl. Images were acquired 1 h after intravenous injection of 280 MBq of {sup 18}F-FDG according to the body mass index. PET images were interpreted visually and semiquantitatively by using the maximal standardized uptake value (SUVmax). {sup 18}F-FDG PET/CT showed moderate radiopharmaceutical uptake corresponding to the paravertebral lesion (SUVmax 3.3) and diffuse uptake in the skeleton suspicious for bone marrow neoplastic involvement, with more evident hypermetabolic areas in the left scapula (SUVmax 3.7), right sixth rib (SUVmax 3.5), and left iliac bone (SUVmax 3.4) (Fig. 1). Subsequent bone marrow biopsy confirmed the bone marrow infiltration by plasmablastic cells. Based on these findings, a final diagnosis of plasmablastic lymphoma with bone marrow involvement was performed and the patient was addressed to chemotherapy. Plasmablastic lymphoma is a rare CD20-negative large-cell lymphoma with plasmablastic features occurring primarily in HIV or Epstein-Barr virus positive individuals. Distinguishing this tumor from myeloma could be challenging. The most frequent site of presentation is the oral cavity, whereas extraoral localizations of plasmablastic lymphoma are considered to be very rare and they should be differentiated from extraosseous localization of

Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions

Directory of Open Access Journals (Sweden)

Ghaleb Elyamany

2015-01-01

Full Text Available Plasmablastic lymphoma (PBL is an aggressive subtype of non-Hodgkin’s lymphoma (NHL, which frequently arises in the oral cavity of human immunodeficiency virus (HIV infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM. PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC, or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH are possible options. Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.

Plasmablastic lymphoma of the oral cavity in an HIV-positive patient: staging with 18F-FDG PET/CT

International Nuclear Information System (INIS)

Makis, William; Ciarallo, Anthony; Lisbona, Robert

2011-01-01

Plasmablastic lymphoma of the oral cavity is a very rare and only recently recognized entity that has been identified almost exclusively in HIV-infected individuals. It has a predilection for the oral cavity, often exhibits very aggressive behavior and has a poor prognosis. The use of 18F-FDG PET/CT in the evaluation of HIV-associated lymphomas is a recent development, and its use in the staging of plasmablastic lymphoma of the oral cavity has not been previously reported. This rare report highlights the usefulness of 18F-FDG PET/CT in the staging of plasmablastic lymphoma of the oral cavity

CD3 Positive Gastric Plasmablastic Lymphoma in A HIV Negative Patient: A Case Report

Directory of Open Access Journals (Sweden)

Betül Bolat Küçükzeybek,

2017-03-01

Full Text Available Plasmablastic lymphoma is a rare and aggressive lymphoma characterized by the diffuse proliferation of large neoplastic cells resembling immunoblasts with an immunophenotype of plasma cells. A 47-year-old male was referred to our hospital with gastrointestinal bleeding, and a mass 10 cm in diameter, was detected. An endoscopic biopsy was performed subsequently. Histopathological examination of the biopsy material revealed ulcer, alterations associated with ulcer, and further presented a diffuse infiltration of atypical cells with abundant cytoplasm and pleomorphic nuclei, some with crush artifacts in lamina propria. Immunohistochemically, the tumor cells were negative for cytokeratin, CD2, CD20, and PAX5; but they were positive for CD3, MUM1, CD38 and CD138. Ki67 proliferation index was as high as 95%. The case was signed out as CD3-positive plasmablastic lymphoma with clinical, histopathological and immunohisto-chemical findings. The plasmablastic lymphoma case with an aberrant CD3 expression has been presented here, which is rarely observed in stomach.

CD24(hi)CD27⁺ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.

Science.gov (United States)

de Masson, Adèle; Bouaziz, Jean-David; Le Buanec, Hélène; Robin, Marie; O'Meara, Alix; Parquet, Nathalie; Rybojad, Michel; Hau, Estelle; Monfort, Jean-Benoît; Branchtein, Mylène; Michonneau, David; Dessirier, Valérie; Sicre de Fontbrune, Flore; Bergeron, Anne; Itzykson, Raphaël; Dhédin, Nathalie; Bengoufa, Djaouida; Peffault de Latour, Régis; Xhaard, Aliénor; Bagot, Martine; Bensussan, Armand; Socié, Gérard

2015-03-12

Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. © 2015 by The American Society of Hematology.

Dual-reactive B cells are autoreactive and highly enriched in the plasmablast and memory B cell subsets of autoimmune mice

Science.gov (United States)

Fournier, Emilie M.; Velez, Maria-Gabriela; Leahy, Katelyn; Swanson, Cristina L.; Rubtsov, Anatoly V.; Torres, Raul M.

2012-01-01

Rare dual-reactive B cells expressing two types of Ig light or heavy chains have been shown to participate in immune responses and differentiate into IgG+ cells in healthy mice. These cells are generated more often in autoreactive mice, leading us to hypothesize they might be relevant in autoimmunity. Using mice bearing Igk allotypic markers and a wild-type Ig repertoire, we demonstrate that the generation of dual-κ B cells increases with age and disease progression in autoimmune-prone MRL and MRL/lpr mice. These dual-reactive cells express markers of activation and are more frequently autoreactive than single-reactive B cells. Moreover, dual-κ B cells represent up to half of plasmablasts and memory B cells in autoimmune mice, whereas they remain infrequent in healthy mice. Differentiation of dual-κ B cells into plasmablasts is driven by MRL genes, whereas the maintenance of IgG+ cells is partly dependent on Fas inactivation. Furthermore, dual-κ B cells that differentiate into plasmablasts retain the capacity to secrete autoantibodies. Overall, our study indicates that dual-reactive B cells significantly contribute to the plasmablast and memory B cell populations of autoimmune-prone mice suggesting a role in autoimmunity. PMID:22927551

Plasmablastic lymphoma of the upper gingiva in an HIV-negative elderly patient

Directory of Open Access Journals (Sweden)

Tomohiro Yamada, DDS, PhD

2015-06-01

Full Text Available Plasmablastic lymphoma (PBL is a highly aggressive variant of diffuse large B-cell lymphoma and is usually treated by chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens. However, elderly patients tend to have difficulty with the chemotherapy. We successfully treated an HIV-negative elderly PBL patient with surgery alone. An 87-year-old Japanese man was referred to our hospital because of gingival swelling of the left maxilla. After several examinations, a multilobular 3-cm tumor of the left maxilla and lymph node swelling on the left side of the neck were revealed. The patient was HIV negative and human T-cell leukemia virus negative. He was diagnosed with PBL, or undifferentiated carcinoma/sarcoma, and we performed surgical therapy, radical neck dissection, and a partial maxillectomy. The surgical margin of the resected specimen was negative for tumor cells, and 6 of 27 lymph nodes contained tumor cells. Histologically, the tumor consisted of basophilic large cells with deviated nuclei. Together with the immunohistochemical findings, the final diagnosis was PBL. The patient and his family did not agree to chemotherapy. Nineteen months after surgery, he is fine and no signs of recurrence were observed. Surgery-only therapy may be a reasonable alternative for elderly PBL patients.

Plasmablasts and plasma cells: reconsidering teleost immune system organization.

Science.gov (United States)

Ye, Jianmin; Kaattari, Ilsa; Kaattari, Stephen

2011-12-01

Comparative immunologists have expended extensive efforts in the characterization of early fish B cell development; however, analysis of the post-antigen induction stages of antibody secreting cell (ASC) differentiation has been limited. In contrast, work with murine ASCs has resolved the physically and functionally distinct cells known as plasmablasts, the short-lived plasma cells and long-lived plasma cells. Teleost ASCs are now known to also possess comparable subpopulations, which can greatly differ in such basic functions as lifespan, antigen sensitivity, antibody secretion rate, differentiative potential, and distribution within the body. Understanding the mechanisms by which these subpopulations are produced and distributed is essential for both basic understanding in comparative immunology and practical vaccine engineering. Copyright © 2011 Elsevier Ltd. All rights reserved.

High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma

NARCIS (Netherlands)

Deloose, S. T. P.; Smit, L. A.; Pals, F. T.; Kersten, M.-J.; van Noesel, C. J. M.; Pals, S. T.

2005-01-01

Kaposi sarcoma-associated herpesvirus ( KSHV) is known to be associated with two distinct lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD)/MCD-associated plasmablastic lymphoma. We here report a high incidence of KSHV infection in solid

Local binary pattern variants-based adaptive texture features analysis for posed and nonposed facial expression recognition

Science.gov (United States)

Sultana, Maryam; Bhatti, Naeem; Javed, Sajid; Jung, Soon Ki

2017-09-01

Facial expression recognition (FER) is an important task for various computer vision applications. The task becomes challenging when it requires the detection and encoding of macro- and micropatterns of facial expressions. We present a two-stage texture feature extraction framework based on the local binary pattern (LBP) variants and evaluate its significance in recognizing posed and nonposed facial expressions. We focus on the parametric limitations of the LBP variants and investigate their effects for optimal FER. The size of the local neighborhood is an important parameter of the LBP technique for its extraction in images. To make the LBP adaptive, we exploit the granulometric information of the facial images to find the local neighborhood size for the extraction of center-symmetric LBP (CS-LBP) features. Our two-stage texture representations consist of an LBP variant and the adaptive CS-LBP features. Among the presented two-stage texture feature extractions, the binarized statistical image features and adaptive CS-LBP features were found showing high FER rates. Evaluation of the adaptive texture features shows competitive and higher performance than the nonadaptive features and other state-of-the-art approaches, respectively.

GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

Science.gov (United States)

Jesús, Silvia; Huertas, Ismael; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

2016-01-01

The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

Directory of Open Access Journals (Sweden)

Silvia Jesús

Full Text Available The presence of mutations in glucocerebrosidase (GBA gene is a known factor increasing the risk of developing Parkinson's disease (PD. Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021, earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013, as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

IgG4-Related Disease: Baseline clinical and laboratory features in 125 patients with biopsy-proven disease

Science.gov (United States)

Wallace, Zachary S.; Deshpande, Vikram; Mattoo, Hamid; Mahajan, Vinay S.; Kulikova, Maria; Pillai, Shiv; Stone, John H.

2015-01-01

Purpose IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. No detailed clinical and laboratory assessments have been reported in large numbers of patients with IgG4-RD diagnoses established by strict clinicopathological correlation. Methods We reviewed the baseline features of 125 patients with biopsy-proven disease. The diagnosis was confirmed by pathology review according to consensus diagnostic criteria. Disease activity and damage were assessed by the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Results Of the 125 patients, 103 had active disease and 86 were on no treatment. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher RI, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 (PIgG4+ plasmablast level and RI (R=0.45, P=0.003) was stronger than that of total plasmablasts and RI. Seventy-six (61%) of the patients were male, but no significant differences according to gender were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Glucocorticoids failed to produce sustained remission in the majority of patients. Conclusion Nearly 50% of this patient cohort with biopsy-proven, clinically-active IgG4-RD had normal serum IgG4 concentrations. Serum IgG4 elevation identify a subset with more inflammatory features. IgG4+ plasmablasts correlate well with disease activity. PMID:25988916

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Science.gov (United States)

Jesús, Silvia; Huertas, Ismael; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

2016-01-01

The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants. PMID:28030538

MicroRNAs sequencing unveils distinct molecular subgroups of plasmablastic lymphoma.

Science.gov (United States)

Ambrosio, Maria Raffaella; Mundo, Lucia; Gazaneo, Sara; Picciolini, Matteo; Vara, Prasad Satya; Sayed, Shaheen; Ginori, Alessandro; Lo Bello, Giuseppe; Del Porro, Leonardo; Navari, Mohsen; Ascani, Stefano; Yonis, Amhed; Leoncini, Lorenzo; Piccaluga, Pier Paolo; Lazzi, Stefano

2017-12-08

Plasmablastic lymphoma (PBL) is an aggressive lymphoma, often arising in the context of immunodeficiency and associated with Epstein-Barr virus (EBV) infection. The most frequently detected genetic alteration is the deregulation of MYC gene through the translocation - t(8;14)(q24;q32). The diagnosis of PBL is often challenging because it has an overlap in morphology, immunophenotype, cytogenetics and virus association with other lymphomas and plasma cell neoplasms; further, its molecular basis remains elusive. In the present study we aimed to better define the possible contribution of EBV infection as well as miRNA deregulation in PBL pathogenesis. We studied 23 cases of PBL, 19 Burkitt lymphomas (BL), and 17 extra-medullary plasmacytoma (EMPC). We used qPCR and immunohistochemistry to assess EBV latency patterns, while micro-RNA (miRNA) profiling was performed by next generation sequencing (Illumina) and validated by qPCR. Our analysis revealed a non-canonical EBV latency program with the partial expression of some proteins characterizing latency II and the activation of an abortive lytic cycle. Moreover, we identified miRNA signatures discriminating PBL from BL and EMPC. Interestingly, based on the miRNA profile, PBL appeared constituted by two discrete subgroups more similar to either BL or EMPC, respectively. This pattern was confirmed in an independent set of cases studied by qPCR and corresponded to different clinico-pathological features in the two groups, including HIV infection, MYC rearrangement and disease localization. In conclusion, we uncovered for the first time 1) an atypical EBV latency program in PBL; 2) a miRNA signature distinguishing PBL from the closest malignant counterparts; 3) the molecular basis of PBL heterogeneity.

Quantitative measurement of 18F-FDG PET/CT uptake reflects the expansion of circulating plasmablasts in IgG4-related disease.

Science.gov (United States)

Berti, Alvise; Della-Torre, Emanuel; Gallivanone, Francesca; Canevari, Carla; Milani, Raffaella; Lanzillotta, Marco; Campochiaro, Corrado; Ramirez, Giuseppe Alvise; Bozzalla Cassione, Emanuele; Bozzolo, Enrica; Pedica, Federica; Castiglioni, Isabella; Arcidiacono, Paolo Giorgio; Balzano, Gianpaolo; Falconi, Massimo; Gianolli, Luigi; Dagna, Lorenzo

2017-12-01

[18F]Fluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity. Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters [IgG4-RD Responder Index (RI)], serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation. Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVC-SUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4

Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features.

Science.gov (United States)

Niturad, Cristina Elena; Lev, Dorit; Kalscheuer, Vera M; Charzewska, Agnieszka; Schubert, Julian; Lerman-Sagie, Tally; Kroes, Hester Y; Oegema, Renske; Traverso, Monica; Specchio, Nicola; Lassota, Maria; Chelly, Jamel; Bennett-Back, Odeya; Carmi, Nirit; Koffler-Brill, Tal; Iacomino, Michele; Trivisano, Marina; Capovilla, Giuseppe; Striano, Pasquale; Nawara, Magdalena; Rzonca, Sylwia; Fischer, Ute; Bienek, Melanie; Jensen, Corinna; Hu, Hao; Thiele, Holger; Altmüller, Janine; Krause, Roland; May, Patrick; Becker, Felicitas; Balling, Rudi; Biskup, Saskia; Haas, Stefan A; Nürnberg, Peter; van Gassen, Koen L I; Lerche, Holger; Zara, Federico; Maljevic, Snezana; Leshinsky-Silver, Esther

2017-11-01

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype

Transformation of follicular lymphoma to plasmablastic lymphoma with c-myc gene rearrangement.

Science.gov (United States)

Ouansafi, Ihsane; He, Bing; Fraser, Cory; Nie, Kui; Mathew, Susan; Bhanji, Rumina; Hoda, Rana; Arabadjief, Melissa; Knowles, Daniel; Cerutti, Andrea; Orazi, Attilio; Tam, Wayne

2010-12-01

Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/ BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.

Human Herpesvirus-8 Infection Associated with Kaposi Sarcoma, Multicentric Castleman's Disease, and Plasmablastic Microlymphoma in a Man with AIDS: A Case Report with Review of Pathophysiologic Processes

Directory of Open Access Journals (Sweden)

Christian Eaton

2011-01-01

Full Text Available Kaposi sarcoma (KS, multicentric Castleman's disease (MCD, and plasmablastic microlymphoma, are all linked to human herpesvirus-8 (HHV-8 infection and HIV-induced immunodeficiency. Herein, we describe the case of a Kenyan man diagnosed with HIV in 2000. He deferred highly active antiretroviral therapy (HAART and remained in good health until his CD4+ count declined in 2006. He was hospitalized with bacterial pneumonia in 2008, after which he agreed to take HAART but did so sporadically. In 2010, he was hospitalized with fever, lymphadenopathy, pancytopenia, and an elevated HHV-8 viral load. A lymph node biopsy showed findings consistent with KS, MCD, and plasmablastic microlymphoma. Eight months after starting liposomal doxorubicin, Rituximab, and a new HAART regimen, he has improved clinically, and his HIV and HHV-8 viral loads are suppressed. These three conditions, found in the same lymph node, underscore the inflammatory and malignant potential of HHV-8, particularly in the milieu of HIV-induced immunodeficiency.

Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways.

Science.gov (United States)

Walsh, Alice M; Wechalekar, Mihir D; Guo, Yanxia; Yin, Xuefeng; Weedon, Helen; Proudman, Susanna M; Smith, Malcolm D; Nagpal, Sunil

2017-01-01

This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.

ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin–Siris-like syndrome

Science.gov (United States)

Miyatake, Satoko; Okamoto, Nobuhiko; Stark, Zornitza; Nabetani, Makoto; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Mizuguchi, Takeshi; Ohtake, Akira; Saitsu, Hirotomo; Matsumoto, Naomichi

2017-01-01

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin–Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted. PMID:28250421

ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome.

Science.gov (United States)

Miyatake, Satoko; Okamoto, Nobuhiko; Stark, Zornitza; Nabetani, Makoto; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Mizuguchi, Takeshi; Ohtake, Akira; Saitsu, Hirotomo; Matsumoto, Naomichi

2017-08-01

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin-Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted.

Manifestations of gastrointestinal plasmablastic lymphoma: a case series with literature review.

Science.gov (United States)

Luria, Lynette; Nguyen, Johnny; Zhou, Jun; Jaglal, Michael; Sokol, Lubomir; Messina, Jane L; Coppola, Domenico; Zhang, Ling

2014-09-07

Plasmablastic lymphoma (PBL) rarely occurs in the gastrointestinal (GI) tract with limited studies reported. We reviewed the clinical histories and pathology of four patients with GI PBL at our institute and similar case reports published in peer-reviewed journals. In our first case, a 40 year-old human immunodeficiency virus positive male presented with a hemorrhoid-like sensation, and was diagnosed with PBL via biopsy of a rectal mass. The second case involves a 65 year-old healthy male with bloody diarrhea who was found to have PBL in a resected sigmoid mass. The third patient was a 41 year-old male with a history of Crohn's disease who presented with abdominal pain, diarrhea, and weight loss. A small intestinal mass (PBL) was removed. The fourth patient was a 65-year-old male who was found PBL after surgical resection of bowel for his florid Crohn's disease. He later developed secondary acute myeloid leukemia. Clinical outcome was very poor in 3 out of 4 patients as reported in the literature. One patient survived chemotherapy followed by autologous transplant. The prototypical clinical presentation and variations of PBL can help create a more comprehensive differential diagnosis for GI tumors and establish an appropriate therapeutic guideline.

Clinical and biological features of multiple myeloma involving the gastrointestinal system.

Science.gov (United States)

Talamo, Giampaolo; Cavallo, Federica; Zangari, Maurizio; Barlogie, Bart; Lee, Choon-Kee; Pineda-Roman, Mauricio; Kiwan, Elias; Krishna, Somashekar; Tricot, Guido

2006-07-01

We report 24 cases of multiple myeloma (MM) with involvement of the gastrointestinal (GI) system. We found a strong association with high A lactate dehydrogenase levels, plasmablastic morphology, and A unfavorable karyotype. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The A median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, and median progression-free survival was 4 months. We conclude that MM involving the GI system is associated with adverse biological features and with short-lasting remissions, even after A high-dose chemotherapy.

Impact of highly active antiretroviral therapy in the development and remission of oral plasmablastic lymphoma

Directory of Open Access Journals (Sweden)

Vivian Petersen Wagner

2016-01-01

Full Text Available Plasmablastic lymphoma (PBL represents a rare type of non-Hodgkin lymphoma associated with human immunodeficiency virus (HIV infection. The impact of highly active antiretroviral therapy (HAART in this tumor is poorly known due to its small incidence. This study reports a case of a 33-year-old HIV-positive woman who was referred to the Stomatology Department complaining about a painful gingival growth and cervical nodule both with 20 days of evolution. The lesions appeared 7 months after the patient stopped HAART. The final diagnosis was PBL. After resuming HAART for 45 days, the gingival lesion presented complete remission. The patient continued with HAART alongside chemotherapy. At 24 months follow-up, the patient was stable. The dental surgeon plays an essential role in orientation and retention in care of HIV patients once the adherence of HAART seems to play an important role in PBL development and response to treatment.

A Case of Cutaneous Plasmablastic Lymphoma in HIV/AIDS with Disseminated Cryptococcus

Directory of Open Access Journals (Sweden)

Jun Gong

2013-01-01

Full Text Available We present a case of a patient with HIV/AIDS who presented with a tender left lower extremity cutaneous mass over a site of previous cryptococcal infection and was found to have plasmablastic lymphoma (PBL. The incidence of PBL is estimated to account for less than 5% of all cases of non-Hodgkin lymphoma (NHL in HIV-positive individuals. In fact, there were only two reports of extraoral PBL at the time of a 2003 review. PBL in HIV-positive individuals is an aggressive malignancy that tends to occur in middle-aged males with low CD4 counts, high viral loads, and chronic HIV infection. The definitive diagnosis can be made with biopsy which typically shows malignant lymphoid cells that stain positive for plasma cell markers and negative for B-cell markers. The most common treatment is chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens, but the overall survival rate is poor despite its relative responsiveness to chemotherapy. This case highlights the challenges that remain in improving clinical outcomes, the importance of antiretroviral therapy and HIV disease control, and a potential association between a chronic inflammatory state caused by disseminated Cryptococcus and tumorigenesis in individuals with PBL.

Identifying noncoding risk variants using disease-relevant gene regulatory networks.

Science.gov (United States)

Gao, Long; Uzun, Yasin; Gao, Peng; He, Bing; Ma, Xiaoke; Wang, Jiahui; Han, Shizhong; Tan, Kai

2018-02-16

Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Directory of Open Access Journals (Sweden)

Zhiyv Niu

2018-03-01

Full Text Available ObjectiveThe aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.Patients and methodsClinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.ResultsGenetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser. The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1 have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1 has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.ConclusionThe findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features.

Science.gov (United States)

Niu, Zhiyv; Pontifex, Carly Sabine; Berini, Sarah; Hamilton, Leslie E; Naddaf, Elie; Wieben, Eric; Aleff, Ross A; Martens, Kristina; Gruber, Angela; Engel, Andrew G; Pfeffer, Gerald; Milone, Margherita

2018-01-01

The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1 , respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the

Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma

International Nuclear Information System (INIS)

Jung, Tae-Sik; Kim, Tae-Yong; Kim, Kyung-Won

2007-01-01

We performed this study to compare the clinicopathologic features and outcomes between the patients with poorly differentiated thyroid carcinoma (PDTC) and the patients with the aggressive variants of papillary thyroid carcinoma (PTC). To evaluate the prognostic factors for survival of the patients with PDTC, we selected 49 patients with PDTC and 23 patients with the aggressive variants of PTC from three hospitals during the recent 15 years. The five-year survival rate and clinicopathologic features of the patients with PDTC were not different from those of the patients with the aggressive variants of PTC. Univariate analysis revealed the significant poor prognostic factors for survival of the patients with PDTC and the aggressive variants of PTC as follows: an age more than 45 years, a tumor size larger than 4 cm, the presence of tumor invasion to extrathyroidal tissue or the trachea, the presence of cervical lymph node invasion, the presence of distant metastasis, the absence of high-dose radioactive iodine (RAI) therapy, and tumor, nodes and metastasis (TNM) stage II, III and IV. Distant metastasis and high-dose RAI therapy were independent significant predictors for survival of the patients with PDTC and the aggressive variants of PTC on multivariate analysis. However, distant metastasis was the only independent significant predictors for survival of the patients with PDTC excluding patients with the aggressive variants of PTC. (author)

Linfomas plasmoblásticos del tracto gastrointestinal en pacientes con sida Plasmablastic lymphoma of the gastrointestinal tract in AIDS patients

Directory of Open Access Journals (Sweden)

Alejandro Avilés-Salas

2011-12-01

was to review the clinical-pathologic features of PL of the gastrointestinal tract in 5 patients with HIV/aids disease. We performed a retrospective study of PL of the gastrointestinal tract diagnosed at the National Institute of Cancer at Mexico City, from 2000 to 2009. Clinical and pathological information was obtained and immunohistochemical studies were performed in paraffin-embedded tissue sections. The presence of Epstein-Barr Virus (EBV was examined by in situ polymerase chain reaction (PCR. Four male and 1 female were included with a median of age of 29 years. Three tumors involved the ano-rectal area, one tumor the ascendant colon and one tumor the stomach. All tumors were histologically characterized by a monotonous proliferation of large lymphoid cell with plasmablastic features. Tumor cells were CD 138 / MUM-1positive and CD 20 / PAX-5 negative in all cases. EVB genome was detected by in situ PCR in 4 cases. The median of follow-up was 18 months, and revealed that three patients are alive with neoplasm disease and two patients are still alive with no evidence of the neoplasm. Recognition of this entity by pathologists and clinicians is important in order to establish the correct diagnosis and the early treatment of these patients.

Novel de novo pathogenic variant in the NR2F2 gene in a boy with congenital heart defect and dysmorphic features.

Science.gov (United States)

Upadia, Jariya; Gonzales, Patrick R; Robin, Nathaniel H

2018-04-16

The NR2F2 gene plays an important role in angiogenesis and heart development. Moreover, this gene is involved in organogenesis in many other organs in mouse models. Variants in this gene have been reported in a number of patients with nonsyndromic atrioventricular septal defect, and in one patient with congenital heart defect and dysmorphic features. Here we report an 11-month-old Caucasian male with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect. He was later found to have a pathogenic mutation in the NR2F2 gene by whole exome sequencing. This is the second instance in which an NR2F2 mutation has been identified in a child with a congenital heart defect and other anomalies. This case suggests that some variants in NR2F2 may cause syndromic forms of congenital heart defect. © 2018 Wiley Periodicals, Inc.

Ultrasonographic imaging of papillary thyroid carcinoma variants

Energy Technology Data Exchange (ETDEWEB)

Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2017-04-15

Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

Pediatric cervical spine in emergency: radiographic features of normal anatomy, variants and pitfalls.

Science.gov (United States)

Adib, Omar; Berthier, Emeline; Loisel, Didier; Aubé, Christophe

2016-12-01

Injuries of the cervical spine are uncommon in children. The distribution of injuries, when they do occur, differs according to age. Young children aged less than 8 years usually have upper cervical injuries because of the anatomic and biomechanical properties of their immature spine, whereas older children, whose biomechanics more closely resemble those of adults, are prone to lower cervical injuries. In all cases, the pediatric cervical spine has distinct radiographic features, making the emergency radiological analysis of it difficult. Such features as hypermobility between C2 and C3, pseudospread of the atlas on the axis, pseudosubluxation, the absence of lordosis, anterior wedging of vertebral bodies, pseudowidening of prevertebral soft tissue and incomplete ossification of synchondrosis can be mistaken for traumatic injuries. The interpretation of a plain radiograph of the pediatric cervical spine following trauma must take into account the age of the child, the location of the injury and the mechanism of trauma. Comprehensive knowledge of the specific anatomy and biomechanics of the childhood spine is essential for the diagnosis of suspected cervical spine injury. With it, the physician can, on one hand, differentiate normal physes or synchondroses from pathological fractures or ligamentous disruptions and, on the other, identify any possible congenital anomalies that may also be mistaken for injury. Thus, in the present work, we discuss normal radiological features of the pediatric cervical spine, variants that may be encountered and pitfalls that must be avoided when interpreting plain radiographs taken in an emergency setting following trauma.

Pediatric cervical spine in emergency: radiographic features of normal anatomy, variants and pitfalls

International Nuclear Information System (INIS)

Adib, Omar; Berthier, Emeline; Loisel, Didier; Aube, Christophe

2016-01-01

Injuries of the cervical spine are uncommon in children. The distribution of injuries, when they do occur, differs according to age. Young children aged less than 8 years usually have upper cervical injuries because of the anatomic and biomechanical properties of their immature spine, whereas older children, whose biomechanics more closely resemble those of adults, are prone to lower cervical injuries. In all cases, the pediatric cervical spine has distinct radiographic features, making the emergency radiological analysis of it difficult. Such features as hypermobility between C2 and C3, pseudospread of the atlas on the axis, pseudosubluxation, the absence of lordosis, anterior wedging of vertebral bodies, pseudowidening of prevertebral soft tissue and incomplete ossification of synchondrosis can be mistaken for traumatic injuries. The interpretation of a plain radiograph of the pediatric cervical spine following trauma must take into account the age of the child, the location of the injury and the mechanism of trauma. Comprehensive knowledge of the specific anatomy and biomechanics of the childhood spine is essential for the diagnosis of suspected cervical spine injury. With it, the physician can, on one hand, differentiate normal physes or synchondroses from pathological fractures or ligamentous disruptions and, on the other, identify any possible congenital anomalies that may also be mistaken for injury. Thus, in the present work, we discuss normal radiological features of the pediatric cervical spine, variants that may be encountered and pitfalls that must be avoided when interpreting plain radiographs taken in an emergency setting following trauma. (orig.)

Pediatric cervical spine in emergency: radiographic features of normal anatomy, variants and pitfalls

Energy Technology Data Exchange (ETDEWEB)

Adib, Omar; Berthier, Emeline; Loisel, Didier; Aube, Christophe [University Hospital of Angers, Department of Radiology, Angers (France)

2016-12-15

Injuries of the cervical spine are uncommon in children. The distribution of injuries, when they do occur, differs according to age. Young children aged less than 8 years usually have upper cervical injuries because of the anatomic and biomechanical properties of their immature spine, whereas older children, whose biomechanics more closely resemble those of adults, are prone to lower cervical injuries. In all cases, the pediatric cervical spine has distinct radiographic features, making the emergency radiological analysis of it difficult. Such features as hypermobility between C2 and C3, pseudospread of the atlas on the axis, pseudosubluxation, the absence of lordosis, anterior wedging of vertebral bodies, pseudowidening of prevertebral soft tissue and incomplete ossification of synchondrosis can be mistaken for traumatic injuries. The interpretation of a plain radiograph of the pediatric cervical spine following trauma must take into account the age of the child, the location of the injury and the mechanism of trauma. Comprehensive knowledge of the specific anatomy and biomechanics of the childhood spine is essential for the diagnosis of suspected cervical spine injury. With it, the physician can, on one hand, differentiate normal physes or synchondroses from pathological fractures or ligamentous disruptions and, on the other, identify any possible congenital anomalies that may also be mistaken for injury. Thus, in the present work, we discuss normal radiological features of the pediatric cervical spine, variants that may be encountered and pitfalls that must be avoided when interpreting plain radiographs taken in an emergency setting following trauma. (orig.)

Influenza virus sequence feature variant type analysis: evidence of a role for NS1 in influenza virus host range restriction.

Science.gov (United States)

Noronha, Jyothi M; Liu, Mengya; Squires, R Burke; Pickett, Brett E; Hale, Benjamin G; Air, Gillian M; Galloway, Summer E; Takimoto, Toru; Schmolke, Mirco; Hunt, Victoria; Klem, Edward; García-Sastre, Adolfo; McGee, Monnie; Scheuermann, Richard H

2012-05-01

Genetic drift of influenza virus genomic sequences occurs through the combined effects of sequence alterations introduced by a low-fidelity polymerase and the varying selective pressures experienced as the virus migrates through different host environments. While traditional phylogenetic analysis is useful in tracking the evolutionary heritage of these viruses, the specific genetic determinants that dictate important phenotypic characteristics are often difficult to discern within the complex genetic background arising through evolution. Here we describe a novel influenza virus sequence feature variant type (Flu-SFVT) approach, made available through the public Influenza Research Database resource (www.fludb.org), in which variant types (VTs) identified in defined influenza virus protein sequence features (SFs) are used for genotype-phenotype association studies. Since SFs have been defined for all influenza virus proteins based on known structural, functional, and immune epitope recognition properties, the Flu-SFVT approach allows the rapid identification of the molecular genetic determinants of important influenza virus characteristics and their connection to underlying biological functions. We demonstrate the use of the SFVT approach to obtain statistical evidence for effects of NS1 protein sequence variations in dictating influenza virus host range restriction.

Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH: revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma

Directory of Open Access Journals (Sweden)

Lu Xin-Yan

2009-11-01

Full Text Available Abstract Background Plasmablastic lymphoma (PL is a subtype of diffuse large B-cell lymphoma (DLBCL. Studies have suggested that tumors with PL morphology represent a group of neoplasms with clinopathologic characteristics corresponding to different entities including extramedullary plasmablastic tumors associated with plasma cell myeloma (PCM. The goal of the current study was to evaluate the genetic similarities and differences among PL, DLBCL (AIDS-related and non AIDS-related and PCM using array-based comparative genomic hybridization. Results Examination of genomic data in PL revealed that the most frequent segmental gain (> 40% include: 1p36.11-1p36.33, 1p34.1-1p36.13, 1q21.1-1q23.1, 7q11.2-7q11.23, 11q12-11q13.2 and 22q12.2-22q13.3. This correlated with segmental gains occurring in high frequency in DLBCL (AIDS-related and non AIDS-related cases. There were some segmental gains and some segmental loss that occurred in PL but not in the other types of lymphoma suggesting that these foci may contain genes responsible for the differentiation of this lymphoma. Additionally, some segmental gains and some segmental loss occurred only in PL and AIDS associated DLBCL suggesting that these foci may be associated with HIV infection. Furthermore, some segmental gains and some segmental loss occurred only in PL and PCM suggesting that these lesions may be related to plasmacytic differentiation. Conclusion To the best of our knowledge, the current study represents the first genomic exploration of PL. The genomic aberration pattern of PL appears to be more similar to that of DLBCL (AIDS-related or non AIDS-related than to PCM. Our findings suggest that PL may remain best classified as a subtype of DLBCL at least at the genome level.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene

2017-04-17

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Semantic prioritization of novel causative genomic variants

KAUST Repository

Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

2017-01-01

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD).

Science.gov (United States)

Balasubramaniam, Shanti; Lewis, B; Mock, D M; Said, H M; Tarailo-Graovac, M; Mattman, A; van Karnebeek, C D; Thorburn, D R; Rodenburg, R J; Christodoulou, J

2017-01-01

Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with

Primary central nervous system plasmablastic lymphoma presenting in human immunodeficiency virus-negative but Epstein-Barr virus-positive patient: A case report

Directory of Open Access Journals (Sweden)

Zhang Li

2012-05-01

Full Text Available Abstract We report a 32-year-old Outer Mongolian man, with plasmablastic lymphoma (PBL primarily occured in the central nervous system and diagnosed by surgical resection. This patient appeared headache and Magnetic resonance imaging (MRI showed multiple lesions in the right cerebral hemisphere including the right frontal-parietal lobe and right basal ganglia and the left cerebellum, he was diagnosed as lymphoma by stereotactic biopsy in January 2009 in local hospital, and was given radiotherapy 33 times after the biopsy. The patient was admitted to The Military General Hospital of Beijing PLA., Beijing, P.R. China on March 9th, 2011, with chief complaints of right limbs convulsioned suddenly, then fell down and lose of his consciousness, then awoke after 4 to 5 minutes, with symptoms of angulus oris numbness and the right upper limb powerless ten days ago. MRI of the brain revealed a well-defined hyperdense and enhancing mass in the left frontal-parietal lobe, the meninges are closely related, there was extensive peritumoural edema noted with pressure effects, as evident by effacement of the left lateral ventricles and a 0.5 cm shift of the midline to the right side. Surgical resection showed markedly atypical, large singly dispersed or cohesive proliferation of plasmacytoid cells with frequent abnormal mitoses and binucleation, some neoplastic cells were large with round or oval nuclei and showed coarse chromatin and smaller or unapparent nucleoli, some neoplastic cells with prominent nucleoli, apoptosis and necrosis were often presented. Immunohistochemistry staining and gene rearrangement together with other supportive investigation confirmed the diagnosis of primary central nervous system plasmablastic lymphoma. A month later, he was started on chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, leurocristime and prednisone for a week. Other supportive treatment was provided for symptomatic epilepsy. The patient regained

Variant Review with the Integrative Genomics Viewer.

Science.gov (United States)

Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

2017-11-01

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

Primary plasmablastic lymphoma of the central nervous system in an immunocompetent man: A case report and review of literature

Directory of Open Access Journals (Sweden)

Rama Kumari Badyal

2014-01-01

Full Text Available Plasmablastic lymphoma (PBL is an aggressive non-Hodgkin lymphoma classically occurring in individuals infected with human immunodeficiency virus (HIV. It has a predilection for the oral cavity and jaw. However, recent case reports have shown this variety of lymphoma in the stomach, lung, nasal cavity, cervical lymph nodes and jejunum in HIV-negative individuals. In this manuscript we report a case of primary PBL of brain in an HIV-negative heterosexual man, who presented with multiple episodes of seizures and hemiparesis. It proved a diagnostic challenge as initial stereotactic brain biopsy showed only few necrotic fragments and possibility of glioblastoma multiforme was rendered. Later patient underwent craniotomy and subsequent histopathology combined with immunohistochemistry led us in making a correct diagnosis of extramedullary PBL. Extensive systemic work up failed to reveal any disease outside the central nervous system. Only single case of primary PBL of brain in HIV-negative individual has been reported until date. To the best of our knowledge, this is the second report to suggest such an association.

Simple and complex dysembryoplastic neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology

Energy Technology Data Exchange (ETDEWEB)

Campos, Alexandre R.; Clusmann, Hans; Lehe, Marec von; Schramm, Johannes [University of Bonn Medical Center, Department of Neurosurgery, Bonn (Germany); Niehusmann, Pitt; Becker, Albert J. [University of Bonn Medical Center, Department of Neuropathology, Bonn (Germany); Urbach, Horst [University of Bonn Medical Center, Department of Radiology, Bonn (Germany)

2009-07-15

Dysembryoplastic neuroepithelial tumors (DNTs) are long-term epilepsy associated tumors subdivided into simple and complex variants. The purpose of this study was to relate different DNT components identified on magnetic resonance imaging (MRI) to histopathological features and to test the hypothesis that glial nodules as a histopathological feature of complex variants induce an occasional glioma misdiagnosis. Clinical, MRI, and histopathologic features of DNTs operated between 1988 and 2008 were reviewed. From a total of 61 DNTs, 48 simple and 13 complex variants were identified. Multiple or single pseudocysts in a cortical/subcortical location with small cysts sometimes separated from the tumor represented the glioneuronal element and were found in all DNTs. FLAIR hyperintense tissue was found between pseudocysts but - in neocortical DNTs - also circumscript in deeper tumor parts. Calcification and hemorrhages in this location occurred in four of 13 complex variants, and one of these patients was also the only one with tumor growth. Patients with complex variants had earlier seizure onset, and complex variants were more often located outside the temporal lobe. Although complex variants represented a higher diagnostic challenge, misdiagnoses also occurred in simple variants. One of five of DNTs showed contrast enhancement, which varied on follow-up studies with enhancing parts becoming nonenhancing and vice versa. The glioneuronal element is readily identifiable on MRI and should be considered to support the DNT diagnosis. Complex DNT variants have a different clinical profile and a more variable histopathological and MRI appearance; however, misdiagnoses occasionally also occur in simple variants. (orig.)

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

Science.gov (United States)

Schönewolf-Greulich, B; Tejada, M-I; Stephens, K; Hadzsiev, K; Gauthier, J; Brøndum-Nielsen, K; Pfundt, R; Ravn, K; Maortua, H; Gener, B; Martínez-Bouzas, C; Piton, A; Rouleau, G; Clayton-Smith, J; Kleefstra, T; Bisgaard, A-M; Tümer, Z

2016-06-01

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with kiaa2022 pathogenic variants and review of the literature.

Science.gov (United States)

Lorenzo, Melissa; Stolte-Dijkstra, Irene; van Rheenen, Patrick; Smith, Ronald Garth; Scheers, Tom; Walia, Jagdeep S

2018-04-25

KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. © 2018 Wiley Periodicals, Inc.

Variant of Rett syndrome and CDKL5 gene

DEFF Research Database (Denmark)

Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

2012-01-01

UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all...

Ultrasonographic Features of Papillary Thyroid Carcinomas According to Their Subtypes

Directory of Open Access Journals (Sweden)

Hye Jin Baek

2018-05-01

Full Text Available BackgroundThe ultrasonographic characteristics and difference for various subtypes of papillary thyroid carcinoma (PTC are still unclear. The aim of this study was to compare the ultrasonographic features of PTC according to its subtype in patients undergoing thyroid surgery.MethodsIn total, 140 patients who underwent preoperative thyroid ultrasonography (US and thyroid surgery between January 2016 and December 2016 were included. The ultrasonographic features and the Korean Thyroid Imaging Reporting and Data System (K-TIRADS category of each thyroid nodule were retrospectively evaluated by a single radiologist, and differences in ultrasonographic features according to the PTC subtype were assessed.ResultsAccording to histopathological analyses, there were 97 classic PTCs (62.2%, 34 follicular variants (21.8%, 5 tall cell variants (3.2%, 2 oncocytic variants (1.3%, 1 Warthin-like variant (0.6%, and 1 diffuse sclerosing variant (0.6%. Most PTCs were classified under K-TIRADS category 5. Among the ultrasonographic features, the nodule margin and the presence of calcification were significantly different among the PTC subtypes. A spiculated/microlobulated margin was the most common type of margin, regardless of the PTC subtype. In particular, all tall cell variants exhibited a spiculated/microlobulated margin. The classic PTC group exhibited the highest prevalence of intranodular calcification, with microcalcification being the most common. The prevalence of multiplicity and nodal metastasis was high in the tall cell variant group.ConclusionThe majority of PTCs in the present study belonged to K-TIRADS category 5, regardless of the subtype. Our findings suggest that ultrasonographic features are not useful for distinguishing PTC subtypes.

DANN: a deep learning approach for annotating the pathogenicity of genetic variants.

Science.gov (United States)

Quang, Daniel; Chen, Yifei; Xie, Xiaohui

2015-03-01

Annotating genetic variants, especially non-coding variants, for the purpose of identifying pathogenic variants remains a challenge. Combined annotation-dependent depletion (CADD) is an algorithm designed to annotate both coding and non-coding variants, and has been shown to outperform other annotation algorithms. CADD trains a linear kernel support vector machine (SVM) to differentiate evolutionarily derived, likely benign, alleles from simulated, likely deleterious, variants. However, SVMs cannot capture non-linear relationships among the features, which can limit performance. To address this issue, we have developed DANN. DANN uses the same feature set and training data as CADD to train a deep neural network (DNN). DNNs can capture non-linear relationships among features and are better suited than SVMs for problems with a large number of samples and features. We exploit Compute Unified Device Architecture-compatible graphics processing units and deep learning techniques such as dropout and momentum training to accelerate the DNN training. DANN achieves about a 19% relative reduction in the error rate and about a 14% relative increase in the area under the curve (AUC) metric over CADD's SVM methodology. All data and source code are available at https://cbcl.ics.uci.edu/public_data/DANN/. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

ADULT VARIANT BARTTER’S SYNDROME- A CASE REPORT

Directory of Open Access Journals (Sweden)

Ishwar Sidappa Hasabi

2017-02-01

Full Text Available BACKGROUND Bartter syndrome is a group of channelopathies with different genetic origins and molecular pathophysiologies, but sharing common feature of decreased tubular transport of sodium chloride in thick ascending loop of Henle (TAL, 1 although more common in antenatal group. Classic adult variant of Bartter syndrome is a rare entity. We hereby present a rare adult variant of classic Bartter syndrome.

Features of progression of chronic hepatitis C in children with different variants of polymorphism of the gene IL-28B

Directory of Open Access Journals (Sweden)

Berezenko V.S.

2016-03-01

Full Text Available Purpose. To study the features of the progression of chronic hepatitis C in children with different variants of polymorphism of the gene IL-28B. Materials and methods. The study involved 57 children aged 3–18 years with CHC. All patients were involved in clinical, laboratory and instrumental examination. The stage of fibrosis was assessed morphologicallyon a scale METAVIR, by the calculation method — Fibro Test, on APRI index, and by the concentration of hyaluronic acid (HA, transforming growth factor TGF- β1 in serum usingIFA. The SNP genotypes of rs8099917 and rs12979860 lociin IL-28B were determinedby the method of the polymer chain reaction (PCR. A statistical analysis of the data was conducted. Resume. Most of the patients were children with chronic hepatitis C who had genotype CT at rs12979860 locus of the gene IL-28B (54% and the TT geno-type at rs8099917 locus (60%. It was found that fibrogenesis in the liver of patients with chronic hepatitis C depends on the polymorphism of the gene IL-28B. Unfavorable genotypevariants for the development of liver fibrosis are: TT (rs12979860, CT (rs12979860 and TG/GG (rs8099917. Variants CC (rs12979860 and TT (rs8099917 have a beneficial effect on the course of chronic hepatitis C, including patients with a lower stage of fibrosis. To determine the risk of progression of chronic hepatitis C it may be sufficient to determine the polymorphism of rs12979860locusin the gene IL-28B. Conclusions.The polymorphism variants CC (rs12979860 and TT (rs8099917of the gene IL-28Bare more favorable (lower severity of fibrosis in the progression of chronic hepatitis C in children. Variant TT (rs12979860 in the polymorphism of the gene IL-28B is associated with the progression of hepatitis — faster development of liver fibrosis.

The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features

NARCIS (Netherlands)

Ossenkoppele, R.; Pijnenburg, Y.A.L.; Perry, D.C.; Cohn-Sheehy, B.I.; Scheltens, N.M.E.; Vogel, J.W.; Kramer, J.H.; van der Vlies, A.E.; La Joie, R.; Rosen, H.J.; van der Flier, W.M.; Grinberg, L.T.; Rozemuller, A.J.M.; Huang, E.J.; van Berckel, B.N.M.; Miller, B.L.; Barkhof, F.; Jagust, W.J.; Scheltens, P.; Seeley, W.W.; Rabinovici, G.D.

2015-01-01

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical,

MRI features of extraskeletal myxoid chondrosarcoma

Energy Technology Data Exchange (ETDEWEB)

Tateishi, Ukihide; Arai, Yasuaki [National Cancer Center Hospital, Division of Diagnostic Radiology, Tokyo (Japan); Hasegawa, Tadashi [Sapporo Medical University School of Medicine, Department of Clinical Pathology, Sapporo (Japan); Nojima, Takayuki [Kanazawa Medical University, Department of Pathology, Ishikawa (Japan); Takegami, Tsutomu [Kanazawa Medical University, Medical Research Institute, Ishikawa (Japan)

2006-01-01

To describe the MRI features of extraskeletal myxoid chondrosarcoma in comparison with clinicopathologic findings. The study comprised 12 male subjects and seven female subjects with a mean age of 53 years (range 16-76 years). MRI findings, evaluated by two radiologists with agreement by consensus, were compared for histopathologic features. The tumor size ranged from 2.0 cm to 20.0 cm (mean 8.9 cm). Fusion gene transcripts could be detected in 13 (68%) of the 19 cases: EWS-CHN in nine cases, TAF2N-CHN in three, and TFG-TCH in one. There were six fusion-negative cases. Signal characteristics on T1-weighted and T2-weighted MR images were non-specific with regard to each cytogenetic variant. Peripheral enhancement was seen more frequently in tumors with the EWS-CHN variant than in those with other cytogenetic variants. The characteristic pattern of enhancement corresponded to the presence of fibrous septa and peripheral areas of high cellularity within lobules, by correlation with pathologic findings. All cases with TAF2N-CHN or TFG-TCH variants showed invasion of extracompartmental structure, bone, or vessels. Extraskeletal myxoid chondrosarcoma is an uncommon soft-tissue malignancy that may be recognized by MRI features of multi-lobular soft-tissue mass often invading extracompartmental, bony, and vascular structures. (orig.)

Analysis of the energy development variants

International Nuclear Information System (INIS)

Tsvetanov, P.

1990-01-01

Analysis of the variants of energy development is made as the third stage of a procedure of energy-economy interrelations dynamics study, the other two stages being the scenarios description and the formulation of the variants. This stage includes a research on the dimensions and the dynamics of the resources demands, the general features and the trends of the national energy development. There is a presentation of a comparative analysis of the variants in terms of economic indices and energy values, computed by the model IMPACT-B. A resource evaluation of the development variants is given in terms of investments, requirements (direct, indirect and total) and limited national resources demands of the energy system. The trends of the national energy development discussed are: trends characterizing the changes in the structure of the energy consumption, resulting from changes in the economy; trends of the energy system impact on the productivity of labor; general trends of the proportionality in the industrial, the household and services sector development. 16 refs., 16 figs., 4 tabs. (R.Ts.)

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

DEFF Research Database (Denmark)

Schönewolf-Greulich, Bitten; Tejada, Maria-Isabel; Stephens, K

2016-01-01

. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X......-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism...

Component Composition Using Feature Models

DEFF Research Database (Denmark)

Eichberg, Michael; Klose, Karl; Mitschke, Ralf

2010-01-01

interface description languages. If this variability is relevant when selecting a matching component then human interaction is required to decide which components can be bound. We propose to use feature models for making this variability explicit and (re-)enabling automatic component binding. In our...... approach, feature models are one part of service specifications. This enables to declaratively specify which service variant is provided by a component. By referring to a service's variation points, a component that requires a specific service can list the requirements on the desired variant. Using...... these specifications, a component environment can then determine if a binding of the components exists that satisfies all requirements. The prototypical environment Columbus demonstrates the feasibility of the approach....

First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature

Directory of Open Access Journals (Sweden)

Maddalena Migliavacca

2018-02-01

Full Text Available Adenosine deaminase-deficient severe combined immunodeficiency disease (ADA-SCID is a primary immune deficiency characterized by mutations in the ADA gene resulting in accumulation of toxic compounds affecting multiple districts. Hematopoietic stem cell transplantation (HSCT from a matched donor and hematopoietic stem cell gene therapy are the preferred options for definitive treatment. Enzyme replacement therapy (ERT is used to manage the disease in the short term, while a decreased efficacy is reported in the medium-long term. To date, eight cases of lymphomas have been described in ADA-SCID patients. Here we report the first case of plasmablastic lymphoma occurring in a young adult with ADA-SCID on long-term ERT, which turned out to be Epstein–Barr virus associated. The patient previously received infusions of genetically modified T cells. A cumulative analysis of the eight published cases of lymphoma from 1992 to date, and the case here described, reveals a high mortality (89%. The most common form is diffuse large B-cell lymphoma, which predominantly occurs in extra nodal sites. Seven cases occurred in patients on ERT and two after haploidentical HSCT. The significant incidence of immunodeficiency-associated lymphoproliferative disorders and poor survival of patients developing this complication highlight the priority in finding a prompt curative treatment for ADA-SCID.

Odontogenic keratocyst: a peripheral variant.

Science.gov (United States)

Vij, H; Vij, R; Gupta, V; Sengupta, S

2011-01-01

Odontogenic keratocyst, which is developmental in nature, is an intraosseous lesion though on rare occasions it may occur in an extraosseous location. The extraosseous variant is referred to as peripheral odontogenic keratocyst. Though, clinically, peripheral odontogenic keratocyst resembles the gingival cyst of adults, it has histologic features that are pathognomonic of odontogenic keratocyst. This article presents a case of this uncommon entity.

Max-AUC feature selection in computer-aided detection of polyps in CT colonography.

Science.gov (United States)

Xu, Jian-Wu; Suzuki, Kenji

2014-03-01

We propose a feature selection method based on a sequential forward floating selection (SFFS) procedure to improve the performance of a classifier in computerized detection of polyps in CT colonography (CTC). The feature selection method is coupled with a nonlinear support vector machine (SVM) classifier. Unlike the conventional linear method based on Wilks' lambda, the proposed method selected the most relevant features that would maximize the area under the receiver operating characteristic curve (AUC), which directly maximizes classification performance, evaluated based on AUC value, in the computer-aided detection (CADe) scheme. We presented two variants of the proposed method with different stopping criteria used in the SFFS procedure. The first variant searched all feature combinations allowed in the SFFS procedure and selected the subsets that maximize the AUC values. The second variant performed a statistical test at each step during the SFFS procedure, and it was terminated if the increase in the AUC value was not statistically significant. The advantage of the second variant is its lower computational cost. To test the performance of the proposed method, we compared it against the popular stepwise feature selection method based on Wilks' lambda for a colonic-polyp database (25 polyps and 2624 nonpolyps). We extracted 75 morphologic, gray-level-based, and texture features from the segmented lesion candidate regions. The two variants of the proposed feature selection method chose 29 and 7 features, respectively. Two SVM classifiers trained with these selected features yielded a 96% by-polyp sensitivity at false-positive (FP) rates of 4.1 and 6.5 per patient, respectively. Experiments showed a significant improvement in the performance of the classifier with the proposed feature selection method over that with the popular stepwise feature selection based on Wilks' lambda that yielded 18.0 FPs per patient at the same sensitivity level.

Warty Carcinoma Penis: An Uncommon Variant

Directory of Open Access Journals (Sweden)

Sushma Thapa

2017-01-01

Full Text Available Penile carcinoma frequency varies widely in different parts of the world and comprises 1–10% of all the malignancies in males. Majority of the cases of penile carcinoma are squamous cell carcinoma of penis comprising 60% to 70% of all cases. Warty carcinoma of penis is an unusual neoplasm and a variant of penile squamous cell carcinoma comprising 5%–10% of all the variants. The other histological variants include basaloid, verrucous, papillary, sarcomatous, mixed, and adenosquamous carcinoma. The various histological entities with an exophytic papillary lesions including warty carcinoma are together referred to as the “verruciform” group of neoplasms. The warty carcinoma has to be differentiated from these lesions and is typically distinguished by histological features of hyperkeratosis, arborescent papillomatosis, acanthosis, and prominent koilocytosis with nuclear pleomorphism. We present a case of 65-year-old male with growth measuring 6×4 cm in the penis who underwent total penectomy and was diagnosed as warty carcinoma penis.

Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

NARCIS (Netherlands)

Niturad, Cristina Elena; Lev, Dorit; Kalscheuer, Vera M; Charzewska, Agnieszka; Schubert, Julian; Lerman-Sagie, Tally; Kroes, Hester Y.; Oegema, Renske; Traverso, Monica; Specchio, Nicola; Lassota, Maria; Chelly, Jamel; Bennett-Back, Odeya; Carmi, Nirit; Koffler-Brill, Tal; Iacomino, Michele; Trivisano, Marina; Capovilla, Giuseppe; Striano, Pasquale; Nawara, Magdalena; Rzoca, Sylwia; Fischer, Ute; Bienek, Melanie; Jensen, Corinna; Hu, Hao; Thiele, Holger; Altmüller, Janine; Krause, Roland; May, Patrick; Becker, Felicitas; Balling, Rudi; Biskup, Saskia; Haas, Stefan A.; Nürnberg, Peter; Van Gassen, Koen L.I.; Lerche, Holger; Zara, Federico; Maljevic, Snezana; Leshinsky-Silver, Esther

2017-01-01

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical

DeepPVP: phenotype-based prioritization of causative variants using deep learning

KAUST Repository

Boudellioua, Imene

2018-05-02

Background: Prioritization of variants in personal genomic data is a major challenge. Recently, computational methods that rely on comparing phenotype similarity have shown to be useful to identify causative variants. In these methods, pathogenicity prediction is combined with a semantic similarity measure to prioritize not only variants that are likely to be dysfunctional but those that are likely involved in the pathogenesis of a patient\\'s phenotype. Results: We have developed DeepPVP, a variant prioritization method that combined automated inference with deep neural networks to identify the likely causative variants in whole exome or whole genome sequence data. We demonstrate that DeepPVP performs significantly better than existing methods, including phenotype-based methods that use similar features. DeepPVP is freely available at https://github.com/bio-ontology-research-group/phenomenet-vp Conclusions: DeepPVP further improves on existing variant prioritization methods both in terms of speed as well as accuracy.

Impact of Pathogen Population Heterogeneity and Stress-Resistant Variants on Food Safety.

Science.gov (United States)

Abee, T; Koomen, J; Metselaar, K I; Zwietering, M H; den Besten, H M W

2016-01-01

This review elucidates the state-of-the-art knowledge about pathogen population heterogeneity and describes the genotypic and phenotypic analyses of persister subpopulations and stress-resistant variants. The molecular mechanisms underlying the generation of persister phenotypes and genetic variants are identified. Zooming in on Listeria monocytogenes, a comparative whole-genome sequence analysis of wild types and variants that enabled the identification of mutations in variants obtained after a single exposure to lethal food-relevant stresses is described. Genotypic and phenotypic features are compared to those for persistent strains isolated from food processing environments. Inactivation kinetics, models used for fitting, and the concept of kinetic modeling-based schemes for detection of variants are presented. Furthermore, robustness and fitness parameters of L. monocytogenes wild type and variants are used to model their performance in food chains. Finally, the impact of stress-resistant variants and persistence in food processing environments on food safety is discussed.

Solid variant aneurysmal bone cyst in the distal fibular metaphysis: radiologic and pathologic challenges to diagnosis

Directory of Open Access Journals (Sweden)

Elizabeth M. Johnson, MD

2017-09-01

Full Text Available Solid variant aneurysmal bone cyst is a rare benign bone lesion, representing a small fraction of all aneurysmal bone cysts. The imaging appearance and histologic features may overlap with other benign and malignant neoplasms, posing a diagnostic dilemma for clinicians, pathologists, and radiologists. We present a case of solid variant aneurysmal bone cyst of the distal fibula and review the radiologic and histologic features important for diagnosis.

The follicular variant of papillary thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

Science.gov (United States)

Scharpf, Joseph; Kamani, Dipti; Sadow, Peter M; Randolph, Gregory W

2017-01-01

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new terminology proposed for encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Recently, thyroid cancer incidence has increased dramatically, without affecting related mortality rate. This increase is widely attributed to the intensified surveillance leading to a substantial increase in the diagnosis of small classic papillary thyroid cancers and EFVPTCs. Recent studies emphasize the indolent behavior of the EFVPTC. Recently, there has been a reclassification of EFVPTC as NIFTP, a benign entity. The financial and emotional burden of 'cancer' diagnosis and treatment can be significant. This review recapitulates the literature supporting the reclassification of EFVPTC as NIFTP, a benign entity, and reviews standardized diagnostic criteria for EFVPTC. The information highlighted in this review will affect surgical decision making and may promote the offering of hemithyroidectomy over a total thyroidectomy to some patients with 'indeterminate' cytopathological category; postoperative radioiodine ablation will not be required for NIFTP patients.

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Science.gov (United States)

Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

2018-02-22

PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

A machine learning model to determine the accuracy of variant calls in capture-based next generation sequencing.

Science.gov (United States)

van den Akker, Jeroen; Mishne, Gilad; Zimmer, Anjali D; Zhou, Alicia Y

2018-04-17

Next generation sequencing (NGS) has become a common technology for clinical genetic tests. The quality of NGS calls varies widely and is influenced by features like reference sequence characteristics, read depth, and mapping accuracy. With recent advances in NGS technology and software tools, the majority of variants called using NGS alone are in fact accurate and reliable. However, a small subset of difficult-to-call variants that still do require orthogonal confirmation exist. For this reason, many clinical laboratories confirm NGS results using orthogonal technologies such as Sanger sequencing. Here, we report the development of a deterministic machine-learning-based model to differentiate between these two types of variant calls: those that do not require confirmation using an orthogonal technology (high confidence), and those that require additional quality testing (low confidence). This approach allows reliable NGS-based calling in a clinical setting by identifying the few important variant calls that require orthogonal confirmation. We developed and tested the model using a set of 7179 variants identified by a targeted NGS panel and re-tested by Sanger sequencing. The model incorporated several signals of sequence characteristics and call quality to determine if a variant was identified at high or low confidence. The model was tuned to eliminate false positives, defined as variants that were called by NGS but not confirmed by Sanger sequencing. The model achieved very high accuracy: 99.4% (95% confidence interval: +/- 0.03%). It categorized 92.2% (6622/7179) of the variants as high confidence, and 100% of these were confirmed to be present by Sanger sequencing. Among the variants that were categorized as low confidence, defined as NGS calls of low quality that are likely to be artifacts, 92.1% (513/557) were found to be not present by Sanger sequencing. This work shows that NGS data contains sufficient characteristics for a machine-learning-based model to

Persistent trigeminal artery/persistent trigeminal artery variant and coexisting variants of the head and neck vessels diagnosed using 3 T MRA

International Nuclear Information System (INIS)

Bai, M.; Guo, Q.; Li, S.

2013-01-01

Aim: To report the prevalence and characteristic features of persistent trigeminal artery (PTA), PTA variant (PTAV), and other variants of the head and neck vessels, identified using magnetic resonance angiography (MRA). Materials and methods: The three-dimensional (3D) time of flight (TOF) MRA and 3D contrast-enhanced (CE) MRA images of 6095 consecutive patients who underwent 3 T MRA at Liaocheng People's Hospital from 1 September 2008 through 31 May 2012 were retrospectively reviewed and analysed. Thirty-two patients were excluded because of suboptimal image quality or internal carotid artery (ICA) occlusion. Results: The prevalence of both PTA and PTAV was 0.63% (PTA, 26 cases; PTAV, 12 cases). The prevalence of coexisting variants of the head and neck vessels in cases of PTA/PTAV was 52.6% (20 of 38 cases). The vascular variants that coexisted with cases of PTA/PTAV were as follows: the intracranial arteries varied in 10 cases, the origin of the supra-aortic arteries varied in nine cases, the vertebral artery (VA) varied in 14 cases, and six cases displayed fenestrations. Fifteen of the 20 cases contained more than two types of variants. Conclusion: The prevalence of both PTA and PTAV was 0.63%. Although PTA and PTAV are rare vascular variants, they frequently coexist with other variants of the head and neck vessels. Multiple vascular variations can coexist in a single patient. Recognizing PTA, PTAV, and other variants of the head and neck vessels is crucial when planning a neuroradiological intervention or surgery. Recognizing the medial PTA is very important in clinical practice when performing trans-sphenoidal surgery on the pituitary as failure to do so could result in massive haemorrhage

[Clinico-pathogenetic variants of chronic gastritis].

Science.gov (United States)

Chernin, V V; Dzhulaĭ, G S

2004-01-01

To evaluate specific features of the course of chronic gastritis (CG), morphofunctional condition of gastric mucosa, vegetative regulation, adrenergic and cholinergic shifts, histamine metabolism and effects of exogenic and endogenic risk factors in CG patients; to study clinicopathogenetic variants of CG. A total of 311 CG patients aged from 16 to 72 years were studied. They were divided into three groups by their gastric mucosa condition. The control group consisted of 30 healthy donors. The following parameters were studied: visual and histological condition of gastric mucosa, total acidity, the levels of free hydrochloric acid, pepsin, bioelectric gastric activity, general autonomic tonicity, cholinesterase activity. Three clinicopathogenetic variants of the disease have been identified. Variant 1 was characterized by a recurrent course, subjective manifestation of the disease only in exacerbation, surface (primarily antral) mucosal affection, normal or enhanced secretory and motor functions of the stomach, adequate reaction of acid production to caffeine and histamine stimulation, parasympathicotonia, absolute hyperhistaminemia, relative hypoacetylcholinemia, subnormal urinary excretion of adrenalin. Variant 2 manifested with rare recurrences, longer and more severe exacerbations, frequent spontaneous and provoked aggravations, moderate focal atrophy of the mucosa, secretory insufficiency with adequate reaction to histamine and minor to caffeine stimuli, hypomotor gastric dyskinesia, vegetative eutonia, normohistaminemia, absolute hypoacetylcholinemia, subnormal urinary excretion of noradrenaline. Variant 3 runs without definite remissions and exacerbations, with continuous abdominal pain and dyspepsia, frequent spontaneous aggravations, marked extended mucosal atrophy with secretory insufficiency up to achlorhydria, no stimulation of acid production in response to caffeine and histamine, gastric hypomotility, sympathicotonia, absolute hypohistaminemia

Performance comparison of various time variant filters

Energy Technology Data Exchange (ETDEWEB)

Kuwata, M [JEOL Engineering Co. Ltd., Akishima, Tokyo (Japan); Husimi, K

1996-07-01

This paper describes the advantage of the trapezoidal filter used in semiconductor detector system comparing with the other time variant filters. The trapezoidal filter is the compose of a rectangular pre-filter and a gated integrator. We indicate that the best performance is obtained by the differential-integral summing type rectangular pre-filter. This filter is not only superior in performance, but also has the useful feature that the rising edge of the output waveform is linear. We introduce an example of this feature used in a high-energy experiment. (author)

Genetic Epidemiology, Hematological and Clinical Features of Hemoglobinopathies in Iran

OpenAIRE

Rahimi, Zohreh

2013-01-01

There is large variation in the molecular genetics and clinical features of hemoglobinopathies in Iran. Studying structural variants of hemoglobin demonstrated that the ?-chain variants of hemoglobin S and D-Punjab are more prevalent in the Fars (southwestern Iran) and Kermanshah (western Iran) provinces, respectively. Also, ? -chain variants of Hb Q-Iran and Hb Setif are prevalent in western Iran. The molecular basis and clinical severity of thalassemias are extremely heterogenous among Iran...

In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features

Science.gov (United States)

Ibáñez-Costa, Alejandro; Gahete, Manuel D.; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A.; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D.; Dieguez, Carlos; Castaño, Justo P.; Luque, Raúl M.

2015-01-01

Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas comparedwith normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24–72 h) increased GH and ACTH secretion, Ca2+ and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors. PMID:25737012

Lack of Frank Agrammatism in the Nonfluent Agrammatic Variant of Primary Progressive Aphasia

Directory of Open Access Journals (Sweden)

Naida L. Graham

2016-09-01

Full Text Available Background/Aims: Frank agrammatism, defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors, is variably reported in patients with nonfluent variant primary progressive aphasia (nfPPA. This study addressed whether frank agrammatism is typical in agrammatic nfPPA patients when this feature is not required for diagnosis. Method: We assessed grammatical production in 9 patients who satisfied current diagnostic criteria. Although the focus was agrammatism, motor speech skills were also evaluated to determine whether dysfluency arose primarily from apraxia of speech (AOS, instead of, or in addition to, agrammatism. Volumetric MRI analyses provided impartial imaging-supported diagnosis. Results: The majority of cases exhibited neither frank agrammatism nor AOS. Conclusion: There are nfPPA patients with imaging-supported diagnosis and preserved motor speech skills who do not exhibit frank agrammatism, and this may persist beyond the earliest stages of the illness. Because absence of frank agrammatism is a subsidiary diagnostic feature in the logopenic variant of PPA, this result has implications for differentiation of the nonfluent and logopenic variants, and indicates that PPA patients with nonfluent speech in the absence of frank agrammatism or AOS do not necessarily have the logopenic variant.

Prebiotic Competition between Information Variants, With Low Error Catastrophe Risks

Directory of Open Access Journals (Sweden)

Radu Popa

2015-07-01

Full Text Available During competition for resources in primitive networks increased fitness of an information variant does not necessarily equate with successful elimination of its competitors. If variability is added fast to a system, speedy replacement of pre-existing and less-efficient forms of order is required as novel information variants arrive. Otherwise, the information capacity of the system fills up with information variants (an effect referred as “error catastrophe”. As the cost for managing the system’s exceeding complexity increases, the correlation between performance capabilities of information variants and their competitive success decreases, and evolution of such systems toward increased efficiency slows down. This impasse impedes the understanding of evolution in prebiotic networks. We used the simulation platform Biotic Abstract Dual Automata (BiADA to analyze how information variants compete in a resource-limited space. We analyzed the effect of energy-related features (differences in autocatalytic efficiency, energy cost of order, energy availability, transformation rates and stability of order on this competition. We discuss circumstances and controllers allowing primitive networks acquire novel information with minimal “error catastrophe” risks. We present a primitive mechanism for maximization of energy flux in dynamic networks. This work helps evaluate controllers of evolution in prebiotic networks and other systems where information variants compete.

Accurate genotyping across variant classes and lengths using variant graphs

DEFF Research Database (Denmark)

Sibbesen, Jonas Andreas; Maretty, Lasse; Jensen, Jacob Malte

2018-01-01

of read k-mers to a graph representation of the reference and variants to efficiently perform unbiased, probabilistic genotyping across the variation spectrum. We demonstrate that BayesTyper generally provides superior variant sensitivity and genotyping accuracy relative to existing methods when used...... collecting a set of candidate variants across discovery methods, individuals and databases, and then realigning the reads to the variants and reference simultaneously. However, this realignment problem has proved computationally difficult. Here, we present a new method (BayesTyper) that uses exact alignment...... to integrate variants across discovery approaches and individuals. Finally, we demonstrate that including a ‘variation-prior’ database containing already known variants significantly improves sensitivity....

Cribriform-Morular Variant of Papillary Thyroid Carcinoma: Clinical and Pathological Features of 30 Cases.

Science.gov (United States)

Akaishi, Junko; Kondo, Tetsuo; Sugino, Kiminori; Ogimi, Yuna; Masaki, Chie; Hames, Kiyomi Y; Yabuta, Tomonori; Tomoda, Chisato; Suzuki, Akifumi; Matsuzu, Kenichi; Uruno, Takashi; Ohkuwa, Keiko; Kitagawa, Wataru; Nagahama, Mitsuji; Katoh, Ryohei; Ito, Koichi

2018-04-25

Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is rare; it may occur in cases of familial adenomatous polyposis (FAP) or be sporadic. To clarify the clinicopathological features of CMV-PTC, the medical records of these patients were investigated retrospectively. Between 1979 and 2016, a total of 17,062 cases with PTC underwent initial surgery at Ito Hospital. Of these, 30 (0.2%) cases histologically diagnosed with CMV-PTC were reviewed. The patients were all women, with a mean age at the time of surgery of 24 years. Seven (23%) cases were thought to have FAP because they had colonic polyposis or a family history of FAP or APC gene mutation. The remaining 23 (77%) were thought to be sporadic. Multiple tumors were detected in 6 cases, with a solitary tumor in 24. One patient had lung metastasis at diagnosis. Eleven patients underwent total thyroidectomy or subtotal thyroidectomy, and 19 underwent lobectomy. Twenty-six (87%) patients underwent neck lymph node dissection. Three patients had tumor metastasis in central lymph nodes, but these were incidentally detected metastatic classical PTC (cPTC) based on histological examination. In this series, there were no cases of LN metastases of CMV-PTC. During a mean follow-up of 15 years, one patient had new cPTC in the remnant thyroid after initial surgery, and the other patients showed no signs of recurrence. CMV-PTC occurred in young women, their long-term prognosis was excellent. Total thyroidectomy is recommended for FAP-associated CMV-PTC, but modified neck lymph node dissection is not necessary.

Annotating DNA variants is the next major goal for human genetics.

Science.gov (United States)

Cutting, Garry R

2014-01-02

Clinical genetic testing has undergone a dramatic transformation in the past two decades. Diagnostic laboratories that previously tested for well-established disease-causing DNA variants in a handful of genes have evolved into sequencing factories identifying thousands of variants of known and unknown medical consequence. Sorting out what does and does not cause disease in our genomes is the next great challenge in making genetics a central feature of healthcare. I propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. Human geneticists are well placed to coordinate a systematic evaluation of variants in collaboration with basic scientists and clinicians. Sharing of knowledge, data, methods, and tools will aid both researchers and healthcare workers in achieving their common goal of defining the pathogenic potential of variants. Generation of variant annotations will inform genetic testing and will deepen our understanding of gene and protein function, thereby aiding the search for molecular targeted therapies. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Crystallographic features of lath martensite in low-carbon steel

International Nuclear Information System (INIS)

Kitahara, Hiromoto; Ueji, Rintaro; Tsuji, Nobuhiro; Minamino, Yoritoshi

2006-01-01

Electron backscattering diffraction with field-emission scanning electron microscopy was used to analyze crystallographically the lath martensite structure in a 0.20% carbon steel. The crystallographic features of the lath martensite structure, of the order of the prior austenite grain size or larger, were clarified. Although the orientations of the martensite crystals were scattered around the ideal variant orientations, the martensite in this steel maintained the Kurdjumov-Sachs (K-S) orientation relationship. The procedures of the crystallographic analysis of the martensite (ferrite) phase with the K-S orientation relationship were explained in detail. Variant analysis showed that all 24 possible variants did not necessarily appear within a single prior austenite grain and that all six variants did not necessarily appear within each packet. Specific combinations of two variants appeared within local regions (sub-blocks), indicating a strict rule for variant selection. Prior austenite grain boundaries and most of the packet boundaries were clearly recognized. However, it was difficult to determine the block boundaries within the sub-blocks

Cellulase variants

Science.gov (United States)

Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

2015-07-14

This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

Microcystic Variant of Urothelial Carcinoma

Directory of Open Access Journals (Sweden)

Anthony Kodzo-Grey Venyo

2013-01-01

Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

Imaging features of multicentric Castleman's disease in HIV infection

International Nuclear Information System (INIS)

Hillier, J.C.; Shaw, P.; Miller, R.F.; Cartledge, J.D.; Nelson, M.; Bower, M.; Francis, N.; Padley, S.P.

2004-01-01

AIM: To describe the computed tomography (CT) features of human immunodeficiency virus (HIV)-associated Castleman's disease. MATERIALS AND METHODS: Nine HIV-positive patients with biopsy-proven Castleman's disease were studied. Clinical and demographic data, CD4 count, histological diagnosis and human herpes type 8 (HHV8) serology or immunostaining results were recorded. CT images were reviewed independently by two radiologists. RESULTS: CT findings included splenomegaly (n=7) and peripheral lymph node enlargement (axillary n=8, inguinal n=4). All nodes displayed mild to avid enhancement after intravenous administration of contrast material. Hepatomegaly was evident in seven patients. Other features included abdominal (n=6) and mediastinal (n=5) lymph node enlargement and pulmonary abnormalities (n=4). Patterns of parenchymal abnormality included bronchovascular nodularity (n=2), consolidation (n=1) and pleural effusion (n=2). On histological examination eight patients (spleen n=3, lymph node n=9, lung n=1 bone marrow n=1) had the plasma cell variant and one had mixed hyaline-vascular/plasma cell variant. The majority had either positive immunostaining for HHV8 or positive serology (n=8). CONCLUSION: Common imaging features of multicentric Castleman's disease in HIV infection are hepatosplenomegaly and peripheral lymph node enlargement. Although these imaging features may suggest the diagnosis in the appropriate clinical context, they lack specificity and so biopsy is needed for diagnosis. In distinction from multicentric Castleman's disease in other populations the plasma cell variant is most commonly encountered, splenomegaly is a universal feature and there is a strong association with Kaposi's sarcoma

DeepPVP: phenotype-based prioritization of causative variants using deep learning

KAUST Repository

Boudellioua, Imene; Kulmanov, Maxat; Schofield, Paul N; Gkoutos, Georgios V; Hoehndorf, Robert

2018-01-01

phenotype-based methods that use similar features. DeepPVP is freely available at https://github.com/bio-ontology-research-group/phenomenet-vp Conclusions: DeepPVP further improves on existing variant prioritization methods both in terms of speed as well

A variant of special relativity and long-distance astronomy.

Science.gov (United States)

Segal, I E

1974-03-01

THE REDSHIFT, MICROWAVE BACKGROUND, AND OTHER OBSERVABLE ASTRONOMICAL FEATURES ARE DEDUCED FROM TWO THEORETICAL ASSUMPTIONS: (1) global space-time is a certain variant of Minkowski space, locally indistinguishable in causality and covariance features but globally admitting the full conformal group as symmetries although having a spherical space component; (2) the true energy operator corresponds to a certain generator of this group which is not globally scale-covariant, whereas laboratory frequency measurements are inevitably such and correspond to the conventional energy operator [unk]/i[unk]/[unk]t.

Anatomic features involved in technical complexity of partial nephrectomy.

Science.gov (United States)

Hou, Weibin; Yan, Weigang; Ji, Zhigang

2015-01-01

Nephrometry score systems, including RENAL nephrometry, preoperative aspects and dimensions used for an anatomical classification system, C-index, diameter-axial-polar nephrometry, contact surface area score, calculating resected and ischemized volume, renal tumor invasion index, surgical approach renal ranking score, zonal NePhRO score, and renal pelvic score, have been reviewed. Moreover, salient anatomic features like the perinephric fat and vascular variants also have been discussed. We then extract 7 anatomic characteristics, namely tumor size, spatial location, adjacency, exophytic/endophytic extension, vascular variants, pelvic anatomy, and perinephric fat as important features for partial nephrectomy. For novice surgeons, comprehensive and adequate anatomic consideration may help them in their early clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

Science.gov (United States)

Binder, Zev A; Wilson, Kelli M; Salmasi, Vafi; Orr, Brent A; Eberhart, Charles G; Siu, I-Mei; Lim, Michael; Weingart, Jon D; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Kassam, Amin B; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J; Gallia, Gary L

2016-01-01

Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

Somatic cancer variant curation and harmonization through consensus minimum variant level data

Directory of Open Access Journals (Sweden)

Deborah I. Ritter

2016-11-01

Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

CDKL5 variants

Science.gov (United States)

Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

2017-01-01

Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

Variant patterns of Subject-Verb agreement in Portuguese: morphological and phonological issues

Directory of Open Access Journals (Sweden)

Maria Antónia Mota

2013-12-01

Full Text Available In this paper, we start from a basic assumption: agreement is a most relevant operation for the Portuguese language speakers as a whole. The data from different varieties of Portuguese support this view, both in the Subject-Verb domain and within the NP, as well as the fact that speakers don’t prefer the simplest solutions: the most productive plural agreement forms are the most complex ones, morphologically and phonologically. We focus the discussion on the interplay between different linguistic factors intervening in and promoting variant overt and covert patterns of agreement (the existence of agreement and the presence of visible marks, as expected in standard canonical schemes, constitute two separate questions. More specifically, we claim that it is worth to take into account the matching between the morphological and the phonological properties and features of the verb cells, in order to fully understand the attested variant outputs and the variant patterns of subject-verb agreement. We assume that the 3rdplural person-number marker has to be described in morphophonological terms, and we conclude that agreement is a morpho-phono-syntactic process, sensitive to the lexical-semantic features and discourse properties of the controller.

On the correspondence of last variants of 5-dimensional theories

International Nuclear Information System (INIS)

Gavrilov, V.R.; Karnaukhov, A.V.

1984-01-01

The paper deals with determining importance and analysis of the recently suggested Schmutzer unified constructive field theory. The well-known variants of 5- and more-dimensional theories are classified. Basic features of theories of first generation (Kaluza-Klein), second generation (scalar-tensor theories of Jordan and Brance-Dikke) and theories of third and fourth generations are noted. It is specially stressed that in contrast to the monadic formalism, the projective formalism in principle does not admit the introduction of dependence on the fifth coordinate and therefore of geometrization of the right part of the Einstein and MaxWell equations analogous to variants of the third and fourth generations

Wrapper-based selection of genetic features in genome-wide association studies through fast matrix operations

Science.gov (United States)

2012-01-01

Background Through the wealth of information contained within them, genome-wide association studies (GWAS) have the potential to provide researchers with a systematic means of associating genetic variants with a wide variety of disease phenotypes. Due to the limitations of approaches that have analyzed single variants one at a time, it has been proposed that the genetic basis of these disorders could be determined through detailed analysis of the genetic variants themselves and in conjunction with one another. The construction of models that account for these subsets of variants requires methodologies that generate predictions based on the total risk of a particular group of polymorphisms. However, due to the excessive number of variants, constructing these types of models has so far been computationally infeasible. Results We have implemented an algorithm, known as greedy RLS, that we use to perform the first known wrapper-based feature selection on the genome-wide level. The running time of greedy RLS grows linearly in the number of training examples, the number of features in the original data set, and the number of selected features. This speed is achieved through computational short-cuts based on matrix calculus. Since the memory consumption in present-day computers can form an even tighter bottleneck than running time, we also developed a space efficient variation of greedy RLS which trades running time for memory. These approaches are then compared to traditional wrapper-based feature selection implementations based on support vector machines (SVM) to reveal the relative speed-up and to assess the feasibility of the new algorithm. As a proof of concept, we apply greedy RLS to the Hypertension – UK National Blood Service WTCCC dataset and select the most predictive variants using 3-fold external cross-validation in less than 26 minutes on a high-end desktop. On this dataset, we also show that greedy RLS has a better classification performance on independent

Cough Variant Asthma in Medical Outpatient Department of a Tertiary Care Hospital in Bangladesh

OpenAIRE

Rukhsana Parvin; Shekhar Bhattacharjee; Swapna Bhattacharjee

2013-01-01

Background: Cough variant asthma (CVA) is a subset of asthma where the only symptom is chronic persistent cough. Many cases go unrecognized due to lack of proper evaluation. Response to asthma medication with features supportive of airway hypersensitivity helps in management of this disease. Objective: To find out the proportion of cough variant asthma among the patients attending medicine outpatient department of Enam Medical College, Savar, Dhaka. Materials and Methods: This cross sectional...

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

Science.gov (United States)

Rafiq, Muhammad Arshad; Leblond, Claire S; Saqib, Muhammad Arif Nadeem; Vincent, Akshita K; Ambalavanan, Amirthagowri; Khan, Falak Sher; Ayaz, Muhammad; Shaheen, Naseema; Spiegelman, Dan; Ali, Ghazanfar; Amin-ud-Din, Muhammad; Laurent, Sandra; Mahmood, Huda; Christian, Mehtab; Ali, Nadir; Fennell, Alanna; Nanjiani, Zohair; Egger, Gerald; Caron, Chantal; Waqas, Ahmed; Ayub, Muhammad; Rasheed, Saima; Forgeot d'Arc, Baudouin; Johnson, Amelie; So, Joyce; Brohi, Muhammad Qasim; Mottron, Laurent; Ansar, Muhammad; Vincent, John B; Xiong, Lan

2015-06-25

Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

[Specificities of the logopenic variant of primary progressive aphasia].

Science.gov (United States)

Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

2015-01-01

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

[Homozygous ectonucleotide pyrophosphatase/phosphodiesterase 1 variants in a girl with hypophosphatemic rickets and literature review].

Science.gov (United States)

Liu, Z Q; Chen, X B; Song, F Y; Gao, K; Qiu, M F; Qian, Y; Du, M

2017-11-02

Objective: To investigate the clinical features and genetic characteristics of patients with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene variants. Method: The clinical data of a patient with ENPP1 homozygous variants from Capital Institute of Pediatrics was collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center from Biotechnology Information and PubMed by using search term "ENPP1" , "hypophosphatemic rickets" . The literature retrieval was confined from 1980 to February 2017. The clinical manifestations, bone metabolism examinations, X-RAY and genotypes were reviewed. Result: Our patient was an 11 years old girl, with 7 years history of lower limb malformation. She showed significant valgus deformity of the knee (genu valgum). Metabolic examination revealed reduced level of plasma phosphate (0.86 mmol/L), a normal level of plasma calcium (2.30 mmol/L) and an elevated alkaline phosphatase level of 688 IU/L. The calcium-phosphorus product was 25.9. A homozygous nonsense variants of ENPP1 gene, c.783C>G (p.Tyr261X) in exon 7 was identified in the patient. Both parents were heterozygous carriers. Literature review identified 3 Chinese patients from one publication and 17 cases from twenty one publications around the world. None of the patients was found PHEX variants which is the most common variants among hypophosphatemic rickets patients. The disease onset age was 11 months to 10 years. Eight patients had short stature, five patients had the history of generalized arterial calcification of infancy. Four suffered from deafness, three showed localized calcifications of arteries, three patients manifested pseudoxanthoma elasticum and two suffered from ossification of posterior longitudinal ligament. Nine missense variants, six splicing variants and 4 nonsense variants were reported among these twenty patients. c.783C>G was found in two Chinese patients

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

Science.gov (United States)

Schneider, Nayê Balzan; Pastor, Tatiane; Paula, André Escremim de; Achatz, Maria Isabel; Santos, Ândrea Ribeiro Dos; Vianna, Fernanda Sales Luiz; Rosset, Clévia; Pinheiro, Manuela; Ashton-Prolla, Patricia; Moreira, Miguel Ângelo Martins; Palmero, Edenir Inêz

2018-05-01

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice-site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one-third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease

NARCIS (Netherlands)

van der Tol, Linda; Verhamme, Camiel; van Schaik, Ivo N.; van der Kooi, Anneke J.; Hollak, Carla E. M.; Biegstraaten, Marieke

2016-01-01

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite

Chinese wine classification system based on micrograph using combination of shape and structure features

Science.gov (United States)

Wan, Yi

2011-06-01

Chinese wines can be classification or graded by the micrographs. Micrographs of Chinese wines show floccules, stick and granule of variant shape and size. Different wines have variant microstructure and micrographs, we study the classification of Chinese wines based on the micrographs. Shape and structure of wines' particles in microstructure is the most important feature for recognition and classification of wines. So we introduce a feature extraction method which can describe the structure and region shape of micrograph efficiently. First, the micrographs are enhanced using total variation denoising, and segmented using a modified Otsu's method based on the Rayleigh Distribution. Then features are extracted using proposed method in the paper based on area, perimeter and traditional shape feature. Eight kinds total 26 features are selected. Finally, Chinese wine classification system based on micrograph using combination of shape and structure features and BP neural network have been presented. We compare the recognition results for different choices of features (traditional shape features or proposed features). The experimental results show that the better classification rate have been achieved using the combinational features proposed in this paper.

Integrating functional data to prioritize causal variants in statistical fine-mapping studies.

Directory of Open Access Journals (Sweden)

Gleb Kichaev

2014-10-01

Full Text Available Standard statistical approaches for prioritization of variants for functional testing in fine-mapping studies either use marginal association statistics or estimate posterior probabilities for variants to be causal under simplifying assumptions. Here, we present a probabilistic framework that integrates association strength with functional genomic annotation data to improve accuracy in selecting plausible causal variants for functional validation. A key feature of our approach is that it empirically estimates the contribution of each functional annotation to the trait of interest directly from summary association statistics while allowing for multiple causal variants at any risk locus. We devise efficient algorithms that estimate the parameters of our model across all risk loci to further increase performance. Using simulations starting from the 1000 Genomes data, we find that our framework consistently outperforms the current state-of-the-art fine-mapping methods, reducing the number of variants that need to be selected to capture 90% of the causal variants from an average of 13.3 to 10.4 SNPs per locus (as compared to the next-best performing strategy. Furthermore, we introduce a cost-to-benefit optimization framework for determining the number of variants to be followed up in functional assays and assess its performance using real and simulation data. We validate our findings using a large scale meta-analysis of four blood lipids traits and find that the relative probability for causality is increased for variants in exons and transcription start sites and decreased in repressed genomic regions at the risk loci of these traits. Using these highly predictive, trait-specific functional annotations, we estimate causality probabilities across all traits and variants, reducing the size of the 90% confidence set from an average of 17.5 to 13.5 variants per locus in this data.

Invasive lobular carcinoma with extracellular mucin as a distinct variant of lobular carcinoma: a case report

OpenAIRE

Haltas, Hacer; Bayrak, Reyhan; Yenidunya, Sibel; Kosehan, Dilek; Sen, Meral; Akin, Kayihan

2012-01-01

Abstract The differences between invasive lobular and ductal carcinomas affect the diagnostic and therapeutic management for patients with breast cancer. In most cases, this can be accomplished because of distinct histomorphologic features. However, occasionally, this task may become quite difficult, in particular when dealing with the variants of infiltrating lobular carcinoma. Lobular carcinoma has been considered a variant of mucin-secreting carcinoma with only intracytoplasmic mucin. The ...

Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases.

Science.gov (United States)

Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt; Calabrese, Olga; Felloni, Beatrice; Scusa, Maria Flora; Di Marco, Pietro; Borelli, Paolo; Bonuccelli, Ubaldo; Julu, Peter O O; Nielsen, Jytte Bieber; Morin, Bodil; Hansen, Stig; Gobbi, Giuseppe; Visconti, Paola; Pintaudi, Maria; Edvige, Veneselli; Romanelli, Anna; Bianchi, Fabrizio; Casarano, Manuela; Battini, Roberta; Cioni, Giovanni; Ariani, Francesca; Renieri, Alessandra; Benincasa, Alberto; Delamont, Robert S; Zappella, Michele

2012-02-01

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

CT diagnosis of rare histological variant of hepatocellular carcinoma

International Nuclear Information System (INIS)

Li Huaibo; Feng Zhipeng; Duan Shaoyin; Zhaugn Xiangrong

2009-01-01

Objective: To explore and understand the CT findings of 5 rare histological variants of hepatocellular carcinoma. Methods: CT findings of 31 cases of rare histological variants confirmed by surgery and pathology were analyzed retrospectively. Results: 13 cases were clear cell hepatocellular carcinoma. 3 cases of them showed patchy fat density in plain scans. Enhanced CT showed features of 'fast in fast out' which was similar to the common hepatocellular carcinoma. 4 cases belonged to sclerosis hepatocellular carcinoma. They appeared as heterogeneous, slowly enhancement on arterial phase images, and delay enhancement on portal venous phase and delay phase images. 9 cases belonged to mixed hepatocellular carcinoma. 5 cases of them showed inhomogeneous enhancement and 4 without enhancement during arterial phase, 3 cases showed delay enhancement and 4 without during portal venous and delay phase. 3 cases were fibrolamellar hepatocellular carcinoma. All showed obvious and fastly enhancement on arterial phase images, subsided slowly on the portal venous and delay phase images, showing features of 'fast in slow out', no enhancement was seen in the central scar. Shrinkage phenomenon on the surface of liver could be seen on the CT plain scans in sclerosis, mixed and fibrolamellar hepatocellular carcinoma. 2 cases were the type of dense hepatocellular carcinoma. The surrounding part in the 2 cases were slightly enhanced, while the most part of the center were not enhanced similar to necrosis. Conclusion: The CT findings of rate histological variant of hepatocellular carcinoma are characteristic. Analyzing the CT plain and enhancement finding is helpful to the diagnosis of these types of hepatocellular carcinoma. (authors)

The anatomic basis for localized occipital thinning: A normal anatomic variant

International Nuclear Information System (INIS)

Haden, M.A.; Keats, T.E.

1982-01-01

The radiographic evidence presented in this case confirms that the asymptomatic, incidentally found occipital radiolucencies previously described by Keats are not a problem in differential diagnosis of inner table erosion. The entity appears to be a developmental variant with typical features and occurring in a characteristic location. (orig.)

Influence of population diversity on neurovirulence potential of plaque purified L-Zagreb variants.

Science.gov (United States)

Ivancic-Jelecki, Jelena; Forcic, Dubravko; Jagusic, Maja; Kosutic-Gulija, Tanja; Mazuran, Renata; Balija, Maja Lang; Isakov, Ofer; Shomron, Noam

2016-04-29

Despite continuing research efforts, determinants of mumps virus virulence are still largely unknown. One of consequences of this is difficulty in striking a balance between efficacy and safety of live attenuated mumps vaccines. Among mumps vaccine strains associated with occurrence of postvaccinal aseptic meningitis is L-Zagreb, developed by further attenuation of vaccine strain L-3. Starting from an archived L-Zagreb sample with suboptimal neuroattenuation score, we isolated different viral variants and compared their genetic and phenotypic properties, in investigation of neurovirulence markers. Six different L-Zagreb variants were isolated by plaque purification. Their neurovirulent status was determined by rat-based neurovirulence test; population structure was determined by deep sequencing. We isolated one well neuroattenuated viral variant, two marginally neuroattenuated, and three insufficiently neuroattenuated. No genetic markers of neurovirulence could be identified. None of variants had detectable amounts of defective interfering particles. Two characteristics set insufficiently neuroattenuated variants apart from less-neurovirulent ones: elevated variability level in regions 1293-3314, 5363-7773 and 9382-11657, and/or elevated number of mutations present in frequencies ≥ 1%. The most neurovirulent variants possessed both of these features. Distinctive heterogeneity profiles were obtained for insufficiently neuroattenuated L-Zagreb variants. No markers that would discriminate between marginally and well neuroattenuated variants were identified. The findings of this study may serve as a guideline during development of an improved L3/L-Zagreb vaccine strain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analysis on early clinical features of behavioral variant frontotemporal dementia

Directory of Open Access Journals (Sweden)

Guan-jun LI

2017-11-01

Full Text Available Background Although the early behavioral symptoms of behavioral variant frontotemporal dementia (bvFTD are prominent, early diagnosis for bvFTD is difficult due to confusion with other mental disorders, and lack of sensitivity and specificity of diagnostic criteria, etc. In this paper, we summarized the important reviews in recent years and analyzed the clinical characteristics of bvFTD patients to improve the detection of early symptoms in bvFTD. Methods Twenty-three possible or probable bvFTD patients were diagnosed according to International Behavioral Variant Frontotemporal Dementia Criteria Consortium (FTDC. Self-designed questionnaires designed by Shanghai Mental Health Center were used to collect sociodemographic data and general information of patients. Their clinical characteristics were summarized, including abnormal behaviors, cognitive impairment, psychotic symptoms and other symptoms. Mini-Mental State Examination (MMSE, Activities of Daily Living (ADL and Clinical Dementia Rating Scale (CDR were used to make neuropsychological tests and compare with similar overseas studies (control group, N = 66. Results Eleven male patients and 12 female patients were included in our study. Compared with control group, the average age of onset [(50.83 ± 11.55 years vs. (57.00 ± 10.00 years; t = 3.863, P = 0.000] and average age of diagnosis [(53.22 ± 11.55 years vs. (61.00 ± 9.00 years; t = 13.423, P = 0.000] of bvFTD patients were smaller. The study showed that bvFTD patients had more apathy or indolence [95.65% (22/23 vs. 65.15% (43/66; χ2 = 8.057, P = 0.005], loss of sympathy or empathy [95.65% (22/23 vs. 33.33% (22/66; χ2 = 26.499, P = 0.000], while patients in control group showed more derepression behavior [98.48% (65/66 vs. 52.17% (12/23; χ2 = 27.514, P = 0.000] and continuous, stiff, obsessive and/or ritualized behavior [95.45% (63/66 vs. 30.43% (7/23; adjusted χ2 = 39.159, P = 0.000]. For cognitive impairment, bvFTD patients

A novel multi-variant epitope ensemble vaccine against avian leukosis virus subgroup J.

Science.gov (United States)

Wang, Xiaoyu; Zhou, Defang; Wang, Guihua; Huang, Libo; Zheng, Qiankun; Li, Chengui; Cheng, Ziqiang

2017-12-04

The hypervariable antigenicity and immunosuppressive features of avian leukosis virus subgroup J (ALV-J) has led to great challenges to develop effective vaccines. Epitope vaccine will be a perspective trend. Previously, we identified a variant antigenic neutralizing epitope in hypervariable region 1 (hr1) of ALV-J, N-LRDFIA/E/TKWKS/GDDL/HLIRPYVNQS-C. BLAST analysis showed that the mutation of A, E, T and H in this epitope cover 79% of all ALV-J strains. Base on this data, we designed a multi-variant epitope ensemble vaccine comprising the four mutation variants linked with glycine and serine. The recombinant multi-variant epitope gene was expressed in Escherichia coli BL21. The expressed protein of the variant multi-variant epitope gene can react with positive sera and monoclonal antibodies of ALV-J, while cannot react with ALV-J negative sera. The multi-variant epitope vaccine that conjugated Freund's adjuvant complete/incomplete showed high immunogenicity that reached the titer of 1:64,000 at 42 days post immunization and maintained the immune period for at least 126 days in SPF chickens. Further, we demonstrated that the antibody induced by the variant multi-variant ensemble epitope vaccine recognized and neutralized different ALV-J strains (NX0101, TA1, WS1, BZ1224 and BZ4). Protection experiment that was evaluated by clinical symptom, viral shedding, weight gain, gross and histopathology showed 100% chickens that inoculated the multi-epitope vaccine were well protected against ALV-J challenge. The result shows a promising multi-variant epitope ensemble vaccine against hypervariable viruses in animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia

Science.gov (United States)

Piguet, O; Hornberger, M; Shelley, B P.; Kipps, C M.; Hodges, J R.

2009-01-01

Background: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) relies on criteria that are constraining and potentially ambiguous. Some features are open to clinical interpretation and their prevalence unknown. This study investigated the sensitivity of current diagnostic criteria in a large group of patients with bvFTD. Methods: Forty-five patients with clear evidence of bvFTD as judged by progressive clinical decline (>3 years) with marked frontal features and significant frontal brain atrophy on brain MRI were included. Thirty-two have died; pathologic confirmation of frontotemporal lobar degeneration was found in all 18 coming to autopsy. We established the prevalence of core and supportive diagnostic features at presentation and with disease progression. Results: Only 25/45 patients (56%) showed all five core features necessary for a diagnosis of bvFTD at initial presentation and 33/45 (73%) as their disease progressed. Two core features, emotional blunting and loss of insight, were never observed in 25% and 13% of cases. Executive dysfunction, hyperorality, mental inflexibility, and distractibility were the only supportive features present in >50% of cases at initial presentation. Although not a diagnostic feature, impaired activities of daily living was present in 33/45 patients (73%). Conclusions: Strict application of the criteria misses a significant proportion of patients. Many supportive features have low prevalence and are clinically not useful. Revision of the criteria to include level of certainty (definite, probable, possible) dependent on the number of features present and the presence of ancillary information (e.g., brain atrophy, neuropsychological abnormalities, impaired activities of daily living) is encouraged. GLOSSARY ACE = Addenbrooke’s Cognitive Examination; ADL = activities of daily living; bvFTD = behavioral variant frontotemporal dementia; MMSE = Mini-Mental State Examination. PMID:19237702

Effects of brand variants on smokers' choice behaviours and risk perceptions.

Science.gov (United States)

Hoek, Janet; Gendall, Philip; Eckert, Christine; Kemper, Joya; Louviere, Jordan

2016-03-01

Australian tobacco companies have introduced evocative variant names that could re-create the aspirational connotations plain packaging aims to remove. To inform future regulation, we explored how brand descriptors affected smokers' responses to plain packs featuring different variant name combinations. An online survey of 254 daily smokers or social smokers aged between 18 and 34 used a within-subjects best-worst experiment to estimate the relative effects of variant names. A 2×4×4×4 design contained four attributes: quality (premium or none), taste (smooth, fine, rich or none) connotation (classic, midnight, infinite or none) and colour (red, blue, white or none). In a between-subjects component, respondents evaluated one of two alternative packs according to its perceived harm and ease of quitting. The most important variant attribute was connotation, followed by taste, colour and quality; within these attributes, the most attractive descriptors were 'classic' and 'smooth'. We identified four distinct segments that differed significantly in their sociodemographic attributes and variant preferences, although not in their perceptions of the harm or quitting ease associated with two different variants. Some descriptors significantly enhance the appeal of tobacco products among different groups of smokers and may undermine plain packaging's dissuasive intent. Policymakers should explicitly regulate variant names to avoid the 'poetry on a package' evident in Australia. Options include disallowing new descriptors, limiting the number of descriptors permitted or banning descriptors altogether. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Functional significance of rare neuroligin 1 variants found in autism.

Directory of Open Access Journals (Sweden)

Moe Nakanishi

2017-08-01

Full Text Available Genetic mutations contribute to the etiology of autism spectrum disorder (ASD, a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3, a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1 is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

FEATURES OF THE CLINICAL SIGNIFICANCE OF POLYMORPHIC VARIANTS OF ENOS AND AGTR2 GENES IN PATIENTS WITH CAD

Directory of Open Access Journals (Sweden)

A. L. Khokhlov

2016-01-01

Full Text Available Coronary heart disease (CHD is a major cause of mortality. Morphological substrate of CHD in most cases is atherosclerosis, which is based on structural genes polymorphism eNOS and AGTR2. The aim of the study was to study the prevalence of eNOS and AGTR2 genes in patients with coronary artery disease and the association of these genes with coronary heart disease. The study involved 187 patients aged 36 to 86 years (62,2±11,2 with different forms of CHD: stable and unstable angina, myocardial infarction and 45 people without CHD. Determination of gene polymorphisms was performed by real-time PCR analyzer of nucleic acids IQ 5 Bio-Rad. Statistical analysis was performed using Statistica 10.0. The study revealed a significant difference between the incidence of homozygous AA allelic variant gene AGTR2 group of patients with myocardial infarction and the comparison group; polymorphic variant AA AGTR2 gene is associated with earlier onset of coronary artery disease; It found that carriers of the polymorphic variant gene GA AGTR2 beginning statistically CHD occurred significantly later than in carriers of alleles GG and AA; age CHD debut TT allele carriers of the eNOS gene is associated with an earlier onset of the disease and statistically significantly different from the age of first CHD in carriers of alleles of polymorphic variants of GG and GT; revealed a positive correlation between the polymorphic allele AGTR2 gene with the presence of arterial hypertension in patients with coronary artery disease; It determined that the T allele carriers of the polymorphic gene eNOS is associated more early onset of hypertension, found the association of the polymorphic allele gene AGTR2 the need to use higher doses of ACE inhibitor — perindopril.

Complex branchial fistula: a variant arch anomaly.

Science.gov (United States)

De Caluwé, D; Hayes, R; McDermott, M; Corbally, M T

2001-07-01

A 5-year-old boy presented with an infected left-sided branchial fistula. Despite antibiotic treatment and repeated excision of the fistula, purulent discharge from the wound persisted. Three-dimensional computed tomography (3D CT) reconstruction greatly facilitated the diagnosis and management of this case by showing the course of the fistulous tract. The complexity of the tract suggests that this represents a variant arch anomaly because it contains features of first, second, third, and fourth arch remnants. Copyright 2001 by W.B. Saunders Company.

Frequency and clinicopathological correlations of histopathological variants of idiopathic focal segmental glomerulosclerosis in nephrotic adolescents

International Nuclear Information System (INIS)

Shakeel, S.; Mubarak, M.; Kazi, J.I.

2014-01-01

Objective: To determine the frequency and clinicopathological correlations of focal segmental glomerulosclerosis variants in adolescents with idiopathic nephrotic syndrome. Methods: All consecutive adolescents (12 to 18 years) who presented with idiopathic nephrotic syndrome in the period, January 2009 to December 2012, and in whom the histological diagnosis of focal segmental glomerulosclerosis was made on renal biopsies, were included in this prospective study. Their clinical, laboratory and histopathological features at the time of presentation or biopsy were noted from the case files and the biopsy reports. Results: Among 50 adolescents, 34 (68%) were males and 16 (32%) females. The mean age was 15.14+-2.3 years. The mean duration of disease was 6.3+-11.2 months. The mean serum creatinine was 0.96+-0.82 mg/dl. The mean 24-hour urinary protein excretion was 3.8+-0.68 grams. Biopsy indications were steroid-resistant nephritic syndrome in 15 (30%), steroid-dependant nephritic syndrome in 19 (38%) and adolescent nephritic syndrome in 16 (32%) cases. Among the focal segmental glomerulosclerosis variants, 40 (80%) were not otherwise specified, followed by the collapsing variant, which accounted for 8 (16%) cases. The tip and cellular variants, both were found in one (2%) case each. Among the histological features, global glomerulosclerosis was found in 23 (46%) cases, and segmental scarring/collapse in all (100%). A variable degree of tubular atrophy and interstitial fibrosis was noted in 44 (88%) cases. Conclusion: The results from this study indicate that the pattern of focal segmental glomerulosclerosis variants differs markedly in adolescents compared with younger children. (author)

Circulating Gut-Homing (α4β7+) Plasmablast Responses against Shigella Surface Protein Antigens among Hospitalized Patients with Diarrhea.

Science.gov (United States)

Sinha, Anuradha; Dey, Ayan; Saletti, Giulietta; Samanta, Pradip; Chakraborty, Partha Sarathi; Bhattacharya, M K; Ghosh, Santanu; Ramamurthy, T; Kim, Jae-Ouk; Yang, Jae Seung; Kim, Dong Wook; Czerkinsky, Cecil; Nandy, Ranjan K

2016-07-01

Developing countries are burdened with Shigella diarrhea. Understanding mucosal immune responses associated with natural Shigella infection is important to identify potential correlates of protection and, as such, to design effective vaccines. We performed a comparative analysis of circulating mucosal plasmablasts producing specific antibodies against highly conserved invasive plasmid antigens (IpaC, IpaD20, and IpaD120) and two recently identified surface protein antigens, pan-Shigella surface protein antigen 1 (PSSP1) and PSSP2, common to all virulent Shigella strains. We examined blood and stool specimens from 37 diarrheal patients admitted to the Infectious Diseases & Beliaghata General Hospital, Kolkata, India. The etiological agent of diarrhea was investigated in stool specimens by microbiological methods and real-time PCR. Gut-homing (α4β7 (+)) antibody-secreting cells (ASCs) were isolated from patient blood by means of combined magnetic cell sorting and two-color enzyme-linked immunosorbent spot (ELISPOT) assay. Overall, 57% (21 of 37) and 65% (24 of 37) of the patients were positive for Shigella infection by microbiological and real-time PCR assays, respectively. The frequency of α4β7 (+) IgG ASC responders against Ipas was higher than that observed against PSSP1 or PSSP2, regardless of the Shigella serotype isolated from these patients. Thus, α4β7 (+) ASC responses to Ipas may be considered an indirect marker of Shigella infection. The apparent weakness of ASC responses to PSSP1 is consistent with the lack of cross-protection induced by natural Shigella infection. The finding that ASC responses to IpaD develop in patients with recent-onset shigellosis indicates that such responses may not be protective or may wane too rapidly and/or be of insufficient magnitude. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

NIMEFI: gene regulatory network inference using multiple ensemble feature importance algorithms.

Directory of Open Access Journals (Sweden)

Joeri Ruyssinck

Full Text Available One of the long-standing open challenges in computational systems biology is the topology inference of gene regulatory networks from high-throughput omics data. Recently, two community-wide efforts, DREAM4 and DREAM5, have been established to benchmark network inference techniques using gene expression measurements. In these challenges the overall top performer was the GENIE3 algorithm. This method decomposes the network inference task into separate regression problems for each gene in the network in which the expression values of a particular target gene are predicted using all other genes as possible predictors. Next, using tree-based ensemble methods, an importance measure for each predictor gene is calculated with respect to the target gene and a high feature importance is considered as putative evidence of a regulatory link existing between both genes. The contribution of this work is twofold. First, we generalize the regression decomposition strategy of GENIE3 to other feature importance methods. We compare the performance of support vector regression, the elastic net, random forest regression, symbolic regression and their ensemble variants in this setting to the original GENIE3 algorithm. To create the ensemble variants, we propose a subsampling approach which allows us to cast any feature selection algorithm that produces a feature ranking into an ensemble feature importance algorithm. We demonstrate that the ensemble setting is key to the network inference task, as only ensemble variants achieve top performance. As second contribution, we explore the effect of using rankwise averaged predictions of multiple ensemble algorithms as opposed to only one. We name this approach NIMEFI (Network Inference using Multiple Ensemble Feature Importance algorithms and show that this approach outperforms all individual methods in general, although on a specific network a single method can perform better. An implementation of NIMEFI has been made

Pairwise Constraint-Guided Sparse Learning for Feature Selection.

Science.gov (United States)

Liu, Mingxia; Zhang, Daoqiang

2016-01-01

Feature selection aims to identify the most informative features for a compact and accurate data representation. As typical supervised feature selection methods, Lasso and its variants using L1-norm-based regularization terms have received much attention in recent studies, most of which use class labels as supervised information. Besides class labels, there are other types of supervised information, e.g., pairwise constraints that specify whether a pair of data samples belong to the same class (must-link constraint) or different classes (cannot-link constraint). However, most of existing L1-norm-based sparse learning methods do not take advantage of the pairwise constraints that provide us weak and more general supervised information. For addressing that problem, we propose a pairwise constraint-guided sparse (CGS) learning method for feature selection, where the must-link and the cannot-link constraints are used as discriminative regularization terms that directly concentrate on the local discriminative structure of data. Furthermore, we develop two variants of CGS, including: 1) semi-supervised CGS that utilizes labeled data, pairwise constraints, and unlabeled data and 2) ensemble CGS that uses the ensemble of pairwise constraint sets. We conduct a series of experiments on a number of data sets from University of California-Irvine machine learning repository, a gene expression data set, two real-world neuroimaging-based classification tasks, and two large-scale attribute classification tasks. Experimental results demonstrate the efficacy of our proposed methods, compared with several established feature selection methods.

US or MR Imaging Features of Polypoid Endometriosis: A Case Report

International Nuclear Information System (INIS)

Park, Jae Il; Cho, Jae Ho; Kim, Geum Rae; Kim, Mi Jin

2009-01-01

Polypoid endometriosis is a rare variant of endometriosis that is pathologically similar to an endometrial polyp. This lesion is frequently mistaken for a solid neoplasm in clinical, radiological and pathological examinations. The clinical and pathological features of the lesion have been well described in the English literature. However, its imaging features have not been reported in the Korean literature. We describe ultrasound and magnetic resonance imaging features of pathologically-confirmed polypoid endometriosis

US or MR Imaging Features of Polypoid Endometriosis: A Case Report

Energy Technology Data Exchange (ETDEWEB)

Park, Jae Il; Cho, Jae Ho; Kim, Geum Rae; Kim, Mi Jin [Yeungnam University, Gyeongsan (Korea, Republic of)

2009-12-15

Polypoid endometriosis is a rare variant of endometriosis that is pathologically similar to an endometrial polyp. This lesion is frequently mistaken for a solid neoplasm in clinical, radiological and pathological examinations. The clinical and pathological features of the lesion have been well described in the English literature. However, its imaging features have not been reported in the Korean literature. We describe ultrasound and magnetic resonance imaging features of pathologically-confirmed polypoid endometriosis.

Feature-based engineering of compensations in web service environment

DEFF Research Database (Denmark)

Schaefer, Michael; Dolog, Peter

2009-01-01

In this paper, we introduce a product line approach for developing Web services with extended compensation capabilities. We adopt a feature modelling approach in order to describe variable and common compensation properties of Web service variants, as well as service consumer application...

Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

DEFF Research Database (Denmark)

Santiago-Sim, Teresa; Burrage, Lindsay C; Ebstein, Frédéric

2017-01-01

regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated...

Flowers, Dancing, Dresses, and Dolls: Picture Book Representations of Gender-Variant Males

Science.gov (United States)

Sciurba, Katie

2017-01-01

Over the past fifty years, children's picture books have made great strides toward literary equity by including more perspectives from and stories about marginalized groups, such as those whose gender identities do not conform to heteronormative standards. While texts featuring gender-variant male characters engage in topics that are far too often…

Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer.

Science.gov (United States)

Hirasawa, Akira; Imoto, Issei; Naruto, Takuya; Akahane, Tomoko; Yamagami, Wataru; Nomura, Hiroyuki; Masuda, Kiyoshi; Susumu, Nobuyuki; Tsuda, Hitoshi; Aoki, Daisuke

2017-12-22

Pathogenic germline BRCA1 , BRCA2 ( BRCA1/2 ), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1 ), 8 (3.5%; BRCA2 ), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D ), 2 (0.9%; ATM ), 1 (0.4%; MRE11A ), 1 ( FANCC ), and 1 ( GABRA6 ). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2 . Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

Product Variant Master as a Means to Handle Variant Design

DEFF Research Database (Denmark)

Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

1996-01-01

be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules...

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Science.gov (United States)

Quartier, Angélique; Poquet, Hélène; Gilbert-Dussardier, Brigitte; Rossi, Massimiliano; Casteleyn, Anne-Sophie; Portes, Vincent des; Feger, Claire; Nourisson, Elsa; Kuentz, Paul; Redin, Claire; Thevenon, Julien; Mosca-Boidron, Anne-Laure; Callier, Patrick; Muller, Jean; Lesca, Gaetan; Huet, Frédéric; Geoffroy, Véronique; El Chehadeh, Salima; Jung, Matthieu; Trojak, Benoit; Le Gras, Stéphanie; Lehalle, Daphné; Jost, Bernard; Maury, Stéphanie; Masurel, Alice; Edery, Patrick; Thauvin-Robinet, Christel; Gérard, Bénédicte; Mandel, Jean-Louis; Faivre, Laurence; Piton, Amélie

2017-01-01

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up. PMID:28176767

Hepatocellular Carcinoma with Foamy Histiocyte-Like Appearance: A Deceptively Clear Cell Carcinoma Appearing Variant

Directory of Open Access Journals (Sweden)

Takuji Noro

2010-08-01

Full Text Available Hepatocellular carcinoma (HCC shows many pathological features, and it varies architecturally and cytologically. There have been many reports and discussions of the morphological features of HCC. A 63-year-old man was found to have a solitary tumor in liver segment 7 that was diagnosed as HCC. A partial resection of liver segment 7 was performed. Microscopically, the tumor lesion showed a moderately differentiated HCC. There was also a lesion with foamy histiocyte-like cells corresponding to the white lesion in the face of the cut tumor. Immunohistochemical staining showed that they were negative for CD68, S-100, vimentin, and HMB-45. The cytoplasm itself was negative on periodic acid Schiff (PAS and Sudan staining. Without immunohistological analysis, it is difficult to distinguish this HCC variant from clear cell carcinoma or metastases of renal cell carcinoma. It is important to recognize this type as a specific cytological variant of HCC that requires confirmation by immunohistochemistry. This report describes the case of a patient with a morphologically distinctive pattern of HCC with prominent cell cytoplasm that had a foamy histiocyte-like appearance. To the best of our knowledge, this is the first report of this HCC variant.

VAT: a computational framework to functionally annotate variants in personal genomes within a cloud-computing environment.

Science.gov (United States)

Habegger, Lukas; Balasubramanian, Suganthi; Chen, David Z; Khurana, Ekta; Sboner, Andrea; Harmanci, Arif; Rozowsky, Joel; Clarke, Declan; Snyder, Michael; Gerstein, Mark

2012-09-01

The functional annotation of variants obtained through sequencing projects is generally assumed to be a simple intersection of genomic coordinates with genomic features. However, complexities arise for several reasons, including the differential effects of a variant on alternatively spliced transcripts, as well as the difficulty in assessing the impact of small insertions/deletions and large structural variants. Taking these factors into consideration, we developed the Variant Annotation Tool (VAT) to functionally annotate variants from multiple personal genomes at the transcript level as well as obtain summary statistics across genes and individuals. VAT also allows visualization of the effects of different variants, integrates allele frequencies and genotype data from the underlying individuals and facilitates comparative analysis between different groups of individuals. VAT can either be run through a command-line interface or as a web application. Finally, in order to enable on-demand access and to minimize unnecessary transfers of large data files, VAT can be run as a virtual machine in a cloud-computing environment. VAT is implemented in C and PHP. The VAT web service, Amazon Machine Image, source code and detailed documentation are available at vat.gersteinlab.org.

Including product features in process redesign

DEFF Research Database (Denmark)

Hvam, Lars; Hauksdóttir, Dagný; Mortensen, Niels Henrik

2017-01-01

do not take into account how the product features are applied throughout the process, which makes it difficult to obtain a comprehensive understanding of the activities in the processes and to generate significant improvements. The suggested approach models the product family using the so......This article suggests a visual modelling method for integrating models of product features with business process models for redesigning the business processes involving specifications of customer-tailored products and services. The current methods for redesigning these types of business processes......-called product variant master and the business process modelling notation for modelling the process flow. The product model is combined with the process map by identifying features used in each step of the process flow. Additionally, based on the information absorbed from the integrated model, the value stream...

Coexistence of atypical adenoma, adenoma with bizarre nuclei and follicular variant of papillary carcinoma of the thyroid

Directory of Open Access Journals (Sweden)

Teresa Pusiol

2013-01-01

Full Text Available Coexistence of atypical adenoma, adenoma with bizarre nuclei and follicular variant of papillary carcinoma is described in the same thyroid, with study of p53 expression. A 72-year-old woman presented to the endocrinology out-patient unit for a routine follow-up visit. Patient underwent a total thyroidectomy. Histological examination revealed a solid nodular neoplasm with the longest diameter of 0.8 cm in the upper pole of the left lobe. The neoplasm showed the histological features of follicular variant of papillary carcinoma with moderate diffuse immunoreactivity for p53. The lower pole of the right lobe showed two adjacent nodules with histological features respectively of atypical adenoma and adenoma with bizarre nuclei, with strong diffuse immunoreactivity for p53.

Dandy walker variant and bipolar I disorder with graphomania.

Science.gov (United States)

Can, Serdar Suleyman; Karakaş Uğurlu, Görkem; Cakmak, Selcen

2014-07-01

Cerebellum is known to play an important role in coordination and motor functions. In some resent studies it is also considered to be involved in modulation of mood, cognition and psychiatric disorders. Dandy Walker Malformation is a congenital malformation that is characterized by hypoplasia or aplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the posterior fossa. When the volume of posterior fossa is normal, the malformation is called Dandy Walker Variant. Case is a 32 year old male with a 12 year history of Bipolar I Disorder presented with manic and depresive symptoms, including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, loss of appetite, increased immersion in projects, irritability, agressive behavior, impulsivity. Cranial Magnetic Resonance Imaging was compatible to the morphological features of Dandy Walker Variant.

Sparse kernel orthonormalized PLS for feature extraction in large datasets

DEFF Research Database (Denmark)

Arenas-García, Jerónimo; Petersen, Kaare Brandt; Hansen, Lars Kai

2006-01-01

In this paper we are presenting a novel multivariate analysis method for large scale problems. Our scheme is based on a novel kernel orthonormalized partial least squares (PLS) variant for feature extraction, imposing sparsity constrains in the solution to improve scalability. The algorithm...... is tested on a benchmark of UCI data sets, and on the analysis of integrated short-time music features for genre prediction. The upshot is that the method has strong expressive power even with rather few features, is clearly outperforming the ordinary kernel PLS, and therefore is an appealing method...

FunSAV: predicting the functional effect of single amino acid variants using a two-stage random forest model.

Directory of Open Access Journals (Sweden)

Mingjun Wang

Full Text Available Single amino acid variants (SAVs are the most abundant form of known genetic variations associated with human disease. Successful prediction of the functional impact of SAVs from sequences can thus lead to an improved understanding of the underlying mechanisms of why a SAV may be associated with certain disease. In this work, we constructed a high-quality structural dataset that contained 679 high-quality protein structures with 2,048 SAVs by collecting the human genetic variant data from multiple resources and dividing them into two categories, i.e., disease-associated and neutral variants. We built a two-stage random forest (RF model, termed as FunSAV, to predict the functional effect of SAVs by combining sequence, structure and residue-contact network features with other additional features that were not explored in previous studies. Importantly, a two-step feature selection procedure was proposed to select the most important and informative features that contribute to the prediction of disease association of SAVs. In cross-validation experiments on the benchmark dataset, FunSAV achieved a good prediction performance with the area under the curve (AUC of 0.882, which is competitive with and in some cases better than other existing tools including SIFT, SNAP, Polyphen2, PANTHER, nsSNPAnalyzer and PhD-SNP. The sourcecodes of FunSAV and the datasets can be downloaded at http://sunflower.kuicr.kyoto-u.ac.jp/sjn/FunSAV.

Hairy cell leukemia-variant

International Nuclear Information System (INIS)

Quadri, Mohammad I.; Al-Sheikh, Iman H.

2001-01-01

Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant. (author)

No evidence for association of dopamine D2 receptor variant (Ser311/Cys311) with major psychosis

Energy Technology Data Exchange (ETDEWEB)

Sasaki, Tsukasa; Macciardi, F.M.; Badri, F. [Clarke Institute of Psychiatry, Ontario (Canada)] [and others

1996-07-26

We investigated a variant of the dopamine D2 receptor gene (Ser311/Cys311 substitution) in Caucasian patients with schizophrenia (n = 273), delusional disorder (n = 62), bipolar I affective disorder (n = 63), and controls (n = 255). No evidence for association between the receptor variant and any of the diseases was found, even when patients with younger age-of-onset (<25 years) were compared with controls. Futhermore, in a subgroup of schizophrenia patients whom we assessed for negative symptoms, those with the Cys allele did not differ from the remainder of the group. Also, the bipolar affective disorder patients with psychotic features did not show evidence for association with the receptor variant. Thus, our results do not provide evidence for an association between this D2 receptor variant and schizophrenia, or delusional disorder, or bipolar affective disorder. 11 refs., 1 tab.

Contextual Multi-armed Bandits under Feature Uncertainty

Energy Technology Data Exchange (ETDEWEB)

Yun, Seyoung [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Nam, Jun Hyun [Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of); Mo, Sangwoo [Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of); Shin, Jinwoo [Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea, Republic of)

2017-03-03

We study contextual multi-armed bandit problems under linear realizability on rewards and uncertainty (or noise) on features. For the case of identical noise on features across actions, we propose an algorithm, coined NLinRel, having O(T⁷/₈(log(dT)+K√d)) regret bound for T rounds, K actions, and d-dimensional feature vectors. Next, for the case of non-identical noise, we observe that popular linear hypotheses including NLinRel are impossible to achieve such sub-linear regret. Instead, under assumption of Gaussian feature vectors, we prove that a greedy algorithm has O(T²/₃√log d)regret bound with respect to the optimal linear hypothesis. Utilizing our theoretical understanding on the Gaussian case, we also design a practical variant of NLinRel, coined Universal-NLinRel, for arbitrary feature distributions. It first runs NLinRel for finding the ‘true’ coefficient vector using feature uncertainties and then adjust it to minimize its regret using the statistical feature information. We justify the performance of Universal-NLinRel on both synthetic and real-world datasets.

Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

DEFF Research Database (Denmark)

Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

2015-01-01

by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c......Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...... needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...

Comparative analysis of phenotypes features in two common genetic variants of limb-girdle muscular dystrophy

Directory of Open Access Journals (Sweden)

I. V. Sharkova

2015-01-01

Full Text Available The algorithm of differential diagnosis of the two most common genetic variants the limb-girdle muscular dystrophy (LGMD2A and DMD, developed on the basis of a comprehensive survey of 85 patients with a diagnosis specification using techniques of DNA analysis. It is shown that the accurate diagnosis of LGMD genetic types should be based on the results of the clinical and genealogical, biochemical and molecular genetic analysis. The proposed algorithm will significantly reduces the economic and time costs with expensive DNA testing.

Scattering features for lung cancer detection in fibered confocal fluorescence microscopy images.

Science.gov (United States)

Rakotomamonjy, Alain; Petitjean, Caroline; Salaün, Mathieu; Thiberville, Luc

2014-06-01

To assess the feasibility of lung cancer diagnosis using fibered confocal fluorescence microscopy (FCFM) imaging technique and scattering features for pattern recognition. FCFM imaging technique is a new medical imaging technique for which interest has yet to be established for diagnosis. This paper addresses the problem of lung cancer detection using FCFM images and, as a first contribution, assesses the feasibility of computer-aided diagnosis through these images. Towards this aim, we have built a pattern recognition scheme which involves a feature extraction stage and a classification stage. The second contribution relies on the features used for discrimination. Indeed, we have employed the so-called scattering transform for extracting discriminative features, which are robust to small deformations in the images. We have also compared and combined these features with classical yet powerful features like local binary patterns (LBP) and their variants denoted as local quinary patterns (LQP). We show that scattering features yielded to better recognition performances than classical features like LBP and their LQP variants for the FCFM image classification problems. Another finding is that LBP-based and scattering-based features provide complementary discriminative information and, in some situations, we empirically establish that performance can be improved when jointly using LBP, LQP and scattering features. In this work we analyze the joint capability of FCFM images and scattering features for lung cancer diagnosis. The proposed method achieves a good recognition rate for such a diagnosis problem. It also performs well when used in conjunction with other features for other classical medical imaging classification problems. Copyright © 2014 Elsevier B.V. All rights reserved.

Three familial cases of Pasini variant of dominant dystrophic epidermolysis

Directory of Open Access Journals (Sweden)

Seirafi H

1999-07-01

Full Text Available Epidermolysis bullosa (EB is the term applied to a group of disorders whose common primary feature is the formation of blisters following trivial trauma. Hereditary EB comprises 3 major classes: simplex, junctional and dystrophic, and includes more than 23 phenotypes. The albopapuloid pasini variant of dominant dystrophic EB is characterized by a distinctive clinical appearance. In this article, we report this disease in three members of a family (father and two sons.

Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H

DEFF Research Database (Denmark)

Mulkey, Sarah B; Ben-Zeev, Bruria; Nicolai, Joost

2017-01-01

OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide...... patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG...... respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H...

Desmoplastic variant of ameloblastoma of the maxilla: A case report

International Nuclear Information System (INIS)

Koh, Kwang Joon; Park, Ha Na; Kim, Kyoung A

2015-01-01

The desmoplastic variant of ameloblastoma is a rare form of ameloblastoma characterized by unique radiographic and histologic features. A 46-year-old female was referred to our hospital, complaining of swelling in the left upper lip area. Radiographic findings revealed an ill-defined multilocular lesion with a large cystic lesion and thick sclerotic trabeculae on the left anterior maxilla. After the patient underwent partial osteotomy, histologic analysis revealed a desmoplastic ameloblastoma with no evidence of a hybrid lesion or cyst formation. The radiographic findings in the present case were different from those described in previous case reports. These findings are of special importance due to the unfamiliar radiographic and histologic features of this lesion

Stage-I osteochondritis dissecans versus normal variants of ossification in the knee in children

International Nuclear Information System (INIS)

Gebarski, Kathleen; Hernandez, Ramiro J.

2005-01-01

Juvenile osteochondritis dissecans (OCD) has a better prognosis than the adult type. We postulated that the excellent prognosis of juvenile OCD could be explained, at least in part, by the erroneous diagnosis of some developmental variants of ossification as stage-I OCD. Knee MRIs of 38 children, ages 7.5-17.7 years (mean and median age 13 years), were retrospectively reviewed to look for features that might separate normal variants of ossification from stage-I OCD. These included age, gender, site, configuration of the lesion, residual cartilaginous model and presence of edema. Twenty-three patients (32 condyles) had ossification defects with intact articular cartilage suggestive of stage-I lesions. No stage-II lesions were seen in the posterior femoral condyles. Accessory ossification centers were seen in 11/16 posterior condyles and 3/16 central condyles. Spiculation of existing ossification was seen in 12/16 posterior condylar lesions and 1/16 central condyles. There was a predominance of accessory ossifications and spiculations in the patients with 10% or greater residual cartilaginous model. No edema signal greater than diaphyseal red-marrow signal was seen in the posterior condyles. Clinical follow-up ranged from 0.5 to 38 months, with clinical improvement in 22 out of 23 patients. Inclusion of normal variants in the stage-I OCD category might explain, in part, the marked difference in published outcome between the juvenile and adult forms of OCD. Ossification defects in the posterior femoral condyles with intact overlying articular cartilage, accessory ossification centers, spiculation, residual cartilaginous model, and lack of bone-marrow edema are features of developmental variants rather than OCD. (orig.)

Dysmorphic features and developmental outcome of 2-year-old children.

Science.gov (United States)

Seggers, Jorien; Haadsma, Maaike L; Bos, Arend F; Heineman, Maas Jan; Middelburg, Karin J; van den Heuvel, Edwin R; Hadders-Algra, Mijna

2014-11-01

The aim of this study was to assess the associations between dysmorphic features and neurological, mental, psychomotor, and behavioural development in order to improve our understanding of aetiological pathways leading to minor developmental problems. In our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39 weeks, [range 30-43wks]), born after a parental history of subfertility either with or without fertility treatment, were examined. Dysmorphic features were classified as abnormalities (clinically relevant or not), minor anomalies, or common variants according to Merks' classification system. Hempel's neurological assessment resulted in a neurological optimality score (NOS) and fluency score. Mental and psychomotor development were assessed with the Dutch version of the Bayley Scales of Infant Development and behavioural development with the Achenbach Child Behaviour Checklist. Of the different types of dysmorphic feature, clinically relevant abnormalities were most strongly associated with a lower NOS (difference -2.53, 95% confidence interval [CI] -4.23 to -0.83) and fluency score (difference -0.62, 95% CI -1.1 to -0.15). The presence of one or more abnormalities (clinically relevant or not) or one or more common variants was significantly associated with a lower NOS, and the presence of three or more minor anomalies was associated with lower fluency scores. Dysmorphic features were not associated with mental, psychomotor, or behavioural development. As dysmorphic features originate during the first trimester of pregnancy, the association between dysmorphic features and minor alterations in neurodevelopment may suggest an early ontogenetic origin of subtle neurological deviations. © 2014 Mac Keith Press.

Molecular Background of Colorectal Tumors From Patients with Lynch Syndrome Associated With Germline Variants in PMS2.

Science.gov (United States)

Ten Broeke, S W; van Bavel, T C; Jansen, A M L; Gómez-García, E; Hes, F J; van Hest, L P; Letteboer, T G W; Olderode-Berends, M J W; Ruano, D; Spruijt, L; Suerink, M; Tops, C M; van Eijk, R; Morreau, H; van Wezel, T; Nielsen, M

2018-05-11

Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes. We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher's exact test. None of the PMS2-associated CRCs contained any somatic variants in the catenin beta 1 gene (CTNNB1), which encodes β-catenin, whereas 14/24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half of PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%, P=.44) and MSH2 (and 71.4%, P=.035) than with variants in PMS2. In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Non-invasive bioluminescence imaging to monitor the immunological control of a plasmablastic lymphoma-like B cell neoplasia after hematopoietic cell transplantation.

Directory of Open Access Journals (Sweden)

Martin Chopra

Full Text Available To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Igha(tm1(MycJanz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Igha(tm1(MycJanz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.

Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

DEFF Research Database (Denmark)

Rosengren, Anders H; Braun, Matthias; Mahdi, Taman

2012-01-01

The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features ...

A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

Science.gov (United States)

Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

2017-12-01

Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD 50 ) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

Directory of Open Access Journals (Sweden)

Megan Ulmer Carnes

Full Text Available Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR = 1.32, p = 3.87×10(-11. SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345, which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10 in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141 have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141. Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

Peripheral Tissue Involvement in Sporadic, Iatrogenic, and Variant Creutzfeldt-Jakob Disease

Science.gov (United States)

Head, Mark W.; Ritchie, Diane; Smith, Nadine; McLoughlin, Victoria; Nailon, William; Samad, Sazia; Masson, Stephen; Bishop, Matthew; McCardle, Linda; Ironside, James W.

2004-01-01

Human prion diseases are rare fatal neurodegenerative conditions that occur as acquired, familial, or idiopathic disorders. A key event in their pathogenesis is the accumulation of an altered form of the prion protein, termed PrPSc, in the central nervous system. A novel acquired human prion disease, variant Creutzfeldt-Jakob disease, is thought to result from oral exposure to the bovine spongiform encephalopathy agent. This disease differs from other human prion diseases in its neurological, neuropathological, and biochemical phenotype. We have used immunohistochemistry and Western blot techniques to analyze the tissue distribution and biochemical properties of PrPSc in peripheral tissues in a unique series of nine cases of variant Creutzfeldt-Jakob disease. We have compared this with the distribution and biochemical forms found in all of the major subtypes of sporadic Creutzfeldt-Jakob disease and in a case of iatrogenic Creutzfeldt-Jakob disease associated with growth hormone therapy. The results show that involvement of the lymphoreticular system is a defining feature of variant Creutzfeldt-Jakob disease, but that the biochemical isoform of PrPSc found is influenced by the cell type in which it accumulates. PMID:14695328

Variants of cellobiohydrolases

Energy Technology Data Exchange (ETDEWEB)

Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

2018-04-10

Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

Science.gov (United States)

Chen, Wuyan; Perritt, Ashley F; Morissette, Rachel; Dreiling, Jennifer L; Bohn, Markus-Frederik; Mallappa, Ashwini; Xu, Zhi; Quezado, Martha; Merke, Deborah P

2016-09-01

Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity. © 2016 WILEY PERIODICALS, INC.

Invasive lobular carcinoma with extracellular mucin as a distinct variant of lobular carcinoma: a case report

Directory of Open Access Journals (Sweden)

Haltas Hacer

2012-08-01

Full Text Available Abstract The differences between invasive lobular and ductal carcinomas affect the diagnostic and therapeutic management for patients with breast cancer. In most cases, this can be accomplished because of distinct histomorphologic features. However, occasionally, this task may become quite difficult, in particular when dealing with the variants of infiltrating lobular carcinoma. Lobular carcinoma has been considered a variant of mucin-secreting carcinoma with only intracytoplasmic mucin. The presence of extracellular mucin is a feature of ductal carcinoma. Herein is presented a case of lobular carcinoma with extracellular and intracellular mucin in a 43-year-old female patient, and confirmed by immunohistochemistry. Up to the present, infiltrating lobular carcinoma displaying extracellular mucin has not been described in the literature except two case. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1839906067716744

Exploration des variantes d'artefacts logiciels pour une analyse et une migration vers des lignes de produits

OpenAIRE

Martinez , Jabier

2016-01-01

Software Product Lines (SPLs) enable the derivation of a family of products based on variability management techniques. Inspired by the manufacturing industry, SPLs use feature configurations to satisfy different customer needs, along with reusable assets to allow systematic reuse. Capitalizing on existing variants by extracting the common and varying elements is referred to as extractive approaches for SPL adoption. Feature identification is needed to analyse the domain variability. Also, to...

Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

Science.gov (United States)

Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

2016-05-01

Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.

Variants of Moreau's sweeping process

International Nuclear Information System (INIS)

Siddiqi, A.H.; Manchanda, P.

2001-07-01

In this paper we prove the existence and uniqueness of two variants of Moreau's sweeping process -u'(t) is an element of Nc (t) (u(t)), where in one variant we replace u(t) by u'(t) in the right-hand side of the inclusion and in the second variant u'(t) and u(t) are respectively replaced by u''(t) and u'(t). (author)

Characterization of form variants of Xenorhabdus luminescens.

Science.gov (United States)

Gerritsen, L J; de Raay, G; Smits, P H

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed. Images PMID:1622273

Patterns of Dysmorphic Features in Schizophrenia

Science.gov (United States)

Scutt, L.E.; Chow, E.W.C.; Weksberg, R.; Honer, W.G.; Bassett, Anne S.

2011-01-01

Congenital dysmorphic features are prevalent in schizophrenia and may reflect underlying neurodevelopmental abnormalities. A cluster analysis approach delineating patterns of dysmorphic features has been used in genetics to classify individuals into more etiologically homogeneous subgroups. In the present study, this approach was applied to schizophrenia, using a sample with a suspected genetic syndrome as a testable model. Subjects (n = 159) with schizophrenia or schizoaffective disorder were ascertained from chronic patient populations (random, n=123) or referred with possible 22q11 deletion syndrome (referred, n = 36). All subjects were evaluated for presence or absence of 70 reliably assessed dysmorphic features, which were used in a three-step cluster analysis. The analysis produced four major clusters with different patterns of dysmorphic features. Significant between-cluster differences were found for rates of 37 dysmorphic features (P dysmorphic features (P = 0.0001), and validating features not used in the cluster analysis: mild mental retardation (P = 0.001) and congenital heart defects (P = 0.002). Two clusters (1 and 4) appeared to represent more developmental subgroups of schizophrenia with elevated rates of dysmorphic features and validating features. Cluster 1 (n = 27) comprised mostly referred subjects. Cluster 4 (n= 18) had a different pattern of dysmorphic features; one subject had a mosaic Turner syndrome variant. Two other clusters had lower rates and patterns of features consistent with those found in previous studies of schizophrenia. Delineating patterns of dysmorphic features may help identify subgroups that could represent neurodevelopmental forms of schizophrenia with more homogeneous origins. PMID:11803519

Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity.

Science.gov (United States)

Wreesmann, Volkert B; Ghossein, Ronald A; Hezel, Michael; Banerjee, Debenranrath; Shaha, Ashok R; Tuttle, R Michael; Shah, Jatin P; Rao, Pulivarthi H; Singh, Bhuvanesh

2004-08-01

The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms. Copyright 2004 Wiley-Liss, Inc.

Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus.

Science.gov (United States)

Zhang, Xiao-Feng; Guo, Jiangbo; Zhang, Xiuchun; Meulia, Tea; Paul, Pierce; Madden, Laurence V; Li, Dawei; Qu, Feng

2015-10-20

Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants.

Crystallographic features of the martensitic transformation and their impact on variant organization in the intermetallic compound Ni50Mn38Sb12 studied by SEM/EBSD.

Science.gov (United States)

Zhang, Chunyang; Zhang, Yudong; Esling, Claude; Zhao, Xiang; Zuo, Liang

2017-09-01

The mechanical and magnetic properties of Ni-Mn-Sb intermetallic compounds are closely related to the martensitic transformation and martensite variant organization. However, studies of these issues are very limited. Thus, a thorough crystallographic investigation of the martensitic transformation orientation relationship (OR), the transformation deformation and their impact on the variant organization of an Ni 50 Mn 38 Sb 12 alloy using scanning electron microscopy/electron backscatter diffraction (SEM/EBSD) was conducted in this work. It is shown that the martensite variants are hierarchically organized into plates, each possessing four distinct twin-related variants, and the plates into plate colonies, each containing four distinct plates delimited by compatible and incompatible plate interfaces. Such a characteristic organization is produced by the martensitic transformation. It is revealed that the transformation obeys the Pitsch relation ({0[Formula: see text]} A // {2[Formula: see text]} M and 〈0[Formula: see text]1〉 A // 〈[Formula: see text]2〉 M ; the subscripts A and M refer to austenite and martensite, respectively). The type I twinning plane K 1 of the intra-plate variants and the compatible plate interface plane correspond to the respective orientation relationship planes {0[Formula: see text]} A and {0[Formula: see text]} A of austenite. The three {0[Formula: see text]} A planes possessed by each pair of compatible plates, one corresponding to the compatible plate interface and the other two to the variants in the two plates, are interrelated by 60° and belong to a single 〈11[Formula: see text]〉 A axis zone. The {0[Formula: see text]} A planes representing the two pairs of compatible plates in each plate colony belong to two 〈11[Formula: see text]〉 A axis zones having one {0[Formula: see text]} A plane in common. This common plane defines the compatible plate interfaces of the two pairs of plates. The transformation strains to form the

Histone Variants and Composition in the Developing Brain: Should MeCP2 Care?

Science.gov (United States)

Zago, Valentina; Pinar-CabezaDeVaca, Cristina; Vincent, John B; Ausio, Juan

2017-01-01

Specific compositional chromatin features distinguish brain/neuronal chromatin from that of other tissues and are critical to this organ and cell type development and neuroplasticity. These features include a significant turnover of the major constitutive chromosomal proteins, including the (canonical) replication-dependent histones, the replication-independent replacement histone variants, as well as the chromatin associated transcriptional regulator MeCP2 (methyl CpG binding protein 2). Alterations of histones and MeCP2 have already been implicated in many brain disorders. Despite the relevance of histone variants to chromatin structure and function, only recently has some exciting literature started to re-emerge that directly relates them to neuron plasticity and cognition. However, the amount of information available on the functional role of these histones is still very limited. The purpose of this review is to focus attention to this important group of chromatin proteins, which, in the brain, possess overlapping structural and functional roles with the highly abundant presence of MeCP2. There is an imperative need to understand how all these proteins communicate with each other, and future research will hopefully provide us with answers.

SAJCH 613.indd

African Journals Online (AJOL)

the oral cavity in HIV-positive patients. [5] Subsequently, plasmablastic lymphoma has been found to involve other sites and to occur in other immunodeficiency states and in elderly patients.[1,2] Most patients are adults with a male predominance. [2,6] A literature review identified only eight cases of plasmablastic lymphoma ...

The Dens: Normal Development, Developmental Variants and Anomalies, and Traumatic Injuries

Directory of Open Access Journals (Sweden)

William T O′Brien

2015-01-01

Full Text Available Accurate interpretation of cervical spine imagining can be challenging, especially in children and the elderly. The biomechanics of the developing pediatric spine and age-related degenerative changes predispose these patient populations to injuries centered at the craniocervical junction. In addition, congenital anomalies are common in this region, especially those associated with the axis/dens, due to its complexity in terms of development compared to other vertebral levels. The most common congenital variations of the dens include the os odontoideum and a persistent ossiculum terminale. At times, it is necessary to distinguish normal development, developmental variants, and developmental anomalies from traumatic injuries in the setting of acute traumatic injury. Key imaging features are useful to differentiate between traumatic fractures and normal or variant anatomy acutely; however, the radiologist must first have a basic understanding of the spectrum of normal developmental anatomy and its anatomic variations in order to make an accurate assessment. This review article attempts to provide the basic framework required for accurate interpretation of cervical spine imaging with a focus on the dens, specifically covering the normal development and ossification of the dens, common congenital variants and their various imaging appearances, fracture classifications, imaging appearances, and treatment options.

A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance

NARCIS (Netherlands)

van der Tol, L.; Smid, B. E.; Poorthuis, B. J. H. M.; Biegstraaten, M.; Deprez, R. H. Lekanne; Linthorst, G. E.; Hollak, C. E. M.

2014-01-01

Screening for Fabry disease (FD) reveals a high prevalence of individuals with α-galactosidase A (GLA) genetic variants of unknown significance (GVUS). These individuals often do not express characteristic features of FD. A systematic review on FD screening studies was performed to interpret the

Swine Influenza/Variant Influenza Viruses

Science.gov (United States)

... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Pandemic Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

Beta-glucosidase variants and polynucleotides encoding same

Science.gov (United States)

Wogulis, Mark; Harris, Paul; Osborn, David

2017-06-27

The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

A Review of Pathway-Based Analysis Tools That Visualize Genetic Variants

Directory of Open Access Journals (Sweden)

Elisa Cirillo

2017-11-01

Full Text Available Pathway analysis is a powerful method for data analysis in genomics, most often applied to gene expression analysis. It is also promising for single-nucleotide polymorphism (SNP data analysis, such as genome-wide association study data, because it allows the interpretation of variants with respect to the biological processes in which the affected genes and proteins are involved. Such analyses support an interactive evaluation of the possible effects of variations on function, regulation or interaction of gene products. Current pathway analysis software often does not support data visualization of variants in pathways as an alternate method to interpret genetic association results, and specific statistical methods for pathway analysis of SNP data are not combined with these visualization features. In this review, we first describe the visualization options of the tools that were identified by a literature review, in order to provide insight for improvements in this developing field. Tool evaluation was performed using a computational epistatic dataset of gene–gene interactions for obesity risk. Next, we report the necessity to include in these tools statistical methods designed for the pathway-based analysis with SNP data, expressly aiming to define features for more comprehensive pathway-based analysis tools. We conclude by recognizing that pathway analysis of genetic variations data requires a sophisticated combination of the most useful and informative visual aspects of the various tools evaluated.

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

Science.gov (United States)

Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

2016-01-01

Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

A Variational Approach to the Denoising of Images Based on Different Variants of the TV-Regularization

International Nuclear Information System (INIS)

Bildhauer, Michael; Fuchs, Martin

2012-01-01

We discuss several variants of the TV-regularization model used in image recovery. The proposed alternatives are either of nearly linear growth or even of linear growth, but with some weak ellipticity properties. The main feature of the paper is the investigation of the analytic properties of the corresponding solutions.

Congenital anomalies and normal skeletal variants

International Nuclear Information System (INIS)

Guebert, G.M.; Yochum, T.R.; Rowe, L.J.

1987-01-01

Congenital anomalies and normal skeletal variants are a common occurrence in clinical practice. In this chapter a large number of skeletal anomalies of the spine and pelvis are reviewed. Some of the more common skeletal anomalies of the extremities are also presented. The second section of this chapter deals with normal skeletal variants. Some of these variants may simulate certain disease processes. In some instances there are no clear-cut distinctions between skeletal variants and anomalies; therefore, there may be some overlap of material. The congenital anomalies are presented initially with accompanying text, photos, and references, beginning with the skull and proceeding caudally through the spine to then include the pelvis and extremities. The normal skeletal variants section is presented in an anatomical atlas format without text or references

Biometric feature embedding using robust steganography technique

Science.gov (United States)

Rashid, Rasber D.; Sellahewa, Harin; Jassim, Sabah A.

2013-05-01

This paper is concerned with robust steganographic techniques to hide and communicate biometric data in mobile media objects like images, over open networks. More specifically, the aim is to embed binarised features extracted using discrete wavelet transforms and local binary patterns of face images as a secret message in an image. The need for such techniques can arise in law enforcement, forensics, counter terrorism, internet/mobile banking and border control. What differentiates this problem from normal information hiding techniques is the added requirement that there should be minimal effect on face recognition accuracy. We propose an LSB-Witness embedding technique in which the secret message is already present in the LSB plane but instead of changing the cover image LSB values, the second LSB plane will be changed to stand as a witness/informer to the receiver during message recovery. Although this approach may affect the stego quality, it is eliminating the weakness of traditional LSB schemes that is exploited by steganalysis techniques for LSB, such as PoV and RS steganalysis, to detect the existence of secrete message. Experimental results show that the proposed method is robust against PoV and RS attacks compared to other variants of LSB. We also discussed variants of this approach and determine capacity requirements for embedding face biometric feature vectors while maintain accuracy of face recognition.

Impact of Reclassification on Thyroid Nodules with Architectural Atypia: From Non-Invasive Encapsulated Follicular Variant Papillary Thyroid Carcinomas to Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Directory of Open Access Journals (Sweden)

Min Ji Jeon

Full Text Available The follicular variant of papillary thyroid cancer (FVPTC, especially the encapsulated non-invasive subtype, is a controversial entity. Recent study suggested using 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP' for these indolent carcinomas. We evaluated the impact of reclassification from non-invasive encapsulated FVPTCs (EFVPTCs to NIFTPs in the diagnosis of thyroid nodules with architectural atypia.We reviewed 1301 thyroid nodules with architectural atypia in core needle biopsy (CNB specimens obtained from March 2012 to February 2013. Nodules were classified into atypia of undetermined significance with architectural atypia (AUS-A, 984, 76% or follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN, 317, 24%. Among them, diagnostic surgery was performed in 384 nodules (30%.In total, 160 nodules (42% presented final malignant diagnoses including 39 non-invasive encapsulated FVPTCs (10%. The malignancy rate was estimated to be 7-35% in AUS-A nodules and 28-49% in FN/SFN nodules. After reclassification, the malignancy rate was much decreased and estimated to be 5-24% in AUS-A nodules, and 23-39% in FN/SFN nodules. Thyroid nodules with final malignant diagnoses were significantly more likely to have a FN/SFN CNB diagnosis, malignant US features and concomitant nuclear atypia in CNB specimens. However, these factors could not differentiate NIFTPs from other malignancies.After reclassification of non-invasive EFVPTCs to NIFTPs, the malignancy rate of thyroid nodules with architectural atypia in CNB specimens was decreased. However, there were no preoperative factors differentiating other malignancies from NIFTPs. The presence of malignant US features or concomitant nuclear atypia might help clinicians deciding diagnostic surgery but, these features also might indicate NIFTPs.

Correlation of English and Russian proverbs. Some features of bilingual translation

Directory of Open Access Journals (Sweden)

Кончита Карловна Гарсия-Каселес

2012-03-01

Full Text Available This article provides a brief analysis of the national and cultural identity of English and Russian proverbs and sayings in the context of two variants of the world conceptual vision. The main task is to show some features of their translatability and transferability as the substrates of intercultural communication.

A distinct subtype of ''metatropic dysplasia variant'' characterised by advanced carpal skeletal age and subluxation of the radial heads

International Nuclear Information System (INIS)

Nishimura, G.; Satoh, Masato; Aihara, Toshinori; Aida, Noriko; Yamamoto, Takehisa; Ozono, Keiichi

1998-01-01

Background. ''Metatropic dysplasia variants'' are a group of bone dysplasias whose skeletal abnormalities are similar to, but milder than, those of classical metatropic dysplasia. The genetic and phenotypic heterogeneity has not been thoroughly elucidated. Objective. The objective was to designate a distinct subtype of these metatropic dysplasia variants. Materials and methods. The subjects were four Japanese patients, two sporadic cases and two siblings, who all had identical skeletal changes. The radiological features in these patients were compared with those of previously reported metatropic dysplasia variants. Results. Moderate platyspondyly with pear-shaped and/or anterior-tongued vertebral bodies, halberd pelvis, and dumbbell deformity of the tubular bones were regarded as hallmarks of metatropic dysplasia variants. The peculiar skeletal change in our patients was advanced carpal skeletal age in childhood, unlike most patients reported as metatropic dysplasia variants who manifest delayed carpal ossification. Another hallmark was congenital dislocation of the radial heads. A description of a patient with similar skeletal changes was found in the literature. Conclusion. These patients are considered to represent a distinct subgroup of metatropic dysplasia variants. It remains unknown whether the present siblings represent an autosomal recessive trait or an autosomal dominant trait with germinal mosaicism related to increased paternal age. (orig.)

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Directory of Open Access Journals (Sweden)

Mengmeng Du

Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

Relay protection features of frequency-adjustable electric drive

Science.gov (United States)

Kuprienko, V. V.

2018-03-01

The features of relay protection of high-voltage electric motors in composition of the frequency-adjustable electric drive are considered in the article. The influence of frequency converters on the stability of the operation of various types of relay protection used on electric motors is noted. Variants of circuits for connecting relay protection devices are suggested. The need to develop special relay protection devices for a frequency-adjustable electric drive is substantiated.

Association between intracranial plasmacytoma and multiple myeloma: clinicopathological outcome study.

Science.gov (United States)

Schwartz, T H; Rhiew, R; Isaacson, S R; Orazi, A; Bruce, J N

2001-11-01

Intracranial plasmacytomas are rare lesions that can arise from the calvarium, dura, or cranial base and exhibit a benign course unless associated with myeloma. Attention has recently been focused on the role of the cell adhesion molecules CD56 and CD31 in the pathogenesis of myeloma. No such information is available for intracranial plasmacytomas and myeloma-associated lesions. We investigated the relationship between CD56 and CD31 expression, intracranial location, and progression to myeloma for a series of nine intracranial plasmacytomas (three dural, one calvarial, and five cranial base lesions). These parameters were also correlated with proliferation indices, as assessed by MIB-1 immunostaining of the histological sections. A single pathologist (AO) performed immunohistochemical analyses and reviewed all slides. Intracranial plasmacytomas presented more commonly in female patients (89%). The three dural lesions were CD56- and CD31-negative and exhibited MIB-1 staining of less than 10%; no patient developed myeloma or recurrence. Of the five cranial base lesions, three were CD56-positive, none was CD31-positive, and two exhibited MIB-1 labeling of more than 45%, with plasmablastic morphological features. Compared with other intracranial plasmacytomas, five of five patients with cranial base lesions developed bone marrow biopsy-proven myeloma (P myeloma soon after diagnosis. Both of the two highly proliferative plasmablastic lesions recurred, one after gross total resection without radiotherapy and the other after a biopsy and 2000-cGy radiotherapy. Among intracranial plasmacytomas, cranial base location was the strongest predictor of the development of multiple myeloma. Expression of the cell adhesion molecules CD31 and CD56 was not predictive of outcome. Extramedullary dural-based lesions were CD56-negative and were not associated with myeloma. A high proliferation index and plasmablastic morphological features were predictive of a short time to recurrence

Annotating pathogenic non-coding variants in genic regions.

Science.gov (United States)

Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B

2017-08-09

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle.

Science.gov (United States)

Hartman, Emily C; Jakobson, Christopher M; Favor, Andrew H; Lobba, Marco J; Álvarez-Benedicto, Ester; Francis, Matthew B; Tullman-Ercek, Danielle

2018-04-11

Self-assembling proteins are critical to biological systems and industrial technologies, but predicting how mutations affect self-assembly remains a significant challenge. Here, we report a technique, termed SyMAPS (Systematic Mutation and Assembled Particle Selection), that can be used to characterize the assembly competency of all single amino acid variants of a self-assembling viral structural protein. SyMAPS studies on the MS2 bacteriophage coat protein revealed a high-resolution fitness landscape that challenges some conventional assumptions of protein engineering. An additional round of selection identified a previously unknown variant (CP[T71H]) that is stable at neutral pH but less tolerant to acidic conditions than the wild-type coat protein. The capsids formed by this variant could be more amenable to disassembly in late endosomes or early lysosomes-a feature that is advantageous for delivery applications. In addition to providing a mutability blueprint for virus-like particles, SyMAPS can be readily applied to other self-assembling proteins.

Microcystic variant malignant mesothelioma presenting as a localized paraspinal mass

Directory of Open Access Journals (Sweden)

Hyang Mi Ko

2014-01-01

Full Text Available A 58-year-old man presented with productive cough and fever. Computed tomography (CT scan of the chest showed an upper right paraspinal mass. CT-guided fine-needle aspiration biopsy showed lobules of vacuolated cells against a background of myxoid material. The cells demonstrated moderate to severe nuclear atypia and occasional mitoses. Immunohistochemistry revealed tumor cells to be immunoreactive for calretinin, WT-1, D2-40, cytokeratin (CK 7, AE1/AE3, high molecular weight keratin, vimentin and epithelial membrane antigen, and negative for thyroid transcription factor-1, Ber-EP4, carcinoembryonic antigen, S100 protein, CK20, and CDX2. The combined morphologic and immunohistochemical findings confirmed the diagnosis of microcystic variant of localized malignant mesothelioma. The subsequent lung resection showed a pleural-based mass in the right upper lobe and confirmed the diagnosis. Awareness of the existence of unusual morphologic variants and localized forms of mesothelioma are necessary to avoid misdiagnosis of fine needle biopsy samples. Recognition of characteristic cytomorphologic features along with optimal use of panel of immunohistochemistry studies is crucial for making a specific diagnosis.

Cough Variant Asthma in Medical Outpatient Department of a Tertiary Care Hospital in Bangladesh

Directory of Open Access Journals (Sweden)

Rukhsana Parvin

2013-01-01

Full Text Available Background: Cough variant asthma (CVA is a subset of asthma where the only symptom is chronic persistent cough. Many cases go unrecognized due to lack of proper evaluation. Response to asthma medication with features supportive of airway hypersensitivity helps in management of this disease. Objective: To find out the proportion of cough variant asthma among the patients attending medicine outpatient department of Enam Medical College, Savar, Dhaka. Materials and Methods: This cross sectional study was conducted in Enam Medical College Hospital, Savar, Dhaka over a period of two years from July 2009 to July 2011. Cough variant asthma was diagnosed mainly on clinical ground as chronic cough without wheezing, fever, weight loss, shortness of breath or sputum or any other apparent cause that persisted for more than eight weeks with absolutely normal physical examination of chest, normal chest radiography and blood count except raised eosinophil count and IgE level. Patients who met these criteria were given 2 weeks course of inhaler beclomethasone propionate and were assessed for improvement. Those who improved after steroid inhalation were categorised as having cough variant asthma. Results: Out of purposively selected 148 patients complaining only of chronic dry cough for more than eight weeks, 92 patients met the primary selection criteria for cough variant asthma. These 92 patients were given 2 weeks trial of 250 ìgm beclomethasone inhalation twice daily. Seventy nine patients reported almost complete recovery from chronic cough after 2 weeks and were categorized as having CVA. Thirteen patients did not improve and were not categorized as CVA. Conclusion: These findings suggest that cough variant asthma is the most common among the patients with chronic cough not due to any apparent cause. The efficacy of inhaled corticosteroid suggests that early intervention is effective in the treatment of this disease.

Histone variants and lipid metabolism

NARCIS (Netherlands)

Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

2014-01-01

Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

CLEVER: Clique-Enumerating Variant Finder

NARCIS (Netherlands)

Marschall, T.; Costa, I.; Canzar, S.; bauer, m; Klau, G.W.; Schliep, A.; Schönhuth, A.

2012-01-01

Motivation: Next-generation sequencing techniques have facilitated a large-scale analysis of human genetic variation. Despite the advances in sequencing speed, the computational discovery of structural variants is not yet standard. It is likely that many variants have remained undiscovered in most

Synovial sarcoma with relevant immunocytochemistry and special emphasis on the monophasic fibrous variant

Directory of Open Access Journals (Sweden)

Kottu Radhika

2010-01-01

Full Text Available Background: Monophasic fibrous synovial sarcoma (SS is the most common variant of SS. Only a few cytological studies are available on this entity. Bcl-2 protein expression has been described as a characteristic marker of SS and is useful for its differentiation from other sarcomas. Cytokeratin and CD99 are also used in detecting SS. Aims: To evaluate synovial sarcoma and its variants cytomorphologically. Materials and Methods: During a period of 10 years 7 months, i.e. from January 1998 to July 2008, 12 cytologic specimens diagnosed as synovial sarcoma were reviewed. Ten cases were diagnosed as SS on aspiration alone but two cases required ancillary technique i.e., immunocytochemistry staining with bcl-2 and cytokeratin. The smears were stained with Papanicolaou and May-Grόnwald-Giemsa stains. Results: All cytologic specimens in our study had similar appearance. Most smears were highly cellular and were made up of densely packed tri-dimensional groups and singly scattered round to oval cells. Cellular monomorphism and vascular channels within the cell groups were the remarkable findings. Only one case showed cytologic evidence of epithelial differentiation. Bcl-2, cytokeratin, CD99 positivity was seen on immunohistochemistry staining. Results were categorized according to age, sex and morphologic variants. Conclusions: Although cytomorphologic features of synovial sarcomas are characteristic enough to permit its recognition, clinical correlation is necessary for accurate diagnosis. Monophasic variant is the most common entity observed in the present study.

The curation of genetic variants: difficulties and possible solutions.

Science.gov (United States)

Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

2012-12-01

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. Copyright © 2012. Published by Elsevier Ltd.

Word Variant Identification in Old French

Directory of Open Access Journals (Sweden)

Peter Willett

1997-01-01

Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

TREM2 Variants in Alzheimer's Disease

Science.gov (United States)

Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

Whole Exome Sequencing for a Patient with Rubinstein-Taybi Syndrome Reveals de Novo Variants besides an Overt CREBBP Mutation

Directory of Open Access Journals (Sweden)

Hee Jeong Yoo

2015-03-01

Full Text Available Rubinstein-Taybi syndrome (RSTS is a rare condition with a prevalence of 1 in 125,000–720,000 births and characterized by clinical features that include facial, dental, and limb dysmorphology and growth retardation. Most cases of RSTS occur sporadically and are caused by de novo mutations. Cytogenetic or molecular abnormalities are detected in only 55% of RSTS cases. Previous genetic studies have yielded inconsistent results due to the variety of methods used for genetic analysis. The purpose of this study was to use whole exome sequencing (WES to evaluate the genetic causes of RSTS in a young girl presenting with an Autism phenotype. We used the Autism diagnostic observation schedule (ADOS and Autism diagnostic interview revised (ADI-R to confirm her diagnosis of Autism. In addition, various questionnaires were used to evaluate other psychiatric features. We used WES to analyze the DNA sequences of the patient and her parents and to search for de novo variants. The patient showed all the typical features of Autism, WES revealed a de novo frameshift mutation in CREBBP and de novo sequence variants in TNC and IGFALS genes. Mutations in the CREBBP gene have been extensively reported in RSTS patients, while potential missense mutations in TNC and IGFALS genes have not previously been associated with RSTS. The TNC and IGFALS genes are involved in central nervous system development and growth. It is possible for patients with RSTS to have additional de novo variants that could account for previously unexplained phenotypes.

Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype

Directory of Open Access Journals (Sweden)

Nadia Skauli

2016-11-01

Full Text Available Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3, characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

Functional validation of candidate genes detected by genomic feature models

DEFF Research Database (Denmark)

Rohde, Palle Duun; Østergaard, Solveig; Kristensen, Torsten Nygaard

2018-01-01

to investigate locomotor activity, and applied genomic feature prediction models to identify gene ontology (GO) cate- gories predictive of this phenotype. Next, we applied the covariance association test to partition the genomic variance of the predictive GO terms to the genes within these terms. We...... then functionally assessed whether the identified candidate genes affected locomotor activity by reducing gene expression using RNA interference. In five of the seven candidate genes tested, reduced gene expression altered the phenotype. The ranking of genes within the predictive GO term was highly correlated......Understanding the genetic underpinnings of complex traits requires knowledge of the genetic variants that contribute to phenotypic variability. Reliable statistical approaches are needed to obtain such knowledge. In genome-wide association studies, variants are tested for association with trait...

Mapping genetic variations to three-dimensional protein structures to enhance variant interpretation: a proposed framework.

Science.gov (United States)

Glusman, Gustavo; Rose, Peter W; Prlić, Andreas; Dougherty, Jennifer; Duarte, José M; Hoffman, Andrew S; Barton, Geoffrey J; Bendixen, Emøke; Bergquist, Timothy; Bock, Christian; Brunk, Elizabeth; Buljan, Marija; Burley, Stephen K; Cai, Binghuang; Carter, Hannah; Gao, JianJiong; Godzik, Adam; Heuer, Michael; Hicks, Michael; Hrabe, Thomas; Karchin, Rachel; Leman, Julia Koehler; Lane, Lydie; Masica, David L; Mooney, Sean D; Moult, John; Omenn, Gilbert S; Pearl, Frances; Pejaver, Vikas; Reynolds, Sheila M; Rokem, Ariel; Schwede, Torsten; Song, Sicheng; Tilgner, Hagen; Valasatava, Yana; Zhang, Yang; Deutsch, Eric W

2017-12-18

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

Science.gov (United States)

Lanzillotta, Marco; Campochiaro, Corrado; Trimarchi, Matteo; Arrigoni, Gianluigi; Gerevini, Simonetta; Milani, Raffaella; Bozzolo, Enrica; Biafora, Matteo; Venturini, Elena; Cicalese, Maria Pia; Stone, John H; Sabbadini, Maria Grazia; Della-Torre, Emanuel

2017-07-01

A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity. We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio. Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD. Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Matching Real and Synthetic Panoramic Images Using a Variant of Geometric Hashing

Science.gov (United States)

Li-Chee-Ming, J.; Armenakis, C.

2017-05-01

This work demonstrates an approach to automatically initialize a visual model-based tracker, and recover from lost tracking, without prior camera pose information. These approaches are commonly referred to as tracking-by-detection. Previous tracking-by-detection techniques used either fiducials (i.e. landmarks or markers) or the object's texture. The main contribution of this work is the development of a tracking-by-detection algorithm that is based solely on natural geometric features. A variant of geometric hashing, a model-to-image registration algorithm, is proposed that searches for a matching panoramic image from a database of synthetic panoramic images captured in a 3D virtual environment. The approach identifies corresponding features between the matched panoramic images. The corresponding features are to be used in a photogrammetric space resection to estimate the camera pose. The experiments apply this algorithm to initialize a model-based tracker in an indoor environment using the 3D CAD model of the building.

Phenomenological and neuropsychological profile across motor variants of delirium in a palliative care unit

LENUS (Irish Health Repository)

Leonard, Maeve

2011-01-01

Studies using composite measurement of cognition suggest that cognitive performance is similar across motor variants of delirium. The authors assessed neuropsychological and symptom profiles in 100 consecutive cases of DSM-IV delirium allocated to motor subtypes in a palliative-care unit: Hypoactive (N=33), Hyperactive (N=18), Mixed (N=26), and No-Alteration motor groups (N=23). The Mixed group had more severe delirium, with highest scores for DRS-R-98 sleep-wake cycle disturbance, hallucinations, delusions, and language abnormalities. Neither the total Cognitive Test for Delirium nor its five neuropsychological domains differed across Hyperactive, Mixed, and Hypoactive motor groups. Most patients (70%) with no motor alteration had DRS-R-98 scores in the mild or subsyndromal range even though they met DSM-IV criteria. Motor variants in delirium have similar cognitive profiles, but mixed cases differ in expression of several noncognitive features.

Combined analyses of 20 common obesity susceptibility variants

DEFF Research Database (Denmark)

Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels

2010-01-01

Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes.......Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes....

Houston Methodist variant viewer: An application to support clinical laboratory interpretation of next-generation sequencing data for cancer

Directory of Open Access Journals (Sweden)

Paul A Christensen

2017-01-01

Full Text Available Introduction: Next-generation-sequencing (NGS is increasingly used in clinical and research protocols for patients with cancer. NGS assays are routinely used in clinical laboratories to detect mutations bearing on cancer diagnosis, prognosis and personalized therapy. A typical assay may interrogate 50 or more gene targets that encompass many thousands of possible gene variants. Analysis of NGS data in cancer is a labor-intensive process that can become overwhelming to the molecular pathologist or research scientist. Although commercial tools for NGS data analysis and interpretation are available, they are often costly, lack key functionality or cannot be customized by the end user. Methods: To facilitate NGS data analysis in our clinical molecular diagnostics laboratory, we created a custom bioinformatics tool termed Houston Methodist Variant Viewer (HMVV. HMVV is a Java-based solution that integrates sequencing instrument output, bioinformatics analysis, storage resources and end user interface. Results: Compared to the predicate method used in our clinical laboratory, HMVV markedly simplifies the bioinformatics workflow for the molecular technologist and facilitates the variant review by the molecular pathologist. Importantly, HMVV reduces time spent researching the biological significance of the variants detected, standardizes the online resources used to perform the variant investigation and assists generation of the annotated report for the electronic medical record. HMVV also maintains a searchable variant database, including the variant annotations generated by the pathologist, which is useful for downstream quality improvement and research projects. Conclusions: HMVV is a clinical grade, low-cost, feature-rich, highly customizable platform that we have made available for continued development by the pathology informatics community.

A window-based time series feature extraction method.

Science.gov (United States)

Katircioglu-Öztürk, Deniz; Güvenir, H Altay; Ravens, Ursula; Baykal, Nazife

2017-10-01

This study proposes a robust similarity score-based time series feature extraction method that is termed as Window-based Time series Feature ExtraCtion (WTC). Specifically, WTC generates domain-interpretable results and involves significantly low computational complexity thereby rendering itself useful for densely sampled and populated time series datasets. In this study, WTC is applied to a proprietary action potential (AP) time series dataset on human cardiomyocytes and three precordial leads from a publicly available electrocardiogram (ECG) dataset. This is followed by comparing WTC in terms of predictive accuracy and computational complexity with shapelet transform and fast shapelet transform (which constitutes an accelerated variant of the shapelet transform). The results indicate that WTC achieves a slightly higher classification performance with significantly lower execution time when compared to its shapelet-based alternatives. With respect to its interpretable features, WTC has a potential to enable medical experts to explore definitive common trends in novel datasets. Copyright © 2017 Elsevier Ltd. All rights reserved.

Three-dimensional CT features of occipital squama normal anatomy, anatomic variations and fractures

International Nuclear Information System (INIS)

Liu Jungang; Li Xin; Wang Chunxiang; Zhang Lin; Guo Wanhua

2013-01-01

Objective: To evaluate 3D CT features of normal anatomy, anatomic variations and fractures of occipital squama. Methods: The 3D CT features on MIP, VR images were analyzed retrospectively in 589 pediatric cases. The normal anatomy, anatomic variations and fractures of occipital squama were observed respectively, and the differential diagnostic features including the individual location, appearance and extension were analyzed. Results: Four hundred and thirty-three patients (75.2%) showed normal anatomy, including 154 patients with adult occipital anatomical features, 279 patients with posterior intraoccipital synchondrosis, and 37 patients with Kerckring-supraoccipital synchondrosis. When cases with recent trauma history were excluded, 113 patients (19.1%) showed anatomic variants, including unpenetrating sutures and penetrating sutures. The former could be subdivided to Mendosal sutures in 23 cases, superior median fissures in 19 cases, and midline supraoccipital fissures in 4 cases, while the latter could be subdivided to the interparietal bone variations in 54 cases, wormian bones in 23 cases, and accessory bones in 7 cases. Two or more variations coexisted in 33 cases. The occipital squama fractures were shown in 34 cases (5.6%), including linear fractures in 27 cases, comminuted fractures in 3 cases, with depression fracture in one case, separation of cranial sutures in 3 cases, and other fractures associated with variants in 3 cases. The fractures were sharp, or jagged, without limitation of the occification. Conclusion: There are different 3D CT features of normal anatomy, anatomic variations and fractures of occipital squama in children, which are important for making the accurate diagnosis. (authors)

Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.

Science.gov (United States)

Ben-Salem, Salma; Sobreira, Nara; Akawi, Nadia A; Al-Shamsi, Aisha M; John, Anne; Pramathan, Thachillath; Valle, David; Ali, Bassam R; Al-Gazali, Lihadh

2016-01-01

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence. © 2015 Wiley Periodicals, Inc.

Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

Science.gov (United States)

Bustamante, M Leonor; Herrera, Luisa; Gaspar, Pablo A; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

2017-10-01

Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. © 2017 Wiley Periodicals, Inc.

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Directory of Open Access Journals (Sweden)

Johnathan Cooper-Knock

2017-11-01

Full Text Available Amyotrophic lateral sclerosis (ALS is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs. We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18. Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033. We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025. Our data are

Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.

Science.gov (United States)

Rao, Shitao; Leung, Cherry She Ting; Lam, Macro Hb; Wing, Yun Kwok; Waye, Mary Miu Yee; Tsui, Stephen Kwok Wing

2017-03-01

To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese. Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest. After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene. This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese. Copyright © 2016 Elsevier B.V. All rights reserved.

Germline Variants of Prostate Cancer in Japanese Families.

Directory of Open Access Journals (Sweden)

Takahide Hayano

Full Text Available Prostate cancer (PC is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family. We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family. We identified two deleterious HOXB13 variants (F127C and G132E. Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3. The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

Detecting rare variants in case-parents association studies.

Directory of Open Access Journals (Sweden)

Kuang-Fu Cheng

Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

Germline-specific H1 variants: the "sexy" linker histones.

Science.gov (United States)

Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

2016-03-01

The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

Variants of glycoside hydrolases

Science.gov (United States)

Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

2011-04-26

The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

Local binary patterns new variants and applications

CERN Document Server

Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

2014-01-01

This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

Variant Creutzfeldt-Jakob Disease (vCJD)

Science.gov (United States)

... Form Controls Cancel Submit Search the CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

Population structure analysis using rare and common functional variants

Directory of Open Access Journals (Sweden)

Ding Lili

2011-11-01

Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

Science.gov (United States)

Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

2018-01-23

Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

Improving biological understanding and complex trait prediction by integrating prior information in genomic feature models

DEFF Research Database (Denmark)

Edwards, Stefan McKinnon

externally founded information, such as KEGG pathways, Gene Ontology gene sets, or genomic features, and estimate the joint contribution of the genetic variants within these sets to complex trait phenotypes. The analysis of complex trait phenotypes is hampered by the myriad of genes that control the trait...

Exercise testing in patients with variant angina: results, correlation with clinical and angiographic features and prognostic significance

International Nuclear Information System (INIS)

Waters, D.D.; Szlachcic, J.; Bourassa, M.G.; Scholl, J.-M.; Theroux, P.

1982-01-01

Eighty-two patients with variant angina underwent a treadmill exercise test using 14 ECG leads, and 67 also underwent exercise thallium-201 scans. The test induced ST elevation in 25 patients (30%), ST depression in 21 (26%) and no ST-segment abnormality in 36 (44%). ST elevation during exercise occurred in the same ECG leads as during spontaneous attacks at rest, and was always associated with a large perfusion defect on the exercise thallium scan. In contrast, exercise-induced ST depression often did not occur in the leads that exhibited ST elevation during episodes at rest. The ST-segment response to exercise did not accurately predict coronary anatomy: Coronary stenoses greater than or equal to 70% were present in 14 of 25 patients (56%) with ST elevation, in 13 of 21 (62%) with ST depression and in 14 of 36 (39%) with no ST-segment abnormality (NS). However, the degree of disease activity did correlate with the result of the exercise test: ST elevation occurred during exercise in 11 of 14 patients who had an average of more than two spontaneous attacks per day, in 12 of 24 who had between two attacks per day and two per week, and in only two of 31 who had fewer than two attacks per week (p<0.005). ST elevation during exercise was reproducible in five of five patients retested during an active phase of their disease, but not in three of three patients who had been angina-free for a least 1 month before the repeat test. We conclude that in variant angina patients, the results of an exercise test correlate well with the degree of disease activity but not with coronary anatomy, and do not define a high-risk subgroup

Data-variant kernel analysis

CERN Document Server

Motai, Yuichi

2015-01-01

Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

Magnetic resonance imaging features of complex Chiari malformation variant of Chiari 1 malformation

Energy Technology Data Exchange (ETDEWEB)

Moore, Hannah E. [Primary Children' s Medical Center, Department of Medical Imaging, Salt Lake City, UT (United States); Moore, Kevin R. [University of Utah School of Medicine, Department of Radiology, Salt Lake City, UT (United States); Primary Children' s Medical Center, Department of Medical Imaging, Salt Lake City, UT (United States)

2014-11-15

Complex Chiari malformation is a subgroup of Chiari 1 malformation with distinct imaging features. Children with complex Chiari malformation are reported to have a more severe clinical phenotype and sometimes require more extensive surgical treatment than those with uncomplicated Chiari 1 malformation. We describe reported MR imaging features of complex Chiari malformation and evaluate the utility of craniometric parameters and qualitative anatomical observations for distinguishing complex Chiari malformation from uncomplicated Chiari 1 malformation. We conducted a retrospective search of the institutional imaging database using the keywords ''Chiari'' and ''Chiari 1'' to identify children imaged during the 2006-2011 time period. Children with Chiari 2 malformation were excluded after imaging review. We used the first available diagnostic brain or cervical spine MR study for data measurement. Standard measurements and observations were made of obex level (mm), cerebellar tonsillar descent (mm), perpendicular distance to basion-C2 line (pB-C2, mm), craniocervical angle (degrees), clivus length, and presence or absence of syringohydromyelia, basilar invagination and congenital craniovertebral junction osseous anomalies. After imaging review, we accessed the institutional health care clinical database to determine whether each subject clinically met criteria for Chiari 1 malformation or complex Chiari malformation. Obex level and craniocervical angle measurements showed statistically significant differences between the populations with complex Chiari malformation and uncomplicated Chiari 1 malformation. Cerebellar tonsillar descent and perpendicular distance to basion-C2 line measurements trended toward but did not meet statistical significance. Odontoid retroflexion, craniovertebral junction osseous anomalies, and syringohydromyelia were all observed proportionally more often in children with complex Chiari malformation than in

Combinations of Genetic Variants Occurring Exclusively in Patients

Directory of Open Access Journals (Sweden)

Erling Mellerup

Full Text Available In studies of polygenic disorders, scanning the genetic variants can be used to identify variant combinations. Combinations that are exclusively found in patients can be separated from those combinations occurring in control persons. Statistical analyses can be performed to determine whether the combinations that occur exclusively among patients are significantly associated with the investigated disorder. This research strategy has been applied in materials from various polygenic disorders, identifying clusters of patient-specific genetic variant combinations that are significant associated with the investigated disorders. Combinations from these clusters are found in the genomes of up to 55% of investigated patients, and are not present in the genomes of any control persons. Keywords: Genetic variants, Polygenic disorder, Combinations of genetic variants, Patient-specific combinations

Radiologic features of cystic, endocrine and other pancreatic neoplasms

International Nuclear Information System (INIS)

Balci, N. Cem; Semelka, Richard C.

2001-01-01

This article presents imaging features of cystic, endocrine and other pancreatic neoplasms. Microcystic adenoma which is composed of small cysts ( 2 cm) are accounted for mucinous cystic neoplasms, its variant along pancreatic duct is ductectatic mucinous cystic neoplasm. Endocrine tumors of pancreas are hypervascular and can be depicted on early dynamic enhanced crosssectional imaging modalities or on angiography when they are <1 cm. Pancreatic metastases and lymphomas are rare neoplasms which should also be included in differential diagnosis for pancreatic masses

Interactive music composition driven by feature evolution.

Science.gov (United States)

Kaliakatsos-Papakostas, Maximos A; Floros, Andreas; Vrahatis, Michael N

2016-01-01

Evolutionary music composition is a prominent technique for automatic music generation. The immense adaptation potential of evolutionary algorithms has allowed the realisation of systems that automatically produce music through feature and interactive-based composition approaches. Feature-based composition employs qualitatively descriptive music features as fitness landmarks. Interactive composition systems on the other hand, derive fitness directly from human ratings and/or selection. The paper at hand introduces a methodological framework that combines the merits of both evolutionary composition methodologies. To this end, a system is presented that is organised in two levels: the higher level of interaction and the lower level of composition. The higher level incorporates the particle swarm optimisation algorithm, along with a proposed variant and evolves musical features according to user ratings. The lower level realizes feature-based music composition with a genetic algorithm, according to the top level features. The aim of this work is not to validate the efficiency of the currently utilised setup in each level, but to examine the convergence behaviour of such a two-level technique in an objective manner. Therefore, an additional novelty in this work concerns the utilisation of artificial raters that guide the system through the space of musical features, allowing the exploration of its convergence characteristics: does the system converge to optimal melodies, is this convergence fast enough for potential human listeners and is the trajectory to convergence "interesting' and "creative" enough? The experimental results reveal that the proposed methodological framework represents a fruitful and robust, novel approach to interactive music composition.

Multifunctional role of the transcription factor Blimp1 in coordinating plasma cell differentiation

Science.gov (United States)

Minnich, Martina; Tagoh, Hiromi; Bönelt, Peter; Axelsson, Elin; Fischer, Maria; Cebolla, Beatriz; Tarakhovsky, Alexander; Nutt, Stephen L.; Jaritz, Markus; Busslinger, Meinrad

2018-01-01

Blimp1 is an essential regulator of plasma cells. Here we studied its functions in plasmablast differentiation by identifying regulated Blimp1 target genes. Blimp1 promoted plasmablast migration and adhesion. It repressed several transcription factor genes and Aicda, thus silencing B-cell-specific gene expression, antigen presentation and class switch recombination in plasmablasts. It directly activated genes, leading to increased expression of the plasma cell regulator IRF4 and proteins involved in immunoglobulin secretion. Blimp1 induced immunoglobulin gene transcription by controlling Igh and Igk 3’ enhancers and regulated the posttranscriptional expression switch from the membrane-bound to secreted immunoglobulin heavy-chain by activating Ell2. Notably, Blimp1 recruited chromatin-remodeling and histone-modifying complexes to regulate its target genes. Hence, many essential functions of plasma cells are under Blimp1 control. PMID:26779602

POLYMORPHIC VARIANTS OF THE GENE OF INTERFERON LAMBDA 3 AND FEATURES OF IMMUNE RESPONSE IN CHILDREN WITH CHRONIC VIRAL HEPATITIS C

Directory of Open Access Journals (Sweden)

T. B. Sentsova

2017-01-01

Full Text Available To study the immune manifestations of the interferon-lambda 3 genepolymorphism in chronic viral hepatitis C, 110 Russian children (54 girls and 56 boys with chronic HCV infection aged from 3 to 17 years were examined. All children were on combined therapy (pegylated interferon + ribavirin. It was found that among the studied polymorphic variants of the IFN-λ 3 gene in children with chronic HCV infection, T allele of the marker rs12979860 is associated with infection and chronization of HCV. The T/T rs12979860 genotype of the IFN-λ3 gene is unfavorable for the course of chronic HCV infection due to low levels of activated T-lymphocytes, intactness of the proinflammatory cytokines TNF-α, IL-6, IL-1α, and interferon-γ inducible protein IP-10. The revealed relation of the polymorphic variants of C/C + C/T locus rs12979860 of INF-λ3 gene with the expression of activated T-lymphocytes discloses the protective nature of these genotypes to the development of chronic HCV infection in children. 

Structural insights into methanol-stable variants of lipase T6 from Geobacillus stearothermophilus.

Science.gov (United States)

Dror, Adi; Kanteev, Margarita; Kagan, Irit; Gihaz, Shalev; Shahar, Anat; Fishman, Ayelet

2015-11-01

Enzymatic production of biodiesel by transesterification of triglycerides and alcohol, catalyzed by lipases, offers an environmentally friendly and efficient alternative to the chemically catalyzed process while using low-grade feedstocks. Methanol is utilized frequently as the alcohol in the reaction due to its reactivity and low cost. However, one of the major drawbacks of the enzymatic system is the presence of high methanol concentrations which leads to methanol-induced unfolding and inactivation of the biocatalyst. Therefore, a methanol-stable lipase is of great interest for the biodiesel industry. In this study, protein engineering was applied to substitute charged surface residues with hydrophobic ones to enhance the stability in methanol of a lipase from Geobacillus stearothermophilus T6. We identified a methanol-stable variant, R374W, and combined it with a variant found previously, H86Y/A269T. The triple mutant, H86Y/A269T/R374W, had a half-life value at 70 % methanol of 324 min which reflects an 87-fold enhanced stability compared to the wild type together with elevated thermostability in buffer and in 50 % methanol. This variant also exhibited an improved biodiesel yield from waste chicken oil compared to commercial Lipolase 100L® and Novozyme® CALB. Crystal structures of the wild type and the methanol-stable variants provided insights regarding structure-stability correlations. The most prominent features were the extensive formation of new hydrogen bonds between surface residues directly or mediated by structural water molecules and the stabilization of Zn and Ca binding sites. Mutation sites were also characterized by lower B-factor values calculated from the X-ray structures indicating improved rigidity.

Determination of uranium by luminescent method (tablet variant)

International Nuclear Information System (INIS)

Sergeev, A.N.; Yufa, B.Ya.

1985-01-01

A new tablet variant of luminescent determination of uranium in rocks is developed. The analytical process includes the following operations: sample decomposition, uranium separation from luminescence quencher impurities, preparation of luminescent sample (tablet), photometry of the tablet. The method has two variants developed: the first one is characterized by a more hard decomposition, sample mass being 0.2 g; the second variant has a better detection limit (5x10 -6 %), the sample mass being 0.2-1 g. Procedures of the sample preparation for both variants of analysis are described

NMNAT1 variants cause cone and cone-rod dystrophy.

Science.gov (United States)

Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

2018-03-01

Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

Novel atomic force microscopy based biopanning for isolation of morphology specific reagents against TDP-43 variants in amyotrophic lateral sclerosis.

Science.gov (United States)

Williams, Stephanie M; Venkataraman, Lalitha; Tian, Huilai; Khan, Galam; Harris, Brent T; Sierks, Michael R

2015-02-12

Because protein variants play critical roles in many diseases including TDP-43 in Amyotrophic Lateral Sclerosis (ALS), alpha-synuclein in Parkinson's disease and beta-amyloid and tau in Alzheimer's disease, it is critically important to develop morphology specific reagents that can selectively target these disease-specific protein variants to study the role of these variants in disease pathology and for potential diagnostic and therapeutic applications. We have developed novel atomic force microscopy (AFM) based biopanning techniques that enable isolation of reagents that selectively recognize disease-specific protein variants. There are two key phases involved in the process, the negative and positive panning phases. During the negative panning phase, phages that are reactive to off-target antigens are eliminated through multiple rounds of subtractive panning utilizing a series of carefully selected off-target antigens. A key feature in the negative panning phase is utilizing AFM imaging to monitor the process and confirm that all undesired phage particles are removed. For the positive panning phase, the target antigen of interest is fixed on a mica surface and bound phages are eluted and screened to identify phages that selectively bind the target antigen. The target protein variant does not need to be purified providing the appropriate negative panning controls have been used. Even target protein variants that are only present at very low concentrations in complex biological material can be utilized in the positive panning step. Through application of this technology, we acquired antibodies to protein variants of TDP-43 that are selectively found in human ALS brain tissue. We expect that this protocol should be applicable to generating reagents that selectively bind protein variants present in a wide variety of different biological processes and diseases.

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming

2013-07-26

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

Directory of Open Access Journals (Sweden)

Faming Liang

Full Text Available Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD, to tackle this problem. The new method simultaneously addresses two issues: (i (Global association test Are there any of the variants associated with the disease, and (ii (Causal variant detection Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Bayesian detection of causal rare variants under posterior consistency.

KAUST Repository

Liang, Faming; Xiong, Momiao

2013-01-01

Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset.

Directory of Open Access Journals (Sweden)

Tjaart A P de Beer

Full Text Available The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%, with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with common exchanges in one dataset being rare in the other. Disease-associated variants exhibit more extreme differences in amino acid size and hydrophobicity. More modelling of the mutational processes at the nucleotide level is needed, but these observations should contribute to an improved prediction of the effects of specific variants in humans.

Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases.

Science.gov (United States)

Itoh, Masayuki; Ide, Shuhei; Iwasaki, Yuji; Saito, Takashi; Narita, Keishi; Dai, Hongmei; Yamakura, Shinji; Furue, Takeki; Kitayama, Hirotsugu; Maeda, Keiko; Takahashi, Eihiko; Matsui, Kiyoshi; Goto, Yu-Ichi; Takeda, Sen; Arima, Masataka

2018-04-01

Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

MRI features of posterior ankle impingement syndrome in ballet dancers: a review of 25 cases

Energy Technology Data Exchange (ETDEWEB)

Peace, K.A.L. E-mail: kalpeace@hotmail.com; Hillier, J.C.; Hulme, A.; Healy, J.C

2004-11-01

AIM: To describe the magnetic resonance imaging (MRI) features of posterior ankle impingement syndrome (PAIS) in classical ballet dancers. MATERIALS AND METHODS: A retrospective review was undertaken of 25 MRI examinations of the ankle performed on 23 ballet dancers over a 26-month period. Images were examined for the presence of osseous and soft-tissue anatomical variants at the posterior ankle and imaging signs of PAIS. All patients presented with symptoms and signs suggestive of PAIS including posterior ankle pain, swelling and stiffness during plantar flexion. RESULTS: Anatomical variants predisposing to PAIS including as os trigonum and tuberosity arising from the superior calcaneum were clearly depicted. The most common imaging feature of PAIS in our series was high T2 signal posterior to the talocalcaneal joint indicating synovitis (n=25). Thickening of the posterior capsule (n=13) and tenosynovitis of flexor hallucis longus (n=17) were also common. An os trigonum was an infrequent finding (n=7). Bone marrow oedema, commonly in the posterior talus (n=10) or in a patchy distribution (n=10) was often noted. CONCLUSION: MRI is a useful diagnostic tool in PAIS, and in the present series, clearly demonstrates the anatomical variants and range of osseous and soft-tissue abnormalities associated with this condition. Prospective studies are needed to understand the significance and importance of individual MRI findings in producing the symptoms of PAIS.

MRI features of posterior ankle impingement syndrome in ballet dancers: a review of 25 cases

International Nuclear Information System (INIS)

Peace, K.A.L.; Hillier, J.C.; Hulme, A.; Healy, J.C.

2004-01-01

AIM: To describe the magnetic resonance imaging (MRI) features of posterior ankle impingement syndrome (PAIS) in classical ballet dancers. MATERIALS AND METHODS: A retrospective review was undertaken of 25 MRI examinations of the ankle performed on 23 ballet dancers over a 26-month period. Images were examined for the presence of osseous and soft-tissue anatomical variants at the posterior ankle and imaging signs of PAIS. All patients presented with symptoms and signs suggestive of PAIS including posterior ankle pain, swelling and stiffness during plantar flexion. RESULTS: Anatomical variants predisposing to PAIS including as os trigonum and tuberosity arising from the superior calcaneum were clearly depicted. The most common imaging feature of PAIS in our series was high T2 signal posterior to the talocalcaneal joint indicating synovitis (n=25). Thickening of the posterior capsule (n=13) and tenosynovitis of flexor hallucis longus (n=17) were also common. An os trigonum was an infrequent finding (n=7). Bone marrow oedema, commonly in the posterior talus (n=10) or in a patchy distribution (n=10) was often noted. CONCLUSION: MRI is a useful diagnostic tool in PAIS, and in the present series, clearly demonstrates the anatomical variants and range of osseous and soft-tissue abnormalities associated with this condition. Prospective studies are needed to understand the significance and importance of individual MRI findings in producing the symptoms of PAIS

Electrophoretic variants of blood proteins in japanese, 5

International Nuclear Information System (INIS)

Fujita, Mikio; Satoh, Chiyoko; Asakawa, Jun-ichi; Nagahata, Yuko; Tanaka, Yoshiko; Hazama, Ryuji; Goriki, Kazuaki.

1985-08-01

The plasma ceruloplasmin (CP) of 22,367 children of atomic bomb survivors in Hiroshima and Nagasaki was examined for variants by electrophoresis. The sample was composed of 14,964 unrelated children and 7,403 siblings of the unrelated persons. A total of seven types of electrophoretic variants were detected; four migrating anodally and three cathodally to the normal B band. We have reported two of these variants, CP A sub(NG1) and CP C sub(NG1), previously but the other five, CP A sub(NG2), CP A sub(HR1), CP A sub(HR2), CP C sub(HR1), and CP C sub(HR2), are newly identified. The allelic frequency of CP*CNG1 was 0.00916, so that the variant is considered to be a polymorphic allele. Homozygosity for the CP*CNG1 allele was detected in five individuals. This is the first report of a homozygous phenotype for a CP variant in a Japanese population. Family study of the new five variants all demonstrated patterns of codominant inheritance. (author)

Association analysis identifies ZNF750 regulatory variants in psoriasis

Directory of Open Access Journals (Sweden)

Birnbaum Ramon Y

2011-12-01

Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism.

Science.gov (United States)

Almeida, Julia; Polvorosa, Maria Angeles; Gonzalez-Quintela, Arturo; Madruga, Ignacio; Marcos, Miguel; Pérez-Nieto, Maria Angeles; Hernandez-Cerceño, Maria Luisa; Orfao, Alberto; Laso, Francisco Javier

2015-08-01

Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27(-) and CD27(+) memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-) /sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig

TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.

Directory of Open Access Journals (Sweden)

Tsutomu Ogata

Full Text Available BACKGROUND: Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We studied three subjects with craniofacial features and hypocalcemia (group 1, two subjects with craniofacial features alone (group 2, and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459 specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. CONCLUSIONS/SIGNIFICANCE: Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.

Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller.

Science.gov (United States)

Xu, Chang; Nezami Ranjbar, Mohammad R; Wu, Zhong; DiCarlo, John; Wang, Yexun

2017-01-03

Detection of DNA mutations at very low allele fractions with high accuracy will significantly improve the effectiveness of precision medicine for cancer patients. To achieve this goal through next generation sequencing, researchers need a detection method that 1) captures rare mutation-containing DNA fragments efficiently in the mix of abundant wild-type DNA; 2) sequences the DNA library extensively to deep coverage; and 3) distinguishes low level true variants from amplification and sequencing errors with high accuracy. Targeted enrichment using PCR primers provides researchers with a convenient way to achieve deep sequencing for a small, yet most relevant region using benchtop sequencers. Molecular barcoding (or indexing) provides a unique solution for reducing sequencing artifacts analytically. Although different molecular barcoding schemes have been reported in recent literature, most variant calling has been done on limited targets, using simple custom scripts. The analytical performance of barcode-aware variant calling can be significantly improved by incorporating advanced statistical models. We present here a highly efficient, simple and scalable enrichment protocol that integrates molecular barcodes in multiplex PCR amplification. In addition, we developed smCounter, an open source, generic, barcode-aware variant caller based on a Bayesian probabilistic model. smCounter was optimized and benchmarked on two independent read sets with SNVs and indels at 5 and 1% allele fractions. Variants were called with very good sensitivity and specificity within coding regions. We demonstrated that we can accurately detect somatic mutations with allele fractions as low as 1% in coding regions using our enrichment protocol and variant caller.

Modal analysis of fluid flows using variants of proper orthogonal decomposition

Science.gov (United States)

Rowley, Clarence; Dawson, Scott

2017-11-01

This talk gives an overview of several methods for analyzing fluid flows, based on variants of proper orthogonal decomposition. These methods may be used to determine simplified, approximate models that capture the essential features of these flows, in order to better understand the dominant physical mechanisms, and potentially to develop appropriate strategies for model-based flow control. We discuss balanced proper orthogonal decomposition as an approximation of balanced truncation, and explain connections with system identification methods such as the eigensystem realization algorithm. We demonstrate the methods on several canonical examples, including a linearized channel flow and the flow past a circular cylinder. Supported by AFOSR, Grant FA9550-14-1-0289.

Identifying structural variants using linked-read sequencing data.

Science.gov (United States)

Elyanow, Rebecca; Wu, Hsin-Ta; Raphael, Benjamin J

2017-11-03

Structural variation, including large deletions, duplications, inversions, translocations, and other rearrangements, is common in human and cancer genomes. A number of methods have been developed to identify structural variants from Illumina short-read sequencing data. However, reliable identification of structural variants remains challenging because many variants have breakpoints in repetitive regions of the genome and thus are difficult to identify with short reads. The recently developed linked-read sequencing technology from 10X Genomics combines a novel barcoding strategy with Illumina sequencing. This technology labels all reads that originate from a small number (~5-10) DNA molecules ~50Kbp in length with the same molecular barcode. These barcoded reads contain long-range sequence information that is advantageous for identification of structural variants. We present Novel Adjacency Identification with Barcoded Reads (NAIBR), an algorithm to identify structural variants in linked-read sequencing data. NAIBR predicts novel adjacencies in a individual genome resulting from structural variants using a probabilistic model that combines multiple signals in barcoded reads. We show that NAIBR outperforms several existing methods for structural variant identification - including two recent methods that also analyze linked-reads - on simulated sequencing data and 10X whole-genome sequencing data from the NA12878 human genome and the HCC1954 breast cancer cell line. Several of the novel somatic structural variants identified in HCC1954 overlap known cancer genes. Software is available at compbio.cs.brown.edu/software. braphael@princeton.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.

Science.gov (United States)

Cole, Suzanne; Walsh, Alice; Yin, Xuefeng; Wechalekar, Mihir D; Smith, Malcolm D; Proudman, Susanna M; Veale, Douglas J; Fearon, Ursula; Pitzalis, Costantino; Humby, Frances; Bombardieri, Michele; Axel, Amy; Adams, Homer; Chiu, Christopher; Sharp, Michael; Alvarez, John; Anderson, Ian; Madakamutil, Loui; Nagpal, Sunil; Guo, Yanxia

2018-05-02

Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.

Individual Distinctive Features of Self-Regulation Processes Peculiar to Students of Different Profiles of Lateral Organization

Science.gov (United States)

Korneeva, Svetlana A.; Zherebnenko, Oksana A.; Mukhamedzyanova, Flera G.; Moskalenko, Svetlana V.; Gorelikova, Olga N.

2016-01-01

The research paper presents an analysis of the interrelation between the lateral organisation profiles' indicators and self-regulation features. The existence of significant distinctions in the processes of self-regulation among respondents with different variants of lateral profiles of the interhemispheric asymmetry is proved, as well as the…

Shear wave elastography diagnosis of the diffuse sclerosing variant of papillary thyroid carcinoma: A case report

OpenAIRE

Xue, Nianyu; Xu, Youfeng; Huang, Pintong; Zhang, Shengmin; Wang, Hongwei; Yu, Fei

2016-01-01

The present study aimed to report the shear wave elastography (SWE) findings in a patient with the diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC). Since patients with DSVPTC may present with typical clinicopathological features and initially appear to have Hashimoto's thyroiditis, a thorough clinical evaluation and an early diagnosis are important. A 20-year-old female patient presented with a 1-month history of a neck mass and sore throat. Conventional ultrasound and SWE ...

Developing consistent pronunciation models for phonemic variants

CSIR Research Space (South Africa)

Davel, M

2006-09-01

Full Text Available Pronunciation lexicons often contain pronunciation variants. This can create two problems: It can be difficult to define these variants in an internally consistent way and it can also be difficult to extract generalised grapheme-to-phoneme rule sets...

Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins.

Science.gov (United States)

Gosselin, R C; Carlin, A C; Dwyre, D M

2011-04-01

Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high-pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. © 2010 Blackwell Publishing Ltd.

American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Science.gov (United States)

Haugen, Bryan R; Sawka, Anna M; Alexander, Erik K; Bible, Keith C; Caturegli, Patrizio; Doherty, Gerard M; Mandel, Susan J; Morris, John C; Nassar, Aziza; Pacini, Furio; Schlumberger, Martin; Schuff, Kathryn; Sherman, Steven I; Somerset, Hilary; Sosa, Julie Ann; Steward, David L; Wartofsky, Leonard; Williams, Michelle D

2017-04-01

American Thyroid Association (ATA) leadership asked the ATA Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Task Force to review, comment on, and make recommendations related to the suggested new classification of encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The task force consists of members from the 2015 guidelines task force with the recusal of three members who were authors on the paper under review. Four pathologists and one endocrinologist were added for this specific review. The manuscript proposing the new classification and related literature were assessed. It is recommended that the histopathologic nomenclature for eFVPTC without invasion be reclassified as a NIFTP, given the excellent prognosis of this neoplastic variant. This is a weak recommendation based on moderate-quality evidence. It is also noted that prospective studies are needed to validate the observed patient outcomes (and test performance in predicting thyroid cancer outcomes), as well as implications on patients' psychosocial health and economics.

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

Science.gov (United States)

Balendra, Rubika; Uphill, James; Collinson, Claire; Druyeh, Ronald; Adamson, Gary; Hummerich, Holger; Zerr, Inga; Gambetti, Pierluigi; Collinge, John; Mead, Simon

2016-04-07

Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

A genetic electrophoretic variant of high-sulfur hair proteins for forensic hair comparisons. I. Characterization of variant high-sulfur proteins of human hair.

Science.gov (United States)

Miyake, B

1989-02-01

In a survey of the proteins from human hair, a genetic electrophoretic variant has been observed in the high-sulfur protein region. S-carboxymethylated proteins were examined by 15% polyacrylamide gel electrophoresis at pH 8.9. Out of 150 unrelated samples of Japanese head hairs analyzed, 107 showed 6 major high-sulfur protein bands (normal) and the remaining 43 samples showed an additional high-sulfur protein band (variant). Of 21 Caucasian samples analyzed only one variant sample was found. Characterization of the proteins by two-dimensional electrophoresis evidenced a variant protein spot which showed an apparent molecular weight of 30 k Da. Isoelectric points of the high-sulfur proteins ranged from 3.25-3.55 and that of variant protein band from 3.3-3.4. Family studies of 21 matings resulting in 49 children indicated that this variant was inherited in an autosomal fashion.

ABCA7 rare variants and Alzheimer disease risk.

Science.gov (United States)

Le Guennec, Kilan; Nicolas, Gaël; Quenez, Olivier; Charbonnier, Camille; Wallon, David; Bellenguez, Céline; Grenier-Boley, Benjamin; Rousseau, Stéphane; Richard, Anne-Claire; Rovelet-Lecrux, Anne; Bacq, Delphine; Garnier, Jean-Guillaume; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, Jean-François; Amouyel, Philippe; Munter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frebourg, Thierry; Redon, Richard; Letenneur, Luc; Dartigues, Jean-François; Pasquier, Florence; Rollin-Sillaire, Adeline; Génin, Emmanuelle; Lambert, Jean-Charles; Hannequin, Didier; Campion, Dominique

2016-06-07

To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants. © 2016 American Academy of Neurology.

Electrophoretic variants of blood proteins in Japanese, 7

International Nuclear Information System (INIS)

Satoh, Chiyoko; Takahashi, Norio; Kimura, Yasukazu; Miura, Akiko; Kaneko, Junko; Fujita, Mikio; Toyama, Kyoko.

1986-11-01

A total of 16,835 children, of whom 11,737 are unrelated, from Hiroshima and Nagasaki were examined for erythrocyte cytoplasmic glutamate-oxaloacetate transaminase (GOT1) by starch gel electrophoresis. A variant allele named GOT1*2HR1 which seems to be identical with GOT1*2 was encountered in polymorphic frequency. Five kinds of rare variants, 3NG1, 4NG1, 5NG1, 6HR1, and 7NG1 were encountered in a total of 109 children. Except for 7NG1 for which complete family study was unable, family studies confirmed the genetic nature of these rare variants, since for all instances in which both parents could be examined, one of the parents exhibited the same variant as that of their child. Thermostability profiles of these six variants were normal. The enzyme activities of five were decreased, while the value of one was normal compared to that of GOT1 1. (author)

AB093. Report of a SMARCA4 variant identified in a patient with Coffin-Siris syndrome

Science.gov (United States)

Loke, Mun Fai; Jamuar, Saumya Shekhar; Lim, Eileen Chew Ping; Tan, Ene Choo

2017-01-01

Background Coffin-Siris syndrome (CSS, OMIM 614609) is a rare condition that affects multiple body systems. Hallmarks of this condition include developmental disability, abnormalities of the fifth fingers or toes, and characteristic facial features. Here, the case of a 4-year-old Chinese boy with lateral flaring and thick eyebrows, long eyelashes, coarse facies, left single palmar crease, absent of both fifth toenails, posterior cleft palate, umbilical hernia and congenital nystagmus is presented. The boy also has bilateral developmental dysplasia of the hip, which has not been reported in CSS. Methods Genomic DNA was extracted from peripheral blood samples collected from the patient and parents. Targeted next generation sequencing of the patient sample was performed on the Illumina MiSeq system using the TruSight One panel that covers >4,800 clinically relevant genes. Alignment and variant calling was carried out using the on-instrument MiSeq Reporter software, and the VCF file generated was annotated and filtered using WANNOVAR. The presence of the variant and the de novo status was confirmed by Sanger sequencing of patient and parental samples. Results A heterozygous c.3127C>T variant was detected in exon 23 of the SMARCA4 gene in the patient. It was not present in his parents. The de novo variant is predicted to cause a p. (Arg1043Trp) missense substitution of a highly conserved amino acid in the SNF2-related domain of the SMARCA4 protein, and can be classified as likely pathogenic for CSS based on the ACMG/AMP 2015 guidelines. This variant is not in the Exome Sequencing Project, 1000 Genomes Project and Exome Aggregation Consortium databases, although it has been reported previously in a patient with CSS. Conclusions The SMARCA4 gene encodes the ATP-hydroxylase containing subunits of the BAF complex and variants are expected to influence the ATP-hydrolase activity and affect downstream processes such as DNA packaging and gene expression.

PredictSNP2: A Unified Platform for Accurately Evaluating SNP Effects by Exploiting the Different Characteristics of Variants in Distinct Genomic Regions.

Science.gov (United States)

Bendl, Jaroslav; Musil, Miloš; Štourač, Jan; Zendulka, Jaroslav; Damborský, Jiří; Brezovský, Jan

2016-05-01

An important message taken from human genome sequencing projects is that the human population exhibits approximately 99.9% genetic similarity. Variations in the remaining parts of the genome determine our identity, trace our history and reveal our heritage. The precise delineation of phenotypically causal variants plays a key role in providing accurate personalized diagnosis, prognosis, and treatment of inherited diseases. Several computational methods for achieving such delineation have been reported recently. However, their ability to pinpoint potentially deleterious variants is limited by the fact that their mechanisms of prediction do not account for the existence of different categories of variants. Consequently, their output is biased towards the variant categories that are most strongly represented in the variant databases. Moreover, most such methods provide numeric scores but not binary predictions of the deleteriousness of variants or confidence scores that would be more easily understood by users. We have constructed three datasets covering different types of disease-related variants, which were divided across five categories: (i) regulatory, (ii) splicing, (iii) missense, (iv) synonymous, and (v) nonsense variants. These datasets were used to develop category-optimal decision thresholds and to evaluate six tools for variant prioritization: CADD, DANN, FATHMM, FitCons, FunSeq2 and GWAVA. This evaluation revealed some important advantages of the category-based approach. The results obtained with the five best-performing tools were then combined into a consensus score. Additional comparative analyses showed that in the case of missense variations, protein-based predictors perform better than DNA sequence-based predictors. A user-friendly web interface was developed that provides easy access to the five tools' predictions, and their consensus scores, in a user-understandable format tailored to the specific features of different categories of variations. To

COMPARISON OF THE TEST VARIANTS IN ENTRANCE EXAMINATIONS

Directory of Open Access Journals (Sweden)

KLŮFA, Jindřich

2016-12-01

Full Text Available The paper contains an analysis of the differences of number of points in the test in mathematics between test variants, which were used in the entrance examinations at the Faculty of Business Administration at University of Economics in Prague in 2015. The differences may arise due to the varying difficulty of variants for students, but also because of the different level of knowledge of students who write these variants. This problem we shall study in present paper. The aim of this paper is to study dependence of the results of entrance examinations in mathematics on test variants. The results obtained will be used for further improvement of the admission process at University of Economics.

Superior and inferior vena cavae: Embryology, variants, and pathology

International Nuclear Information System (INIS)

Mendelson, D.S.; Mitty, H.; Janus, C.; Gendal, E.; Berson, B.

1987-01-01

The superior and inferior venae cavae may be involved in a host of disease processes. Knowledge of the normal anatomy and variants of these structures is valuable in interpreting plain films and the results of angiographic procedures and all cross-sectional modalities. The authors review the embryology of venae cavae and proceed to describe their normal anatomy and variants. An awareness of the variants can prevent mistaking variants for pathologic processes. Finally, the authors describe pathology involving these vessels and demonstrate the radiographic manifestations

Behavioural-variant frontotemporal dementia: An update

Directory of Open Access Journals (Sweden)

Olivier Piguet

Full Text Available ABSTRACT Behavioural-variant frontotemporal dementia (bvFTD is characterised by insidious changes in personality and interpersonal conduct that reflect progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation and decision making. The underlying pathology is heterogeneous and classified according to the presence of intraneuronal inclusions of tau, TDP-43 or occasionally FUS. Biomarkers to detect these histopathological changes in life are increasingly important with the development of disease-modifying drugs. Gene mutations have been found which collectively account for around 10-20% of cases including a novel hexanucleotide repeat on chromosome 9 (C9orf72. The recently reviewed International Consensus Criteria for bvFTD propose three levels of diagnostic certainly: possible, probable and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process with support from neuropsychological testing designed to detect impairment in decision-making, emotion processing and social cognition. Brain imaging is important for increasing the level of diagnosis certainty. Carer education and support remain of paramount importance.

Golden Rule of Morphology and Variants of Word forms

Directory of Open Access Journals (Sweden)

Hlaváčová Jaroslava

2017-12-01

Full Text Available In many languages, some words can be written in several ways. We call them variants. Values of all their morphological categories are identical, which leads to an identical morphological tag. Together with the identical lemma, we have two or more wordforms with the same morphological description. This ambiguity may cause problems in various NLP applications. There are two types of variants – those affecting the whole paradigm (global variants and those affecting only wordforms sharing some combinations of morphological values (inflectional variants. In the paper, we propose means how to tag all wordforms, including their variants, unambiguously. We call this requirement “Golden rule of morphology”. The paper deals mainly with Czech, but the ideas can be applied to other languages as well.

Feature Selection via Chaotic Antlion Optimization.

Directory of Open Access Journals (Sweden)

Hossam M Zawbaa

Full Text Available Selecting a subset of relevant properties from a large set of features that describe a dataset is a challenging machine learning task. In biology, for instance, the advances in the available technologies enable the generation of a very large number of biomarkers that describe the data. Choosing the more informative markers along with performing a high-accuracy classification over the data can be a daunting task, particularly if the data are high dimensional. An often adopted approach is to formulate the feature selection problem as a biobjective optimization problem, with the aim of maximizing the performance of the data analysis model (the quality of the data training fitting while minimizing the number of features used.We propose an optimization approach for the feature selection problem that considers a "chaotic" version of the antlion optimizer method, a nature-inspired algorithm that mimics the hunting mechanism of antlions in nature. The balance between exploration of the search space and exploitation of the best solutions is a challenge in multi-objective optimization. The exploration/exploitation rate is controlled by the parameter I that limits the random walk range of the ants/prey. This variable is increased iteratively in a quasi-linear manner to decrease the exploration rate as the optimization progresses. The quasi-linear decrease in the variable I may lead to immature convergence in some cases and trapping in local minima in other cases. The chaotic system proposed here attempts to improve the tradeoff between exploration and exploitation. The methodology is evaluated using different chaotic maps on a number of feature selection datasets. To ensure generality, we used ten biological datasets, but we also used other types of data from various sources. The results are compared with the particle swarm optimizer and with genetic algorithm variants for feature selection using a set of quality metrics.

N-terminal nesprin-2 variants regulate β-catenin signalling

Energy Technology Data Exchange (ETDEWEB)

Zhang, Qiuping; Minaisah, Rose-Marie; Ferraro, Elisa; Li, Chen; Porter, Lauren J.; Zhou, Can; Gao, Fang; Zhang, Junyi; Rajgor, Dipen; Autore, Flavia; Shanahan, Catherine M.; Warren, Derek T., E-mail: derek.warren@kcl.ac.uk

2016-07-15

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeats of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.

Novel interactions of two α-Hb variants with SEA deletion α0-thalassemia: hematological and molecular analyses.

Science.gov (United States)

Srivorakun, Hataichanok; Singha, Kritsada; Fucharoen, Goonnapa; Fucharoen, Supan

2018-04-01

To report the hematological and molecular features as well as diagnostic aspects of the hitherto un-described interactions of two rare α-globin chain variants with α 0 -thalassemia commonly found among Southeast Asian populations. The study was done on two adult Thai patients (P1 and P2) who had hypochromic microcytic anemia. Hb analysis was carried out using high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Mutations were identified by PCR and related techniques. Hb analysis of P1 using HPLC showed a normal Hb pattern, but CE demonstrated an abnormal peak at zone 7. DNA sequencing identified a CCG-CTG mutation at codon 95 of the α2 globin gene corresponding to the Hb G-Georgia [α95(G2)Pro → Leu(α2)] previously undescribed in the Thai population. In contrast, Hb analysis of P2 demonstrated an abnormal peak not fully separated from Hb A on HPLC, but not on CE. DNA analysis identified the rarely described Hb Nakhon Ratchasima [α63(E12)Ala → Val(α2)] mutation. Routine DNA analysis detected the SEA deletion α 0 -thalassemia in trans to the Hb variants in both cases. Hematological parameters were compared with those of patients with compound heterozygote for other α-globin variants and α 0 -thalassemia previously documented. Identification of the patients confirmed that interaction of these rare Hb variants with α 0 -thalassemia does not lead to the Hb H disease. Differentiation of these two Hb variants from other clinically relevant hemoglobinopathies in a routine setting is, however, necessary. This can be accomplished using a combined Hb-HPLC and CE analysis followed by PCR-RFLP assays.

Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants.

Science.gov (United States)

Ungar, Rachel A; Giri, Neelam; Pao, Maryland; Khincha, Payal P; Zhou, Weiyin; Alter, Blanche P; Savage, Sharon A

2018-06-01

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease. © 2018 Wiley Periodicals, Inc.

Sensorineural deafness, distinctive facial features, and abnormal cranial bones: a new variant of Waardenburg syndrome?

Science.gov (United States)

Gad, Alona; Laurino, Mercy; Maravilla, Kenneth R; Matsushita, Mark; Raskind, Wendy H

2008-07-15

The Waardenburg syndromes (WS) account for approximately 2% of congenital sensorineural deafness. This heterogeneous group of diseases currently can be categorized into four major subtypes (WS types 1-4) on the basis of characteristic clinical features. Multiple genes have been implicated in WS, and mutations in some genes can cause more than one WS subtype. In addition to eye, hair, and skin pigmentary abnormalities, dystopia canthorum and broad nasal bridge are seen in WS type 1. Mutations in the PAX3 gene are responsible for the condition in the majority of these patients. In addition, mutations in PAX3 have been found in WS type 3 that is distinguished by musculoskeletal abnormalities, and in a family with a rare subtype of WS, craniofacial-deafness-hand syndrome (CDHS), characterized by dysmorphic facial features, hand abnormalities, and absent or hypoplastic nasal and wrist bones. Here we describe a woman who shares some, but not all features of WS type 3 and CDHS, and who also has abnormal cranial bones. All sinuses were hypoplastic, and the cochlea were small. No sequence alteration in PAX3 was found. These observations broaden the clinical range of WS and suggest there may be genetic heterogeneity even within the CDHS subtype. 2008 Wiley-Liss, Inc.

Fundamental Characteristics of Industrial Variant Specification Systems

DEFF Research Database (Denmark)

Hansen, Benjamin Loer; Hvam, Lars

2004-01-01

fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

The Chiari III malformation: an unusual and asymptomatic variant in an 11-year old child

International Nuclear Information System (INIS)

Sirikci, Akif; Bayazit, Yildirim A.; Bayram, Metin

2001-01-01

Chiari III malformation is an extremely rare condition, and is characterized by the hindbrain herniation into a low occipital or high cervical encephalocele together with the pathologic and imaging features of the Chiari II malformation. In this report, an unusual variant of the Chiari III malformation was diagnosed in an 11-year-old girl. She had an encephalocele operation when she was a newborn, and has been asymptomatic since then. The clinical and imaging findings of this case were presented

The Chiari III malformation: an unusual and asymptomatic variant in an 11-year old child

Energy Technology Data Exchange (ETDEWEB)

Sirikci, Akif E-mail: sirikci@yahoo.com; Bayazit, Yildirim A.; Bayram, Metin

2001-09-01

Chiari III malformation is an extremely rare condition, and is characterized by the hindbrain herniation into a low occipital or high cervical encephalocele together with the pathologic and imaging features of the Chiari II malformation. In this report, an unusual variant of the Chiari III malformation was diagnosed in an 11-year-old girl. She had an encephalocele operation when she was a newborn, and has been asymptomatic since then. The clinical and imaging findings of this case were presented.

POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

Directory of Open Access Journals (Sweden)

Tomohiro Kitano

Full Text Available A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants were successfully identified in 15 probands (2.5% among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants

Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

Directory of Open Access Journals (Sweden)

Bryony A. Thompson

2015-03-01

Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

HFE gene variants affect iron in the brain.

Science.gov (United States)

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Differential Expression Profile of ZFX Variants Discriminates Breast Cancer Subtypes

Science.gov (United States)

Pourkeramati, Fatemeh; Asadi, Malek Hossein; Shakeri, Shahryar; Farsinejad, Alireza

2018-05-13

ZFX is a transcriptional regulator in embryonic stem cells that plays an important role in pluripotency and self-renewal. ZFX is widely expressed in pluripotent stem cells and is down-regulated during differentiation of embryonic stem cells. ZFX has five different variants that encode three different protein isoforms. While several reports have determined the overexpression of ZFX in a variety of somatic cancers, the expression of ZFX-spliced variants in cancer cells is not well-understood. We investigated the expression of ZFX variants in a series of breast cancer tissues and cell lines using quantitative PCR. The expression of ZFX variant 1/3 was higher in tumor tissue compared to marginal tissue. In contrast, the ZFX variant 5 was down-regulated in tumor tissues. While the ZFX variant 1/3 and ZFX variant 5 expression significantly increased in low-grade tumors, ZFX variant 4 was strongly expressed in high-grade tumors and demonstrating lymphatic invasion. In addition, our result revealed a significant association between the HER2 status and the expression of ZFX-spliced variants. Our data suggest that the expression of ZFX-spliced transcripts varies between different types of breast cancer and may contribute to their tumorigenesis process. Hence, ZFX-spliced transcripts could be considered as novel tumor markers with a probable value in diagnosis, prognosis, and therapy of breast cancer.

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Science.gov (United States)

Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

2018-01-01

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

Structures of Gate Loop Variants of the AcrB Drug Efflux Pump Bound by Erythromycin Substrate.

Directory of Open Access Journals (Sweden)

Abdessamad Ababou

Full Text Available Gram-negative bacteria such as E. coli use tripartite efflux pumps such as AcrAB-TolC to expel antibiotics and noxious compounds. A key feature of the inner membrane transporter component, AcrB, is a short stretch of residues known as the gate/switch loop that divides the proximal and distal substrate binding pockets. Amino acid substitutions of the gate loop are known to decrease antibiotic resistance conferred by AcrB. Here we present two new AcrB gate loop variants, the first stripped of its bulky side chains, and a second in which the gate loop is removed entirely. By determining the crystal structures of the variant AcrB proteins in the presence and absence of erythromycin and assessing their ability to confer erythromycin tolerance, we demonstrate that the gate loop is important for AcrB export activity but is not required for erythromycin binding.

Poisson Approximation-Based Score Test for Detecting Association of Rare Variants.

Science.gov (United States)

Fang, Hongyan; Zhang, Hong; Yang, Yaning

2016-07-01

Genome-wide association study (GWAS) has achieved great success in identifying genetic variants, but the nature of GWAS has determined its inherent limitations. Under the common disease rare variants (CDRV) hypothesis, the traditional association analysis methods commonly used in GWAS for common variants do not have enough power for detecting rare variants with a limited sample size. As a solution to this problem, pooling rare variants by their functions provides an efficient way for identifying susceptible genes. Rare variant typically have low frequencies of minor alleles, and the distribution of the total number of minor alleles of the rare variants can be approximated by a Poisson distribution. Based on this fact, we propose a new test method, the Poisson Approximation-based Score Test (PAST), for association analysis of rare variants. Two testing methods, namely, ePAST and mPAST, are proposed based on different strategies of pooling rare variants. Simulation results and application to the CRESCENDO cohort data show that our methods are more powerful than the existing methods. © 2016 John Wiley & Sons Ltd/University College London.

Cellulase variants with improved expression, activity and stability, and use thereof

Science.gov (United States)

Aehle, Wolfgang; Bott, Richard R; Bower, Benjamin; Caspi, Jonathan; Estell, David A; Goedegebuur, Frits; Hommes, Ronaldus W.J.; Kaper, Thijs; Kelemen, Bradley; Kralj, Slavko; Van Lieshout, Johan; Nikolaev, Igor; Van Stigt Thans, Sander; Wallace, Louise; Vogtentanz, Gudrun; Sandgren, Mats

2014-03-25

The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

Cellulase variants with improved expression, activity and stability, and use thereof

Energy Technology Data Exchange (ETDEWEB)

Aehle, Wolfgang; Bott, Richard R.; Bower, Benjamin S.; Caspi, Jonathan; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus Joannes; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Van Lieshout, Johannes Franciscus Thomas; Nikolaev, Igor; Wallace, Louise; Van Stigt Thans, Sander; Vogtentanz, Gudrun; Sandgren, Mats

2016-12-20

The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

Genetic variants of ghrelin in metabolic disorders.

Science.gov (United States)

Ukkola, Olavi

2011-11-01

An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. Copyright © 2011 Elsevier Inc. All rights reserved.

Isolation of a variant of Candida albicans.

Science.gov (United States)

Buckley, H R; Price, M R; Daneo-Moore, L

1982-01-01

During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell. Images PMID:6752021

Isolation of a variant of Candida albicans.

Science.gov (United States)

Buckley, H R; Price, M R; Daneo-Moore, L

1982-09-01

During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell.

Improved medical image modality classification using a combination of visual and textual features.

Science.gov (United States)

Dimitrovski, Ivica; Kocev, Dragi; Kitanovski, Ivan; Loskovska, Suzana; Džeroski, Sašo

2015-01-01

In this paper, we present the approach that we applied to the medical modality classification tasks at the ImageCLEF evaluation forum. More specifically, we used the modality classification databases from the ImageCLEF competitions in 2011, 2012 and 2013, described by four visual and one textual types of features, and combinations thereof. We used local binary patterns, color and edge directivity descriptors, fuzzy color and texture histogram and scale-invariant feature transform (and its variant opponentSIFT) as visual features and the standard bag-of-words textual representation coupled with TF-IDF weighting. The results from the extensive experimental evaluation identify the SIFT and opponentSIFT features as the best performing features for modality classification. Next, the low-level fusion of the visual features improves the predictive performance of the classifiers. This is because the different features are able to capture different aspects of an image, their combination offering a more complete representation of the visual content in an image. Moreover, adding textual features further increases the predictive performance. Finally, the results obtained with our approach are the best results reported on these databases so far. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dataset of mitochondrial genome variants in oncocytic tumors

Directory of Open Access Journals (Sweden)

Lihua Lyu

2018-04-01

Full Text Available This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.

Biochemical characteristics of glucose-6-phosphate dehydrogenase variants among the Malays of Singapore with report of a new non-deficient (GdSingapore) and three deficient variants.

Science.gov (United States)

Saha, N; Hong, S H; Wong, H A; Jeyaseelan, K; Tay, J S

1991-12-01

Biochemical characteristics of one non-deficient fast G6PD variant (GdSingapore) and six different deficient variants (three new, two Mahidol, one each of Indonesian and Mediterranean) were studied among the Malays of Singapore. The GdSingapore variant had normal enzyme activity (82%) and fast electrophoretic mobilities (140% in TEB buffer, 160% in phosphate and 140% in Tris-HCl buffer systems respectively). This variant is further characterized by normal Km for G6P; utilization of analogues (Gal6P, 2dG6P; dAmNADP), heat stability and pH optimum. The other six deficient G6PD variants had normal electrophoretic mobility in TEB buffer with enzyme activities ranging from 1 to 12% of GdB+. The biochemical characteristics identity them to be 2 Mahidol, 1 Indonesian and 1 Mediterranean variants and three new deficient variants.

Characterization of form variants of Xenorhabdus luminescens.

NARCIS (Netherlands)

Gerritsen, L.J.M.; Raay, de G.; Smits, P.H.

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in

Genetic epidemiology, hematological and clinical features of hemoglobinopathies in Iran.

Science.gov (United States)

Rahimi, Zohreh

2013-01-01

There is large variation in the molecular genetics and clinical features of hemoglobinopathies in Iran. Studying structural variants of hemoglobin demonstrated that the β-chain variants of hemoglobin S and D-Punjab are more prevalent in the Fars (southwestern Iran) and Kermanshah (western Iran) provinces, respectively. Also, α-chain variants of Hb Q-Iran and Hb Setif are prevalent in western Iran. The molecular basis and clinical severity of thalassemias are extremely heterogenous among Iranians due to the presence of multiethnic groups in the country. β-Thalassemia is more prevalent in northern and southern Iran. Among 52 different β-thalassemia mutations that have been identified among Iranian populations, IVSII-1 G:A is the most frequent mutation in most parts of the country. The presence of IVS I-5 G:C mutation with high frequency in southeastern Iran might reflect gene flow from neighboring countries. A wide spectrum of α-thalassemia alleles has been detected among Iranians with -α(3.7 kb) as the most prevalent α-thalassemia mutation. The prevention program of thalassemia birth in Iran has reduced the birth rate of homozygous β-thalassemia since the implementation of the program in 1997. In this review genetic epidemiology, clinical and hematological aspects of hemoglobinopathies, and the prevention programs of β-thalassemia in Iran will be discussed.

Genetic Epidemiology, Hematological and Clinical Features of Hemoglobinopathies in Iran

Directory of Open Access Journals (Sweden)

Zohreh Rahimi

2013-01-01

Full Text Available There is large variation in the molecular genetics and clinical features of hemoglobinopathies in Iran. Studying structural variants of hemoglobin demonstrated that the β-chain variants of hemoglobin S and D-Punjab are more prevalent in the Fars (southwestern Iran and Kermanshah (western Iran provinces, respectively. Also, α-chain variants of Hb Q-Iran and Hb Setif are prevalent in western Iran. The molecular basis and clinical severity of thalassemias are extremely heterogenous among Iranians due to the presence of multiethnic groups in the country. β-Thalassemia is more prevalent in northern and southern Iran. Among 52 different β-thalassemia mutations that have been identified among Iranian populations, IVSII-1 G:A is the most frequent mutation in most parts of the country. The presence of IVS I-5 G:C mutation with high frequency in southeastern Iran might reflect gene flow from neighboring countries. A wide spectrum of α-thalassemia alleles has been detected among Iranians with as the most prevalent α-thalassemia mutation. The prevention program of thalassemia birth in Iran has reduced the birth rate of homozygous β-thalassemia since the implementation of the program in 1997. In this review genetic epidemiology, clinical and hematological aspects of hemoglobinopathies, and the prevention programs of β-thalassemia in Iran will be discussed.

Identificação de variantes de hemoglobina em doadores de sangue Identification of hemoglobin variants in blood donor

Directory of Open Access Journals (Sweden)

Ana C. Bonini-Domingos

2004-03-01

Full Text Available Hemoglobinopathies are the most common genetic diseases and affect a great number of individuals in the world, with diverse clinical complications ranging from the almost unnoticeable to lethal consequences. In Brazil the occurrence of hemoglobinopathies is very frequent and influenced by the ethnical groups that are the basis of populations in different regions. The phenotype may be influenced by environmental and genetic factors and by migration. An understanding of these genetic diseases is important for the health and quality of life of the population. In this work we assessed the presence of Hb variants in blood donors from São José do Rio Preto and region, and we observed the occurrence of variants including Hb S and Hb C but in particular the so-called "S-Like" variants. Good determination of the forms of variant hemoglobins is very important to give better guidance to blood donors and their families, and to improve the quality of blood transfusion.

Mouse ribosomal RNA genes contain multiple differentially regulated variants.

Directory of Open Access Journals (Sweden)

Hung Tseng

2008-03-01

Full Text Available Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA. The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs, which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active, two are expressed in some tissues (selectively active, and two are not expressed (silent. These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA.

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

Science.gov (United States)

Renault, Anne-Laure; Mebirouk, Noura; Fuhrmann, Laetitia; Bataillon, Guillaume; Cavaciuti, Eve; Le Gal, Dorothée; Girard, Elodie; Popova, Tatiana; La Rosa, Philippe; Beauvallet, Juana; Eon-Marchais, Séverine; Dondon, Marie-Gabrielle; d'Enghien, Catherine Dubois; Laugé, Anthony; Chemlali, Walid; Raynal, Virginie; Labbé, Martine; Bièche, Ivan; Baulande, Sylvain; Bay, Jacques-Olivier; Berthet, Pascaline; Caron, Olivier; Buecher, Bruno; Faivre, Laurence; Fresnay, Marc; Gauthier-Villars, Marion; Gesta, Paul; Janin, Nicolas; Lejeune, Sophie; Maugard, Christine; Moutton, Sébastien; Venat-Bouvet, Laurence; Zattara, Hélène; Fricker, Jean-Pierre; Gladieff, Laurence; Coupier, Isabelle; Chenevix-Trench, Georgia; Hall, Janet; Vincent-Salomon, Anne; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Lesueur, Fabienne

2018-04-17

The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological

Treatment of spelling variants in Setswana monolingual dictionaries

African Journals Online (AJOL)

user

. ..... Table 8: Variants of Names of persons and places. Setswana variants. English. Aforika, Aferika. Africa. Baebele, Babele, Beibele. Bible. Ennyelane, Engelane ..... MWEs. As in variation amongst individual words, the MWEs such as idioms.

Human papillomavirus variants among Inuit women in northern Quebec, Canada.

Science.gov (United States)

Gauthier, Barbara; Coutlée, Francois; Franco, Eduardo L; Brassard, Paul

2015-01-01

Inuit communities in northern Quebec have high rates of human papillomavirus (HPV) infection, cervical cancer and cervical cancer-related mortality as compared to the Canadian population. HPV types can be further classified as intratypic variants based on the extent of homology in their nucleotide sequences. There is limited information on the distribution of intratypic variants in circumpolar areas. Our goal was to describe the HPV intratypic variants and associated baseline characteristics. We collected cervical cell samples in 2002-2006 from 676 Inuit women between the ages of 15 and 69 years in Nunavik. DNA isolates from high-risk HPVs were sequenced to determine the intratypic variant. There were 149 women that were positive for HPVs 16, 18, 31, 33, 35, 45, 52, 56 or 58 during follow-up. There were 5 different HPV16 variants, all of European lineage, among the 57 women positive for this type. There were 8 different variants of HPV18 present and all were of European lineage (n=21). The majority of samples of HPV31 (n=52) were of lineage B. The number of isolates and diversity of the other HPV types was low. Age was the only covariate associated with HPV16 variant category. These frequencies are similar to what was seen in another circumpolar region of Canada, although there appears to be less diversity as only European variants were detected. This study shows that most variants were clustered in one lineage for each HPV type.

Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.

Science.gov (United States)

Beyer, Ulrike; Brand, Frank; Martens, Helge; Weder, Julia; Christians, Arne; Elyan, Natalie; Hentschel, Bettina; Westphal, Manfred; Schackert, Gabriele; Pietsch, Torsten; Hong, Bujung; Krauss, Joachim K; Samii, Amir; Raab, Peter; Das, Anibh; Dumitru, Claudia A; Sandalcioglu, I Erol; Hakenberg, Oliver W; Erbersdobler, Andreas; Lehmann, Ulrich; Reifenberger, Guido; Weller, Michael; Reijns, Martin A M; Preller, Matthias; Wiese, Bettina; Hartmann, Christian; Weber, Ruthild G

2017-12-01

In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequencing, we identified novel ADAR and RNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutations ADAR,c.577C>G;p.(P193A) and RNASEH2B,c.529G>A;p.(A177T) in the germline of familial glioma patients as well as in test and validation cohorts of glioblastomas and prostate carcinomas versus ethnicity-matched controls, whereby rare RNASEH2B variants were significantly more frequent in familial glioma patients. Tumors with ADAR or RNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carrying ADAR or RNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced by ADAR and RNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the AGS genes ADAR and RNASEH2B and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis, consistent with a genetic basis underlying inflammation-driven malignant transformation in glioma and prostate carcinoma development.

Genetic variants influencing phenotypic variance heterogeneity.

Science.gov (United States)

Ek, Weronica E; Rask-Andersen, Mathias; Karlsson, Torgny; Enroth, Stefan; Gyllensten, Ulf; Johansson, Åsa

2018-03-01

Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene × gene or gene × environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

Method of generating ploynucleotides encoding enhanced folding variants

Energy Technology Data Exchange (ETDEWEB)

Bradbury, Andrew M.; Kiss, Csaba; Waldo, Geoffrey S.

2017-05-02

The invention provides directed evolution methods for improving the folding, solubility and stability (including thermostability) characteristics of polypeptides. In one aspect, the invention provides a method for generating folding and stability-enhanced variants of proteins, including but not limited to fluorescent proteins, chromophoric proteins and enzymes. In another aspect, the invention provides methods for generating thermostable variants of a target protein or polypeptide via an internal destabilization baiting strategy. Internally destabilization a protein of interest is achieved by inserting a heterologous, folding-destabilizing sequence (folding interference domain) within DNA encoding the protein of interest, evolving the protein sequences adjacent to the heterologous insertion to overcome the destabilization (using any number of mutagenesis methods), thereby creating a library of variants. The variants in the library are expressed, and those with enhanced folding characteristics selected.

Causal correlations between genes and linguistic features: The mechanism of gradual language evolution

OpenAIRE

Dediu, D.

2008-01-01

The causal correlations between human genetic variants and linguistic (typological) features could represent the mechanism required for gradual, accretionary models of language evolution. The causal link is mediated by the process of cultural transmission of language across generations in a population of genetically biased individuals. The particular case of Tone, ASPM and Microcephalin is discussed as an illustration. It is proposed that this type of genetically-influenced linguistic bias, c...

Influenza A (H3N2) Variant Virus

Science.gov (United States)

... Swine Variant Pandemic Other Influenza A (H3N2) Variant Virus Language: English (US) Español Recommend on Facebook Tweet Share Compartir Influenza viruses that normally circulate in pigs are called “variant” ...

Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

OpenAIRE

Tanna, P.; Strauss, R. W.; Fujinami, K.; Michaelides, M.

2017-01-01

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genot...

Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

OpenAIRE

Tanna, Preena; Strauss, Rupert W; Fujinami, Kaoru; Michaelides, Michel

2016-01-01

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4. Significant advances have been made over the last 10?years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and geno...

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

Science.gov (United States)

Malysz, Jozef; Talamo, Giampaolo; Zhu, Junjia; Clarke, Loren E; Bayerl, Michael G; Ali, Liaqat; Helm, Klaus F; Chung, Catherine G

2016-05-01

Disease-specific skin lesions are rare in patients with multiple myeloma (MM). We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. We identified 13 patients with cutaneous lesions of MM. Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. The study group was relatively small. Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Ankle fracture spur sign is pathognomonic for a variant ankle fracture.

Science.gov (United States)

Hinds, Richard M; Garner, Matthew R; Lazaro, Lionel E; Warner, Stephen J; Loftus, Michael L; Birnbaum, Jacqueline F; Burket, Jayme C; Lorich, Dean G

2015-02-01

The hyperplantarflexion variant ankle fracture is composed of a posterior tibial lip fracture with posterolateral and posteromedial fracture fragments separated by a vertical fracture line. This infrequently reported injury pattern often includes an associated "spur sign" or double cortical density at the inferomedial tibial metaphysis. The objective of this study was to quantitatively establish the association of the ankle fracture spur sign with the hyperplantarflexion variant ankle fracture. Our clinical database of operative ankle fractures was retrospectively reviewed for the incidence of hyperplantarflexion variant and nonvariant ankle fractures as determined by assessment of injury radiographs, preoperative advanced imaging, and intraoperative observation. Injury radiographs were then evaluated for the presence of the spur sign, and association between the spur sign and variant fractures was analyzed. The incidence of the hyperplantarflexion variant fracture among all ankle fractures was 6.7% (43/640). The spur sign was present in 79% (34/43) of variant fractures and absent in all nonvariant fractures, conferring a specificity of 100% in identifying variant fractures. Positive predictive value and negative predictive value were 100% and 99%, respectively. The ankle fracture spur sign was pathognomonic for the hyperplantarflexion variant ankle fracture. It is important to identify variant fractures preoperatively as patient positioning, operative approach, and fixation construct of variant fractures often differ from those employed for osteosynthesis of nonvariant fractures. Identification of the spur sign should prompt acquisition of advanced imaging to formulate an appropriate operative plan to address the variant fracture pattern. Level III, retrospective comparative study. © The Author(s) 2014.

Holoprosencephaly Variant

Directory of Open Access Journals (Sweden)

J Gordon Millichap

2003-01-01

Full Text Available The clinical manifestations in 15 patients (6 boys and 9 girls with middle interhemispheric variant (MIH of holoprosencephaly (HPE were compared with classic subtypes (alobar, semilobar, and lobar of HPE in a multicenter study at Stanford University School of Medicine and Lucile Packard Children’s Hospital; Children’s Hospital of Philadelphia; University of California at San Francisco; Texas Scottish Rite Hospital, Dallas; and Kennedy Krieger Institute, Baltimore, MD.

Investigation of the role of TCF4 rare sequence variants in schizophrenia.

Science.gov (United States)

Basmanav, F Buket; Forstner, Andreas J; Fier, Heide; Herms, Stefan; Meier, Sandra; Degenhardt, Franziska; Hoffmann, Per; Barth, Sandra; Fricker, Nadine; Strohmaier, Jana; Witt, Stephanie H; Ludwig, Michael; Schmael, Christine; Moebus, Susanne; Maier, Wolfgang; Mössner, Rainald; Rujescu, Dan; Rietschel, Marcella; Lange, Christoph; Nöthen, Markus M; Cichon, Sven

2015-07-01

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

SDS, a structural disruption score for assessment of missense variant deleteriousness

Directory of Open Access Journals (Sweden)

Thanawadee ePreeprem

2014-04-01

Full Text Available We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites.The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation.

Special Features of Induction Annealing of Friction Stir Welded Joints of Medium-Alloy Steels

Science.gov (United States)

Priymak, E. Yu.; Stepanchukova, A. V.; Bashirova, E. V.; Fot, A. P.; Firsova, N. V.

2018-01-01

Welded joints of medium-alloy steels XJY750 and 40KhN2MA are studied in the initial condition and after different variants of annealing. Special features of the phase transformations occurring in the welded steels are determined. Optimum modes of annealing are recommended for the studied welded joints of drill pipes, which provide a high level of mechanical properties including the case of impact loading.

Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants.

Science.gov (United States)

Tada, Hayato; Kawashiri, Masa-Aki; Yamagishi, Masakazu

2017-04-01

Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.

A variational Bayes discrete mixture test for rare variant association.

Science.gov (United States)

Logsdon, Benjamin A; Dai, James Y; Auer, Paul L; Johnsen, Jill M; Ganesh, Santhi K; Smith, Nicholas L; Wilson, James G; Tracy, Russell P; Lange, Leslie A; Jiao, Shuo; Rich, Stephen S; Lettre, Guillaume; Carlson, Christopher S; Jackson, Rebecca D; O'Donnell, Christopher J; Wurfel, Mark M; Nickerson, Deborah A; Tang, Hua; Reiner, Alexander P; Kooperberg, Charles

2014-01-01

Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that "aggregate" tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.

Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene.

Science.gov (United States)

Backer, Julie De; Braverman, Alan C

2018-05-01

Predominant cardiovascular manifestations in the spectrum of Heritable Thoracic Aortic Disease include by default aortic root aneurysms- and dissections, which may be associated with aortic valve disease. Mitral- and tricuspid valve prolapse are other commonly recognized features. Myocardial disease, characterized by heart failure and/or malignant arrhythmias has been reported in humans and in animal models harboring pathogenic variants in the Fibrillin1 gene. Description of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis (US). We report on three cases from two families presenting end-stage heart failure (in two) and lethal arrhythmias associated with moderate left ventricular dilatation (in one). All three cases harbor a pathogenic variant in the SMAD3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys-Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease. These unusual presentations warrant awareness for myocardial disease in patients harboring pathogenic variants in genes causing Heritable Thoracic Aortic Disease and indicate the need for prospective studies in larger cohorts. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Glucose 6-phosphate dehydrogenase variants in Japan.

Science.gov (United States)

Miwa, S

1980-01-01

Fifty-four cases of glucose 6-phosphate dehydrogenase (G6PD) deficiency have so far been reported in Japan. Among them, 21 G6PD variants have been characterized. Nineteen out of the 21 variants were characterized in our laboratory and G6PD Heian and "Kyoto" by others. G6PD Tokyo, Tokushima, Ogikubo, Kurume, Fukushima, Yokohama, Yamaguchi, Wakayama, Akita, Heian and "Kyoto" were classified as Class 1, because all these cases showed chronic hemolytic anemia and severe enzyme deficiency. All these variants showed thermal instability. G6PD Mediterranean-like, Ogori, Gifu and Fukuoka were classified as Class 2, whereas G6PD Hofu, B(-) Chinese, Ube, Konan, Kamiube and Kiwa belonged to Class 3. All the 6 Class 3 variants were found as the results of the screening tests. The incidence of the deficiency in Japanese seems to be 0.1-0.5% but that of the cases which may slow drug-induced hemolysis would be much less. G6PD Ube and Konan appear to be relatively common in Japan.

QSAR models for prediction of chromatographic behavior of homologous Fab variants.

Science.gov (United States)

Robinson, Julie R; Karkov, Hanne S; Woo, James A; Krogh, Berit O; Cramer, Steven M

2017-06-01

While quantitative structure activity relationship (QSAR) models have been employed successfully for the prediction of small model protein chromatographic behavior, there have been few reports to date on the use of this methodology for larger, more complex proteins. Recently our group generated focused libraries of antibody Fab fragment variants with different combinations of surface hydrophobicities and electrostatic potentials, and demonstrated that the unique selectivities of multimodal resins can be exploited to separate these Fab variants. In this work, results from linear salt gradient experiments with these Fabs were employed to develop QSAR models for six chromatographic systems, including multimodal (Capto MMC, Nuvia cPrime, and two novel ligand prototypes), hydrophobic interaction chromatography (HIC; Capto Phenyl), and cation exchange (CEX; CM Sepharose FF) resins. The models utilized newly developed "local descriptors" to quantify changes around point mutations in the Fab libraries as well as novel cluster descriptors recently introduced by our group. Subsequent rounds of feature selection and linearized machine learning algorithms were used to generate robust, well-validated models with high training set correlations (R 2  > 0.70) that were well suited for predicting elution salt concentrations in the various systems. The developed models then were used to predict the retention of a deamidated Fab and isotype variants, with varying success. The results represent the first successful utilization of QSAR for the prediction of chromatographic behavior of complex proteins such as Fab fragments in multimodal chromatographic systems. The framework presented here can be employed to facilitate process development for the purification of biological products from product-related impurities by in silico screening of resin alternatives. Biotechnol. Bioeng. 2017;114: 1231-1240. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Dandy-Walker variant in Coffin-Siris syndrome.

Science.gov (United States)

Imai, T; Hattori, H; Miyazaki, M; Higuchi, Y; Adachi, S; Nakahata, T

2001-04-22

We describe a five-month-old male infant with Coffin-Siris syndrome, the so-called Dandy-Walker variant (hypoplasia of the cerebellar vermis with cystic dilatation of the fourth ventricle, but without enlargement of the posterior fossa), and partial agenesis of the corpus callosum. Dandy-Walker malformation and mega cisterna magna, but not Dandy-Walker variant, have been reported in Coffin-Siris syndrome. The presence of Dandy-Walker variant in the infant we described confirms that the full continuum of the Dandy-Walker complex can occur in Coffin-Siris syndrome. The yet unidentified gene(s) for the syndrome may be related to the development of the hindbrain. Copyright 2001 Wiley-Liss, Inc.

Discrete-Feature Modelling of Groundwater Flow and Solute Transport for SR-Can Review. External review contribution in support of SKI's and SSI's review of SR-Can

Energy Technology Data Exchange (ETDEWEB)

Geier, Joel (Clearwater Hardrock Consulting, Corvallis, OR (US))

2008-03-15

Discrete-feature models were developed to represent the main classes of water-conducting features at the Laxemar and Forsmark candidate sites for a high-level radioactive waste repository. The models encompass features on scales ranging from individual fractures 2 m or larger in radius around deposition holes, or spalled zones around deposition holes and tunnels, to deformation zones on the scale of kilometres. Equivalent discontinuum features are used to represent the aggregate properties of fractures outside of the vicinity of deposition holes where an explicit representation is used. Deposition hole locations within the repository layout are conditioned to each stochastic realization of the discrete-fracture population, using a full-perimeter-intersection criterion to identify discriminating fractures that pose a seismic risk, and a simulated pilot-hole criterion to exclude deposition-hole locations with excessive flows. The utilization factors of 0.70 obtained here for the full repository at Forsmark and = 0.53 for the full repository at Laxemar are significantly lower than the corresponding values = 0.93 and 0.88 for the most nearly comparable case presented in the SR-Can Main Report. Further investigation is needed to discern whether this discrepancy is primarily due to possible nonconservative assumptions in SKB's analytical modelling approach, or due to artefacts of the simulation approach using finite domains, which could lead to overly conservative values in the present study. Flows through the discrete-feature model variants are calculated by finite-element simulation. Distributions of flows to deposition holes are presented for the Laxemar base case and for an initial suite of variants for Forsmark. Results for Forsmark indicate that the distribution of flow to deposition holes is robust with respect to the set of variants considered, and that a given single realization of the discrete-fracture network (DFN) submodel produces representative results

A population-specific uncommon variant in GRIN3A associated with schizophrenia.

Science.gov (United States)

Takata, Atsushi; Iwayama, Yoshimi; Fukuo, Yasuhisa; Ikeda, Masashi; Okochi, Tomo; Maekawa, Motoko; Toyota, Tomoko; Yamada, Kazuo; Hattori, Eiji; Ohnishi, Tetsuo; Toyoshima, Manabu; Ujike, Hiroshi; Inada, Toshiya; Kunugi, Hiroshi; Ozaki, Norio; Nanko, Shinichiro; Nakamura, Kazuhiko; Mori, Norio; Kanba, Shigenobu; Iwata, Nakao; Kato, Tadafumi; Yoshikawa, Takeo

2013-03-15

Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency way to discover risk variants with larger effects. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

CDKL5 variants: Improving our understanding of a rare neurologic disorder.

Science.gov (United States)

Hector, Ralph D; Kalscheuer, Vera M; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E S; Cobb, Stuart R

2017-12-01

To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

Gain-of-function HCN2 variants in genetic epilepsy.

Science.gov (United States)

Li, Melody; Maljevic, Snezana; Phillips, A Marie; Petrovski, Slave; Hildebrand, Michael S; Burgess, Rosemary; Mount, Therese; Zara, Federico; Striano, Pasquale; Schubert, Julian; Thiele, Holger; Nürnberg, Peter; Wong, Michael; Weisenberg, Judith L; Thio, Liu Lin; Lerche, Holger; Scheffer, Ingrid E; Berkovic, Samuel F; Petrou, Steven; Reid, Christopher A

2018-02-01

Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism. © 2017 Wiley Periodicals, Inc.

Nonrandom Distribution of miRNAs Genes and Single Nucleotide Variants in Keratoconus Loci.

Directory of Open Access Journals (Sweden)

Dorota M Nowak

Full Text Available Despite numerous studies, the causes of both development and progression of keratoconus remain elusive. Previous studies of this disorder focused mainly on one or two genetic factors only. However, in the analysis of such complex diseases all potential factors should be taken into consideration. The purpose of this study was a comprehensive analysis of known keratoconus loci to uncover genetic factors involved in this disease causation in the general population, which could be omitted in the original studies. In this investigation genomic data available in various databases and experimental own data were assessed. The lists of single nucleotide variants and miRNA genes localized in reported keratoconus loci were obtained from Ensembl and miRBase, respectively. The potential impact of nonsynonymous amino acid substitutions on protein structure and function was assessed with PolyPhen-2 and SIFT. For selected protein genes the ranking was made to choose those most promising for keratoconus development. Ranking results were based on topological features in the protein-protein interaction network. High specificity for the populations in which the causative sequence variants have been identified was found. In addition, the possibility of links between previously analyzed keratoconus loci was confirmed including miRNA-gene interactions. Identified number of genes associated with oxidative stress and inflammatory agents corroborated the hypothesis of their effect on the disease etiology. Distribution of the numerous sequences variants within both exons and mature miRNA which forces you to search for a broader look at the determinants of keratoconus. Our findings highlight the complexity of the keratoconus genetics.

Variants of Phosphotriesterase for the Enhanced Detoxification of the Chemical Warfare Agent VR.

Science.gov (United States)

Bigley, Andrew N; Mabanglo, Mark F; Harvey, Steven P; Raushel, Frank M

2015-09-08

The V-type organophosphorus nerve agents are among the most hazardous compounds known. Previous efforts to evolve the bacterial enzyme phosphotriesterase (PTE) for the hydrolytic decontamination of VX resulted in the identification of the variant L7ep-3a, which has a kcat value more than 2 orders of magnitude higher than that of wild-type PTE for the hydrolysis of VX. Because of the relatively small size of the O-ethyl, methylphosphonate center in VX, stereoselectivity is not a major concern. However, the Russian V-agent, VR, contains a larger O-isobutyl, methylphosphonate center, making stereoselectivity a significant issue since the SP-enantiomer is expected to be significantly more toxic than the RP-enantiomer. The three-dimensional structure of the L7ep-3a variant was determined to a resolution of 2.01 Å (PDB id: 4ZST ). The active site of the L7ep-3a mutant has revealed a network of hydrogen bonding interactions between Asp-301, Tyr-257, Gln-254, and the hydroxide that bridges the two metal ions. A series of new analogues that mimic VX and VR has helped to identify critical structural features for the development of new enzyme variants that are further enhanced for the catalytic detoxification of VR and VX. The best of these mutants has been shown to have a reversed stereochemical preference for the hydrolysis of VR-chiral center analogues. This mutant hydrolyzes the two enantiomers of VR 160- and 600-fold faster than wild-type PTE hydrolyzes the SP-enantiomer of VR.

Effects of common hemoglobin variants on HbA1c measurements in China: results for α- and β-globin variants measured by six methods.

Science.gov (United States)

Xu, Anping; Chen, Weidong; Xia, Yong; Zhou, Yu; Ji, Ling

2018-04-07

HbA1c is a widely used biomarker for diabetes mellitus management. Here, we evaluated the accuracy of six methods for determining HbA1c values in Chinese patients with common α- and β-globin chains variants in China. Blood samples from normal subjects and individuals exhibiting hemoglobin variants were analyzed for HbA1c, using Sebia Capillarys 2 Flex Piercing (C2FP), Bio-Rad Variant II Turbo 2.0, Tosoh HLC-723 G8 (ver. 5.24), Arkray ADAMS A1c HA-8180V fast mode, Cobas c501 and Trinity Ultra2 systems. DNA sequencing revealed five common β-globin chain variants and three common α-globin chain variants. The most common variant was Hb E, followed by Hb New York, Hb J-Bangkok, Hb G-Coushatta, Hb Q-Thailand, Hb G-Honolulu, Hb Ube-2 and Hb G-Taipei. Variant II Turbo 2.0, Ultra2 and Cobas c501 showed good agreement with C2FP for most samples with variants. HLC-723 G8 yielded no HbA1c values for Hb J-Bangkok, Hb Q-Thailand and Hb G-Honolulu. Samples with Hb E, Hb G-Coushatta, Hb G-Taipei and Hb Ube-2 produced significant negative biases for HLC-723 G8. HA-8180V showed statistically significant differences for Hb E, Hb G-Coushatta, Hb G-Taipei, Hb Q-Thailand and Hb G-Honolulu. HA-8180V yielded no HbA1c values for Hb J-Bangkok. All methods showed good agreement for samples with Hb New York. Some common hemoglobin variants can interfere with HbA1c determination by the most popular methods in China.

Re-Ranking Sequencing Variants in the Post-GWAS Era for Accurate Causal Variant Identification

Science.gov (United States)

Faye, Laura L.; Machiela, Mitchell J.; Kraft, Peter; Bull, Shelley B.; Sun, Lei

2013-01-01

Next generation sequencing has dramatically increased our ability to localize disease-causing variants by providing base-pair level information at costs increasingly feasible for the large sample sizes required to detect complex-trait associations. Yet, identification of causal variants within an established region of association remains a challenge. Counter-intuitively, certain factors that increase power to detect an associated region can decrease power to localize the causal variant. First, combining GWAS with imputation or low coverage sequencing to achieve the large sample sizes required for high power can have the unintended effect of producing differential genotyping error among SNPs. This tends to bias the relative evidence for association toward better genotyped SNPs. Second, re-use of GWAS data for fine-mapping exploits previous findings to ensure genome-wide significance in GWAS-associated regions. However, using GWAS findings to inform fine-mapping analysis can bias evidence away from the causal SNP toward the tag SNP and SNPs in high LD with the tag. Together these factors can reduce power to localize the causal SNP by more than half. Other strategies commonly employed to increase power to detect association, namely increasing sample size and using higher density genotyping arrays, can, in certain common scenarios, actually exacerbate these effects and further decrease power to localize causal variants. We develop a re-ranking procedure that accounts for these adverse effects and substantially improves the accuracy of causal SNP identification, often doubling the probability that the causal SNP is top-ranked. Application to the NCI BPC3 aggressive prostate cancer GWAS with imputation meta-analysis identified a new top SNP at 2 of 3 associated loci and several additional possible causal SNPs at these loci that may have otherwise been overlooked. This method is simple to implement using R scripts provided on the author's website. PMID:23950724

Height-reducing variants and selection for short stature in Sardinia

NARCIS (Netherlands)

Zoledziewska, Magdalena; Sidore, Carlo; Chiang, Charleston W K; Sanna, Serena; Mulas, Antonella; Steri, Maristella; Busonero, Fabio; Marcus, Joseph H; Marongiu, Michele; Maschio, Andrea; Ortega Del Vecchyo, Diego; Floris, Matteo; Meloni, Antonella; Delitala, Alessandro; Concas, Maria Pina; Murgia, Federico; Biino, Ginevra; Vaccargiu, Simona; Nagaraja, Ramaiah; Lohmueller, Kirk E; Timpson, Nicholas J; Soranzo, Nicole; Tachmazidou, Ioanna; Dedoussis, George; Zeggini, Eleftheria; Uzzau, Sergio; Jones, Chris; Lyons, Robert; Angius, Andrea; Abecasis, Gonçalo R; Novembre, John; Schlessinger, David; Cucca, Francesco

We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent

Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.

Science.gov (United States)

Picconi, María Alejandra; Alonio, Lidia Virginia; Sichero, Laura; Mbayed, Viviana; Villa, Luisa Lina; Gronda, Jorge; Campos, Rodolfo; Teyssié, Angélica

2003-04-01

Cervical carcinoma is the leading cause of cancer death in Quechua indians from Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants, 106 HPV-16 positive cervical samples were studied, including 33 low-grade squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with normal colposcopy and cytology. HPV genome variability was examined in the L1 and E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also analyzed by PCR-sequencing. Most variants belonged to the European branch with subtle differences that depended on the viral gene fragment studied. Only about 10% of the specimens had non-European variants, including eight Asian-American, two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the samples were identical to HPV-16 prototype, while 57% corresponded to variants. Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of variants, including 69% of European, 19% Asian-American, and 12% Asian. We identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated it in the Asian-American branch. The high proportion of European variants may reflect Spanish colonial influence on these native Inca descendants. The predominance of HPV-16 variants in pathologic samples when compared to normal controls could have implications for the natural history of cervical lesions. Copyright 2003 Wiley-Liss, Inc.

Managing Process Variants in the Process Life Cycle

NARCIS (Netherlands)

Hallerbach, A.; Bauer, Th.; Reichert, M.U.

2007-01-01

When designing process-aware information systems, often variants of the same process have to be specified. Each variant then constitutes an adjustment of a particular process to specific requirements building the process context. Current Business Process Management (BPM) tools do not adequately

Genetics Home Reference: GM2-gangliosidosis, AB variant

Science.gov (United States)

... Resources Genetic Testing (1 link) Genetic Testing Registry: Tay-Sachs disease, variant AB General Information from MedlinePlus (5 links) ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type AB ...

Ameloblastomatous calcifying odontogenic cyst: A rare histologic variant

Directory of Open Access Journals (Sweden)

Basavaraj N Kallalli

2015-01-01

Full Text Available Ameloblastoma is a well-known odontogenic tumor that can be associated with calcifying odontogenic cysts (COCs, but only a few reports give its clinical and radiographic features. Calcifying odontogenic cyst was first categorized as a distinct entity by Gorlin et al., and has been named after him since then. Calcifying odontogenic cyst is an uncommon developmental odontogenic lesion that demonstrates histopathologic diversity. It is well known that this lesion can occur in association with odontogenic tumors such as complex odontoma and ameloblastoma. The term COC was not included by the World Health Organization (WHO in its report of 2005 and is called calcifying cystic odontogenic tumor (CCOT. Histopathologic examination of ameloblastomatous CCOT reveals ameloblastic islands containing ghost cells. Although association of ameloblastoma with this lesion is important, only a few cases have been reported in literature. The present case report is of ameloblastomatous calcifying cystic odontogenic tumor, a rare histologic variant, in a 20-year-old male patient in the left mandibular posterior region.

A brainstem variant of reversible posterior leukoencephalopathy syndrome

Energy Technology Data Exchange (ETDEWEB)

Kitaguchi, H.; Tomimoto, H.; Terada, K. [Kyoto University, Department of Neurology, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Miki, Y.; Yamamoto, A. [Kyoto University, Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Satoi, H.; Kanda, M. [Ijinkai Takeda General Hospital, Department of Neurology, Fushimi-ku, Kyoto (Japan); Fukuyama, H. [Kyoto University, Human Brain Research Center, Graduate School of Medicine, Sakyo-ku, Kyoto (Japan)

2005-09-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is caused by various heterogeneous factors, the commonest being hypertension, followed by nonhypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. Patients with RPLS exhibit bilateral white and gray matter abnormalities in the posterior aspects of the cerebral hemispheres. However, this syndrome may affect the brainstem predominantly, and these cases are designated as hypertensive brainstem encephalopathy. We present here two patients with reversible brainstem encephalopathy: one with hypertension and the other without hypertension. These patients presented with swelling and diffuse hyperintensities of the brainstem in fluid-attenuated inversion-recovery (FLAIR) and T2-weighted MRI, but with relatively mild clinical symptoms. They recovered without major neurological deficits, but had residual lacunar lesions in the pons. Reversible brainstem encephalopathy with characteristic MRI features was found in both hypertensive and nonhypertensive patients. These patients were diagnosed with a brainstem variant of RPLS, which is potentially fully reversible after an adequate treatment, and therefore should be carefully differentiated from other brainstem disease conditions. (orig.)

A brainstem variant of reversible posterior leukoencephalopathy syndrome

International Nuclear Information System (INIS)

Kitaguchi, H.; Tomimoto, H.; Terada, K.; Miki, Y.; Yamamoto, A.; Satoi, H.; Kanda, M.; Fukuyama, H.

2005-01-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is caused by various heterogeneous factors, the commonest being hypertension, followed by nonhypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. Patients with RPLS exhibit bilateral white and gray matter abnormalities in the posterior aspects of the cerebral hemispheres. However, this syndrome may affect the brainstem predominantly, and these cases are designated as hypertensive brainstem encephalopathy. We present here two patients with reversible brainstem encephalopathy: one with hypertension and the other without hypertension. These patients presented with swelling and diffuse hyperintensities of the brainstem in fluid-attenuated inversion-recovery (FLAIR) and T2-weighted MRI, but with relatively mild clinical symptoms. They recovered without major neurological deficits, but had residual lacunar lesions in the pons. Reversible brainstem encephalopathy with characteristic MRI features was found in both hypertensive and nonhypertensive patients. These patients were diagnosed with a brainstem variant of RPLS, which is potentially fully reversible after an adequate treatment, and therefore should be carefully differentiated from other brainstem disease conditions. (orig.)

[Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies].

Science.gov (United States)

Romero-Sánchez, Consuelo; Gómez Gutiérrez, Alberto; Duarte, Yurani; Amazo, Constanza; Manosalva, Clara; Chila M, Lorena; Casas-Gómez, María Consuelo; Briceño Balcázar, Ignacio

2015-10-01

Oxygen transport is altered in hemoglobinopathies. To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

Key features of human episodic recollection in the cross-episode retrieval of rat hippocampus representations of space.

Directory of Open Access Journals (Sweden)

Eduard Kelemen

2013-07-01

Full Text Available Neurophysiological studies focus on memory retrieval as a reproduction of what was experienced and have established that neural discharge is replayed to express memory. However, cognitive psychology has established that recollection is not a verbatim replay of stored information. Recollection is constructive, the product of memory retrieval cues, the information stored in memory, and the subject's state of mind. We discovered key features of constructive recollection embedded in the rat CA1 ensemble discharge during an active avoidance task. Rats learned two task variants, one with the arena stable, the other with it rotating; each variant defined a distinct behavioral episode. During the rotating episode, the ensemble discharge of CA1 principal neurons was dynamically organized to concurrently represent space in two distinct codes. The code for spatial reference frame switched rapidly between representing the rat's current location in either the stationary spatial frame of the room or the rotating frame of the arena. The code for task variant switched less frequently between a representation of the current rotating episode and the stable episode from the rat's past. The characteristics and interplay of these two hippocampal codes revealed three key properties of constructive recollection. (1 Although the ensemble representations of the stable and rotating episodes were distinct, ensemble discharge during rotation occasionally resembled the stable condition, demonstrating cross-episode retrieval of the representation of the remote, stable episode. (2 This cross-episode retrieval at the level of the code for task variant was more likely when the rotating arena was about to match its orientation in the stable episode. (3 The likelihood of cross-episode retrieval was influenced by preretrieval information that was signaled at the level of the code for spatial reference frame. Thus key features of episodic recollection manifest in rat hippocampal

Genetics in psychiatry: common variant association studies

Directory of Open Access Journals (Sweden)

Buxbaum Joseph D

2010-03-01

Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

Science.gov (United States)

Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

2013-01-01

Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

Genetics Home Reference: Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant

Science.gov (United States)

... SBBYS variant Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant Printable PDF Open All Close All Enable ... collapse boxes. Description The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is a rare ...

Cryptanalysis of RSA and its variants

CERN Document Server

Hinek, M Jason

2009-01-01

Thirty years after RSA was first publicized, it remains an active research area. Although several good surveys exist, they are either slightly outdated or only focus on one type of attack. Offering an updated look at this field, Cryptanalysis of RSA and Its Variants presents the best known mathematical attacks on RSA and its main variants, including CRT-RSA, multi-prime RSA, and multi-power RSA. Divided into three parts, the book first introduces RSA and reviews the mathematical background needed for the majority of attacks described in the remainder of the text. It then brings together all of the most popular mathematical attacks on RSA and its variants. For each attack presented, the author includes a mathematical proof if possible or a mathematical justification for attacks that rely on assumptions. For the attacks that cannot be proven, he gives experimental evidence to illustrate their practical effectiveness. Focusing on mathematical attacks that exploit the structure of RSA and specific parameter choic...

Numerically-quantified two dimensionality of microstructure evolution accompanying variant selection of FePd

International Nuclear Information System (INIS)

Ueshima, N; Yoshiya, M; Yasuda, H; Fukuda, T; Kakeshita, T

2015-01-01

Through three-dimensional (3D) simulations of microstructure evolution by phase-field modeling (PFM), microstructures have been quantified during their time evolution by an image processing technique with particular attention to the shape of variants in the course of variant selection. It is found that the emerging variants exhibit planar shapes rather than 3D shapes due to the elastic field around the variants arising upon disorder-to-order transition to the L1 0 phase. The two-dimensionality is more pronounced as variant selection proceeds. Although three equivalent variants compete for dominance under an external field, one of the three variants vanishes before final competition occurs between the remaining variants, which can be explained by the elastic strain energy. These numerical analyses provide better understanding of the microstructure evolution in a more quantitative manner, including the small influence of the third variant, and the results obtained confirm that the understanding of variant selection obtained from two-dimensional (2D) simulations by PFM is valid. (paper)

Assessment of Functional Effects of Unclassified Genetic Variants

NARCIS (Netherlands)

Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

2008-01-01

Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

Assessment of Functional Effects of Unclassified Genetic Variants

NARCIS (Netherlands)

Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

Canine parvovirus: the worldwide occurrence of antigenic variants.

Science.gov (United States)

Miranda, Carla; Thompson, Gertrude

2016-09-01

The most important enteric virus infecting canids is canine parvovirus type 2 (CPV-2). CPV is the aetiologic agent of a contagious disease, mainly characterized by clinical gastroenteritis signs in younger dogs. CPV-2 emerged as a new virus in the late 1970s, which could infect domestic dogs, and became distributed in the global dog population within 2 years. A few years later, the virus's original type was replaced by a new genetic and antigenic variant, called CPV-2a. Around 1984 and 2000, virus variants with the single change to Asp or Glu in the VP2 residue 426 were detected (sometimes termed CPV-2b and -2c). The genetic and antigenic changes in the variants have also been correlated with changes in their host range; in particular, in the ability to replicate in cats and also host range differences in canine and other tissue culture cells. CPV-2 variants have been circulating among wild carnivores and have been well-documented in several countries around the world. Here, we have reviewed and summarized the current information about the worldwide distribution and evolution of CPV-2 variants since they emerged, as well as the host ranges they are associated with.

SNCA 3'UTR genetic variants in patients with Parkinson's disease and REM sleep behavior disorder.

Science.gov (United States)

Toffoli, M; Dreussi, E; Cecchin, E; Valente, M; Sanvilli, N; Montico, M; Gagno, S; Garziera, M; Polano, M; Savarese, M; Calandra-Buonaura, G; Placidi, F; Terzaghi, M; Toffoli, G; Gigli, G L

2017-07-01

REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD. We recruited 113 consecutive patients with a diagnosis of iRBD (56 patients) or PD (with or without RBD, 57 patients). Sequencing of SNCA-3'UTR was performed on genomic DNA extracted from peripheral blood samples. Bioinformatic analyses were carried out to predict the potential effect of the identified genetic variants on microRNA binding. We found three SNCA-3'UTR SNPs (rs356165, rs3857053, rs1045722) to be more frequent in PD patients than in iRBD patients (p = 0.014, 0.008, and 0.008, respectively). Four new or previously reported but not annotated specific genetic variants (KP876057, KP876056, NM_000345.3:c*860T>A, NM_000345.3:c*2320A>T) have been observed in the RBD population. The in silico approach highlighted that these variants could affect microRNA-mediated gene expression control. Our data show specific SNPs in the SNCA-3'UTR that may bear a risk for RBD to be associated with PD. Moreover, new genetic variants were identified in patients with iRBD.

Delineation of concentration ranges and longitudinal changes of human plasma protein variants.

Directory of Open Access Journals (Sweden)

Olgica Trenchevska

Full Text Available Human protein diversity arises as a result of alternative splicing, single nucleotide polymorphisms (SNPs and posttranslational modifications. Because of these processes, each protein can exists as multiple variants in vivo. Tailored strategies are needed to study these protein variants and understand their role in health and disease. In this work we utilized quantitative mass spectrometric immunoassays to determine the protein variants concentration of beta-2-microglobulin, cystatin C, retinol binding protein, and transthyretin, in a population of 500 healthy individuals. Additionally, we determined the longitudinal concentration changes for the protein variants from four individuals over a 6 month period. Along with the native forms of the four proteins, 13 posttranslationally modified variants and 7 SNP-derived variants were detected and their concentration determined. Correlations of the variants concentration with geographical origin, gender, and age of the individuals were also examined. This work represents an important step toward building a catalog of protein variants concentrations and examining their longitudinal changes.

Migraine Variants in Children

Science.gov (United States)

... Headaches in Children FAQ Migraine Variants In Children Children Get Migraines Too! Learn More Migraine Information Find Help Doctors & Resources Get Connected Join the Conversation Follow Us on Social Media Company About News Resources Privacy Policy Contact Phone: ...

Listeners' processing of a given reduced word pronunciation variant directly reflects their exposure to this variant: Evidence from native listeners and learners of French.

Science.gov (United States)

Brand, Sophie; Ernestus, Mirjam

2018-05-01

In casual conversations, words often lack segments. This study investigates whether listeners rely on their experience with reduced word pronunciation variants during the processing of single segment reduction. We tested three groups of listeners in a lexical decision experiment with French words produced either with or without word-medial schwa (e.g., /ʀvy/ and /ʀvy/ for revue). Participants also rated the relative frequencies of the two pronunciation variants of the words. If the recognition accuracy and reaction times (RTs) for a given listener group correlate best with the frequencies of occurrence holding for that given listener group, recognition is influenced by listeners' exposure to these variants. Native listeners' relative frequency ratings correlated well with their accuracy scores and RTs. Dutch advanced learners' accuracy scores and RTs were best predicted by their own ratings. In contrast, the accuracy and RTs from Dutch beginner learners of French could not be predicted by any relative frequency rating; the rating task was probably too difficult for them. The participant groups showed behaviour reflecting their difference in experience with the pronunciation variants. Our results strongly suggest that listeners store the frequencies of occurrence of pronunciation variants, and consequently the variants themselves.

The pathogenicity of genetic variants previously associated with left ventricular non-compaction

DEFF Research Database (Denmark)

Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza

2016-01-01

BACKGROUND: Left ventricular non-compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC-associated variants that are common in the background population remains unknown. The aim of this study was to provide...... an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically...... searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine...

Network perturbation by recurrent regulatory variants in cancer.

Directory of Open Access Journals (Sweden)

Kiwon Jang

2017-03-01

Full Text Available Cancer driving genes have been identified as recurrently affected by variants that alter protein-coding sequences. However, a majority of cancer variants arise in noncoding regions, and some of them are thought to play a critical role through transcriptional perturbation. Here we identified putative transcriptional driver genes based on combinatorial variant recurrence in cis-regulatory regions. The identified genes showed high connectivity in the cancer type-specific transcription regulatory network, with high outdegree and many downstream genes, highlighting their causative role during tumorigenesis. In the protein interactome, the identified transcriptional drivers were not as highly connected as coding driver genes but appeared to form a network module centered on the coding drivers. The coding and regulatory variants associated via these interactions between the coding and transcriptional drivers showed exclusive and complementary occurrence patterns across tumor samples. Transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.

Variants at the 9p21 locus and melanoma risk

International Nuclear Information System (INIS)

Maccioni, Livia; Rachakonda, Panduranga Sivaramakrishna; Bermejo, Justo Lorenzo; Planelles, Dolores; Requena, Celia; Hemminki, Kari; Nagore, Eduardo; Kumar, Rajiv

2013-01-01

The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3’ UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A–allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes

Spatial distributions of Pseudomonas fluorescens colony variants in mixed-culture biofilms.

Science.gov (United States)

Workentine, Matthew L; Wang, Siyuan; Ceri, Howard; Turner, Raymond J

2013-07-28

The emergence of colony morphology variants in structured environments is being recognized as important to both niche specialization and stress tolerance. Pseudomonas fluorescens demonstrates diversity in both its natural environment, the rhizosphere, and in laboratory grown biofilms. Sub-populations of these variants within a biofilm have been suggested as important contributors to antimicrobial stress tolerance given their altered susceptibility to various agents. As such it is of interest to determine how these variants might be distributed in the biofilm environment. Here we present an analysis of the spatial distribution of Pseudomonas fluorescens colony morphology variants in mixed-culture biofilms with the wildtype phenotype. These findings reveal that two variant colony morphotypes demonstrate a significant growth advantage over the wildtype morphotype in the biofilm environment. The two variant morphotypes out-grew the wildtype across the entire biofilm and this occurred within 24 h and was maintained through to 96 h. This competitive advantage was not observed in homogeneous broth culture. The significant advantage that the variants demonstrate in biofilm colonization over the wildtype denotes the importance of this phenotype in structured environments.

Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.

Science.gov (United States)

Melchionda, Laura; Fang, Mingyan; Wang, Hairong; Fugnanesi, Valeria; Morbin, Michela; Liu, Xuanzhu; Li, Wenyan; Ceccherini, Isabella; Farina, Laura; Savoiardo, Mario; D'Adamo, Pio; Zhang, Jianguo; Costa, Alfredo; Ravaglia, Sabrina; Ghezzi, Daniele; Zeviani, Massimo

2013-05-01

We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander's disease (AOAD), suggesting different expression of the same, genetically determined, condition. Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells. Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene. Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.

Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance.

Science.gov (United States)

Saxena, R; Georgopoulos, N A; Braaten, T J; Bjonnes, A C; Koika, V; Panidis, D; Welt, C K

2015-06-01

Are PCOS risk variants identified in women of Han Chinese ethnicity also associated with risk of PCOS or the phenotypic features of PCOS in European women? One variant, rs2268361-T, in the intron of FSHR was associated with PCOS and lower FSH levels, while another variant rs705702-G near the RAB5B and SUOX genes was associated with insulin and glucose levels after oral glucose testing in women with PCOS of European ethnicity. Three of the eleven variants associated with PCOS in the Han Chinese genome-wide association studies were also associated with PCOS in at least one European population when corrected for multiple testing (DENND1A, THADA and YAP1). However, additional replication is needed to establish the importance of these variants in European women and to determine the relationship to PCOS phenotypic traits. The study was a case-control examination in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston (Boston 1). Replication was performed in women from Greece (cases n = 884 and controls n = 311) and an additional cohort from Boston (Boston electronic medical record (EMR); n = 350 cases and n = 1258 controls). Women had PCOS defined by the National Institutes of Health criteria in Boston 1 and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. The second cohort from Boston was defined using the EMR and natural language processing. Allele frequencies for variants associated with PCOS in Han Chinese women were examined in PCOS cases and controls, along with the relationship to quantitative traits. A variant rs2268361-T in an intron of FSHR was associated with PCOS (0.84 [0.76-0.93], OR [95% CI]; P = 0.002). The rs2268361-T was associated with lower FSH levels (-0.15 ± 0.05; P = 0.0029). A variant rs705702-G near RAB5B and SUOX was

Genomic constitution of an H-2:Tla variant leukemia.

Science.gov (United States)

Shen, F W; Chaganti, R S; Doucette, L A; Litman, G W; Steinmetz, M; Hood, L; Boyse, E A

1984-10-01

A TL+ leukemia of a (B6 X A)F1 hybrid mouse (H-2b/H-2a) was previously subjected to immunoselection against H-2a by passage in (B6 X A.SW)F1 mice (H-2b/H-2s). A variant leukemia line was obtained that serologically lacked not only the H-2a phenotype but also the TL phenotype determined by the linked cis Tlaa allele of strain A. The H-2b phenotype and the TL phenotype of the Tlab allele of the B6 strain, which is expressed only by leukemia cells, were retained by the variant. Southern blotting with an H-2 cDNA probe that identifies restriction fragment polymorphisms distinguishing alleles of the H-2 and Tla regions of the B6 and A strains indicates that both the H-2a and Tlaa alleles are missing from the genome of this H-2a:Tlaa negative variant. Since the variant has two apparently unaltered chromosomes 17, where the H-2:Tla complex is situated, and since the intensity of bands in Southern blotting is suggestive of H-2b homozygosity, it is considered that loss of the H-2a:Tlaa haplotype by the variant was accompanied by duplication of the H-2b:Tlab haplotype. The implied change from heterozygosity to homozygosity that the variant has undergone with respect to H-2:Tla was not paralleled by a similar change at the three other loci tested, since the variant retained heterozygosity for Pep-3 (chromosome 1), Gpi-1 (chromosome 7), and Es-1 (chromosome 8).

Efficient utilization of rare variants for detection of disease-related genomic regions.

Directory of Open Access Journals (Sweden)

Lei Zhang

2010-12-01

Full Text Available When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing and YRI (Yoruba people of Ibadan populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions.

Changes in classification of genetic variants in BRCA1 and BRCA2.

Science.gov (United States)

Kast, Karin; Wimberger, Pauline; Arnold, Norbert

2018-02-01

Classification of variants of unknown significance (VUS) in the breast cancer genes BRCA1 and BRCA2 changes with accumulating evidence for clinical relevance. In most cases down-staging towards neutral variants without clinical significance is possible. We searched the database of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) for changes in classification of genetic variants as an update to our earlier publication on genetic variants in the Centre of Dresden. Changes between 2015 and 2017 were recorded. In the group of variants of unclassified significance (VUS, Class 3, uncertain), only changes of classification towards neutral genetic variants were noted. In BRCA1, 25% of the Class 3 variants (n = 2/8) changed to Class 2 (likely benign) and Class 1 (benign). In BRCA2, in 50% of the Class 3 variants (n = 16/32), a change to Class 2 (n = 10/16) or Class 1 (n = 6/16) was observed. No change in classification was noted in Class 4 (likely pathogenic) and Class 5 (pathogenic) genetic variants in both genes. No up-staging from Class 1, Class 2 or Class 3 to more clinical significance was observed. All variants with a change in classification in our cohort were down-staged towards no clinical significance by a panel of experts of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevention in families with Class 3 variants should be based on pedigree based risks and should not be guided by the presence of a VUS.

Identifying genetic variants that affect viability in large cohorts.

Directory of Open Access Journals (Sweden)

Hakhamanesh Mostafavi

2017-09-01

Full Text Available A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers, consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3. Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD, body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

Protein variants in Hiroshima and Nagasaki: tales of two cities.

Science.gov (United States)

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-12-01

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation

Feature reduction and payload location with WAM steganalysis

Science.gov (United States)

Ker, Andrew D.; Lubenko, Ivans

2009-02-01

WAM steganalysis is a feature-based classifier for detecting LSB matching steganography, presented in 2006 by Goljan et al. and demonstrated to be sensitive even to small payloads. This paper makes three contributions to the development of the WAM method. First, we benchmark some variants of WAM in a number of sets of cover images, and we are able to quantify the significance of differences in results between different machine learning algorithms based on WAM features. It turns out that, like many of its competitors, WAM is not effective in certain types of cover, and furthermore it is hard to predict which types of cover are suitable for WAM steganalysis. Second, we demonstrate that only a few the features used in WAM steganalysis do almost all of the work, so that a simplified WAM steganalyser can be constructed in exchange for a little less detection power. Finally, we demonstrate how the WAM method can be extended to provide forensic tools to identify the location (and potentially content) of LSB matching payload, given a number of stego images with payload placed in the same locations. Although easily evaded, this is a plausible situation if the same stego key is mistakenly re-used for embedding in multiple images.

Dedifferentiated chondrosarcoma of the larynx: Radiological, gross, microscopic and clinical features.

Science.gov (United States)

Magliocca, Kelly R; Edgar, Mark A; Corey, Amanda; Villari, Craig R

2017-10-01

Laryngeal chondrosarcoma is an uncommon malignancy with a predilection for the cricoid cartilage of adult male patients. Although rare, identification of aggressive chondrosarcoma variants, such as dedifferentiated chondrosarcoma (DDCS) may influence preoperative patient counseling, definitive surgical management, potential implementation of post-operative adjuvant therapy and prognosis. Herein we describe clinical and imaging features of laryngeal DDCS, the unique perspective of fresh and formalin fixed macroscopic examination, a spectrum of histopathologic findings, and detail the full course of the patient's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Following of erosive wash of soil in variants with different intercrops

Directory of Open Access Journals (Sweden)

Barbora Badalíková

2010-01-01

Full Text Available In a pilot experiment established in a sugar beet growing region the erosive washing away of soil was studied in the years 2006 to 2008. The area is located at an altitude of 246 m with the long-term mean precipitation of 500 mm and the mean annual temperature of 8.4 °C. The soils are classified as Chernozem, moderately heavy, loamy, with a good supply of nutrients, humus content of 2.30 % and an alkaline soil reaction. Slope gradient is 12 %, exposition is NE. To study the role of intercrops in erosion control, three variants were established after the harvest of the main crop, two variants with different intercrops and one (control with no intercrop. These were Variant 1 with Secale cereale L. var. multicaule METZG. ex ALEF., a non-freezing intercrop, Variant 2 with cluster mallow (Malva verticillata L., a freezing intercrop, and a control variant with no intercrop. In Variant 1 Secale cereale L. var. multicaule was desiccated with the herbicide Roundup in early spring. All the variants involved maize as the main crop. In variants 1 and 2, maize was sown in intercrop residues after seedbed preparation by Vario and a compactor. In Variant 3 maize was sown after conventional seedbed preparation. For assessment of soil conditions soil samples were taken to determine soil physical and chemical properties and water content in the soil. Soil loss by erosion was determined using specially-designed pockets. Erosive washing away of soil was monitored during the entire growing season of maize. The variants in which intercrops were used were found very effective in soil erosion control. In Variant 3 (control without surface crop residues, the washing away of soil was recorded with each heavy torrential rain. During the all years the total amount of soil loss by erosion in this treatment was 2.25 t . ha−1.

Hepatitis E Virus Variant in Farmed Mink, Denmark

DEFF Research Database (Denmark)

Krog, Jesper Schak; Breum, Solvej Østergaard; Jensen, Trine Hammer

2013-01-01

Hepatitis E virus (HEV) is a zoonotic virus for which pigs are the primary animal reservoir. To investigate whether HEV occurs in mink in Denmark, we screened feces and tissues from domestic and wild mink. Our finding of a novel HEV variant supports previous findings of HEV variants in a variety...

Efficient population-scale variant analysis and prioritization with VAPr.

Science.gov (United States)

Birmingham, Amanda; Mark, Adam M; Mazzaferro, Carlo; Xu, Guorong; Fisch, Kathleen M

2018-04-06

With the growing availability of population-scale whole-exome and whole-genome sequencing, demand for reproducible, scalable variant analysis has spread within genomic research communities. To address this need, we introduce the Python package VAPr (Variant Analysis and Prioritization). VAPr leverages existing annotation tools ANNOVAR and MyVariant.info with MongoDB-based flexible storage and filtering functionality. It offers biologists and bioinformatics generalists easy-to-use and scalable analysis and prioritization of genomic variants from large cohort studies. VAPr is developed in Python and is available for free use and extension under the MIT License. An install package is available on PyPi at https://pypi.python.org/pypi/VAPr, while source code and extensive documentation are on GitHub at https://github.com/ucsd-ccbb/VAPr. kfisch@ucsd.edu.

IL10 low-frequency variants in Behçet's disease patients.

Science.gov (United States)

Matos, Mafalda; Xavier, Joana M; Abrantes, Patrícia; Sousa, Inês; Rei, Nádia; Davatchi, Fereydoun; Shahram, Farhad; Jesus, Gorete; Barcelos, Filipe; Vedes, Joana; Salgado, Manuel; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Moraes-Fontes, Maria Francisca; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Vaz Patto, José; Crespo, Jorge; Oliveira, Sofia A

2017-05-01

To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Gaze-independent brain-computer interfaces based on covert attention and feature attention

Science.gov (United States)

Treder, M. S.; Schmidt, N. M.; Blankertz, B.

2011-10-01

There is evidence that conventional visual brain-computer interfaces (BCIs) based on event-related potentials cannot be operated efficiently when eye movements are not allowed. To overcome this limitation, the aim of this study was to develop a visual speller that does not require eye movements. Three different variants of a two-stage visual speller based on covert spatial attention and non-spatial feature attention (i.e. attention to colour and form) were tested in an online experiment with 13 healthy participants. All participants achieved highly accurate BCI control. They could select one out of thirty symbols (chance level 3.3%) with mean accuracies of 88%-97% for the different spellers. The best results were obtained for a speller that was operated using non-spatial feature attention only. These results show that, using feature attention, it is possible to realize high-accuracy, fast-paced visual spellers that have a large vocabulary and are independent of eye gaze.

Two Novel Variants Affecting CDKL5 Transcript Associated with Epileptic Encephalopathy.

Science.gov (United States)

Neupauerová, Jana; Štěrbová, Katalin; Vlčková, Markéta; Sebroňová, Věra; Maříková, Tat'ána; Krůtová, Marcela; David, Staněk; Kršek, Pavel; Žaliová, Markéta; Seeman, Pavel; Laššuthová, Petra

2017-10-01

Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.

Common genetic variants influence human subcortical brain structures

Science.gov (United States)

Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

2015-01-01

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

Common genetic variants influence human subcortical brain structures.

Science.gov (United States)

Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

2015-04-09

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Identification of a consistent pattern of mutations in neurovirulent variants derived from the sabin vaccine strain of poliovirus type 2.

OpenAIRE

Equestre, M; Genovese, D; Cavalieri, F; Fiore, L; Santoro, R; Perez Bercoff, R

1991-01-01

Complete nucleotide sequencing of the RNAs of two unrelated neurovirulent isolates of Sabin-related poliovirus type 2 revealed that two nucleotides and one amino acid (amino acid 143 in the major capsid protein VP1) consistently departed from the sequences of the nonneurovirulent poliovirus type 2 712 and Sabin vaccine strains. This pattern of mutation appeared to be a feature common to all neurovirulent variants of poliovirus type 2.

Functional significance of SPINK1 promoter variants in chronic pancreatitis.

Science.gov (United States)

Derikx, Monique H M; Geisz, Andrea; Kereszturi, Éva; Sahin-Tóth, Miklós

2015-05-01

Chronic pancreatitis is a progressive inflammatory disorder of the pancreas, which often develops as a result of genetic predisposition. Some of the most frequently identified risk factors affect the serine protease inhibitor Kazal type 1 (SPINK1) gene, which encodes a trypsin inhibitor responsible for protecting the pancreas from premature trypsinogen activation. Recent genetic and functional studies indicated that promoter variants in the SPINK1 gene might contribute to disease risk in carriers. Here, we investigated the functional effects of 17 SPINK1 promoter variants using luciferase reporter gene expression assay in four different cell lines, including three pancreatic acinar cell lines (rat AR42J with or without dexamethasone-induced differentiation and mouse 266-6) and human embryonic kidney 293T cells. We found that most variants caused relatively small changes in promoter activity. Surprisingly, however, we observed significant variations in the effects of the promoter variants in the different cell lines. Only four variants exhibited consistently reduced promoter activity in all acinar cell lines, confirming previous reports that variants c.-108G>T, c.-142T>C, and c.-147A>G are risk factors for chronic pancreatitis and identifying c.-52G>T as a novel risk variant. In contrast, variant c.-215G>A, which is linked with the disease-associated splice-site mutation c.194 + 2T>C, caused increased promoter activity, which may mitigate the overall effect of the pathogenic haplotype. Our study lends further support to the notion that sequence evaluation of the SPINK1 promoter region in patients with chronic pancreatitis is justified as part of the etiological investigation. Copyright © 2015 the American Physiological Society.

Differences in the Load-Velocity Profile Between 4 Bench-Press Variants.

Science.gov (United States)

García-Ramos, Amador; Pestaña-Melero, Francisco Luis; Pérez-Castilla, Alejandro; Rojas, Francisco Javier; Haff, Guy Gregory

2018-03-01

To compare the load-velocity relationship between 4 variants of the bench-press (BP) exercise. The full load-velocity relationship of 30 men was evaluated by means of an incremental loading test starting at 17 kg and progressing to the individual 1-repetition maximum (1RM) in 4 BP variants: concentric-only BP, concentric-only BP throw (BPT), eccentric-concentric BP, and eccentric-concentric BPT. A strong and fairly linear relationship between mean velocity (MV) and %1RM was observed for the 4 BP variants (r 2  > .96 for pooled data and r 2  > .98 for individual data). The MV associated with each %1RM was significantly higher in the eccentric-concentric technique than in the concentric-only technique. The only significant difference between the BP and BPT variants was the higher MV with the light to moderate loads (20-70%1RM) in the BPT using the concentric-only technique. MV was significantly and positively correlated between the 4 BP variants (r = .44-.76), which suggests that the subjects with higher velocities for each %1RM in 1 BP variant also tend to have higher velocities for each %1RM in the 3 other BP variants. These results highlight the need for obtaining specific equations for each BP variant and the existence of individual load-velocity profiles.

Influence of APOE and RNF219 on Behavioral and Cognitive Features of Female Patients Affected by Mild Cognitive Impairment or Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Alessandra Mosca

2018-04-01

Full Text Available The risk for Alzheimer’s disease (AD is associated with the presence of the 4 allele of Apolipoprotein E (APOE gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD. Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients.

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Science.gov (United States)

Karbassi, Izabela; Maston, Glenn A; Love, Angela; DiVincenzo, Christina; Braastad, Corey D; Elzinga, Christopher D; Bright, Alison R; Previte, Domenic; Zhang, Ke; Rowland, Charles M; McCarthy, Michele; Lapierre, Jennifer L; Dubois, Felicita; Medeiros, Katelyn A; Batish, Sat Dev; Jones, Jeffrey; Liaquat, Khalida; Hoffman, Carol A; Jaremko, Malgorzata; Wang, Zhenyuan; Sun, Weimin; Buller-Burckle, Arlene; Strom, Charles M; Keiles, Steven B; Higgins, Joseph J

2016-01-01

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.

Science.gov (United States)

Schrader, Kasmintan A; Cheng, Donavan T; Joseph, Vijai; Prasad, Meera; Walsh, Michael; Zehir, Ahmet; Ni, Ai; Thomas, Tinu; Benayed, Ryma; Ashraf, Asad; Lincoln, Annie; Arcila, Maria; Stadler, Zsofia; Solit, David; Hyman, David M; Hyman, David; Zhang, Liying; Klimstra, David; Ladanyi, Marc; Offit, Kenneth; Berger, Michael; Robson, Mark

2016-01-01

Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. To estimate the burden of germline variants identified through routine clinical tumor sequencing. Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99

Extension twin variant selection during uniaxial compression of a magnesium alloy

DEFF Research Database (Denmark)

Pei, Y.; Godfrey, A.; Jiang, J.

2012-01-01

is also observed in that smaller grains are less likely to contain lower ranked twin variants. For both 5% and 10% compression no clear relationship exists between the volume fraction of each twin variant in a given grain population and the Schmid factor for the twin variant. A positive linear......Samples of the magnesium alloy AZ31 have been deformed by compression to strains of 5% and 10% and microstructural observations made to investigate the activation of specific {1 0 1¯ 2} extension twin variants. The twinning has been analyzed on a grain-by-grain basis for more than 260 grains...... to determine both the number of extension twin variants in each grain, and the volume fraction of each. At 5% strain approx. 30% of the grains contain twins corresponding to variants with the third or lower ranked Schmid factor, with the fraction increasing to 40% after 10% compression. A grain size effect...

A geometric framework for evaluating rare variant tests of association.

Science.gov (United States)

Liu, Keli; Fast, Shannon; Zawistowski, Matthew; Tintle, Nathan L

2013-05-01

The wave of next-generation sequencing data has arrived. However, many questions still remain about how to best analyze sequence data, particularly the contribution of rare genetic variants to human disease. Numerous statistical methods have been proposed to aggregate association signals across multiple rare variant sites in an effort to increase statistical power; however, the precise relation between the tests is often not well understood. We present a geometric representation for rare variant data in which rare allele counts in case and control samples are treated as vectors in Euclidean space. The geometric framework facilitates a rigorous classification of existing rare variant tests into two broad categories: tests for a difference in the lengths of the case and control vectors, and joint tests for a difference in either the lengths or angles of the two vectors. We demonstrate that genetic architecture of a trait, including the number and frequency of risk alleles, directly relates to the behavior of the length and joint tests. Hence, the geometric framework allows prediction of which tests will perform best under different disease models. Furthermore, the structure of the geometric framework immediately suggests additional classes and types of rare variant tests. We consider two general classes of tests which show robustness to noncausal and protective variants. The geometric framework introduces a novel and unique method to assess current rare variant methodology and provides guidelines for both applied and theoretical researchers. © 2013 Wiley Periodicals, Inc.

CEACAM6 gene variants in inflammatory bowel disease.

Science.gov (United States)

Glas, Jürgen; Seiderer, Julia; Fries, Christoph; Tillack, Cornelia; Pfennig, Simone; Weidinger, Maria; Beigel, Florian; Olszak, Torsten; Lass, Ulrich; Göke, Burkhard; Ochsenkühn, Thomas; Wolf, Christiane; Lohse, Peter; Müller-Myhsok, Bertram; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2011-04-29

The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

CEACAM6 gene variants in inflammatory bowel disease.

Directory of Open Access Journals (Sweden)

Jürgen Glas

Full Text Available BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC and its ileal expression is increased in patients with Crohn's disease (CD. Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD. METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC, and 1,350 healthy, unrelated controls was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839. In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

Características morfoanatômicas da epiderme foliar de plantas variantes e não variantes somaclonais de bananeiras (Musa sp. Colla cv. Prata-anã cultivadas in vitro Morphoanatomical characteristics of the leaf epidermis of variant plants and somaclonal non-variants of banana trees (Musa sp. Colla cv. Prata-anã cultivated in vitro

Directory of Open Access Journals (Sweden)

Guilherme Araújo Lacerda

2008-03-01

Full Text Available A variação somaclonal corresponde ao aparecimento de plantas anormais durante o processo de multiplicação in vitro, principalmente relacionada à estatura, no caso o gigantismo. O objetivo deste trabalho foi averiguar as diferenças morfoanatômicas da epiderme foliar na tentativa de diferenciar as plantas de 'Prata-anã' em relação aos seus variantes somaclonais. A análise por microscopia eletrônica de varredura mostrou uma diferença significativa entre o diâmetro polar dos estômatos da 'Prata-anã' não variante e suas variantes, ambas em condições in vitro, observando-se que o mesmo não ocorre para as plantas in vivo. O número médio de estômatos é menor nas plantas variantes somaclonais, porém sem diferenças significativas a não ser para a planta PIII. A descamação de cera é evidente somente nas plantas variantes de ambos os materiais (in vitro e in vivo. Conclui-se que os caracteres morfoanatômicos da epiderme foliar, como densidade estomática, diâmetro estomático polar e a uniformidade da cera atuam como marcadores morfológicos para caracterizar as plantas micropropagadas de 'Prata-anã' em relação aos seus variantes somaclonais para a característica gigantismo.Somaclonal variation corresponds to the emergence of abnormal plants during the process of multiplication in vitro, mainly related to stature, in the case the gigantism. The aim of this work was to discover morphoanatomical differences of the leaf epidermis in an attempt to differentiate plants of "Prata-anã" from their somaclonal variants. Analysis by scanning electronic microscopy showed significant difference between the polar diameter of the stomata of the "Prata-anã" non-variant and its variants, both in vitro. The same does not happen for plants in vivo. The average number of stomata is lower in the somaclonal variant plants, but without significant differences except for plant PIII. Wax peeling is only evident in the variant plants of both the

The follicular variant of papillary thyroid carcinoma: Characteristics of preoperative ultrasonography and cytology

International Nuclear Information System (INIS)

Yoon, Jung Hyun; Kwon, Hyeong Ju; Kim, Eun Kyung; Moon, Hee Jung; Kwak, Jin Young

2016-01-01

The goal of this study was to validate the ultrasonography (US) and cytopathological features that are used in the diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) and to characterize the role of BRAFV600E mutation analysis in the diagnosis of FVPTC. From May 2012 to February 2014, 40 thyroid nodules from 40 patients (mean age, 56.2 years; range, 26 to 81 years) diagnosed with FVPTC were included in this study. The US features of the nodules were analyzed and the nodules were classified as probably benign or suspicious for malignancy. Twenty-three thyroid nodules (57.5%) underwent BRAFV600E mutation analysis. Clinical information and histopathologic results were obtained by reviewing the medical records of the patients. Thirty nodules (75.0%) were classified as suspicious for malignancy, while 10 (25.0%) were classified as probably benign. Seven of the eight nodules (87.5%) with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology showed suspicious US features, while one of the two nodules (50.0%) with follicular neoplasm cytology presented suspicious US features. Five of the 23 nodules (21.7%) that underwent BRAFV600E mutation analysis had positive results, all of which were diagnosed as suspicious for malignancy or malignant based on cytology. None of the nodules with benign, AUS/FLUS, or follicular neoplasm cytology were positive for the BRAFV600E mutation. US features allow nodules to be classified as suspicious for malignancy, and the presence of suspicious US features in nodules with ambiguous cytology may aid in the diagnosis of FVPTC. BRAFV600E mutation analysis is of limited value in the diagnosis of FVPTC

The follicular variant of papillary thyroid carcinoma: Characteristics of preoperative ultrasonography and cytology

Energy Technology Data Exchange (ETDEWEB)

Yoon, Jung Hyun; Kwon, Hyeong Ju; Kim, Eun Kyung; Moon, Hee Jung; Kwak, Jin Young [Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2016-01-15

The goal of this study was to validate the ultrasonography (US) and cytopathological features that are used in the diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) and to characterize the role of BRAFV600E mutation analysis in the diagnosis of FVPTC. From May 2012 to February 2014, 40 thyroid nodules from 40 patients (mean age, 56.2 years; range, 26 to 81 years) diagnosed with FVPTC were included in this study. The US features of the nodules were analyzed and the nodules were classified as probably benign or suspicious for malignancy. Twenty-three thyroid nodules (57.5%) underwent BRAFV600E mutation analysis. Clinical information and histopathologic results were obtained by reviewing the medical records of the patients. Thirty nodules (75.0%) were classified as suspicious for malignancy, while 10 (25.0%) were classified as probably benign. Seven of the eight nodules (87.5%) with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology showed suspicious US features, while one of the two nodules (50.0%) with follicular neoplasm cytology presented suspicious US features. Five of the 23 nodules (21.7%) that underwent BRAFV600E mutation analysis had positive results, all of which were diagnosed as suspicious for malignancy or malignant based on cytology. None of the nodules with benign, AUS/FLUS, or follicular neoplasm cytology were positive for the BRAFV600E mutation. US features allow nodules to be classified as suspicious for malignancy, and the presence of suspicious US features in nodules with ambiguous cytology may aid in the diagnosis of FVPTC. BRAFV600E mutation analysis is of limited value in the diagnosis of FVPTC.

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

NARCIS (Netherlands)

Shimelis, Hermela; Mesman, Romy L. S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M. G. R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B.; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olson, Janet E.; Olswold, Curtis; Oosterwijk, Jan J. C.; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D. P.; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C.; Stram, Daniel O.; Swerdlow, Anthony; teo, Soo H.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J.; van der Kolk, Lizet E.; Wang, Qin; Winqvist, Robert; Wu, Anna H.; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B. M.; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F.; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N. A.; Goldgar, David E.; Carreira, Aura; Vreeswijk, Maaike P. G.; Couch, Fergus J.

2017-01-01

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk

Predicting effects of noncoding variants with deep learning-based sequence model.

Science.gov (United States)

Zhou, Jian; Troyanskaya, Olga G

2015-10-01

Identifying functional effects of noncoding variants is a major challenge in human genetics. To predict the noncoding-variant effects de novo from sequence, we developed a deep learning-based algorithmic framework, DeepSEA (http://deepsea.princeton.edu/), that directly learns a regulatory sequence code from large-scale chromatin-profiling data, enabling prediction of chromatin effects of sequence alterations with single-nucleotide sensitivity. We further used this capability to improve prioritization of functional variants including expression quantitative trait loci (eQTLs) and disease-associated variants.

VPA: an R tool for analyzing sequencing variants with user-specified frequency pattern

Directory of Open Access Journals (Sweden)

Hu Qiang

2012-01-01

Full Text Available Abstract Background The massive amounts of genetic variant generated by the next generation sequencing systems demand the development of effective computational tools for variant prioritization. Findings VPA (Variant Pattern Analyzer is an R tool for prioritizing variants with specified frequency pattern from multiple study subjects in next-generation sequencing study. The tool starts from individual files of variant and sequence calls and extract variants with user-specified frequency pattern across the study subjects of interest. Several position level quality criteria can be incorporated into the variant extraction. It can be used in studies with matched pair design as well as studies with multiple groups of subjects. Conclusions VPA can be used as an automatic pipeline to prioritize variants for further functional exploration and hypothesis generation. The package is implemented in the R language and is freely available from http://vpa.r-forge.r-project.org.

Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

Energy Technology Data Exchange (ETDEWEB)

Jans, L., E-mail: lennartjans@hotmail.com [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Jaremko, J., E-mail: jjaremko@gmail.com [Department of Radiology, University of Alberta Hospital, 8440-112 Street, Edmonton T6G 2B7, Alberta (Canada); Ditchfield, M., E-mail: Michael.ditchfield@southernhealth.org.au [Department of Radiology, Monash University Clayton Campus, Wellington Road, Clayton 3800, VIC (Australia); De Coninck, T., E-mail: Tinekedeconinck@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Huysse, W., E-mail: Wouter.huysse@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Moon, A., E-mail: Anna.moon@rch.org.au [Department of Radiology, Royal Children' s Hospital, Flemington Road, Parkville 3052, VIC (Australia); Verstraete, K., E-mail: Koenraad.verstraete@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium)

2012-11-15

Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9-14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9-14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

International Nuclear Information System (INIS)

Jans, L.; Jaremko, J.; Ditchfield, M.; De Coninck, T.; Huysse, W.; Moon, A.; Verstraete, K.

2012-01-01

Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9–14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9–14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

Optical Properties Of Polymeric Films Of Bacteriorhodopsin And Its Functional Variants: New Materials For Optical Information Processing

Science.gov (United States)

Hampp, Norbert; Braeuchle, Christoph R.; Oesterhelt, Dieter

1990-01-01

Purple membrane (PM) from Halobacterium halobium consists of a two-dimensional crystal of the photochromic retinal protein bacteriorhodopsin (BR). Purple membrane embedded in inert polymer matrices can be used as reversible recording medium in holography. The thermal and photochemical stability (at least 100.000 recording cycles at room temperature), the high quantum yield (70%), the high resolution (~ 5000 lines/mm) and the wide spectral range (400-680 nm) of these films are promising features for any possible technical application. The variability of this material was restricted to chemical modifications of the chromophoric group for a long time. new class of BR based recording media is introduced by the availability of variants of BR with a modified amino acid sequence. After generation of a mutant strain PM variants can be easily produced by the same cultivation and purification procedures as the PM of the wildtype and therefore are available in virtually unlimited amounts, too. As an example the properties of PM-films containing the variant BR-326, which differs from the wildtype by a single amino acid, are reported here. The improved diffraction efficiency (~ 2-fold) and increased sensitivity (~ 50%) of films containing BR-326 give an impression of the new possibilities for optimizing reversible recording media by biochemical and gentechnological methods as an alternative or an addition to conventional chemical methods.

Evaluating how variants of floristic quality assessment indicate wetland condition.

Science.gov (United States)

Kutcher, Thomas E; Forrester, Graham E

2018-03-28

Biological indicators are useful tools for the assessment of ecosystem condition. Multi-metric and multi-taxa indicators may respond to a broader range of disturbances than simpler indicators, but their complexity can make them difficult to interpret, which is critical to indicator utility for ecosystem management. Floristic Quality Assessment (FQA) is an example of a biological assessment approach that has been widely tested for indicating freshwater wetland condition, but less attention has been given to clarifying the factors controlling its response. FQA quantifies the aggregate of vascular plant species tolerance to habitat degradation (conservatism), and model variants have incorporated species richness, abundance, and indigenity (native or non-native). To assess bias, we tested FQA variants in open-canopy freshwater wetlands against three independent reference measures, using practical vegetation sampling methods. FQA variants incorporating species richness did not correlate with our reference measures and were influenced by wetland size and hydrogeomorphic class. In contrast, FQA variants lacking measures of species richness responded linearly to reference measures quantifying individual and aggregate stresses, suggesting a broad response to cumulative degradation. FQA variants incorporating non-native species, and a variant additionally incorporating relative species abundance, improved performance over using only native species. We relate our empirical findings to ecological theory to clarify the functional properties and implications of the FQA variants. Our analysis indicates that (1) aggregate conservatism reliably declines with increased disturbance; (2) species richness has varying relationships with disturbance and increases with site area, confounding FQA response; and (3) non-native species signal human disturbance. We propose that incorporating species abundance can improve FQA site-level relevance with little extra sampling effort. Using our

Family studies to find rare high risk variants in migraine.

Science.gov (United States)

Hansen, Rikke Dyhr; Christensen, Anne Francke; Olesen, Jes

2017-12-01

Migraine has long been known as a common complex disease caused by genetic and environmental factors. The pathophysiology and the specific genetic susceptibility are poorly understood. Common variants only explain a small part of the heritability of migraine. It is thought that rare genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families. A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising application of a family approach to migraine. PubMed was searched to find studies that looked for rare genetic variants in common complex diseases through a family-based design using NGS, excluding studies looking for de-novo mutations, or using a candidate-gene approach and studies on cancer. All issues from Nature Genetics and PLOS genetics 2014, 2015 and 2016 (UTAI June) were screened for relevant papers. Reference lists from included and other relevant papers were also searched. For the description of the family-based study design using NGS an in-house protocol was used. Thirty-two successful studies, which covered 16 different common complex diseases, were included in this paper. We also found a single migraine study. Twenty-three studies found one or a few family specific

Holographic representation of space-variant systems: system theory.

Science.gov (United States)

Marks Ii, R J; Krile, T F

1976-09-01

System theory for holographic representation of linear space-variant systems is derived. The utility of the resulting piecewise isoplanatic approximation (PIA) is illustrated by example application to the invariant system, ideal magnifier, and Fourier transformer. A method previously employed to holographically represent a space-variant system, the discrete approximation, is shown to be a special case of the PIA.

Normal variants of skin in neonates

Directory of Open Access Journals (Sweden)

Kulkarni M

1996-01-01

Full Text Available 2221 consecutive live births taking place between March 1994 and February 1995 were evaluated for a minimum period of 5 days to note for the occurrence of various normal anatomical variants specially those of skin. Birth weight, gestational age, maternal age, socio-economic status and consanguinity were carefully recorded in all the cases. Mongolian spots (72%, Epstein pearls (43.8%, Milia (26.2% and Erythema toxicum (25.2%, were the common dermatological variants noted. Maturity of the babies and possibly genetic factors (consanguinity are important factors in their causation as ordered in our study.

Promising Variants of Initiation of Martensitic γ - α Transformation in Iron Alloys by a Couple of Elastic Waves

Science.gov (United States)

Kashchenko, M. P.; Chashchina, V. G.

2016-01-01

Variants of initiation of growth of crystals of α-martensite by couples of elastic waves propagating in directions γ and γ in singles crystals of Fe31Ni are suggested. The dynamic theory is used to show that the expected orientations of habit planes {110}γ, {001}γ and {559}γ differ from the typical {31015}γ. Possible features of tetragonality of martensite crystals are discussed. The power of the sources of ultrasound required for initiation of γ - α martensitic transformation is estimated.

Variant Plasmodium ovale isolated from a patient infected in Ghana

Directory of Open Access Journals (Sweden)

Petersen Eskild

2011-01-01

Full Text Available Abstract Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago.

High-performance web services for querying gene and variant annotation.

Science.gov (United States)

Xin, Jiwen; Mark, Adam; Afrasiabi, Cyrus; Tsueng, Ginger; Juchler, Moritz; Gopal, Nikhil; Stupp, Gregory S; Putman, Timothy E; Ainscough, Benjamin J; Griffith, Obi L; Torkamani, Ali; Whetzel, Patricia L; Mungall, Christopher J; Mooney, Sean D; Su, Andrew I; Wu, Chunlei

2016-05-06

Efficient tools for data management and integration are essential for many aspects of high-throughput biology. In particular, annotations of genes and human genetic variants are commonly used but highly fragmented across many resources. Here, we describe MyGene.info and MyVariant.info, high-performance web services for querying gene and variant annotation information. These web services are currently accessed more than three million times permonth. They also demonstrate a generalizable cloud-based model for organizing and querying biological annotation information. MyGene.info and MyVariant.info are provided as high-performance web services, accessible at http://mygene.info and http://myvariant.info . Both are offered free of charge to the research community.

A systematic approach to assessing the clinical significance of genetic variants.

Science.gov (United States)

Duzkale, H; Shen, J; McLaughlin, H; Alfares, A; Kelly, M A; Pugh, T J; Funke, B H; Rehm, H L; Lebo, M S

2013-11-01

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Knowledge discovery in variant databases using inductive logic programming.

Science.gov (United States)

Nguyen, Hoan; Luu, Tien-Dao; Poch, Olivier; Thompson, Julie D

2013-01-01

Understanding the effects of genetic variation on the phenotype of an individual is a major goal of biomedical research, especially for the development of diagnostics and effective therapeutic solutions. In this work, we describe the use of a recent knowledge discovery from database (KDD) approach using inductive logic programming (ILP) to automatically extract knowledge about human monogenic diseases. We extracted background knowledge from MSV3d, a database of all human missense variants mapped to 3D protein structure. In this study, we identified 8,117 mutations in 805 proteins with known three-dimensional structures that were known to be involved in human monogenic disease. Our results help to improve our understanding of the relationships between structural, functional or evolutionary features and deleterious mutations. Our inferred rules can also be applied to predict the impact of any single amino acid replacement on the function of a protein. The interpretable rules are available at http://decrypthon.igbmc.fr/kd4v/.

Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error.

Science.gov (United States)

Kim, Wonkuk; Londono, Douglas; Zhou, Lisheng; Xing, Jinchuan; Nato, Alejandro Q; Musolf, Anthony; Matise, Tara C; Finch, Stephen J; Gordon, Derek

2012-01-01

As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to those data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have

Diverse Functional Properties of Wilson Disease ATP7B Variants

Science.gov (United States)

Huster, Dominik; Kühne, Angelika; Bhattacharjee, Ashima; Raines, Lily; Jantsch, Vanessa; Noe, Johannes; Schirrmeister, Wiebke; Sommerer, Ines; Sabri, Osama; Berr, Frieder; Mössner, Joachim; Stieger, Bruno; Caca, Karel; Lutsenko, Svetlana

2012-01-01

BACKGROUND & AIMS Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. METHODS We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper (64Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. RESULTS Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. CONCLUSIONS Variants in ATP7B associated with Wilson disease disrupt the protein’s transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotype–phenotype correlation and mechanisms of disease pathogenesis. PMID:22240481

Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

Science.gov (United States)

Farfel, Jose M; Yu, Lei; Buchman, Aron S; Schneider, Julie A; De Jager, Philip L; Bennett, David A

2016-08-02

To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies. © 2016 American Academy of Neurology.

Ultrastructural studies on variants of Streptomyces SP-765 obtained after gamma irradiation

International Nuclear Information System (INIS)

Spasova, D.I.; Krystev, Kh.I.; Todorov, I.O.; Dzhedzheva, G.M.; Popov, M.S.

1988-01-01

The study has been carried out with two variants of Streptomyces SP-765, gray and olygosporous, obtained after 1000 Gy gamma irradiation of spore suspension from the initial strain. The gray variant has chains of spores which are oval or oblong with rounded-off edges. Sporulation is highly inhibited in the olygosporous variant. Eleven electron-microscopic pictures of ultrathin sections from colonies of the two variants are presented. The gray variant reveals the presence of a large number of lyzed cells, spores, and scarce vegetative cells; typical of the lyzed cells are the spherical and highly osmiophilic formations on the outer and inner surface of their cytoplasmic membrane. The oligosporous variant shows lyzed cells of various sizes, cells void of content with thick walls, relativelly small number of vegetative cells and individual wall-less cells, shperoplast and protoplast formation, lamellar membrane structure of nearly all cells. Both lyzed and vegetable cells have individual anomalous form containing daughter cells. The conclusion is made that gray and oligosporous variants of Streptomyces SP-765, obtained after irradiation of its spores, possess different ultrastructural organization

Incidental copy-number variants identified by routine genome testing in a clinical population

Science.gov (United States)

Boone, Philip M.; Soens, Zachry T.; Campbell, Ian M.; Stankiewicz, Pawel; Cheung, Sau Wai; Patel, Ankita; Beaudet, Arthur L.; Plon, Sharon E.; Shaw, Chad A.; McGuire, Amy L.; Lupski, James R.

2013-01-01

Purpose Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained. Methods Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed. Results In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition. Conclusion Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient. PMID:22878507

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

Science.gov (United States)

Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

2018-01-09

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

Reversion in variants from a duplication strain of Aspergillus nidulans

International Nuclear Information System (INIS)

Menezes, E.M.; Azevedo, J.L.

1978-01-01

Strains of Aspergillus nidulans with a chromosome segment in duplicate, one in normal position and one translocated to another chromosome, are unstable at mitosis. In addition to variants which result from deletions in either of the duplicate segments, which usually have improved morphology, they produce variants with deteriorated morphology. Three deteriorated variants reverted frequently to parental type morphology, both spontaneously and after ultra-violet treatment. Of six reversions analysed genetically, five were due to suppressors and one was probably due to back mutation. The suppressors segregated as single genes and were not linked to the mutation which they suppress. The instability of these so-called 'deteriorated' variants is discussed in relation to mitotic instability phenomena in A. nidulans. (orig.) [de

A case report of the clear cell variant of gallbladder carcinoma.

Science.gov (United States)

Maharaj, Ravi; Cave, Christo; Sarran, Kevin; Bascombe, Nigel; Dan, Dilip; Greaves, Wesley; Warner, Wayne A

2017-01-01

Clear cell gallbladder carcinoma accounts for less than 1% of all gallbladder malignancies and demonstrates its unique histopathological characteristics in patients with no prior medical illness or familial predisposition. Here we present a case of a 56-year-old female, with no prior medical conditions presented with a 2-month history of upper abdominal pain. Routine hematological and biochemical tests were unremarkable. An abdominal ultrasound revealed the presence of a gallbladder calculi, and a fundic mass while magnetic resonance cholangiopancreatography revealed a 8.0cm×3.5cm gallbladder mass. Computed tomography imaging excluded any distant haematogenous metastases. An open cholecystectomy with lymphadenectomy was proceeded by staging laparoscopy. Upon pathologic investigation, the morphologic and immunophenotypic features supported a diagnosis of clear cell variant of gallbladder carcinoma. Pathological prognostications for primary clear cell gall bladder carcinomas are not well defined due to the rarity of cases and possible misidentification as secondary metastases. Foci of adenocarcinoma within the tumor along with immunohistochemical staining probes can be informative in consideration of differential diagnosis. In these cases, clinical case management should be personalized for increased survival with the possible incorporation of next generation sequencing approaches to guide therapeutic algorithms. We discuss this exceedingly rare case of the clear cell variant of gallbladder carcinoma in detail, highlighting some of the diagnostic, and clinical challenges. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Clinicopathologic, Immunohistochemical, and Molecular Features of Histiocytoid Sweet Syndrome.

Science.gov (United States)

Alegría-Landa, Victoria; Rodríguez-Pinilla, Socorro María; Santos-Briz, Angel; Rodríguez-Peralto, José Luis; Alegre, Victor; Cerroni, Lorenzo; Kutzner, Heinz; Requena, Luis

2017-07-01

Histiocytoid Sweet syndrome is a rare histopathologic variant of Sweet syndrome. The nature of the histiocytoid infiltrate has generated considerable controversy in the literature. The main goal of this study was to conduct a comprehensive overview of the immunohistochemical phenotype of the infiltrate in histiocytoid Sweet syndrome. We also analyze whether this variant of Sweet syndrome is more frequently associated with hematologic malignancies than classic Sweet syndrome. This is a retrospective case series study of the clinicopathologic, immunohistochemical, and molecular features of 33 patients with a clinicopathologic diagnosis of histiocytoid Sweet syndrome was conducted in the dermatology departments of 5 university hospitals and a private laboratory of dermatopathology. The clinical, histopathological, immunohistochemical, and follow-up features of 33 patients with histiocytoid Sweet syndrome were analyzed. In some cases, cytogenetic studies of the dermal infiltrate were also performed. We compare our findings with those of the literature. The dermal infiltrate from the 33 study patients (20 female; median age, 49 years; age range, 5-93 years; and 13 male; median age, 42 years; age range, 4-76 years) was mainly composed of myeloperoxidase-positive immature myelomonocytic cells with histiocytoid morphology. No cytogenetic anomalies were found in the infiltrate except in 1 case in which neoplastic cells of chronic myelogenous leukemia were intermingled with the cells of histiocytoid Sweet syndrome. Authentic histiocytes were also found in most cases, with a mature immunoprofile, but they appeared to be a minor component of the infiltrate. Histiocytoid Sweet syndrome was not more frequently related with hematologic malignancies than classic neutrophilic Sweet syndrome. The dermal infiltrate of cutaneous lesions of histiocytoid Sweet syndrome is composed mostly of immature cells of myeloid lineage. This infiltrate should not be interpreted as leukemia cutis.

Diagnosing, monitoring and managing behavioural variant frontotemporal dementia.

Science.gov (United States)

Piguet, Olivier; Kumfor, Fiona; Hodges, John

2017-09-02

Behavioural variant frontotemporal dementia is characterised by insidious changes in personality and interpersonal conduct that reflect progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation and decision making. The underlying pathology is heterogeneous and classified according to the presence of intraneuronal inclusions of tau, TDP-43 or, occasionally, fused in sarcoma proteins. Biomarkers to detect these histopathological changes in life are increasingly important with the development of disease-modifying drugs. A number of gene abnormalities have been identified, the most common being an expansion in the C9orf72 gene, which together account for most familial cases. The 2011 international consensus criteria propose three levels of diagnostic certainty: possible, probable and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process, with support from neuropsychological testing designed to detect impairment in decision making, emotion processing and social cognition. Brain imaging is important for increasing the level of diagnosis certainty over time. Carer education and support remain of paramount importance.

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

DEFF Research Database (Denmark)

Winham, Stacey J; Pirie, Ailith; Chen, Yian Ann

2016-01-01

). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1......=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival...

Micromechanics of transformation-induced plasticity and variant coalescence

International Nuclear Information System (INIS)

Marketz, F.; Fischer, F.D.; University for Mining and Metallurgy, Leoben; Tanaka, K.

1996-01-01

Quantitative micromechanics descriptions of both transformation-induced plasticity (TRIP) associated with the martensitic transformation in an Fe-Ni alloy and of variant coalescence in a Cu-Al-Ni shape memory alloy are presented. The macroscopic deformation behavior of a polycrystalline aggregate as a result of the rearrangements within the crystallites is modelled with the help of a finite element based periodic microfield approach. In the case of TRIP the parent→martensite transformation is described by microscale thermodynamic and kinetic equations taking into account internal stress states. The simulation of a classical experiment on TRIP allows to quantify the Magee-effect and the Greenwood-Johnson effect. Furthermore, the development of the martensitic microstructure is studied with respect to the stress-assisted transformation of preferred variants. In the case of variant coalescence the strain energy due to internal stress states has an important influence on the mechanical behavior. Formulating the reorientation process on the size scale of self-accommodating plate groups in terms of the mobility of the boundaries between martensitic variants the macroscopic behavior in uniaxial tension is predicted by an incremental modelling procedure. Furthermore, influence of energy dissipation on the overall behavior is quantified. (orig.)

TIAM1 variants improve clinical outcome in neuroblastoma.

Science.gov (United States)

Sanmartín, Elena; Yáñez, Yania; Fornés-Ferrer, Victoria; Zugaza, José L; Cañete, Adela; Castel, Victoria; Font de Mora, Jaime

2017-07-11

Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease. The detected variants are located within the different domains of TIAM1 that signal to the upstream regulator RAS and downstream effector molecules MYC and RAC, which are all implicated in neuroblastoma etiology and progression. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification. Given the function of these signaling molecules in cell survival, proliferation, differentiation and neurite outgrowth, our data suggest that the TIAM1-mediated network is essential to neuroblastoma and thus, inhibiting TIAM1 reflects a rational strategy for improving therapy efficacy in neuroblastoma.

Quantitative Missense Variant Effect Prediction Using Large-Scale Mutagenesis Data.

Science.gov (United States)

Gray, Vanessa E; Hause, Ronald J; Luebeck, Jens; Shendure, Jay; Fowler, Douglas M

2018-01-24

Large datasets describing the quantitative effects of mutations on protein function are becoming increasingly available. Here, we leverage these datasets to develop Envision, which predicts the magnitude of a missense variant's molecular effect. Envision combines 21,026 variant effect measurements from nine large-scale experimental mutagenesis datasets, a hitherto untapped training resource, with a supervised, stochastic gradient boosting learning algorithm. Envision outperforms other missense variant effect predictors both on large-scale mutagenesis data and on an independent test dataset comprising 2,312 TP53 variants whose effects were measured using a low-throughput approach. This dataset was never used for hyperparameter tuning or model training and thus serves as an independent validation set. Envision prediction accuracy is also more consistent across amino acids than other predictors. Finally, we demonstrate that Envision's performance improves as more large-scale mutagenesis data are incorporated. We precompute Envision predictions for every possible single amino acid variant in human, mouse, frog, zebrafish, fruit fly, worm, and yeast proteomes (https://envision.gs.washington.edu/). Copyright © 2017 Elsevier Inc. All rights reserved.

Leapfrog variants of iterative methods for linear algebra equations

Science.gov (United States)

Saylor, Paul E.

1988-01-01

Two iterative methods are considered, Richardson's method and a general second order method. For both methods, a variant of the method is derived for which only even numbered iterates are computed. The variant is called a leapfrog method. Comparisons between the conventional form of the methods and the leapfrog form are made under the assumption that the number of unknowns is large. In the case of Richardson's method, it is possible to express the final iterate in terms of only the initial approximation, a variant of the iteration called the grand-leap method. In the case of the grand-leap variant, a set of parameters is required. An algorithm is presented to compute these parameters that is related to algorithms to compute the weights and abscissas for Gaussian quadrature. General algorithms to implement the leapfrog and grand-leap methods are presented. Algorithms for the important special case of the Chebyshev method are also given.

Characterization of Canine parvovirus 2 variants circulating in Greece.

Science.gov (United States)

Ntafis, Vasileios; Xylouri, Eftychia; Kalli, Iris; Desario, Costantina; Mari, Viviana; Decaro, Nicola; Buonavoglia, Canio

2010-09-01

The aim of the present study was to characterize Canine parvovirus 2 (CPV-2) variants currently circulating in Greece. Between March 2008 and March 2009, 167 fecal samples were collected from diarrheic dogs from different regions of Greece. Canine parvovirus 2 was detected by standard polymerase chain reaction, whereas minor groove binder probe assays were used to distinguish genetic variants and discriminate between vaccine and field strains. Of 84 CPV-2-positive samples, 81 CPV-2a, 1 CPV-2b, and 2 CPV-2c were detected. Vaccine strains were not detected in any sample. Sequence analysis of the VP2 gene of the 2 CPV-2c viruses revealed up to 100% amino acid identity with the CPV-2c strains previously detected in Europe. The results indicated that, unlike other European countries, CPV-2a remains the most common variant in Greece, and that the CPV-2c variant found in Europe is also present in Greece.

wANNOVAR: annotating genetic variants for personal genomes via the web.

Science.gov (United States)

Chang, Xiao; Wang, Kai

2012-07-01

High-throughput DNA sequencing platforms have become widely available. As a result, personal genomes are increasingly being sequenced in research and clinical settings. However, the resulting massive amounts of variants data pose significant challenges to the average biologists and clinicians without bioinformatics skills. We developed a web server called wANNOVAR to address the critical needs for functional annotation of genetic variants from personal genomes. The server provides simple and intuitive interface to help users determine the functional significance of variants. These include annotating single nucleotide variants and insertions/deletions for their effects on genes, reporting their conservation levels (such as PhyloP and GERP++ scores), calculating their predicted functional importance scores (such as SIFT and PolyPhen scores), retrieving allele frequencies in public databases (such as the 1000 Genomes Project and NHLBI-ESP 5400 exomes), and implementing a 'variants reduction' protocol to identify a subset of potentially deleterious variants/genes. We illustrated how wANNOVAR can help draw biological insights from sequencing data, by analysing genetic variants generated on two Mendelian diseases. We conclude that wANNOVAR will help biologists and clinicians take advantage of the personal genome information to expedite scientific discoveries. The wANNOVAR server is available at http://wannovar.usc.edu, and will be continuously updated to reflect the latest annotation information.

Differences in antimicrobial susceptibility of pigmented and unpigmented colonial variants of Mycobacterium avium.

Science.gov (United States)

Stormer, R S; Falkinham, J O

1989-01-01

Unpigmented colonial variants were isolated from pigmented Mycobacterium avium isolates recovered from patients with acquired immunodeficiency syndrome and the environment. The variants were interconvertible: the rate of transition from unpigmented to pigmented type was 4.0 x 10(-5) variants per cell per generation. The unpigmented variants were more tolerant to antibiotics, especially beta-lactams, and Cd2+ and Cu2+ salts than were their pigmented parents. Both pigmented and unpigmented variants of the strains produced beta-lactamase, although beta-lactamase did not appear to be a determinant of beta-lactam susceptibility. Pigmented variants grew more rapidly in a number of commonly used mycobacterial media, were more hydrophobic, and had higher carotenoid contents than their unpigmented segregants. PMID:2808669

Identification of POMC exonic variants associated with substance dependence and body mass index.

Directory of Open Access Journals (Sweden)

Fan Wang

Full Text Available Risk of substance dependence (SD and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC.POMC exons were Sanger sequenced in 280 African Americans (AAs and 308 European Americans (EAs. Among them, 311 (167 AAs and 114 EAs were affected with substance (alcohol, cocaine, opioid and/or marijuana dependence and 277 (113 AAs and164 EAs were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571 and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI, with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj = 0.005; Obese: P(adj = 0.018; Overweight+Obese: P(adj = 0.002 but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df = 0.026; alcohol dependence: P(FET,1df = 0.027; cocaine dependence: P(FET,1df = 0.007; marijuana dependence: P(FET,1df = 0.050 (the P-value from cocaine dependence analysis survived Bonferroni correction. There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD.These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert

Collision tumor of the thyroid: follicular variant of papillary carcinoma and squamous carcinoma

Directory of Open Access Journals (Sweden)

Kane Subhadra V

2006-09-01

Full Text Available Abstract Background Collision tumors of the thyroid gland are a rare entity. We present a case of a follicular variant of papillary carcinoma and squamous carcinoma in the thyroid. To the best of our knowledge, this is the first documentation of a collision tumor with a papillary carcinoma and a squamous carcinoma within the thyroid gland. The clinicopathological features and immunohistochemical profile are reported. The theories of origin, epidemiology and management are discussed with a literature review. Case presentation A 65 year old woman presented with a large thyroid swelling of 10 years duration and with swellings on the back and scalp which were diagnosed to be a follicular variant of papillary thyroid carcinoma with metastasis. Clinical examination, radiology and endoscopy ruled out any other abnormality of the upper aerodigestive tract. The patient was treated surgically with a total thyroidectomy with central compartment clearance and bilateral selective neck dissections. The histopathology revealed a collision tumor with components of both a follicular variant of papillary carcinoma and a squamous carcinoma. Immunohistochemical analysis confirmed the independent origin of these two primary tumors. Adjuvant radio iodine therapy directed toward the follicular derived component of the thyroid tumor and external beam radiotherapy for the squamous component was planned. Conclusion Collision tumors of the thyroid gland pose a diagnostic as well as therapeutic challenge. Metastasis from distant organs and contiguous primary tumors should be excluded. The origins of squamous cancer in the thyroid gland must be established to support the true evolution of a collision tumor and to plan treatment. Treatment for collision tumors depends upon the combination of primary tumors involved and each component of the combination should be treated like an independent primary. The reporting of similar cases with longer follow-up will help define the

Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.

Directory of Open Access Journals (Sweden)

Elza Rakhimova

Full Text Available Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.

Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women

Directory of Open Access Journals (Sweden)

Do Kyeong Song

2014-08-01

Full Text Available BackgroundThe fat mass and obesity-associated (FTO gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS. Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.MethodsWe recruited 432 women with PCOS (24±5 years and 927 healthy women with regular menstrual cycles (27±5 years and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.ResultsLogistic regression revealed that the G/G genotype (rs1421085, 1.6%, the C/C genotype (rs17817449, 1.6%, and the A/A genotype (rs8050136, 1.6% were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05. The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05 and higher free testosterone levels (P=0.053 to 0.063 compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI. When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.ConclusionThe rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: report of a case and review of the literature.

Science.gov (United States)

Woo, Victoria L; Landesberg, Regina; Imel, Erik A; Singer, Steven R; Folpe, Andrew L; Econs, Michael J; Kim, Taeyun; Harik, Lara R; Jacobs, Thomas P

2009-12-01

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. Most of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO.

Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis

Science.gov (United States)

Marciante, Kristin D.; Durda, Jon P.; Heckbert, Susan R.; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A.; Tamraz, Bani; Kroetz, Deanna L.; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C.; Glazer, Nicole L.; Li, Guo; Austin, Thomas R.; Taylor, Kent D.; Rotter, Jerome I.; Jaquish, Cashell E.; Kwok, Pui-Yan; Tracy, Russell P.; Psaty, Bruce M.

2011-01-01

Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Results Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63). Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. PMID:21386754

Monocular SLAM for autonomous robots with enhanced features initialization.

Science.gov (United States)

Guerra, Edmundo; Munguia, Rodrigo; Grau, Antoni

2014-04-02

This work presents a variant approach to the monocular SLAM problem focused in exploiting the advantages of a human-robot interaction (HRI) framework. Based upon the delayed inverse-depth feature initialization SLAM (DI-D SLAM), a known monocular technique, several but crucial modifications are introduced taking advantage of data from a secondary monocular sensor, assuming that this second camera is worn by a human. The human explores an unknown environment with the robot, and when their fields of view coincide, the cameras are considered a pseudo-calibrated stereo rig to produce estimations for depth through parallax. These depth estimations are used to solve a related problem with DI-D monocular SLAM, namely, the requirement of a metric scale initialization through known artificial landmarks. The same process is used to improve the performance of the technique when introducing new landmarks into the map. The convenience of the approach taken to the stereo estimation, based on SURF features matching, is discussed. Experimental validation is provided through results from real data with results showing the improvements in terms of more features correctly initialized, with reduced uncertainty, thus reducing scale and orientation drift. Additional discussion in terms of how a real-time implementation could take advantage of this approach is provided.

Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes.

Science.gov (United States)

Astuti, Galuh D N; van den Born, L Ingeborgh; Khan, M Imran; Hamel, Christian P; Bocquet, Béatrice; Manes, Gaël; Quinodoz, Mathieu; Ali, Manir; Toomes, Carmel; McKibbin, Martin; El-Asrag, Mohammed E; Haer-Wigman, Lonneke; Inglehearn, Chris F; Black, Graeme C M; Hoyng, Carel B; Cremers, Frans P M; Roosing, Susanne

2018-01-10

Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( SNRNP200 ) and Zinc Finger Protein 513 ( ZNF513 ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( DHX32 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

Improved prediction of genetic predisposition to psychiatric disorders using genomic feature best linear unbiased prediction models

DEFF Research Database (Denmark)

Rohde, Palle Duun; Demontis, Ditte; Børglum, Anders

is enriched for causal variants. Here we apply the GFBLUP model to a small schizophrenia case-control study to test the promise of this model on psychiatric disorders, and hypothesize that the performance will be increased when applying the model to a larger ADHD case-control study if the genomic feature...... contains the causal variants. Materials and Methods: The schizophrenia study consisted of 882 controls and 888 schizophrenia cases genotyped for 520,000 SNPs. The ADHD study contained 25,954 controls and 16,663 ADHD cases with 8,4 million imputed genotypes. Results: The predictive ability for schizophrenia.......6% for the null model). Conclusion: The improvement in predictive ability for schizophrenia was marginal, however, greater improvement is expected for the larger ADHD data....

HABP2 G534E Variant in Papillary Thyroid Carcinoma.

Directory of Open Access Journals (Sweden)

Jerneja Tomsic

Full Text Available The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536 was genotyped in blood DNA from 179 PTC families (one affected individual per family, 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

Directory of Open Access Journals (Sweden)

Filipović-Tričković Jelena

2017-01-01

Full Text Available Fanconi anemia is rare inherited disease characterized by wide spectrum of congenital anomalies, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. Molecular genetic analysis of mutations in FANC genes is of a great importance for diagnosis confirmation, prenatal and carrier testing, as well as for prediction of chemotherapy outcome and disease complications. In this study we performed screening of frequently affected regions of FANCD2 gene for sequence variants in six unrelated FA-D2 patients in Serbia. This is the first molecular analysis of FANCD2 gene in Serbian FA-D2 patients. A total of 10 sequence variants were detected, one in homozygous, and nine in heterozygous state. Two variants were found within exons, and eight within introns, in deep intronic regions. In-silico analysis showed that among all detected variants one exon variant and three intron variants might have impact on splicing mechanism. Heterozygous variants found in intron 3, c.206-246delG; exon 26, c.2396 C>A and intron 28, c.2715+573 C>T were not previously reported. In-silico analysis revealed that among them, two (intron 3, c.206-246 delG and exon 26, c.2396 C>A could be novel disease-causing mutations. Many variants were found in more than one patient, including those unreported, indicating their possible ethnic association. Great number of variants in some patients suggests their non-random emergence in Fanconi anemia pathway. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173046

Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

Science.gov (United States)

2017-10-01

resistant prostate cancer ; docetaxel; cabazitaxel; chemotherapy; androgen receptor splice variants; microtubule; ligand-binding domain; microtubule... receptor splice variants (AR-Vs) are associated with resistance to taxane chemotherapy in castration- resistant prostate cancer (CRPC). However, this...androgen receptor inhibitors in prostate cancer . Nat Rev Cancer . 2015;15:701–11.

PET/TAC: Basic principles, physiological variants and artifacts; PET/TAC: Generalidades, variantes fisiologicas y artefactos

Energy Technology Data Exchange (ETDEWEB)

Jimenez V, A.M. [Especialista en Medicina Nuclear, Profa. Depto. Radiologia de la Facultad de Medicina, Universidad Complutense de Madrid, Madrid (Spain)

2007-07-01

This presentation is about the basic principles, physiologic variants and devices that work in the PET/TAC technique. Next the conclusions obtained in the same one are presented: For a correct evaluation of the PET/TAC images with FDG is necessary the knowledge of the image acquisition technique, as well as of the physiologic distribution of the FDG, variants of the normality, benign causes of captation and more frequent devices. The introduction of this hybrid procedure allows the correct anatomical localization and identification of the deposits of FDG largely avoiding false or doubtful interpretations, but it can also originate not specific devices existent in the conventional PET. The previous knowledge of the possible devices will make possible in certain cases its elimination and in other its identification avoiding incorrect interpretations. (Author)

Structure of chymotrypsin variant B from Atlantic cod, Gadus morhua

DEFF Research Database (Denmark)

Leth-Larsen, Rikke; Asgeirsson, B; Thórólfsson, M

1996-01-01

The amino-acid sequence of chymotrypsin variant B isolated from the pyloric caeca of Atlantic cod has been elucidated. The characterization of the primary structure is based on N-terminal Edman degradation and mass spectrometry of the native protein and enzymatically derived peptides. Chymotrypsi...... autolysis sites, cod variant B only contains a single autolysis site. The three-dimensional structures of the A- and B-variants of cod has been modelled on the known crystal structure of bovine alpha-chymotrypsin showing almost superimposable structures....

Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

DEFF Research Database (Denmark)

Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo

2016-01-01

male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression...

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.

Science.gov (United States)

Klaassens, Merel; Morrogh, Deborah; Rosser, Elisabeth M; Jaffer, Fatima; Vreeburg, Maaike; Bok, Levinus A; Segboer, Tim; van Belzen, Martine; Quinlivan, Ros M; Kumar, Ajith; Hurst, Jane A; Scott, Richard H

2015-05-01

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.

Rare human papillomavirus 16 E6 variants reveal significant oncogenic potential

Directory of Open Access Journals (Sweden)

Tommasino Massimo

2011-06-01

Full Text Available Abstract The aim of this study was to determine whether low prevalence human papillomavirus (HPV 16 E6 variants differ from high prevalence types in their functional abilities. We evaluated functions relevant to carcinogenesis for the rarely-detected European variants R8Q, R10G and R48W as compared to the commonly detected L83V. Human immortalized keratinocytes (NIKS stably transduced with the E6 variants were used in most functional assays. Low and high prevalence E6 variants displayed similar abilities in abrogation of growth arrest and inhibition of p53 elevation induced by actinomycin D. Differences were detected in the abilities to dysregulate stratification and differentiation of NIKS in organotypic raft cultures, modulate detachment induced apoptosis (anoikis and hyperactivate Wnt signaling. No distinctive phenotype could be assigned to include all rare variants. Like L83V, raft cultures derived from variants R10G and R48W similarly induced hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment with significantly lower expression of keratin 10. Unlike L83V, both variants, and particularly R48W, induced increased levels of anoikis upon suspension in semisolid medium. R8Q induced a unique phenotype characterized by thin organotypic raft cultures, low expression of keratin 10, and high expression of keratins 5 and 14 throughout all raft layers. Interestingly, in a reporter based assay R8Q exhibited a higher ability to augment TCF/β-catenin transcription. The data suggests that differences in E6 variant prevalence in cervical carcinoma may not be related to the carcinogenic potential of the E6 protein.

Differences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease.

Science.gov (United States)

Huh, Young Eun; Park, Jongkyu; Suh, Mee Kyung; Lee, Sang Eun; Kim, Jumin; Jeong, Yuri; Kim, Hee-Tae; Cho, Jin Whan

2015-08-01

In Parkinson variant of multiple system atrophy (MSA-P), patterns of early speech impairment and their distinguishing features from Parkinson's disease (PD) require further exploration. Here, we compared speech data among patients with early-stage MSA-P, PD, and healthy subjects using quantitative acoustic and perceptual analyses. Variables were analyzed for men and women in view of gender-specific features of speech. Acoustic analysis revealed that male patients with MSA-P exhibited more profound speech abnormalities than those with PD, regarding increased voice pitch, prolonged pause time, and reduced speech rate. This might be due to widespread pathology of MSA-P in nigrostriatal or extra-striatal structures related to speech production. Although several perceptual measures were mildly impaired in MSA-P and PD patients, none of these parameters showed a significant difference between patient groups. Detailed speech analysis using acoustic measures may help distinguish between MSA-P and PD early in the disease process. Copyright © 2015 Elsevier Inc. All rights reserved.

Genomewide association study identifies no major founder variant in ...

Indian Academy of Sciences (India)

2013-12-10

Dec 10, 2013 ... variant in Caucasian moyamoya disease ... 1Department of Health and Environmental Sciences, Kyoto University Graduate ... a low prevalence in European countries (Goto and Yonekawa. 1992; Kuroda and Houkin 2008). We have found that the p.R4810K variant in the ring finger protein 213 (RNF213).

Denaturing gradient gel electrophoresis (DGGE as a powerful novel alternative for differentiation of epizootic ISA virus variants.

Directory of Open Access Journals (Sweden)

Marisela Carmona

Full Text Available Infectious Salmon Anemia is a devastating disease critically affecting world-wide salmon production. Chile has been particularly stricken by this disease which in all cases has been directly related with its causative agent, a novel orthomyxovirus which presents specific and distinctive infective features. Among these, two molecular markers have been directly associated with pathogenicity in two of the eight RNA sub genomic coding units of the virus: an insertion hot spot region present in viral segment 5 and a Highly Polymorphic Region (HPR located in viral segment 6. Here we report the successful adaptation of a PCR-dependent denaturing gel electrophoresis technique (DGGE, which enables differentiation of selected reported HPR epizootic variants detected in Chile. At the same time, the technique allows us to distinguish one nucleotide differences in sequences associated with the intriguing, and still not well-understood, insertion events which tend to occur on RNA Segment 5. Thus, the versatility of the technique opens new opportunities for improved understanding of the complex biology of all ISA variants as well as possible applications to other highly variable pathogens.

Variants in TNFAIP3, STAT4 and c12orf30 loci associated with multiple auto-immune diseases are also associated with Juvenile Idiopathic Arthritis

Science.gov (United States)

Prahalad, Sampath; Hansen, Sterling; Whiting, April; Guthery, Stephen L.; Clifford, Bronte; McNally, Bernadette; Zeft, Andrew S.; Bohnsack, John F.; Jorde, Lynn B.

2010-01-01

Objectives Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA, to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. Methods Cases were 445 children with JIA, and controls were 643 healthy adults. Eight single nucleotide polymorphisms (SNPs) in 7 loci [TNFAIP3 (rs10499194 and rs6920220), RSBN1 (rs6679677), C12ORF30 (rs17696736), TRAF1 (rs3761847), IL2RA (rs2104286), PTPN2 (rs2542151), and STAT4 (rs7574865)] were genotyped by the TaqMan assay. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. Results The strongest associations were observed for TNFAIP3 variants rs10499194 (OR: 0.74 (0.61-0.91); p <0.004), and TNFAIP3 rs6920220 (OR: 1.3 (1.05-1.61); p <0.02). We also observed associations between JIA and STAT4 (OR: 1.24 (1.02-1.51); p <0.03) and C12ORF30 (OR: 1.2 (1.01-1.43); p <0.04) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1, and RSBN1 were not associated with JIA. After stratification by JIA subtype, TNFAIP3 and C12ORF30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. Conclusions We have demonstrated associations between JIA and variants in TNFAIP3, STAT4 and C12ORF30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors. PMID:19565500

Screening for common copy-number variants in cancer genes.

Science.gov (United States)

Tyson, Jess; Majerus, Tamsin M O; Walker, Susan; Armour, John A L

2010-12-01

For most cases of colorectal cancer that arise without a family history of the disease, it is proposed that an appreciable heritable component of predisposition is the result of contributions from many loci. Although progress has been made in identifying single nucleotide variants associated with colorectal cancer risk, the involvement of low-penetrance copy number variants is relatively unexplored. We have used multiplex amplifiable probe hybridization (MAPH) in a fourfold multiplex (QuadMAPH), positioned at an average resolution of one probe per 2 kb, to screen a total of 1.56 Mb of genomic DNA for copy number variants around the genes APC, AXIN1, BRCA1, BRCA2, CTNNB1, HRAS, MLH1, MSH2, and TP53. Two deletion events were detected, one upstream of MLH1 in a control individual and the other in APC in a colorectal cancer patient, but these do not seem to correspond to copy number polymorphisms with measurably high population frequencies. In summary, by means of our QuadMAPH assay, copy number measurement data were of sufficient resolution and accuracy to detect any copy number variants with high probability. However, this study has demonstrated a very low incidence of deletion and duplication variants within intronic and flanking regions of these nine genes, in both control individuals and colorectal cancer patients. Copyright © 2010 Elsevier Inc. All rights reserved.

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

KAUST Repository

Blackburn, Patrick R.; Xu, Zhi; Tumelty, Kathleen E.; Zhao, Rose W.; Monis, William J.; Harris, Kimberly G.; Gass, Jennifer M.; Cousin, Margot A.; Boczek, Nicole J.; Mitkov, Mario V.; Cappel, Mark A.; Francomano, Clair A.; Parisi, Joseph E.; Klee, Eric W.; Faqeih, Eissa; Alkuraya, Fowzan S.; Layne, Matthew D.; McDonnell, Nazli B.; Atwal, Paldeep S.

2018-01-01

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome

KAUST Repository

Blackburn, Patrick R.

2018-03-29

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Coronary artery anatomy and variants

Energy Technology Data Exchange (ETDEWEB)

Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)

2011-12-15

Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

NARCIS (Netherlands)

Schonewolf-Greulich, B.; Tejada, M.I.; Stephens, K.; Hadzsiev, K.; Gauthier, J.; Brondum-Nielsen, K.; Pfundt, R.P.; Ravn, K.; Maortua, H.; Gener, B.; Martinez-Bouzas, C.; Piton, A.; Rouleau, G.; Clayton-Smith, J.; Kleefstra, T.; Bisgaard, A.M.; Tumer, Z.

2016-01-01

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair

Analysis of mtDNA sequence variants in colorectal adenomatous polyps

Directory of Open Access Journals (Sweden)

Grizzle William

2010-10-01

Full Text Available Abstract Colorectal tumors mostly arise from sporadic adenomatous polyps. Polyps are defined as a mass of cells that protrudes into the lumen of the colon. Adenomatous polyps are benign neoplasms that, by definition display some characteristics of dysplasia. It has been shown that polyps were benign tumors which may undergo malignant transformation. Adenomatous polyps have been classified into three histologic types; tubular, tubulovillous, and villous with increasing malignant potential. The ability to differentially diagnose these colorectal adenomatous polyps is important for therapeutic intervention. To date, little efforts have been directed to identifying genetic changes involved in adenomatous polyps. This study was designed to examine the relevance of mitochondrial genome alterations in the three adenomatous polyps. Using high resolution restriction endonucleases and PCR-based sequencing, fifty-seven primary fresh frozen tissues of adenomatous polyps (37 tumors and 20 matched surrounding normal tissues obtained from the southern regional Cooperative Human Tissue Network (CHTN and Grady Memorial Hospital at Atlanta were screened with three mtDNA regional primer pairs that spanned 5.9 kbp. Results from our data analyses revealed the presence of forty-four variants in some of these mitochondrial genes that the primers spanned; COX I, II, III, ATP 6, 8, CYT b, ND 5, 6 and tRNAs. Based on the MITODAT database as a sequence reference, 25 of the 44 (57% variants observed were unreported. Notably, a heteroplasmic variant C8515G/T in the MT-ATP 8 gene and a germline variant 8327delA in the tRNAlys was observed in all the tissue samples of the three adenomatous polyps in comparison to the referenced database sequence. A germline variant G9055A in the MT-ATP 6 gene had a frequency of 100% (17/17 in tubular and 57% (13/23 in villous adenomas; no corresponding variant was in tubulovillous adenomas. Furthermore, A9006G variant at MT-ATP 6 gene was

The characteristics of transferrin variants by carbohydrate-deficient transferrin tests using capillary zone electrophoresis.

Science.gov (United States)

Yoo, Gilsung; Kim, Juwon; Yoon, Kap Joon; Lee, Jong-Han

2018-04-17

Transferrin is the major plasma transport protein for iron. We aimed to investigate the characteristics of transferrin variant by carbohydrate-deficient transferrin (CDT) test using capillary zone electrophoresis. We retrospectively analyzed the CDT tests of 2449 patients from March 2009 to May 2017 at a tertiary hospital in Korea. CDT was quantified using a Capillarys 2 system (Sebia, Lisses, France) by capillary zone electrophoresis. The characteristics of variant transferrin patterns using electropherogram of CDT tests were analyzed. Seventy-seven (3.1%) patients were classified as variant transferrin. Mean age of these patients was 51.8 years, and the male-to-female ratio was 3.5:1. The most common variants were the BC variants (n = 37), followed by the CD variants (n = 27), unclear patterns (n = 7), BD variants (n = 3), CC variants (n = 2), misclassification (n = 1). In the variant Tf group, the most common disease was alcoholic liver cirrhosis (n = 22, 28.6%), followed by the toxic effects of substances (n = 17, 22.1%), and mental and behavioral disorders attributable to alcohol (n = 11, 14.3%). Nonvariant group showed a predominance of the toxic substance effects (n = 880, 37.1%), a personal history of suicide attempts (n = 634, 26.7%), and mental and behavioral disorders due to alcohol (n = 336, 14.2%). We analyzed the basic characteristics of variant transferrin by CDT tests using capillary zone electrophoresis. The prevalence of variant transferrin was 3.1% of the study subjects. Male patients, alcohol abusers, and liver cirrhosis patients predominated in the variant transferrin population. Further prospective studies are warranted to elucidate variant transferrin in clinical practice. © 2018 Wiley Periodicals, Inc.

Human papillomavirus type 16 molecular variants in Guarani Indian women from Misiones, Argentina.

Science.gov (United States)

Tonon, Sergio Andrés; Basiletti, Jorge; Badano, Ines; Alonio, Lidia Virginia; Villa, Luisa Lina; Teyssie, Angélica Rita; Picconi, María Alejandra

2007-01-01

To identify human papillomavirus type 16 (HPV16) E6 and L1 molecular variants infecting Guarani Indian women settled in Misiones, Argentina, a region with a high prevalence of cervical cancer. Some intratypic molecular variants of HPV16 have been associated with greater oncogenic risk, but their implication in the etiology of cervical cancer is still uncertain. Seventy HPV16 positive cervical samples from Guarani Indian women settled in two different areas of Misiones, Argentina, (34 from the northern area and 36 from the central area), were analyzed. Thirty-seven had normal cytology, 18 had a low-grade squamous intraepithelial lesion (LGSIL), and 15 a high-grade squamous intraepithelial lesion (HGSIL). HPV16 E6 and L1 molecular variants were identified by PCR, followed by dot blot hybridization with 23 and 12 biotinylated oligonucleotide probes, respectively. The frequency of HPV16 variants over the Guarani population was 51% EP (European prototype), 32% E-350G, 9% Af1-a (African 1), 4% E-6862C, 3% Af2-a, and 1% AA-a (Asian-American). The distribution of variants was not homogeneous in the two areas under analysis, with the northern area being more diverse showing 74% of European variants, while the central area presented exclusively E variants. No statistically significant association was found between any particular variant and grade of cervical lesion. This study reports for the first time HPV16 E6 and L1 molecular variants infecting women from an aboriginal community inhabiting a rainforest region of South America. The presence of E class variants could be attributed primarily to contacts with the Spanish conquerors, and Af variants from African slaves introduced later in the South American continent.

Functionally significant, rare transcription factor variants in tetralogy of Fallot.

Directory of Open Access Journals (Sweden)

Ana Töpf

Full Text Available Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF.We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1 in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network.This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.

OVAS: an open-source variant analysis suite with inheritance modelling.

Science.gov (United States)

Mozere, Monika; Tekman, Mehmet; Kari, Jameela; Bockenhauer, Detlef; Kleta, Robert; Stanescu, Horia

2018-02-08

The advent of modern high-throughput genetics continually broadens the gap between the rising volume of sequencing data, and the tools required to process them. The need to pinpoint a small subset of functionally important variants has now shifted towards identifying the critical differences between normal variants and disease-causing ones. The ever-increasing reliance on cloud-based services for sequence analysis and the non-transparent methods they utilize has prompted the need for more in-situ services that can provide a safer and more accessible environment to process patient data, especially in circumstances where continuous internet usage is limited. To address these issues, we herein propose our standalone Open-source Variant Analysis Sequencing (OVAS) pipeline; consisting of three key stages of processing that pertain to the separate modes of annotation, filtering, and interpretation. Core annotation performs variant-mapping to gene-isoforms at the exon/intron level, append functional data pertaining the type of variant mutation, and determine hetero/homozygosity. An extensive inheritance-modelling module in conjunction with 11 other filtering components can be used in sequence ranging from single quality control to multi-file penetrance model specifics such as X-linked recessive or mosaicism. Depending on the type of interpretation required, additional annotation is performed to identify organ specificity through gene expression and protein domains. In the course of this paper we analysed an autosomal recessive case study. OVAS made effective use of the filtering modules to recapitulate the results of the study by identifying the prescribed compound-heterozygous disease pattern from exome-capture sequence input samples. OVAS is an offline open-source modular-driven analysis environment designed to annotate and extract useful variants from Variant Call Format (VCF) files, and process them under an inheritance context through a top-down filtering schema of

Biochemical characterization of the GM2 gangliosidosis B1 variant

Directory of Open Access Journals (Sweden)

Tutor J.C.

2004-01-01

Full Text Available The deficiency of the A isoenzyme of ß-hexosaminidase (Hex produced by different mutations of the gene that codes for the alpha subunit (Tay-Sachs disease has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic alpha subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-ß-D-glucosaminide, may offer a valid alternative. The presence of an alpha subunit in the alphaß heterodimer Hex A means that its activation energy (41.8 kJ/mol is significantly lower than that of the ßß homodimer Hex B (75.1 kJ/mol; however, as mutation inactivates the alpha subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme.

HGVS Recommendations for the Description of Sequence Variants: 2016 Update.

Science.gov (United States)

den Dunnen, Johan T; Dalgleish, Raymond; Maglott, Donna R; Hart, Reece K; Greenblatt, Marc S; McGowan-Jordan, Jean; Roux, Anne-Francoise; Smith, Timothy; Antonarakis, Stylianos E; Taschner, Peter E M

2016-06-01

The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at http://www.HGVS.org/varnomen. © 2016 WILEY PERIODICALS, INC.

Identifying pathogenicity of human variants via paralog-based yeast complementation.

Directory of Open Access Journals (Sweden)

Fan Yang

2017-05-01

Full Text Available To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97% were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

DSA analysis of the normal and variant hepatic arterial anatomy

International Nuclear Information System (INIS)

Lv Penghua; Wang Jie; Shi Haibing; Feng Yaoliang; Chen Huizhu; Chen Yuqin

2005-01-01

Objective: To observe and analyze the normal and variant hepatic arterial anatomy by DSA. Methods: One thousand and two hundreds patients with routine celiac and/or selective hepatic arteriography from November 1994 to March 2003 were retrospectively analyzed, some of them were further simultaneously undergone superior mesenteric arteriography, left gastric arteriography or inferior phrenic arteriography etc. Results: 873 (72.8%) patients had the standard hepatic arterial anatomy. 156(13.0%) patients had variant left hepatic arteries (LHAs), 120(10.0%) with variant right hepatic arteries (RHAs) and 21 (1.8%) of a variant anatomy involving both LHA and RHA. The common hepatic artery (CHA) of 1170 (97.5%) patients originated from the celiac artery. 92.0% proper hepatic artery (PHA) was the direct extension of CHA. The RHA was mainly (89.8%) derived from the PHA. There was some variation of the middle hepatic artery (MHA) with more than 62.2% arising from the LHA. The LHA was derived from the PHA (44.6%) or the RHA(30.2%) or other arteries (25.2%). Conclusions: The knowledge of normal and variant anatomy of hepatic vasculature by DSA may be very helpful for intervention therapy and hepatosurgery. (authors)

RareVar: A Framework for Detecting Low-Frequency Single-Nucleotide Variants.

Science.gov (United States)

Hao, Yangyang; Xuei, Xiaoling; Li, Lang; Nakshatri, Harikrishna; Edenberg, Howard J; Liu, Yunlong

2017-07-01

Accurate identification of low-frequency somatic point mutations in tumor samples has important clinical utilities. Although high-throughput sequencing technology enables capturing such variants while sequencing primary tumor samples, our ability for accurate detection is compromised when the variant frequency is close to the sequencer error rate. Most current experimental and bioinformatic strategies target mutations with ≥5% allele frequency, which limits our ability to understand the cancer etiology and tumor evolution. We present an experimental and computational modeling framework, RareVar, to reliably identify low-frequency single-nucleotide variants from high-throughput sequencing data under standard experimental protocols. RareVar protocol includes a benchmark design by pooling DNAs from already sequenced individuals at various concentrations to target variants at desired frequencies, 0.5%-3% in our case. By applying a generalized, linear model-based, position-specific error model, followed by machine-learning-based variant calibration, our approach outperforms existing methods. Our method can be applied on most capture and sequencing platforms without modifying the experimental protocol.

Antigen Loss Variants: Catching Hold of Escaping Foes.

Science.gov (United States)

Vyas, Maulik; Müller, Rolf; Pogge von Strandmann, Elke

2017-01-01

Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

Multiple Functional Variants in cis Modulate PDYN Expression.

Science.gov (United States)

Babbitt, Courtney C; Silverman, Jesse S; Haygood, Ralph; Reininga, Jennifer M; Rockman, Matthew V; Wray, Gregory A

2010-02-01

Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro. We identified five polymorphisms within the 5' flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.

Human GRIN2B variants in neurodevelopmental disorders

Directory of Open Access Journals (Sweden)

Chun Hu

2016-10-01

Full Text Available The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-d-aspartate receptor (NMDAR gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD, attention deficit hyperactivity disorder (ADHD, developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies.

Radioimmunological activity of 22K variant of human growth hormone

International Nuclear Information System (INIS)

Camillo, M.A.P.; Ribela, M.T.C.P.; Rogero, J.R.

1986-01-01

From a preparation of human growth hormone its integral variant (hGH-22K) was isolated by isoelectric focusing, having a pI of 5,20 and relative mobility (Rm) of 0,621 in the polyacrylamide gel electrophoresis. Several experiments for the characterization of the isolated variant were carried out. The immunological properties was tested by radioimmunoassay (RIE), in which the activity of the isolated variant and the activity of the total preparation were compared. The dose response-curves obtained by RIE were found to be considered parallels (p [pt

Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Science.gov (United States)

Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles

2016-01-01

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806