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  1. Genetics Home Reference: Wolfram syndrome

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Wolfram syndrome Wolfram syndrome Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Wolfram syndrome is a condition that affects many of the ...

  2. DIDMOAD (Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Masoud Nashibi

    2016-07-01

    Full Text Available Wolfram syndrome was first described by physician D J Wolfram and Wagener in 1938. This autosomal recessive syndrome is also referred to as DIDMOAD syndrome which stands for Diabetes Insipidus, Insulin Dependent Diabetes Mellitus, Optic Atrophy and Deafness

  3. Wolfram syndrome 1 and Wolfram syndrome 2.

    Science.gov (United States)

    Rigoli, Luciana; Di Bella, Chiara

    2012-08-01

    Wolfram syndrome 1 (WS1) is an autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DI DM OA D syndrome) associated with other variable clinical manifestations. The causative gene for WS1 (WFS1) encoding wolframin maps to chromosome 4p16.1. Wolframin has an important function in maintaining the homeostasis of the endoplasmic reticulum (ER) in pancreatic β cells. Recently, another causative gene, CISD2, has been identified in patients with a type of Wolfram syndrome (WS2) resulting in early optic atrophy, diabetes mellitus, deafness, decreased lifespan, but not diabetes insipidus. The CISD2-encoded protein ERIS (endoplasmic reticulum intermembrane small protein) also localizes to ER, but does not interact directly with wolframin. ERIS maps to chromosome 4q22. Numerous studies have shown an interesting similarity between WFS1 and CISD2 genes. Experimental studies demonstrated that the Cisd2 knockout (Cisd2) mouse shows premature aging and typical symptoms of Wolfram syndrome. These researches provide interesting insight into the relation of neurodegenerative diseases, mitochondrial disorders, and autophagy and are useful for the pathophysiological understanding of both Wolfram syndrome and mitochondrial-mediated premature aging. The knowledge of WS1 and WS2 pathogenesis, and of the interactions between WFS1 and CISD2 genes, is useful for accurate diagnostic classification and for diagnosis of presymptomatic individuals.

  4. Wolfram Syndrome. Case report.

    Science.gov (United States)

    Tarała, Wojciech; Drachal, Elzbieta; Mazur, Artur; Korczowski, Bartosz; Szadkowska, Agnieszka; Zmysłowska, Agnieszka; Młynarski, Wojciech

    2016-01-01

    Wolfram syndrome is a rare neurodegenerative and genetic disorder, characterized by insulin-dependent diabetes mellitus, caused by non-autoimmune loss of β cells, as well as optic atrophy; the disease is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Patients that demonstrate diabetes mellitus are also affected by: optic atrophy in the first decade of their life, diabetes insipidus and sensorineural deafness in the second decade, and urinary tract and neurological abnormalities in the third decade of their life. Patients with Wolfram syndrome usually die due to central respiratory failures caused by brain stem atrophy in their third or at the beginning of their fourth decade of life. The authors present a case of two female siblings with diagnosed Wolfram syndrome that have been diagnosed with diabetes mellitus, optic atrophy, and urological abnormalities. Early diagnosis and adequate hormonal supplementation can improve their quality of life. © Polish Society for Pediatric Endocrinology and Diabetology.

  5. [Familial Wolfram syndrome].

    Science.gov (United States)

    Bessahraoui, M; Paquis, V; Rouzier, C; Bouziane-Nedjadi, K; Naceur, M; Niar, S; Zennaki, A; Boudraa, G; Touhami, M

    2014-11-01

    Wolfram syndrome (WS) is a rare autosomal recessive progressive neurodegenerative disorder, and it is mainly characterized by the presence of diabetes mellitus and optic atrophy. Other symptoms such as diabetes insipidus, deafness, and psychiatric disorders are less frequent. The WFS1 gene, responsible for the disease and encoding for a transmembrane protein called wolframin, was localized in 1998 on chromosome 4p16. In this report, we present a familial observation of Wolfram syndrome (parents and three children). The propositus was a 6-year-old girl with diabetes mellitus and progressive visual loss. Her family history showed a brother with diabetes mellitus, optic atrophy, and deafness since childhood and a sister with diabetes mellitus, optic atrophy, and bilateral hydronephrosis. Thus, association of these familial and personal symptoms is highly suggestive of Wolfram syndrome. The diagnosis was confirmed by molecular analysis (biology), which showed the presence of WFS1 homozygous mutations c.1113G>A (p.Trp371*) in the three siblings and a heterozygote mutation in the parents. Our observation has demonstrated that pediatricians should be aware of the possibility of Wolfram syndrome when diagnosing optic atrophy in diabetic children. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. Atypical presentations of Wolframs syndrome

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    S Saran

    2012-01-01

    Full Text Available Background: Wolfram syndrome is a rare hereditary or sporadic neurodegenerative disorder also known as DIDMOAD. The classically described presentation is of insulin-dependent diabetes, followed by optic atrophy, central diabetes insipidus, and sensory neural deafness. Also included are less well-described presentations of Wolframs syndrome. We here present three cases of atypical presentation of this syndrome. Case 1: A 15-year-old boy with insulin-dependent diabetes was presented for evaluation of depressive symptoms associated with suicidal tendency. Neuropsychiatric manifestations are described with Wolframs syndrome, and wolframin gene, in recessive inheritance, is associated with psychiatric illnesses without other manifestations of Wolframs syndrome. Case 2: A 17-year-old diabetic boy on insulin with good control of blood sugar presented for evaluation of delayed puberty. Central hypogonadism and other anterior pituitary hormone dysfunctions are the less publicized hormone dysfunctions in Wolframs syndrome. Case 3: A 23-year-old female who was on insulin for diabetes for the past 14 years, got admitted for evaluation of sudden loss of vision. This patient had developed a vitreous hemorrhage and, on evaluation, was found to have optic atrophy, sensory neural hearing loss, and diabetes insipidus, and presented differently from the gradual loss of vision described in Wolframs syndrome. Conclusion: Wolframs syndrome being a multisystem degenerative disorder can have myriad other manifestations than the classically described features. Neuropsychiatric manifestations, depression with suicidal risk, central hypogonadism, and secondary adrenal insufficiency are among the less well-described manifestations of this syndrome.

  7. Wolfram syndrome: MAMs' connection?

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    Delprat, Benjamin; Maurice, Tangui; Delettre, Cécile

    2018-03-06

    Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca 2+ transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed "mitochondria-associated ER membranes" (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.

  8. Hearing impairment in genotyped Wolfram syndrome patients.

    NARCIS (Netherlands)

    Plantinga, R.F.; Pennings, R.J.E.; Huygen, P.L.M.; Bruno, R.; Eller, P.; Barrett, T.G.; Vialettes, B.; Paquis-Fluklinger, V.; Lombardo, F.; Cremers, C.W.R.J.

    2008-01-01

    OBJECTIVES: Wolfram syndrome is a progressive neurodegenerative syndrome characterized by the features "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We sought to study the audiometric data of genotyped Wolfram syndrome patients with sensorineural hearing impairment.

  9. Wolfram syndrome: a clinicopathologic correlation.

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    Hilson, Justin B; Merchant, Saumil N; Adams, Joe C; Joseph, Jeffrey T

    2009-09-01

    Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a neurodegenerative disorder characterized by diabetes mellitus and optic atrophy as well as diabetes insipidus and deafness in many cases. We report the post-mortem neuropathologic findings of a patient with Wolfram syndrome and correlate them with his clinical presentation. In the hypothalamus, neurons in the paraventricular and supraoptic nuclei were markedly decreased and minimal neurohypophyseal tissue remained in the pituitary. The pontine base and inferior olivary nucleus showed gross shrinkage and neuron loss, while the cerebellum was relatively unaffected. The visual system had moderate to marked loss of retinal ganglion neurons, commensurate loss of myelinated axons in the optic nerve, chiasm and tract, and neuron loss in the lateral geniculate nucleus but preservation of the primary visual cortex. The patient's inner ear showed loss of the organ of Corti in the basal turn of the cochleae and mild focal atrophy of the stria vascularis. These findings correlated well with the patient's high-frequency hearing loss. The pathologic findings correlated closely with the patient's clinical symptoms and further support the concept of Wolfram syndrome as a neurodegenerative disorder. Our findings extend prior neuropathologic reports of Wolfram syndrome by providing contributions to our understanding of eye, inner ear and olivopontine pathology in this disease.

  10. Wolfram Syndrome: Diagnosis, Management, and Treatment.

    Science.gov (United States)

    Urano, Fumihiko

    2016-01-01

    Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.

  11. A Case of Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Gholamali Naderian

    2010-01-01

    Full Text Available Purpose: To report a case of Wolfram syndrome characterized by early onset diabetes mellitus and progressive optic atrophy. Case Report: A 20-year-old male patient with diabetes mellitus type I presented with best corrected visual acuity of 1/10 in both eyes with correction of -0.25+1.50@55 and -0.25+1.50@131 in his right and left eyes, respectively. Bilateral optic atrophy was evident on fundus examination. The patient also had diabetes insipidus, neurosensory deafness, neurogenic bladder, polyuria and extra-residual voiding indicating atony of the urinary tract, combined with delayed sexual maturity. Conclusion: One should consider Wolfram syndrome in patients with juvenile onset diabetes mellitus and hearing loss. Ophthalmological examination may disclose optic atrophy; urologic examinations are vital in such patients.

  12. Element 74, the Wolfram Versus Tungsten Controversy

    Energy Technology Data Exchange (ETDEWEB)

    Holden,N.E.

    2008-08-11

    Two and a quarter centuries ago, a heavy mineral ore was found which was thought to contain a new chemical element called heavy stone (or tungsten in Swedish). A few years later, the metal was separated from its oxide and the new element (Z=74) was called wolfram. Over the years since that time, both the names wolfram and tungsten were attached to this element in various countries. Sixty years ago, IUPAC chose wolfram as the official name for the element. A few years later, under pressure from the press in the USA, the alternative name tungsten was also allowed by IUPAC. Now the original, official name 'wolfram' has been deleted by IUPAC as one of the two alternate names for the element. The history of this controversy is described here.

  13. MRI of Wolfram syndrome (DIDMOAD)

    Energy Technology Data Exchange (ETDEWEB)

    Galluzzi, P.; Filosomi, G.; Vallone, I.M.; Venturi, C. [Dept. of Neuroradiology, Policlinico ' ' Le Scotte' ' , Siena (Italy); Bardelli, A.M. [Dept. of Ophthalmological Sciences, Unit of Paediatric Ophthalmology, University of Siena (Italy)

    1999-10-01

    Wolfram syndrome (DIDMOAD) is a rare diffuse neurodegenerative disorder characterised by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and a wide variety of abnormalities of the central nervous system, urinary tract and endocrine glands. It may be familial or sporadic. Reported features on MRI of the brain are absence of the physiological high signal of the posterior lobe of the pituitary, shrinkage of optic nerves, chiasm and tracts, atrophy of the hypothalamic region, brain stem, cerebellum, and cerebral cortex. We report a 12-year-old girl with a 5-year history without brain stem, cerebellar or cerebral atrophy. MRI showed an unusual feature: a focus of high signal on PD- and T2-weighted images in the right substantia nigra. This is consistent with previously reported neuropathological post-mortem studies, but has never been reported in vivo. (orig.)

  14. MRI of Wolfram syndrome (DIDMOAD)

    International Nuclear Information System (INIS)

    Galluzzi, P.; Filosomi, G.; Vallone, I.M.; Venturi, C.; Bardelli, A.M.

    1999-01-01

    Wolfram syndrome (DIDMOAD) is a rare diffuse neurodegenerative disorder characterised by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and a wide variety of abnormalities of the central nervous system, urinary tract and endocrine glands. It may be familial or sporadic. Reported features on MRI of the brain are absence of the physiological high signal of the posterior lobe of the pituitary, shrinkage of optic nerves, chiasm and tracts, atrophy of the hypothalamic region, brain stem, cerebellum, and cerebral cortex. We report a 12-year-old girl with a 5-year history without brain stem, cerebellar or cerebral atrophy. MRI showed an unusual feature: a focus of high signal on PD- and T2-weighted images in the right substantia nigra. This is consistent with previously reported neuropathological post-mortem studies, but has never been reported in vivo. (orig.)

  15. Association of Wolfram syndrome with Fallot tetralogy in a girl.

    Science.gov (United States)

    Korkmaz, Hüseyin A; Demir, Korcan; Hazan, Filiz; Yıldız, Melek; Elmas, Özlem N; Özkan, Behzat

    2016-06-01

    Wolfram syndrome (DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a rare neurodegenerative disorder. Mutations of the WFS1 (wolframin) on chromosome 4 are responsible for the clinical manifestations in majority of patients with Wolfram syndrome. Wolfram syndrome is also accompanied by neurologic and psychiatric disorders, urodynamic abnormalities, restricted joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotrophic hypogonadism in males and diabetic microvascular disorders. There are very limited data in the literature regarding cardiac malformations associated in children with Wolfram syndrome. A 5-year-old girl with Wolfram syndrome and tetralogy of Fallot is presented herein. Sociedad Argentina de Pediatría.

  16. A case Report of Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Zahra Razavi

    2007-01-01

    Full Text Available Wolfram syndrome is the association of diabetes mellitus, optic atrophy, diabetes insipidus and sensorineural deafness and is sometimes called DIDMOAD (Diabetes Insipidus, Diabets Mellitus, Optic Atrophy, and Deafness. It is a rare autosomal recessive disease with prevalence of one per 770,000. Natural history of Wolfram syndrome suggests that most patients will eventually develop most complications of this progressive neurodegenerative disorder. Juvenile–onset diabetes mellitus and optic atrophy are the best available diagnostic criteria for Wolfram syndrome. In this report clinical features of a patient with DIDMOAD syndrome is presented. A 12 year old male presented with short standing diabetes mellitus and diabetes insipidus. Further investigations showed bilateral optic atrophy, mild hearing loss and short stature. His parents were relative and he is first case in his family.

  17. Radiological findings in Wolfram syndrome

    International Nuclear Information System (INIS)

    Hadidy, Azmy M.; Jarrah, Nadim S.; Al-Till, Maha I.; Ajlouni, Kamal M.; El-Shanti, Haten E.

    2004-01-01

    To determine the precise radiologic findings in Wolfram syndrome (WFS) patients using objective techniques in order to better define the reference population for the clinicl evaluation. 16 patients (6 males, 10 female) with WFS found in 4 families were included in this study.14 patients with WFS-2 came from 3 families while 2 patients with EFS-1 came from one family. All patients were studied at Jordan University Hospital, Amman,Jordan from January 2001 to January 2003 by definite radiologic techniques as part of a thorough clinical comprehesive assesment. These incclude intravenous urography, abdominal and pelvic ultrasonography, barium meal, upper gastrointestinal endoscopy and magnetic resonance imaging with and without contrasts to the brain and the pituitary glands.5 of the female ptients had a small uterus. Spina bifida was found in 7, hydronephrosis in 9 and hydroureter in 5 patiets. Peptic ulcer was detected in 10 out of 14 available patients and helicobacter pylori in 7 out of 16 patients. Atrophy was detected was detected in all brains, 9 brain stems, 12 cerebellums and 14 optic tracts of all patients. The size of pituitary glands was variable. The particular radiological assesment of the patients with WFS proved that, urinary tract dialtation was detected in WFS-1and WFS-2 patients though all WFS-2 patients.No significant radiologic difference was between patients with WFS-1 and WFS-2. (author)

  18. Heinz-Wolfram Kasemir: His Collected Works

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    Schultz, Colin

    2014-04-01

    The story of Heinz-Wolfram Kasemir's scientific research is the not-uncommon tale of a researcher forced to the fringes for pushing hypotheses that ran against the grain. In the AGU monograph Heinz-Wolfram Kasemir: His Collected Works, Vladislav Mazur and Lothar Ruhnke pull together all of Kasemir's published works, some of them translated from German, in one place for the first time. In this interview, Vladislav Mazur shares with Eos a look into Kasemir's life and work, the science of atmospheric electricity and lightning, and an insider perspective on how science changes course.

  19. Hearing impairment in genotyped Wolfram syndrome patients.

    Science.gov (United States)

    Plantinga, Rutger F; Pennings, Ronald J E; Huygen, Patrick L M; Bruno, Rocco; Eller, Philipp; Barrett, Timothy G; Vialettes, Bernard; Paquis-Fluklinger, Veronique; Lombardo, Fortunato; Cremers, Cor W R J

    2008-07-01

    Wolfram syndrome is a progressive neurodegenerative syndrome characterized by the features "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We sought to study the audiometric data of genotyped Wolfram syndrome patients with sensorineural hearing impairment. Pure tone threshold data of 23 Wolfram syndrome patients were used for cross-sectional analysis in subgroups (age less than 16 years or between 19 and 25 years, gender, and origin). All subgroups, with 1 exception, showed a fairly similar type of hearing impairment with, on average, thresholds of about 25 dB (range, 0 to 65 dB) at 0.25 to 1 kHz, gently sloping downward to about 60 dB (range, 25 to 95 dB) at 8 kHz. The subgroup of Dutch women, which was excluded from the calculations of the average hearing thresholds, showed a higher degree of hearing impairment. Only the latter subgroup showed progression; however, contrary to the previous longitudinal analysis, progression was not significant in the present cross-sectional analysis, presumably because of the high degree of cross-subject variability. This unique collection of audiometric data from genotyped Wolfram syndrome patients shows no substantial progression in sensorineural hearing impairment with advancing age, no relation to the types of WFS1 mutations identified, and, with exclusion of the subgroup of Dutch female patients, no significant sex-related differences.

  20. Diabetes and Neurodegeneration in Wolfram Syndrome

    Science.gov (United States)

    Rohayem, Julia; Ehlers, Christian; Wiedemann, Bärbel; Holl, Reinhard; Oexle, Konrad; Kordonouri, Olga; Salzano, Giuseppina; Meissner, Thomas; Burger, Walter; Schober, Edith; Huebner, Angela; Lee-Kirsch, Min Ae

    2011-01-01

    OBJECTIVE To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. RESEARCH DESIGN AND METHODS The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS WSD was diagnosed earlier than type 1 diabetes (5.4 ± 3.8 vs. 7.9 ± 4.2 years; P diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P 7.5% (P = 0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P = 0.028). CONCLUSIONS Endoplasmic reticulum stress–mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease. PMID:21602428

  1. A Case with Wolfram (DIDMOAD Syndrome

    Directory of Open Access Journals (Sweden)

    Bulent Altunoluk

    2012-09-01

    Full Text Available Wolfram syndrome, seen in 1/770000 of the population is an autosomal recessive dysmorphogenetical disease with unknown pathogenesis. It is characterized with the association of diabetes insipidus, diabetes mellitus, optic atrophy and deafness, and also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness. Patients demonstrate diabetes mellitus followed by optic atrophy in the first decade,diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade.We present a boy 14 years old who had been followed-up with the diagnosis of Wolfram syndrome in this article. He had been followed-up with juvenile-onset diabetes mellitus for 9 years. Physical and laboratory exam revealed neurogenic bladder, deafness and optic defect. We emphasize the importance of family screening regarding the early diagnosis of Wolfram syndrome in the other individuals of the family since the disease shows an autosomal recessive inheritance.

  2. Wolfram syndrome: Case report | Atipo-Tsiba | East African Medical ...

    African Journals Online (AJOL)

    The third type or Wolfram-like syndrome is autosomal dominant, differs from the first two by the late onset of optic atrophy and diabetes mellitus type 1 (after adolescence) and hearing impairment is not always present. We report the first documented case of Wolfram syndrome at the University Hospital of Brazzaville in a nine ...

  3. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

    OpenAIRE

    Lu, Simin; Kanekura, Kohsuke; Hara, Takashi; Mahadevan, Jana; Spears, Larry D.; Oslowski, Christine M.; Martinez, Rita; Yamazaki-Inoue, Mayu; Toyoda, Masashi; Neilson, Amber; Blanner, Patrick; Brown, Cris M.; Semenkovich, Clay F.; Marshall, Bess A.; Hershey, Tamara

    2014-01-01

    Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes and neurodegeneration, and is considered a prototype of human endoplasmic reticulum (ER) disease. Wolfram syndrome is caused by loss of function mutations of Wolfram syndrome 1 or Wolfram syndrome 2 genes, which encode transmembrane proteins localized to the ER. Despite its rarity, Wolfram syndrome represents the best human disease model currently available to identify drugs and biomarkers associated with E...

  4. [Wolfram syndrome: clinical and genetic analysis in two sisters].

    Science.gov (United States)

    Conart, J-B; Maalouf, T; Jonveaux, P; Guerci, B; Angioi, K

    2011-10-01

    Wolfram syndrome is a severe genetic disorder defined by the association of diabetes mellitus, optic atrophy, deafness, and diabetes insipidus. Two sisters complained of progressive visual loss. Fundus examination evidenced optic atrophy. Their past medical history revealed diabetes mellitus and deafness since childhood. The association of these symptoms made the diagnosis of Wolfram syndrome possible. It was confirmed by molecular analysis, which evidenced composite WFS1 heterozygous mutations inherited from both their mother and father. Ophthalmologists should be aware of the possibility of Wolfram syndrome when diagnosing optic atrophy in diabetic children. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  5. Síndrome de Wolfram: relato de caso Wolfram syndrome: case report

    Directory of Open Access Journals (Sweden)

    Bruno Machado Fontes

    2004-12-01

    Full Text Available A síndrome de Wolfram consiste na associação de diabetes mellitus e atrofia óptica. Outros achados comuns são surdez neurossensorial, alterações do trato urinário e distúrbios neurológicos. Tem padrão de herança autossômico recessivo com penetrância incompleta e expressividade variável. O objetivo deste relato é apresentar paciente que apresenta todas as características da síndrome de Wolfram (ou síndrome DIDMOAD. JFP, negro, 23 anos, apresenta diabetes mellitus e insipidus, atrofia óptica, surdez neurossensorial, polineuropatia periférica, neuropatia autonômica, bexiga neurogênica, dilatação do trato urinário, infecções repetidas do trato urinário e azoospermia. Os exames clínico-oftalmológico, retinografia, angiografia fluoresceínica, eletrorretinografia (ERG e potencial visual evocado (PVE mostram padrão de normalidade retiniana e de atrofia de nervos ópticos. A síndrome de Wolfram deve ser lembrada em casos de atrofia óptica associados a diabetes, poliúria, polidipsia ou a qualquer uma das alterações apresentadas.Wolfram syndrome consists of the association of diabetes mellitus with optic atrophy. Other common findings are deafness, urinary tract and neurological disorders. It is an autossomic recessive disease, with incomplete penetrance and variable expressivity. The aim of this case report is to describe a patient who presents all the characteristics of Wolfram syndrome (DIDMOAD syndrome. JFP, African - American, 23 years old, presents with diabetes mellitus and insipidus, optic atrophy, deafness, peripheral polyneuropathy, autonomic neuropathy, neurogenic bladder, urinary tract dilation with recurrent infections, and azoospermia. Clinical examination, retinography, fluorescein angiogram, eletroretinography (ERG and visual evocated potencial (VEP revealed no retinal disorders and bilateral optic atrophy. Wolfram syndrome must be remembered in cases of optic atrophy in association with diabetes

  6. Wolfram (DIDMOAD syndrome: A Case report

    Directory of Open Access Journals (Sweden)

    Abdullah Kürsat Cingü

    2009-01-01

    Full Text Available A 10 years old boy admitted to Ophthalmology Clinic with the complaint of low vision. His ophthalmologic examination showed decreased visual acuity as counting fingers from 2 meters in both eyes. Biomicroscopic examination of his both eyes was normal. Optic atrophy was apparent in his both eyes on fundoscopic examination. He has been followed with the diagnosis of diabetes mellitus type 1 for the last two years and had nocturnal enuresis. He was diagnosed as Wolfram (DIDMOAD syndrome based on the results of clinical and laboratory examinations. His medical management has been carried out carefully however he was no longer able to attend his school. His IQ was within normal ranges and he was referred to a school which educates visually disabled children. Wolfram syndrome can easily be diagnosed in outpatient clinics since it does not require a genetic analysis. Physicians should keep in mind this diagnosis during their daily practice and provide the best management to the patient by achieving interdisciplinary co-operation.

  7. Molecular characterization of WFS1 in patients with Wolfram syndrome.

    NARCIS (Netherlands)

    Ouweland, J.M.W. van den; Cryns, K.; Pennings, R.J.E.; Walraven, I.; Janssen, G.M.; Maassen, J.A.; Veldhuijzen, B.F.; Arntzenius, A.B.; Lindhout, D.; Cremers, C.W.R.J.; Camp, G. van; Dikkeschei, L.D.

    2003-01-01

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  8. Three cases of Wolfram syndrome with different clinical aspects.

    Science.gov (United States)

    Çamtosun, Emine; Şıklar, Zeynep; Kocaay, Pınar; Ceylaner, Serdar; Flanagan, Sarah E; Ellard, Sian; Berberoğlu, Merih

    2015-03-01

    Wolfram syndrome is an autosomal recessive disorder caused by mutations in the WFS1 gene. Clinical heterogeneity has been reported both within and between families with WFS1 mutations. The first case was diagnosed with insulin-dependent diabetes mellitus with positive for pancreatic autoantibodies and had a ketoacidotic attack in the follow-up period. The second case presented initially with optic atrophy and was diagnosed with behavioral and psychiatric problems at an early age. The third case had early onset insulin-dependent diabetes with multiple anomalies and congenital hypothyroidism. Many of these features have not been reported previously in patients with Wolfram syndrome. In all three patients homozygous mutations in WFS1 were identified. Wolfram syndrome is a disease where the characteristic features may present at different times. A diagnosis of Wolfram syndrome should therefore be considered even in the absence of the full spectrum of clinical features.

  9. Optic nerve histopathology in a case of Wolfram Syndrome

    DEFF Research Database (Denmark)

    Ross-Cisneros, Fred N; Pan, Billy X; Silva, Ruwan A

    2013-01-01

    Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis...

  10. Molecular characterization of WFS1 in patients with Wolfram syndrome

    NARCIS (Netherlands)

    Van den Ouweland, JMW; Cryns, K; Pennings, RJE; Walraven, [No Value; Janssen, GMC; Maassen, JA; Veldhuijzen, BFE; Arntzenius, AB; Lindhout, D; Cremers, CWRJ; Van Camp, G; Dikkeschei, LD

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  11. Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.

    Science.gov (United States)

    Lugar, Heather M; Koller, Jonathan M; Rutlin, Jerrel; Marshall, Bess A; Kanekura, Kohsuke; Urano, Fumihiko; Bischoff, Allison N; Shimony, Joshua S; Hershey, Tamara

    2016-02-18

    Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.

  12. Phenotypic characteristics of early Wolfram syndrome.

    Science.gov (United States)

    Marshall, Bess A; Permutt, M Alan; Paciorkowski, Alexander R; Hoekel, James; Karzon, Roanne; Wasson, Jon; Viehover, Amy; White, Neil H; Shimony, Joshua S; Manwaring, Linda; Austin, Paul; Hullar, Timothy E; Hershey, Tamara

    2013-04-27

    Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Eighteen subjects (ages 5.9-25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.

  13. Balance impairment in individuals with Wolfram syndrome

    Science.gov (United States)

    Pickett, Kristen A.; Duncan, Ryan P.; Paciorkowski, Alex R.; Permutt, Alan; Marshall, Bess; Hershey, Tamara; Earhart, Gammon M.

    2012-01-01

    AIM Wolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test. METHOD Balance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals. RESULTS A significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age (p < 0.001, rs = 0.59) among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age. INTERPRETATION Impairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms. PMID:22771154

  14. Balance impairment in individuals with Wolfram syndrome.

    Science.gov (United States)

    Pickett, Kristen A; Duncan, Ryan P; Paciorkowski, Alex R; Permutt, M Alan; Marshall, Bess; Hershey, Tamara; Earhart, Gammon M

    2012-07-01

    Wolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test. Balance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals. A significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age. Impairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Wolfram Syndrome: New Mutations, Different Phenotype

    Science.gov (United States)

    Pasquali, Lorenzo; Lugani, Francesca; Perri, Katia; Russo, Chiara; Tallone, Ramona; Ghiggeri, Gian Marco; Lorini, Renata; d'Annunzio, Giuseppe

    2012-01-01

    Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID:22238590

  16. Early Brain Vulnerability in Wolfram Syndrome

    Science.gov (United States)

    Hershey, Tamara; Lugar, Heather M.; Shimony, Joshua S.; Rutlin, Jerrel; Koller, Jonathan M.; Perantie, Dana C.; Paciorkowski, Alex R.; Eisenstein, Sarah A.; Permutt, M. Alan

    2012-01-01

    Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development. PMID:22792385

  17. Wolfram syndrome: new mutations, different phenotype.

    Directory of Open Access Journals (Sweden)

    Concetta Aloi

    Full Text Available BACKGROUND: Wolfram Syndrome (WS is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym "DIDMOAD". The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. METHODOLOGY/PRINCIPAL FINDINGS: We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females. Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V was found. Two new variants c.2663 C>A and c.1381 A>C were detected. CONCLUSIONS/SIGNIFICANCE: Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10, deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA.

  18. Early brain vulnerability in Wolfram syndrome.

    Directory of Open Access Journals (Sweden)

    Tamara Hershey

    Full Text Available Wolfram Syndrome (WFS is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.

  19. Congenital cataracts in two siblings with Wolfram syndrome.

    Science.gov (United States)

    Mets, Rebecca B; Emery, Sarah B; Lesperance, Marci M; Mets, Marilyn B

    2010-12-01

    Wolfram syndrome is characterized by optic atrophy, insulin dependent diabetes mellitus, diabetes insipidus and deafness. There are several other associated conditions reported in the literature, but congenital or early childhood cataracts are not among them. Observational case series with confirmatory genetic analysis. A pair of siblings, followed over 17 years, who manifest congenital or early childhood cataracts, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. They are both compound heterozygotes for mutations (V415 deletion and A684V substitution) in the WFS1 gene. Their father has congenital sensorineural hearing loss and developed optic atrophy. He is heterozygous for A684V in WFS1. Wolfram syndrome should be in the differential diagnosis of genetic syndromes associated with congenital and early childhood cataracts. Here, we report on a mother who is a phenotypically normal carrier of an autosomal recessive Wolfram syndrome gene, and a father who has some of the findings of the syndrome and carries a single mutation that appears to be responsible for his hearing loss and optic atrophy. Their 2 children are compound heterozygotes and manifest the full Wolfram syndrome, in addition to cataracts.

  20. Relato de um paciente brasileiro com síndrome de Wolfram Report of a Brazilian patient with Wolfram syndrome

    Directory of Open Access Journals (Sweden)

    Paulo R.G. Zen

    2002-12-01

    Full Text Available Objetivos: relatar o caso de um paciente com diagnóstico de síndrome de Wolfram (SW e braquidactilia do tipo E. A síndrome de Wolfram é caracterizada pela presença de diabetes melito, diabetes insípido, atrofia do nervo óptico, alterações do trato urinário, surdez e distúrbios neurológicos e psiquiátricos. No entanto, nem todas as manifestações estarão presentes no momento do diagnóstico, indicando a necessidade de acompanhamento a longo prazo destes pacientes. Este acompanhamento deve ser estendido aos familiares diretos, tendo em vista o risco aumentado da ocorrência de distúrbios psiquiátricos e diabetes melito entre os portadores heterozigotos da síndrome de Wolfram. Descrição: menino, branco, filho de pais não consangüíneos, era hígido até os 4 anos, quando iniciou com polidipsia e poliúria, sendo diagnosticada diabetes melito tipo I. Desde então, faz uso irregular de insulina e segue mal a dieta por problemas socioeconômicos. Foi avaliado pelo serviço de Genética aos 11 anos de idade. Ao exame físico, chamou a atenção a presença de braquidactilia. Durante a investigação complementar, constatou-se atrofia bilateral do nervo óptico, com potencial evocado visual e eletrorretinograma compatíveis com lesão grave de nervo. Ambas retinas eram normais. A presença de diabetes melito insulino-dependente e atrofia do nervo óptico são critérios suficientes para o diagnóstico de síndrome de Wolfram. A investigação molecular confirmou o diagnóstico. Comentários: o presente relato tem o objetivo de alertar os profissionais da área médica para a associação entre o diabetes melito e síndromes monogênicas, como a SW.ABSTRACT Objective: to report a case of a patient diagnosed with Wolfram Syndrome and brachydactyly type E. Wolfram Syndrome is characterized by the presence of diabetes mellitus, diabetes insipidus, atrophy of the optic nerve, alterations of the urinary tract, deafness and neurologic and

  1. [Wolfram syndrome: clinical features, molecular genetics of WFS1 gene].

    Science.gov (United States)

    Tanabe, Katsuya; Matsunaga, Kimie; Hatanaka, Masayuki; Akiyama, Masaru; Tanizawa, Yukio

    2015-02-01

    Wolfram syndrome(WFS: OMIM 222300) is a rare recessive neuro-endocrine degenerative disorder, known as DIDMOAD(Diabetes Insipidus, early-onset Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene(WFS1). The WFS1 protein is an endoplasmic reticulum(ER) embedded protein, which functions in ER calcium homeostasis and unfolded protein responses. Dysregulation of these cellular processes results in the development of ER stress, leading to apoptosis. In addition, abundantly present WFS1 protein in insulin secretory granules plays a role in the intra-granular acidification. However, the phenotypic pleiomorphism and molecular complexity of this disease limit the understanding of WFS. Here we review clinical features, molecular mechanisms and mutations of WFS1 gene that relate to this syndrome.

  2. Wolfram syndrome: A rare mimic of type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Manish Gutch

    2016-01-01

    Full Text Available Wolfram syndrome is a rare autosomal recessive disorder characterized by a constellation of disorders also known as diabetes insipidus, diabetes mellitus (DM, optic atrophy, and deafness. Patients present with DM and optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, and renal outflow tract anomalies and other neurological manifestations later in life. We report a case of a 14-year-old boy who was diagnosed with insulin-dependent DM and subsequently discovered to have optic atrophy, sensorineural hearing loss, and cardiovascular defect with a positive family history. Such cases need to be evaluated thoroughly with respect to Wolfram syndrome and its associated anomalies.

  3. Cranial magnetic resonance imaging of wolfram (DIDMOAD) syndrome

    International Nuclear Information System (INIS)

    Pakdemirli, E.; Karabulut, N.; Bir, L.S.; Sermez, Y.

    2005-01-01

    Wolfram syndrome is a rare neurodegenerative disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD). A wide spectrum of abnormalities of the central nervous system, urinary tract and endocrine glands is also observed. We report cranial MRI findings in a 32-year-old female patient with Wolfram syndrome. In addition to the classical features, including absence of the normal high signal of the neurohypophysis, atrophy of visual pathways, the brainstem, cerebellum and cerebral cortex, we observed bilateral hyperintensity on proton density- and T 2 - weighted images related to the optic radiations in the periventricular white matter of the temporal and parieto-occipital lobes, which may reflect gliosis pathologically Copyright (2005) Blackwell Publishing Asia Pty Ltd

  4. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome.

    Science.gov (United States)

    Lu, Simin; Kanekura, Kohsuke; Hara, Takashi; Mahadevan, Jana; Spears, Larry D; Oslowski, Christine M; Martinez, Rita; Yamazaki-Inoue, Mayu; Toyoda, Masashi; Neilson, Amber; Blanner, Patrick; Brown, Cris M; Semenkovich, Clay F; Marshall, Bess A; Hershey, Tamara; Umezawa, Akihiro; Greer, Peter A; Urano, Fumihiko

    2014-12-09

    Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

  5. Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations

    NARCIS (Netherlands)

    Pennings, RJE; Huygen, PLM; van den Ouweland, JMW; Cryns, K; Dikkeschei, LD; Van Camp, G; Cremers, CWRJ

    2004-01-01

    This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and

  6. Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations.

    NARCIS (Netherlands)

    Pennings, R.J.E.; Huygen, P.L.M.; Ouweland, J.M.W. van den; Cryns, K.; Dikkeschei, L.D.; Camp, G. van; Cremers, C.W.R.J.

    2004-01-01

    This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and

  7. Reliability and validity of the Wolfram Unified Rating Scale (WURS).

    Science.gov (United States)

    Nguyen, Chau; Foster, Erin R; Paciorkowski, Alexander R; Viehoever, Amy; Considine, Colleen; Bondurant, Aidena; Marshall, Bess A; Hershey, Tamara

    2012-11-14

    Wolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS). A rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated. The WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach's α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, pScale and reports of mood and behavior (rs>.76, pvalidity (Scale-Content Validity Index=0.83). These preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS.

  8. Wolfram Sendromlu Hastalarda Optik Koherans Tomografi Bulguları

    Directory of Open Access Journals (Sweden)

    Bengü Ekinci Köktekir

    2014-05-01

    Full Text Available Objectives: To report the optical coherence tomography (OCT findings in patients with Wolfram syndrome. Materials and Methods: Four patients who fulfilled the criteria for Wolfram syndrome were recruited to the study. In all patients, OCT was performed with Stratus OCT (OCT-3, Carl Zeiss Meditec, Inc. Germany. The fast retinal nerve fiber layer (RNFL and fast macular thickness protocols were used to measure the RNFL and macular thickness, respectively. The fast optic disc protocol was used to determine the cup-to-disc ratios of the optic disc. All patients were examined with VEP (Retimax, CSO Strumenti Oftalmici, Florence, Italy. Results: In eight eyes of four patients (3 male and 1 female with a mean age of 18.5±2.08 years (range 16-21 years, RNFL, macular thickness, and cup-to-disc ratios were determined. The mean RNFL was 42.2±5.6 µm (range 34.1-49.5 µm, while the mean macular thickness and cup-to-disc ratios were 145±15 µm (range 125-160 µm and 0.79±0.07 (range 0.7-0.92, respectively. There was a moderate negative correlation between VEP latencies and macular and RNFL thicknesses (Spearman correlation coefficient was -0.23 and -0.34, respectively. Conclusions: RNFL loss and secondary optical atrophy are severe complications that may affect the visual acuity in patients with Wolfram syndrome. Retinal changes in these patients may be quantified and can be observed using OCT. (Turk J Ophthalmol 2014; 44: 212-5

  9. Reliability and validity of the Wolfram Unified Rating Scale (WURS

    Directory of Open Access Journals (Sweden)

    Nguyen Chau

    2012-11-01

    Full Text Available Abstract Background Wolfram syndrome (WFS is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS. Methods A rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease. WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age. Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated. Results The WURS had high inter-rater reliability (ICCs>.93, moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91 and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, ps>.76, ps=-.86, p=.001. The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83. Conclusions These preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS.

  10. Endocrine and metabolic aspects of the Wolfram syndrome.

    Science.gov (United States)

    Boutzios, Georgios; Livadas, Sarantis; Marinakis, Evangelos; Opie, Nicole; Economou, Frangiskos; Diamanti-Kandarakis, Evanthia

    2011-08-01

    Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

  11. Glutathione system in Wolfram syndrome 1‑deficient mice.

    Science.gov (United States)

    Porosk, Rando; Kilk, Kalle; Mahlapuu, Riina; Terasmaa, Anton; Soomets, Ursel

    2017-11-01

    Wolfram syndrome 1 (WS) is a rare neurodegenerative disease that is caused by mutations in the Wolfram syndrome 1 (WFS1) gene, which encodes the endoplasmic reticulum (ER) glycoprotein wolframin. The pathophysiology of WS is ER stress, which is generally considered to induce oxidative stress. As WS has a well‑defined monogenetic origin and a model for chronic ER stress, the present study aimed to characterize how glutathione (GSH), a major intracellular antioxidant, was related to the disease and its progression. The concentration of GSH and the activities of reduction/oxidation system enzymes GSH peroxidase and GSH reductase were measured in Wfs1‑deficient mice. The GSH content was lower in most of the studied tissues, and the activities of antioxidative enzymes varied between the heart, kidneys and liver tissues. The results indicated that GSH may be needed for ER stress control; however, chronic ER stress from the genetic syndrome eventually depletes the cellular GSH pool and leads to increased oxidative stress.

  12. Irreducibility and Computational Equivalence 10 Years After Wolfram's A New Kind of Science

    CERN Document Server

    2013-01-01

    It is clear that computation is playing an increasingly prominent role in the development of mathematics, as well as in the natural and social sciences. The work of Stephen Wolfram over the last several decades has been a salient part in this phenomenon helping founding the field of Complex Systems, with many of his constructs and ideas incorporated in his book A New Kind of Science (ANKS) becoming part of the scientific discourse and general academic knowledge--from the now established Elementary Cellular Automata to the unconventional concept of mining the Computational Universe, from today's widespread Wolfram's Behavioural Classification to his principles of Irreducibility and Computational Equivalence. This volume, with a Foreword by Gregory Chaitin and an Afterword by Cris Calude, covers these and other topics related to or motivated by Wolfram's seminal ideas, reporting on research undertaken in the decade following the publication of Wolfram's NKS book. Featuring 39 authors, its 23 contributions are o...

  13. Previously unreported abnormalities in Wolfram Syndrome Type 2.

    Science.gov (United States)

    Akturk, Halis Kaan; Yasa, Seda

    2017-01-01

    Wolfram syndrome (WFS) is a rare autosomal recessive disease with non-autoimmune childhood onset insulin dependent diabetes and optic atrophy. WFS type 2 (WFS2) differs from WFS type 1 (WFS1) with upper intestinal ulcers, bleeding tendency and the lack ofdiabetes insipidus. Li-fespan is short due to related comorbidities. Only a few familieshave been reported with this syndrome with the CISD2 mutation. Here we report two siblings with a clinical diagnosis of WFS2, previously misdiagnosed with type 1 diabetes mellitus and diabetic retinopathy-related blindness. We report possible additional clinical and laboratory findings that have not been pre-viously reported, such as asymptomatic hypoparathyroidism, osteomalacia, growth hormone (GH) deficiency and hepatomegaly. Even though not a requirement for the diagnosis of WFS2 currently, our case series confirm hypogonadotropic hypogonadism to be also a feature of this syndrome, as reported before. © Polish Society for Pediatric Endocrinology and Diabetology.

  14. The prevalence of Wolfram syndrome in a paediatric population with diabetes.

    Science.gov (United States)

    Zmysłowska, Agnieszka; Borowiec, Maciej; Fendler, Wojciech; Jarosz-Chobot, Przemysława; Myśliwiec, Małgorzata; Szadkowska, Agnieszka; Młynarski, Wojciech

    2014-01-01

    Wolfram syndrome (WFS) is the most frequent syndromic form of monogenic diabetes coexisting with optic atrophy and many other disorders. The aim of this study was to estimate the prevalence of Wolfram syndrome among children with diabetes in Poland. These calculations were performed among Polish diabetic children, aged 0-18 years, from three administrative regions between January 2005 and December 2011. Epidemiological data was obtained by matching the results from the EURO-WABBPoland Project and the PolPeDiab Registry. Throughout the study period, we confirmed genetic diagnosis of Wolfram syndrome in 13 patients from Poland. Three patients originated from the studied regions with complete epidemiological data on paediatric diabetes. The total number of patients with diagnosed diabetes in the study equalled 2,568 cases. The prevalence of Wolfram syndrome among Polish children with diabetes is 0.12% (95% Confidence Interval 0.04-0.34%). We estimate that Wolfram syndrome is: 26 to 35 times less frequent than monogenic diabetes (MODY and neonatal diabetes) in the Polish paediatric population.

  15. USING THE WEB-SERVICES WOLFRAM|ALPHA TO SOLVE PROBLEMS IN PROBABILITY THEORY

    Directory of Open Access Journals (Sweden)

    Taras Kobylnyk

    2015-10-01

    Full Text Available The trend towards the use of remote network resources on the Internet clearly delineated. Traditional training combined with increasingly networked, remote technologies become popular cloud computing. Research methods of probability theory are used in various fields. Of particular note is the use of methods of probability theory in psychological and educational research in statistical analysis of experimental data. Conducting such research is impossible without the use of modern information technology. Given the advantages of web-based software, the article describes web-service Wolfram|Alpha. Detailed analysis of the possibilities of using web-service Wolfram|Alpha for solving problems of probability theory. In the case studies described the results of queries for solving of probability theory, in particular the sections random events and random variables. Considered and analyzed the problem of the number of occurrences of event A in n independent trials using Wolfram|Alpha, detailed analysis of the possibilities of using the service Wolfram|Alpha for the study of continuous random variable that has a normal and uniform probability distribution, including calculating the probability of getting the value of a random variable in a given interval. The problem in applying the binomial and hypergeometric probability distribution of a discrete random variable and demonstrates the possibility of using the service Wolfram|Alpha for solving it.

  16. β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome.

    Science.gov (United States)

    Shang, Linshan; Hua, Haiqing; Foo, Kylie; Martinez, Hector; Watanabe, Kazuhisa; Zimmer, Matthew; Kahler, David J; Freeby, Matthew; Chung, Wendy; LeDuc, Charles; Goland, Robin; Leibel, Rudolph L; Egli, Dieter

    2014-03-01

    Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.

  17. Wolfram syndrome (diabetes insipidus, diabetes, optic atrophy, and deafness): clinical and genetic study.

    Science.gov (United States)

    d'Annunzio, Giuseppe; Minuto, Nicola; D'Amato, Elena; de Toni, Teresa; Lombardo, Fortunato; Pasquali, Lorenzo; Lorini, Renata

    2008-09-01

    Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndrome's seriousness.

  18. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases.

    Science.gov (United States)

    Khanim, F; Kirk, J; Latif, F; Barrett, T G

    2001-05-01

    Wolfram syndrome (WS) is the inherited association of juvenile-onset insulin-dependant diabetes mellitus and progressive bilateral optic atrophy. A nuclear gene, WFS1/wolframin, was identified that segregated with disease status and demonstrated an autosomal recessive mode of inheritance. Mutation analysis of the WFS1 gene in WS patients has identified mutations in 90% of patients. Most were compound heterozygotes with private mutations distributed throughout the gene with no obvious hotspots. The private nature of the mutations in WS patients and the low frequencies make it difficult to determine the biological or clinical relevance of these mutations. Mutation screening in patients with psychiatric disorders or diabetes mellitus has also been performed to test the hypothesis that heterozygous carriers of WFS1 gene mutations are at an increased risk following the observation that WS first-degree relatives have a higher frequency of these disorders. Most studies showed no association, however two missense mutations were identified that demonstrated significant association with psychiatric disorders and diabetes mellitus. Population association studies and functional studies of these variants will need to be performed to confirm these preliminary results. The elucidation of functions and functional pathways for the WFS1 gene product and variants will shed light on the effect of such disparate mutations on gene function and their role in the resulting clinical phenotype in WS and associated disorders. Copyright 2001 Wiley-Liss, Inc.

  19. Diabetes mellitus and optic atrophy: study of the Wolfram syndrome

    Science.gov (United States)

    Rivas-Gómez, Bernardette; Reza-Albarrán, Alfredo Adolfo

    2017-01-01

    Wolfram syndrome (WS), also known by the acronym DIDMOAD, is a rare and progresive hereditary disease of autosomal recessive inheritance which minimum ascertainment diagnostic criteria are the occurrence together of diabetes mellitus and optic atrophy before 15 years of age. To describe the clinical, biochemical and molecular profile of WS in a tertiary care hospital in Mexico. We reviewed patients records who fulfill the minimum ascertainment diagnostic criteria of WS presenting between January 1987 and May 2015 in a tertiary care hospital in Mexico. Five patients fulfill the inclusion criteria (three male and two female). Diabetes mellitus was the first manifestation of the syndrome in all of them, with a mean age at diagnosis of 5.8 ± 2.71 years, while the WS diagnosis was established at a mean age of 15.8 ± 8.37 years. All the patients had optic atrophy and two of them presented with the complete DIDMOAD spectrum. We found new associations with autoimmune hepatitis and testicular cancer. This study shows the variability of clinical presentation of WS, as well as two new associations. Copyright: © 2017 SecretarÍa de Salud

  20. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin.

    Science.gov (United States)

    Hofmann, Sabine; Bauer, Matthias F

    2006-07-10

    Wolfram syndrome is caused by mutations in WFS1 encoding wolframin, a polytopic membrane protein of the endoplasmic reticulum. Here, we investigated the molecular pathomechanisms of four missense and two truncating mutations in WFS1. Expression in COS-7 cells as well as direct analysis of patient cells revealed that WFS1 mutations lead to drastically reduced steady-state levels of wolframin. All mutations resulted in highly unstable proteins which were delivered to proteasomal degradation. No wolframin aggregates were found in patient cells suggesting that Wolfram syndrome is not a disease of protein aggregation. Rather, WFS1 mutations cause loss-of-function by cellular depletion of wolframin.

  1. WOLFRAM (DIDMOAD) SENDROMU BULUNAN BİR OLGUDAKİ ORAL BULGULAR (OLGU BİLDİRİMİ)

    OpenAIRE

    Hatipoğlu, Hasan; Hatipoğlu, Müjgan Güngör; Kansu, Özden

    2018-01-01

    Wolfram Sendromu, nadir görülen konjenital, birçok sistemi etkileyebilen sendromdur. Diabetes mellitus,diabetes insipidus, optik atrofi ve sağırlık ile karakterizedir. Hastalarda nörolojik rahatsızlıklar ile üriner sistemrahatsızlıkları ve psikolojik rahatsızlıklar da izlenir. Diabetes mellitus ve optik atrofi ilk ortaya çıkan bulgulardır.Bu olgu raporunda 20 yaşındaki Wolfram sendromlu erkek hastanın klinik ve radyografik ağız bulgularısunulmaktadır.

  2. Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation.

    Science.gov (United States)

    Zmyslowska, A; Borowiec, M; Antosik, K; Szalecki, M; Stefanski, A; Iwaniszewska, B; Jedrzejczyk, M; Pietrzak, I; Mlynarski, W

    2011-11-01

    Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome. Nine patients with clinical symptoms consistent with Wolfram syndrome (at least diabetes mellitus and optic atrophy) and 22 first-degree relatives were examined. The molecular analysis was carried out by direct sequencing of the exons, the exon-intron junctions, and the 5' and 3' untranslated regions of WFS1. Nine different mutations in WFS1 (five of them novel) were identified in the nine patients. Six patients were homozygous for the following mutations: V412fs, S443R, W539X, V659fs. They developed diabetes at a mean age of 5·2 years. Three patients were compound-heterozygous for the following mutations: S167fs, Q392X, Y513fs, W648X, V779G. They developed diabetes at a mean age of 6·5 years. Mean age of diagnosis of diabetes among the Polish patients was typical for Wolfram syndrome; however, compound-heterozygous patients were slightly older at diabetes onset. © 2011 Blackwell Publishing Ltd.

  3. Presentation and clinical course of Wolfram (DIDMOAD) syndrome from North India.

    Science.gov (United States)

    Ganie, M A; Laway, B A; Nisar, S; Wani, M M; Khurana, M L; Ahmad, F; Ahmed, S; Gupta, P; Ali, I; Shabir, I; Shadan, A; Ahmed, A; Tufail, S

    2011-11-01

    Wolfram syndrome, also known as DIDMOAD, is a relatively rare inherited neurodegenerative disorder, first evident in childhood as an association of juvenile-onset diabetes mellitus and optic atrophy, followed by diabetes insipidus and deafness. The aim of the study was to examine the clinical profile of patients with DIDMOAD syndrome presenting to a tertiary care hospital in north India. Clinical presentation of juvenile-onset diabetes mellitus fulfilling the diagnosis of Wolfram syndrome was studied using a prepared standardized form. Subjects with juvenile-onset non-autoimmune diabetes mellitus attending the diabetic clinic at a tertiary care centre in north India were followed for 10 years and a diagnosis of fully developed Wolfram syndrome was confirmed in seven individuals. The series consisted of five male and two female patients with a mean age of 17.5 ±7.34 years. Two subjects had consanguinity and none had any other family member affected. Optic atrophy was present in all, sensorineural hearing loss in 4/7, central diabetes insipidus in 4/7 and nephrogenic diabetes insipidus in 2/7 subjects. The new associations found were: spastic myoclonus, short stature with pancreatic malabsorption, nephrogenic diabetes insipidus, cyanotic heart disease and choledocholithiasis with cholangitis. Genetic analysis revealed mutation in exon 8 of the WFS1 gene in all the cases studied. The present clinical series of Wolfram syndrome reveals a varied clinical presentation of the syndrome and some new associations. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

  4. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.

    Science.gov (United States)

    Rohayem, Julia; Ehlers, Christian; Wiedemann, Bärbel; Holl, Reinhard; Oexle, Konrad; Kordonouri, Olga; Salzano, Giuseppina; Meissner, Thomas; Burger, Walter; Schober, Edith; Huebner, Angela; Lee-Kirsch, Min Ae

    2011-07-01

    To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). Endoplasmic reticulum stress-mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.

  5. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells.

    Science.gov (United States)

    Fonseca, Sonya G; Ishigaki, Shinsuke; Oslowski, Christine M; Lu, Simin; Lipson, Kathryn L; Ghosh, Rajarshi; Hayashi, Emiko; Ishihara, Hisamitsu; Oka, Yoshitomo; Permutt, M Alan; Urano, Fumihiko

    2010-03-01

    Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.

  6. c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness.

    Science.gov (United States)

    Safarpour Lima, Behnam; Ghaedi, Hamid; Daftarian, Narsis; Ahmadieh, Hamid; Jamshidi, Javad; Khorrami, Mehdi; Noroozi, Rezvan; Sohrabifar, Nasim; Assarzadegan, Farhad; Hesami, Omid; Taghavi, Shaghayegh; Ahmadifard, Azadeh; Atakhorrami, Minoo; Rahimi-Aliabadi, Simin; Shahmohammadibeni, Neda; Alehabib, Elham; Andarva, Monavvar; Darvish, Hossein; Emamalizadeh, Babak

    2016-02-01

    Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Bladder dysfunction in Wolfram syndrome is highly prevalent and progresses to megacystis.

    Science.gov (United States)

    Wragg, Ruth; Dias, Renuka P; Barrett, Timothy; McCarthy, Liam

    2018-02-01

    Wolfram syndrome is a rare genetic defect in WFS1 or WSF2(CISD2). It includes diabetes mellitus and insipidis, sensorineural deafness, optic atrophy, but not bladder dysfunction. However, this has appeared a common finding in our national referral clinic, and we sought to quantify this problem. Data were collected from a multidisciplinary team managing all Wolfram patients in the UK. The following was analyzed: age, date of non-invasive urodynamics (NIU), symptoms, bladder capacity, voided volume, post-void residual and uroflow pattern. Bladder capacity was given as percentage predicted bladder capacity (PBC). Bladders were divided into normal, overactive (OAB), and underactive (UAB). Symptoms, bladder behavior, and genotyping were correlated. Data were expressed as median (interquartile range). Forty patients with Wolfram syndrome were identified, and 38 underwent NIU. This showed normal bladder function (n=4), OAB (n=9), UAB (n=25). Symptoms were present in only 11 children. The different patterns of bladder behavior (OAB vs. normal vs. UAB) were significantly associated with different %PBC (36 (29-59)% vs. 105 (93-233)% vs. 100 (77.5-337)%; pWolfram syndrome (~90%), but most children cope (symptoms ~30%). With time there is a significant progression to megacystis, which may represent an underlying neuropathic myogenic failure and is likely to require intervention in the future. Level II (National cohort study of prognosis). Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  8. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

    DEFF Research Database (Denmark)

    Luuk, H.; Koks, S.; Plaas, M.

    2008-01-01

    Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. Patients with Wolfram syndrome display considerable clinical pleiomorphism, and symptoms such as neurological complications and psychiatric...... and psychiatric symptoms found in Wolfram syndrome. Enrichment of Wfs1 protein in the central extended amygdala suggests a role in the modulation of anxiety and fear Udgivelsesdato: 2008/8/20...

  9. Early presentation of gait impairment in Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Pickett Kristen A

    2012-12-01

    Full Text Available Abstract Background Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD individuals may be detectable across the course of the disease. Methods Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups. Results Across all tasks, individuals with WFS walked slower (p = 0.03, took shorter (p ≤ 0.001 and wider (p ≤ 0.001 steps and spent a greater proportion of the gait cycle in double support (p = 0.03 compared to TD individuals. Cadence did not differ between groups (p = 0.62. Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs= 0.564, p = 0.045 and dual task forward walking (rs= 0.720, p = 0.006 tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001. Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03 and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03. Conclusions Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits

  10. Early presentation of gait impairment in Wolfram Syndrome.

    Science.gov (United States)

    Pickett, Kristen A; Duncan, Ryan P; Hoekel, James; Marshall, Bess; Hershey, Tamara; Earhart, Gammon M

    2012-12-08

    Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease. Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups. Across all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs = 0.564, p = 0.045) and dual task forward walking (rs = 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = -0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = -0.64, p = 0.03). Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and

  11. Selective cognitive and psychiatric manifestations in Wolfram Syndrome.

    Science.gov (United States)

    Bischoff, Allison N; Reiersen, Angela M; Buttlaire, Anna; Al-Lozi, Amal; Doty, Tasha; Marshall, Bess A; Hershey, Tamara

    2015-05-30

    Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and

  12. A single base-pair deletion in the WFS1 gene causes Wolfram syndrome.

    Science.gov (United States)

    Pitt, Katherine; James, Chela; Kochar, Inderpal S; Kapoor, Akshay; Jain, Shilpi; Hussain, Khalid; Bennett, Kate

    2011-01-01

    Wolfram syndrome is a progressive neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). The majority of cases are caused by mutations in the WFS1 gene. WFS1 is located at 4p16.1 and encodes wolframin, a transmembrane endoplasmic reticulum (ER) protein involved in the negative regulation of ER stress signalling. To date, over 120 WFS1 mutations have been described. In this study, we report a consanguineous family with three siblings affected by Wolfram syndrome. A homozygous single base pair deletion (c.877delC, L293fsX303) was found in the WFS1 gene in all three affected siblings.

  13. The subtle signs of Wolfram (DIDMOAD) syndrome: not all juvenile diabetes is type 1 diabetes.

    Science.gov (United States)

    Boettcher, Claudia; Brosig, Burkhard; Zimmer, Klaus P; Wudy, Stefan A

    2011-01-01

    Wolfram syndrome (also known as DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, deafness) is an autosomal recessive disorder characterized by the association of childhood non-immune insulin-dependent diabetes mellitus (DM) with progressive bilateral optic atrophy. Additional symptoms including signs of severe neurodegeneration and psychiatric illness are likely to evolve over time resulting in premature death. We report on two siblings of Turkish origin from our diabetes clinic who were diagnosed with Wolfram syndrome after 6 years and 2 years duration of DM, respectively. Subtle symptoms such as attitude changes, growing reading difficulties in the history of children or adolescents with antibody negative and ketone negative DM should alert the treating physician and lead to re-evaluation of the diagnosis, keeping in mind that not all juvenile DM is type 1 DM.

  14. Management of bladder dysfunction in Wolfram syndrome with Mitrofanoff appendicovesicostomy: long-term follow-up.

    Science.gov (United States)

    Mozafarpour, Sarah; Kajbafzadeh, Abdol-Mohammad; Mojtahed, Ali; Mojtahed, Mohammad; Mahboubi, Hossein; Shalileh, Keivan

    2015-07-01

    To present the long-term outcomes of appendicovesicostomy using the Mitrofanoff principle for end-stage Wolfram bladder dysfunction as an alternative to clean intermittent self-catheterization (CIC) per urethra mainly following blindness. Twelve Wolfram patients presenting with bilateral hydroureteronephrosis and advanced bladder dysfunction were included in this study. All patients were managed initially by CIC per urethra. All of these patients became blind during follow-up and were unable to perform urethral CIC independently. Out of these patients, six patients agreed to proceed to appendicovesicostomy. Appendicovesicostomy urinary diversion using the Mitrofanoff principle was performed in these six blind patients. The rest of the patients stopped CIC or performed CIC irregularly. Severe hydroureteronephrosis and large bladders were found in all patients prior to intervention. All patients were able to conduct CIC independently through the stoma and maintained overnight bladder free drainage. In all patients with urinary diversion and CIC, the hydroureteronephrosis was reduced and renal function returned to normal. However, the non-intervention group ended with different degrees of progressive renal failure with three mortalities during the follow-up. We suggest appendicovesicostomy as a safe and lifesaving procedure for long-term management of bladder dysfunction in Wolfram syndrome particularly after progression to blindness. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome.

    Science.gov (United States)

    Hoekel, James; Chisholm, Smith Ann; Al-Lozi, Amal; Hershey, Tamara; Tychsen, Lawrence

    2014-10-01

    To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome. Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning (P Wolfram United Rating Scale. Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker. Copyright © 2014 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  16. Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1.

    Science.gov (United States)

    Sedman, Tuuli; Rünkorg, Kertu; Krass, Maarja; Luuk, Hendrik; Plaas, Mario; Vasar, Eero; Volke, Vallo

    2016-01-01

    Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 μg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.

  17. Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1

    Directory of Open Access Journals (Sweden)

    Tuuli Sedman

    2016-01-01

    Full Text Available Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 μg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.

  18. Primary diagnosis of Wolfram syndrome in an adult patient--case report and description of a novel pathogenic mutation.

    Science.gov (United States)

    Waschbisch, Anne; Volbers, Bastian; Struffert, Tobias; Hoyer, Juliane; Schwab, Stefan; Bardutzky, Juergen

    2011-01-15

    Wolfram syndrome is a rare, autosomal recessive, neurodegenerative disorder presenting with the main clinical symptoms of childhood-onset diabetes mellitus, optic atrophy, diabetes insipidus and deafness (DIDMOAD). Later stages of the disease are dominated by neurological complications and death occurs early in life with a median life expectancy of 30 years. Here we present a 44 year old patient who presented to our hospital with central respiratory failure, cognitive impairment, ataxia and parkinsonism and was first diagnosed with Wolfram syndrome. DNA sequence analysis revealed a novel pathogenic mutation within the WFS1 gene. Advanced clinical and imaging studies performed in this patient highlight the neurodegenerative process in Wolfram syndrome and expand our knowledge on the mutational spectrum of the disease. Copyright © 2010 Elsevier B.V. All rights reserved.

  19. WS1 gene mutation analysis of Wolfram syndrome in a Chinese patient and a systematic review of literatures.

    Science.gov (United States)

    Yu, Guang; Yu, Man-li; Wang, Jia-feng; Gao, Cong-rong; Chen, Zhong-jin

    2010-10-01

    Wolfram syndrome is a rare hereditary disease characterized by diabetes mellitus and optic atrophy. The outcome of this disease is always poor. WFS1 gene mutation is the main cause of this disease. A patient with diabetes mellitus, diabetes insipidus, renal tract disorder, psychiatric abnormality, and cataract was diagnosed with Wolfram syndrome. Mutations in open reading frame (ORF) of WFS1 gene was analyzed by sequencing. Mutations in WFS1 gene was also summarized by a systematic review in Pubmed and Chinese biological and medical database. Sequencing of WFS1 gene in this patient showed a new mutation, 1962G>A, and two other non-sense mutations, 2433A>G and 2565G>A. Systematic review included 219 patients in total and identified 172 WFS1 gene mutations, most of which were located in Exon 8. These mutations in WFS1 gene might be useful in prenatal diagnosis of Wolfram syndrome.

  20. Clinical variability in hereditary optic neuropathies: Two novel mutations in two patients with dominant optic atrophy and Wolfram syndrome.

    Science.gov (United States)

    Galvez-Ruiz, Alberto

    2015-01-01

    Dominant optic atrophy (DOA) and Wolfram syndrome share a great deal of clinical variability, including an association with hearing loss and the presence of optic atrophy at similar ages. The objective of this paper was to discuss the phenotypic variability of these syndromes with respect to the presentation of two clinical cases. We present two patients, each with either DOA or Wolfram syndrome, and contribute to the research literature through our findings of two novel mutations. The overlapping of several clinical characteristics in hereditary optic neuropathies can complicate the differential diagnosis. Future studies are needed to better determine the genotype-phenotype correlation for these diseases.

  1. Diabetes mellitus, diabetes insipidus, optic atrophy, and deafness: A case of Wolfram (DIDMOAD) syndrome.

    Science.gov (United States)

    Maleki, Nasrollah; Bashardoust, Bahman; Zakeri, Anahita; Salehifar, Azita; Tavosi, Zahra

    2015-01-01

    To report a case of Wolfram syndrome (WS) characterized by diabetes mellitus, diabetes insipidus, progressive optic atrophy, and deafness. A 19-year-old female patient, a known case of diabetes mellitus type I from six years before, presented with progressive vision loss since four years earlier. On fundoscopic examination, she had bilateral optic atrophy without diabetic retinopathy. The patient also had diabetes insipidus, neurosensory deafness, and neurogenic bladder. WS should be considered a differential diagnosis in patients with diabetes mellitus who present with optic atrophy, and it is necessary to perform a hearing test as well as collecting 24-h urine output.

  2. Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome

    OpenAIRE

    Khaldon Bodoor; Osama Batiha; Ayman Abu-Awad; Khaldon Al-Sarihin; Haya Ziad; Yousef Jarun; Aya Abu-sheikha; Sara Abu Jalboush; Khoulod S. Alibrahim

    2016-01-01

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder characterized by the presentation of early onset type I diabetes mellitus and optic atrophy with later onset diabetes insipidus and deafness. WFS1 gene was identified on chromosome 4p16.1 as the gene responsible for WS disease given that most of the WS patients were found to carry mutations in this gene. This study was carried out to investigate the molecular spectrum of WFS1 gene in Jordanian families. Molecular a...

  3. A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome.

    Science.gov (United States)

    Noorian, Shahab; Savad, Shahram; Mohammadi, Davood Shah

    2016-05-01

    Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS.

  4. Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro)

    DEFF Research Database (Denmark)

    Yuca, Sevil Ari; Rendtorff, Nanna Dahl; Boulahbel, Houda

    2012-01-01

    Wolfram syndrome, also named "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an inherited association of juvenile-onset diabetes mellitus and optic atrophy as key diagnostic criteria. Renal tract abnormalities and neurodegenerative disorder may occur in the third...... and fourth decade. The wolframin gene, WFS1, associated with this syndrome, is located on chromosome 4p16.1. Many mutations have been described since the identification of WFS1 as the cause of Wolfram syndrome. We identified a new homozygous WFS1 mutation (c.1532T>C; p.Leu511Pro) causing Wolfram syndrome...

  5. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified

    DEFF Research Database (Denmark)

    Hansen, Lars; Eiberg, Hans Rudolf Lytchoff; Barrett, Timothy

    2005-01-01

    Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing...

  6. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype.

    Science.gov (United States)

    de Heredia, Miguel López; Clèries, Ramón; Nunes, Virginia

    2013-07-01

    Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. (i) 15% of published patients do not fulfill the current -inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient's genotypic class; and (vi) disease progression rate might depend on genotypic class. New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.

  7. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease

    NARCIS (Netherlands)

    Cryns, K; Sivakumaran, TA; Van den Ouweland, JMW; Pennings, RJE; Cremers, CWRJ; Flothmann, K; Young, TL; Smith, RJH; Lesperance, MM; Van Camp, G

    2003-01-01

    WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition,

  8. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease.

    NARCIS (Netherlands)

    Cryns, K.; Sivakumaran, T.A.; Ouweland, J.M.W. van den; Pennings, R.J.E.; Cremers, C.W.R.J.; Flothmann, K.; Young, T.L.; Smith, R.J.H.; Lesperance, M.M.; Camp, G. van

    2003-01-01

    WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition,

  9. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.

    Science.gov (United States)

    Cagalinec, Michal; Liiv, Mailis; Hodurova, Zuzana; Hickey, Miriam Ann; Vaarmann, Annika; Mandel, Merle; Zeb, Akbar; Choubey, Vinay; Kuum, Malle; Safiulina, Dzhamilja; Vasar, Eero; Veksler, Vladimir; Kaasik, Allen

    2016-07-01

    Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.

  10. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.

    Directory of Open Access Journals (Sweden)

    Michal Cagalinec

    2016-07-01

    Full Text Available Deficiency of the protein Wolfram syndrome 1 (WFS1 is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy, delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.

  11. Identification of four novel mutations of the WFS1 gene in Iranian Wolfram syndrome pedigrees.

    Science.gov (United States)

    Ghahraman, Martha; Abbaszadegan, Mohammad Reza; Vakili, Rahim; Hosseini, Sousan; Fardi Golyan, Fatemeh; Ghaemi, Nosrat; Forghanifard, Mohammad Mahdi

    2016-12-01

    Wolfram syndrome is a rare neurodegenerative disorder with an autosomal recessive pattern of inheritance characterized by various clinical manifestations. The related gene, WFS1, encodes a transmembrane glycoprotein, named wolframin. Genetic analyses demonstrated that mutations in this gene are associated with WS type 1. Our aim in this study was to sequence WFS1 coding region in Iranian Wolfram syndrome pedigrees. Genomic DNA was extracted from peripheral blood of 12 WS patients and their healthy parents. Exons 2-8 and the exon-intron junctions of WFS1 were sequenced. DNA sequences were compared to the reference using Sequencher software. Molecular analysis of WFS1 revealed six different mutations. Four novel and two previously reported mutations were identified. One novel mutation, c.1379_1381del, is predicted to produce an aberrant protein. A second novel mutation, c.1384G > T, encodes a truncated protein. Novel mutation, c.1097-1107dup (11 bp), causes a frameshift which results in a premature stop codon. We screened for the novel missense mutation, c.1010C > T, in 100 control alleles. This mutation was not found in any of the healthy controls. Our study increased the spectrum of WFS1 mutations and supported the role of WFS1 in susceptibility to WS. We hope that these findings open new horizons to future molecular investigations which may help to prevent and treat this devastating disease.

  12. The effects of disease-related symptoms on daily function in Wolfram Syndrome.

    Science.gov (United States)

    Doty, Tasha; Foster, Erin R; Marshall, Bess; Ranck, Samantha; Hershey, Tamara

    2017-01-01

    To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms. WFS ( n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease-related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined. Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other. The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS.

  13. The effects of disease-related symptoms on daily function in Wolfram Syndrome

    Science.gov (United States)

    Doty, Tasha; Foster, Erin R.; Marshall, Bess; Ranck, Samantha; Hershey, Tamara

    2017-01-01

    OBJECTIVE: To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms. METHODS: WFS (n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease-related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined. RESULTS: Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other. CONCLUSIONS: The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS. PMID:29130034

  14. Fatal Pulmonary Embolism Due to Inherited Thrombophilia Factors in a Child With Wolfram Syndrome.

    Science.gov (United States)

    Küçüktaşçi, Kazim; Semiz, Serap; Balci, Yasemin Işik; Özsari, Tamer; Gürses, Dolunay; Önem, Gökhan; Saçar, Mustafa; Düzcan, Füsun; Yüksel, Doğangün; Semiz, Ender

    2016-10-01

    Wolfram syndrome-1 is a rare and severe autosomal recessive neurodegenerative disease characterized by diabetes mellitus (DM), optic atrophy, diabetes insipidus, and deafness. Poorly controlled type 1 DM increases the risk for thrombosis. However, coexistence of DM and hereditary thrombosis factors is rarely observed. Here we present the case of a 13.5-year-old, nonfollowed girl newly diagnosed with poorly controlled Wolfram syndrome on the basis of the results of clinical and laboratory examinations. On the eighth day after diabetic ketoacidosis treatment, pulmonary embolism developed in the subject. Thrombus identified in the right atrium using echocardiography was treated by emergency thrombectomy. Homozygous mutation in the methylenetetrahydrofolate reductase gene C677T, heterozygous factor-V Leiden mutation, and active protein C resistance were identified in the patient. The patient was lost because of a recurring episode of pulmonary embolism on the 86th day of hospitalization. We present this case to highlight the need for investigating hereditary thrombosis risk factors in diabetic patients in whom thromboembolism develops.

  15. [From gene to disease; mutations in the WFS1-gene as the cause of juvenile type I diabetes mellitus with optic atrophy (Wolfram syndrome)

    NARCIS (Netherlands)

    Pennings, R.J.E.; Dikkeschei, L.D.; Cremers, C.W.R.J.; Ouweland, J.M.W. van den

    2002-01-01

    Wolfram syndrome patients are mainly characterised by juvenile onset diabetes mellitus and optic atrophy. A synonym is the acronym DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness. Diabetes insipidus and sensorineural high-frequency hearing impairment are important additional

  16. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans.

    Science.gov (United States)

    Berry, Vanita; Gregory-Evans, Cheryl; Emmett, Warren; Waseem, Naushin; Raby, Jacob; Prescott, DeQuincy; Moore, Anthony T; Bhattacharya, Shomi S

    2013-12-01

    Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.

  17. Potential of Wolfram technologies in construction and research of econometric models

    Directory of Open Access Journals (Sweden)

    Dmitry A. Vlasov

    2017-12-01

    Full Text Available In the center of attention of article didactic, applied and research potentials of technologies of the modern knowledge base and a set of computing algorithms Wolfram in creation and a research of econometric models. Econometric models and methods traditionally play a special role in applied mathematical training of students of an economic bachelor degree in Plekhanov Russian University of Economics. Within this article experience of forming of content of applied mathematical training of future bachelor of economy and methodical features of use of information technologies in the course of econometric modeling of social and economic situations and teaching subject matters of «The econometrician (basic level» for students of an economic bachelor degree and «The econometrician (advanced level» for students of an economic magistracy is provided. The allocated sixteen tools fully allow to focus attention to development of innovative components of professional competence of future bachelors of economy.

  18. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system.

    Science.gov (United States)

    Kawano, June; Tanizawa, Yukio; Shinoda, Koh

    2008-09-01

    Wolfram syndrome (OMIM 222300) is a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This syndrome has been attributed to mutations in the WFS1 gene, which codes for a putative multi-spanning membrane glycoprotein of the endoplasmic reticulum. The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear. In this study we made a detailed analysis of the distribution of Wfs1 mRNA and protein in the normal mouse visual system by using in situ hybridization and immunohistochemistry. The mRNA and protein were observed in the retina, optic nerve, and brain. In the retina, Wfs1 expression was strong in amacrine and Müller cells, and moderate in photoreceptors and horizontal cells. In addition, it was detectable in bipolar and retinal ganglion cells. Interestingly, moderate Wfs1 expression was seen in the optic nerve, particularly in astrocytes, while little Wfs1 was expressed in the optic chiasm or optic tract. In the brain, moderate Wfs1 expression was observed in the zonal, superficial gray, and intermediate gray layers of the superior colliculus, in the dorsomedial part of the suprachiasmatic nucleus, and in layer II of the primary and secondary visual cortices. Thus, Wfs1 mRNA and protein were widely distributed in the normal mouse visual system. This evidence may provide clues as to the physiological role of Wfs1 protein in the biology of vision, and help to explain the selective vulnerability of the optic nerve to WFS1 loss-of-function. (c) 2008 Wiley-Liss, Inc.

  19. Expansion of the clinical ocular spectrum of Wolfram Syndrome in a family carrying a novel WFS1 gene deletion.

    Science.gov (United States)

    Chacón-Camacho, Oscar; Arce-Gonzalez, Rocio; Granillo-Alvarez, Mariella; Flores-Limas, Sanjuanita; Ramírez, Magdalena; Zenteno, Juan C

    2013-12-01

    To present the results of the clinical and molecular analyses of a familial case of Wolfram Syndrome (WFS) associated with a novel ocular anomaly. Full ophthalmologic examination was performed in two WFS siblings. Visante OCT imaging was used for assessing anterior segment anomalies. Genetic analysis included PCR amplification and exon-by-exon nucleotide sequencing of the WFS1 gene. Ocular anomalies in both affected siblings included congenital cataract, glaucoma, and optic atrophy. Interestingly, microspherophakia, a feature that has not been previously associated with WFS, was observed in both siblings. Genetic analysis disclosed a novel c.1525_1539 homozygous deletion in exon 8 of WFS1 in DNA from both affected patients. The recognition of microspherophakia in two siblings carrying a novel WFS1 mutation expands the clinical and molecular spectrum of Wolfram syndrome.

  20. A novel mutation of WFS1 gene in a Chinese patient with Wolfram syndrome: a case report.

    Science.gov (United States)

    Li, Min; Liu, Jia; Yi, Huan; Xu, Li; Zhong, Xiufeng; Peng, Fuhua

    2018-03-17

    Wolfram syndrome (WS), caused by mutations of the Wolfram syndrome 1 (WFS1) gene on chromosome 4p16.1, is an autosomal recessive disorder characterized by diabetes insipidus (DI), neuro-psychiatric disorders, hearing deficit, and urinary tract anomalies. Here we report a 11-year-old Chinese boy who presented with visual loss, was suspected with optic neuritis (ON) or neuromyelitis optica (NMO) and referred to our department for further diagnosis. Finally he was diagnosed with WS because of diabetes mellitus (DM) and optic atrophy (OA). Eight exons and flanking introns of WFS1 gene were analyzed by sequencing. A novel mutation c.1760G > A in WFS1 gene of exon 8 was identified. This report reviews a case of WS associated with a novel mutation, c.1760G > A in WFS1 gene of exon 8, and emphasizes that WS should be taken into account for juveniles with visual loss and diabetes mellitus.

  1. Designing a Site to Embed and to Interact with Wolfram Alpha Widgets in Math and Sciences Courses

    OpenAIRE

    Delgado Cepeda, Francisco Javier; Santiago Acosta, Rubén Darío

    2013-01-01

    This paper reports design and implementation outcomes at middle development advance of an educative program based on use and construction of widgets on Wolfram Alpha platform at higher education level for engineering and sciences areas. Widgets were created around of Physics and Mathematics curricula under Project Oriented Learning and Blended Learning methodologies. Widgets constructed by teachers are first used by students to appropriate basic concepts of each specific course on a mobile le...

  2. Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease.

    Science.gov (United States)

    Lieber, Daniel S; Vafai, Scott B; Horton, Laura C; Slate, Nancy G; Liu, Shangtao; Borowsky, Mark L; Calvo, Sarah E; Schmahmann, Jeremy D; Mootha, Vamsi K

    2012-01-06

    Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients.

  3. Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea.

    Science.gov (United States)

    Suzuki, Noriomi; Hosoya, Makoto; Oishi, Naoki; Okano, Hideyuki; Fujioka, Masato; Ogawa, Kaoru

    2016-08-03

    Wolfram syndrome is an autosomal recessive disorder of the neuroendocrine system, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, and considered an endoplasmic reticulum disease. Patients show mutations in WFS1, which encodes the 890 amino acid protein wolframin. Although Wfs1 knockout mice develop diabetes, their hearing level is completely normal. In this study, we examined the expression of wolframin in the cochlea of a nonhuman primate common marmoset (Callithrix jacchus) to elucidate the discrepancy in the phenotype between species and the pathophysiology of Wolfram syndrome-associated deafness. The marmoset cochlea showed wolframin immunoreactivity not only in the spiral ligament type I fibrocytes, spiral ganglion neurons, outer hair cells, and supporting cells, but in the stria vascularis basal cells, where wolframin expression was not observed in the previous mouse study. Considering the absence of the deafness phenotype in Wfs1 knockout mice, the expression of wolframin in the basal cells of primates may play an essential role in the maintenance of hearing. Elucidating the function of wolframin protein in the basal cells of primates would be essential for understanding the pathogenesis of hearing loss in patients with Wolfram syndrome, which may lead to the discovery of new therapeutics.

  4. Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease

    Directory of Open Access Journals (Sweden)

    Lieber Daniel S

    2012-01-01

    Full Text Available Abstract Background Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Case Presentation Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. Conclusion This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients.

  5. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy.

    Science.gov (United States)

    Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

    2011-07-29

    Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Congenital central diabetes insipidus and optic atrophy in a Wolfram newborn: is there a role for WFS1 gene in neurodevelopment?

    Science.gov (United States)

    Ghirardello, Stefano; Dusi, Elisa; Castiglione, Bianca; Fumagalli, Monica; Mosca, Fabio

    2014-09-26

    Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus (DM), optic atrophy (OA), central diabetes insipidus (CDI) and deafness (D). The phenotype of the disease has been associated with several mutations in the WFS1 gene, a nuclear gene localized on chromosome 4. Since the discovery of the association between WFS1 gene and Wolfram syndrome, more than 150 mutations have been identified in WS patients. We previously described the first case of perinatal onset of Wolfram syndrome newborn carrying a segmental uniparental heterodysomy affecting the short arm of chromosome 4 responsible for a significant reduction in wolframin expression. Here we review and discuss the pathophysiological mechanisms that we believe responsible for the perinatal onset of Wolfram syndrome as these data strongly suggest a role for WFS1 gene in foetal and neonatal neurodevelopment. We described a male patient of 30 weeks' gestation with intrauterine growth restriction and poly-hydramnios. During the first days of life, the patient showed a 19% weight loss associated with polyuria and hypernatremia. The presence of persistent hypernatremia (serum sodium 150 mEq/L), high plasma osmolarity (322 mOsm/L) and low urine osmolarity (190 mOsm/l) with a Uosm/Posm ratio Wolfram syndrome should be considered in the differential diagnosis of the rare cases of congenital central diabetes insipidus developed in the neonatal period.

  7. A Challenging Form of Non-autoimmune Insulin-Dependent Diabetes in a Wolfram Syndrome Patient with a Novel Sequence Variant.

    Science.gov (United States)

    Paris, Liliana P; Usui, Yoshihiko; Serino, Josefina; Sá, Joaquim; Friedlander, Martin

    2015-06-01

    Wolfram syndrome type 1 is a rare, autosomal recessive, neurodegenerative disorder that is diagnosed when insulin-dependent diabetes of non-auto-immune origin and optic atrophy are concomitantly present. Wolfram syndrome is also designated by DIDMOAD that stands for its most frequent manifestations: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. With disease progression, patients also commonly develop severe neurological and genito-urinary tract abnormalities. When compared to the general type 1 diabetic population, patients with Wolfram Syndrome have been reported to have a form of diabetes that is more easily controlled and with less microvascular complications, such as diabetic retinopathy. We report a case of Wolfram syndrome in a 16-year-old male patient who presented with progressive optic atrophy and severe diabetes with very challenging glycemic control despite intensive therapy since diagnosis at the age of 6. Despite inadequate metabolic control he did not develop any diabetic microvascular complications during the 10-year follow-up period. To further investigate potential causes for this metabolic idiosyncrasy, we performed genetic analyses that revealed a novel combination of homozygous sequence variants that are likely the cause of the syndrome in this family. The identified genotype included a novel sequence variant in the Wolfram syndrome type 1 gene along with a previously described one, which had initially been associated with isolated low frequency sensorineural hearing loss (LFSNHL). Interestingly, our patient did not show any abnormal findings with audiometry testing.

  8. REVIEW OF MATHEMATICAL METHODS AND ALGORITHMS OF MEDICAL IMAGE PROCESSING ON THE EXAMPLE OF TECHNOLOGY OF MEDICAL IMAGE PROCESSING FROM WOLFRAM MATHEMATICA

    Directory of Open Access Journals (Sweden)

    О. E. Prokopchenko

    2015-09-01

    Full Text Available The article analyzes the basic methods and algorithms of mathematical processing of medical images as objects of computer mathematics. The presented methods and computer algorithms of mathematics relevant and may find application in the field of medical imaging - automated processing of images; as a tool for measurement and determination the optical parameters; identification and formation of medical images database. Methods and computer algorithms presented in the article & based on Wolfram Mathematica are also relevant to the problem of modern medical education. As an example of Wolfram Mathematica may be considered appropriate demonstration, such as recognition of special radiographs and morphological imaging. These methods are used to improve the diagnostic significance and value of medical (clinical research and can serve as an educational interactive demonstration. Implementation submitted individual methods and algorithms of computer Wolfram Mathematics contributes, in general, the optimization process of practical processing and presentation of medical images.

  9. REVIEW OF MATHEMATICAL METHODS AND ALGORITHMS OF MEDICAL IMAGE PROCESSING ON THE EXAMPLE OF TECHNOLOGY OF MEDICAL IMAGE PROCESSING FROM WOLFRAM MATHEMATICS

    Directory of Open Access Journals (Sweden)

    O. Ye. Prokopchenko

    2015-10-01

    Full Text Available The article analyzes the basic methods and algorithms of mathematical processing of medical images as objects of computer mathematics. The presented methods and computer algorithms of mathematics relevant and may find application in the field of medical imaging - automated processing of images; as a tool for measurement and determination the optical parameters; identification and formation of medical images database. Methods and computer algorithms presented in the article and based on Wolfram Mathematica are also relevant to the problem of modern medical education. As an example of Wolfram Mathematics may be considered appropriate demonstration, such as recognition of special radiographs and morphological imaging. These methods are used to improve  the diagnostic significance and value of medical (clinical research and can serve as an educational interactive demonstration. Implementation submitted individual methods and algorithms of computer Wolfram Mathematics contributes, in general, the optimization process of practical processing and presentation of medical images.

  10. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

    International Nuclear Information System (INIS)

    Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

    2011-01-01

    Highlights: → We reported a patient with Wolfram syndrome and dilated cardiomyopathy. → We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). → Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. → The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

  11. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Mezghani, Najla [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Mnif, Mouna [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Mkaouar-Rebai, Emna, E-mail: emna_mkaouar@mail2world.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Kallel, Nozha [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Salem, Ikhlass Haj [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Charfi, Nadia; Abid, Mohamed [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

    2011-07-29

    Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

  12. Calidad de vida en familiares de pacientes con Síndrome de Wolfram

    Directory of Open Access Journals (Sweden)

    Gema Esteban Bueno

    2016-04-01

    Full Text Available El Síndrome de Wolfram (S.W. es una enfermedad rara (ER con una prevalencia estimada de 1/770000 habitantes que afecta a múltiples órganos y sistemas, considerándose esta enfermedad como crónica y progresiva. Su diagnóstico implica devastadoras consecuencias a nivel físico, educacional y emocional. Es conocido también por su acrónimo DIDMOAD que son las iniciales de sus principales componentes:Diabetes Insípida, Diabetes Mellitus, Atrofia óptica y sordera (Deafness. Las ER se caracterizan por su baja prevalencia y escasez de conocimientos y tratamientos sobre ellas. Es importante destacar que el 80% poseen una base genética y esto originará en la pareja dudas e incertidumbres ante la idea de tener otro hijo. La presencia en la familia de una ER altera significativamente las relaciones y la calidad de vida del sistema familiar. Este trabajo incide en la importancia de valorar los aspectos psicosociales de cara a poder dar una adecuada atención a estos pacientes no ciñéndose solamente a los aspectos meramente clínicos. El objetivo del presente estudio ha sido conocer la calidad de vida de los familiares de personas afectadas de S.W. y su repercusión en la vida diaria.

  13. The formation processes of oxide phases from polymer-salt complexes of ammonium molybdate and wolframate

    International Nuclear Information System (INIS)

    Valiev, E.; Bogdanov, S.; Pirogov, A.; Teplykh, A.; Ostroushko, A.; Mogilnikov, Yu.

    1999-01-01

    Complete text of publication follows. The thermal decomposition processes of the polymer-salt solutions of ammonium molybdate and wolframate are the basic methods to synthesize the powder catalysts MoO 3 and WO 3 . The results of the investigations of these processes by small angle neutron scattering and X-ray diffraction methods are presented. The parameters of the crystal structure of the oxide phase particles, a particle size distribution function, a specific surface and fractal dimension of particles surface, a volume part and mean particle size have been obtained. It is shown that the best catalytic properties are reached by heating initial samples up to 400 deg C. This state is defined by the mean particle size ∼ 15 nm, the specific surface ∼ 10 m 2 /g, the volume concentrations of particles ∼ 5 x 10 -2 and the fractal dimension of particles surface ∼ 2,5. A general mechanism for the formation of the oxide phases from different polymer-salt solution are established. The processes of the oxide phase formations occurs as the phase transition of the first kind, is also shown. This work has partly supported by state program 'Neutron Matter Investigations' (Project N96/104 and 96/305). (author)

  14. Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome.

    Science.gov (United States)

    Bodoor, Khaldon; Batiha, Osama; Abu-Awad, Ayman; Al-Sarihin, Khaldon; Ziad, Haya; Jarun, Yousef; Abu-Sheikha, Aya; Abu Jalboush, Sara; Alibrahim, Khoulod S

    2016-09-01

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder characterized by the presentation of early onset type I diabetes mellitus and optic atrophy with later onset diabetes insipidus and deafness. WFS1 gene was identified on chromosome 4p16.1 as the gene responsible for WS disease given that most of the WS patients were found to carry mutations in this gene. This study was carried out to investigate the molecular spectrum of WFS1 gene in Jordanian families. Molecular and clinical characterization was performed on five WS patients from two unrelated Jordanian families. Our data indicated that WS patients of the first family harbored two deletion mutations (V415del and F247fs) located in exon 8 and exon 7 respectively, with a compound heterozygous pattern of inheritance; while in the second family, we identified a novel nonsense mutation (W185X) located in exon 5 in the N-terminal cytoplasmic domain with a homozygous pattern of inheritance. This mutation can be considered as loss of function mutation since the resulting truncated protein lost both the transmembrane domain and the C-terminal domain. Additionally, the W185X mutation lies within the CaM binding domain in wolframin protein which is thought to have a role in the regulation of wolframin function in response to calcium levels.

  15. Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1.

    Science.gov (United States)

    Duan, Lian; Li, Qian; Tong, An-Li; Mao, Jiang-Feng; Yu, Miao; Yuan, Tao; Chai, Xiao-Feng; Gu, Feng

    2018-01-01

    Wolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now. We performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described. Six patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10-19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1 . Our series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

  16. Metabolomics of the Wolfram Syndrome 1 Gene (Wfs1) Deficient Mice.

    Science.gov (United States)

    Porosk, Rando; Terasmaa, Anton; Mahlapuu, Riina; Soomets, Ursel; Kilk, Kalle

    2017-12-01

    Wolfram syndrome 1 is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Mutations in the WFS1 gene encoding the wolframin glycoprotein can lead to endoplasmic reticulum stress and unfolded protein responses in cells, but the pathophysiology at whole organism level is poorly understood. In this study, several organs (heart, liver, kidneys, and pancreas) and bodily fluids (trunk blood and urine) of 2- and 6-month old Wfs1 knockout (KO), heterozygote (HZ), and wild-type (WT) mice were analyzed by untargeted and targeted metabolomics using liquid chromatography-mass spectrometry. The key findings were significant perturbations in the metabolism of pancreas and heart before the onset of related clinical signs such as glycosuria that precedes hyperglycemia and thus implies a kidney dysfunction before the onset of classical diabetic nephropathy. The glucose use and gluconeogenesis in KO mice are intensified in early stages, but later the energetic needs are mainly covered by lipolysis. Furthermore, in young mice liver and trunk blood hypouricemia, which in time turns to hyperuricemia, was detected. In summary, we show that the metabolism in Wfs1-deficient mice markedly differs from the metabolism of WT mice in many aspects and discuss the future biological and clinical relevance of these observations.

  17. Optic nerve histopathology in a case of Wolfram Syndrome: a mitochondrial pattern of axonal loss.

    Science.gov (United States)

    Ross-Cisneros, Fred N; Pan, Billy X; Silva, Ruwan A; Miller, Neil R; Albini, Thomas A; Tranebjaerg, Lisbeth; Rendtorff, Nanna D; Lodahl, Marianne; Moraes-Filho, Milton N; Moraes, Milton N; Salomao, Solange R; Berezovsky, Adriana; Belfort, Rubens; Carelli, Valerio; Sadun, Alfredo A

    2013-11-01

    Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four "quadrants": superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the temporal and inferior quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome.

    Science.gov (United States)

    Xavier, Jean; Bourvis, Nadège; Tanet, Antoine; Ramos, Tatiana; Perisse, Didier; Marey, Isabelle; Cohen, David; Consoli, Angèle

    2016-10-01

    Wolfram syndrome (WS, MIM 222300) is a rare autosomal, recessive neurodegenerative disorder associated with mutations in WFS1, a gene that has been associated with bipolar disorder (BD). WS, characterized by the association of juvenile-onset diabetes mellitus (DM) and bilateral progressive optic atrophy (BPOA), encompasses several other clinical features, including cognitive impairments and psychiatric disorders. Detailed data on the psychiatric phenotype are still scarce, and how WS relates to BD is still unknown. A 17-year-old girl with WS was hospitalized for early-onset BD. A multidisciplinary and developmental assessment was carried out to control mood symptoms and address how BD could be related to WS. Besides DM and BPOA, the patient had several risk factors for BD/mood disorders as follows: (1) a history of abuse and maltreatment; (2) a history of specific language disorder and borderline intelligence associated with academic failure; and (3) a comorbid hypothyroidism. Treatment encompassed all aspects of the adolescent's conditions, such as the use of mood stabilizers, addressing psychosocial and scholastic problems, and treating hypothyroid dysfunction. Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.

  19. Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

    Science.gov (United States)

    Titah, Salah Mohamed Cherif; Meunier, Isabelle; Blanchet, Catherine; Lopez, Severine; Rondouin, Gerard; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Paquis-Flucklinger, Veronique; Hamel, Christian P

    2012-01-01

    Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS. Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes. We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant. Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.

  20. Serum Metabolic Fingerprinting Identified Putatively Annotated Sphinganine Isomer as a Biomarker of Wolfram Syndrome.

    Science.gov (United States)

    Zmyslowska, Agnieszka; Ciborowski, Michal; Borowiec, Maciej; Fendler, Wojciech; Pietrowska, Karolina; Parfieniuk, Ewa; Antosik, Karolina; Pyziak, Aleksandra; Waszczykowska, Arleta; Kretowski, Adam; Mlynarski, Wojciech

    2017-11-03

    Wolfram syndrome (WFS) is an example of a rare neurodegenerative disease with coexisting endocrine symptoms including diabetes mellitus as the first clinical symptom. Treatment of WFS is still only symptomatic and associated with poor prognosis. Potential markers of disease progression that could be useful for possible intervention trials are not available. Metabolomics has potential to identify such markers. In the present study, serum fingerprinting by LC-QTOF-MS was performed in patients with WFS (n = 13) and in patients with T1D (n = 27). On the basis of the obtained results, aminoheptadecanediol (17:0 sphinganine isomer) (+50%, p = 0.02), as the most discriminatory metabolite, was selected for validation. The 17:0 sphinganine isomer level was determined using the LC-QQQ method in the samples from WFS patients at two time points and compared with samples obtained from patients with T1D (n = 24) and healthy controls (n = 24). Validation analysis showed higher 17:0 sphinganine isomer level in patients with WFS compared to patients with T1D (p = 0.0097) and control group (p < 0.0001) with progressive reduction of its level after two-year follow-up period. Patients with WFS show a unique serum metabolic fingerprint, differentiating them from patients with T1D. Sphinganine derivate seems to be a marker of the ongoing process of neurodegeneration in WFS patients.

  1. Multiple fractures and impaired bone metabolism in Wolfram syndrome: a case report.

    Science.gov (United States)

    Catalano, Antonino; Bellone, Federica; Cicala, Giuseppe; Giandalia, Annalisa; Morabito, Nunziata; Cucinotta, Domenico; Russo, Giuseppina Tiziana

    2017-01-01

    Wolfram Syndrome (WS) is a rare and lethal disease characterized by optic atrophy, diabetes mellitus, diabetes insipidus, and hearing loss. To date, osteoporotic related fractures have not been reported in affected patients. Here, we describe the case of a man affected by WS complicated by several bone fragility fractures. A 50-year-old Caucasian man was hospitalized because of tibia and fibula fractures. His clinical features included diabetes mellitus, diabetes insipidus, optic atrophy and deafness that were consistent with an unrecognized WS diagnosis, which was confirmed by the identification of a specific mutation in gene WFS1 encoding wolframin. Bone mineral density by phalangeal quantitative ultrasound demonstrated severe osteoporosis, with high serum levels of surrogate markers of bone turn-over. Previously unidentified rib fractures were also detected. To the best of our knowledge, this is the first report of osteoporotic related fractures in a patient affected by WS. Although no effective treatments are currently available to delay the progression of the disease, this case report suggests to evaluate fracture risk in the diagnostic work-up of WS.

  2. [An evaluation of HLA class 2 alleles and anti-islet antibodies as evidence for non-autoimmune diabetes in Wolfram syndrome].

    Science.gov (United States)

    Zmysłowska, Agnieszka; Borowiec, Maciej; Antosik, Karolina; Wyka, Krystyna; Cieślik-Heinrich, Agnieszka; Klich, Izabela; Młynarski, Wojciech

    2010-01-01

    A clinical criterion of the Wolfram syndrome is the coexistence of diabetes and optic atrophy recognized before the age of 15. Diabetes present in Wolfram syndrome is a result of the selective β cell loss and failed insulin secretion which is probably associated with non-autoimmune pathogenesis. The aim of the study was an evaluation of HLA subtypes and presence of β-cell autoantibodies in patients with molecularly confirmed Wolfram syndrome. 9 patients with Wolfram syndrome aged 10-24 years were examined. We also studied 218 patients with type 1 diabetes as a reference group. A control group of 176 healthy individuals was included in the study. Besides the clinical assessment the HLA typing by PCR-SSO was performed. Islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), thyrosine phosphatase antibodies (IA2A) and insulin antibodies (IAA) were also detected. In all nine patients the coexistence of diabetes with optic atrophy was observed and in 8/9 individuals additional symptoms were recognized. In patients with Wolfram syndrome a significantly lower age of diagnosis of diabetes (Me=5.0 years) than in type 1 diabetic children (Me=10.4; p=0.002) was observed. Studies of HLA subtypes demonstrated an increased prevalence of HLA-DQw1, DRB1⋅03 and/or 04 and DR2. A comparison of the frequency of the HLA alleles in patients with Wolfram syndrome with type 1 diabetic children showed a more frequent presence of the DRB1⋅1501 (p=0.03; OR=13.28 (2.44-72.12)) and DQB1⋅06 (p=0.016; OR=10.15 (2.49-41.35)) alleles in patients with Wolfram syndrome. Polish patients with Wolfram syndrome have a different profile of the HLA antigens with the presence of DR2, DQw1 and DRB3/4 allele and are negative for diabetes-related autoantibodies, which may confirm non-autoimmune β-cell destruction in this syndrome.

  3. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

    Science.gov (United States)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu-Wai-Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian-Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis-Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard; Barrett, Timothy G

    2017-07-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  4. Monogenic diabetes syndromes: Locus‐specific databases for Alström, Wolfram, and Thiamine‐responsive megaloblastic anemia

    Science.gov (United States)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu‐Wai‐Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian‐Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis‐Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard

    2017-01-01

    Abstract We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. PMID:28432734

  5. The Presence of Periodic Limb Movement Disorder in a Patient with Diabetes Mellitus and Optic Atrophy (Wolfram Syndrome

    Directory of Open Access Journals (Sweden)

    Bo Seong Kwon

    2014-12-01

    Full Text Available Wolfram syndrome (WFS is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD, together known as DIDMOAD. This syndrome is a rare autosomal recessive neurodegenerative disorder and typically begins wtih insulin-dependent diabetes mellitus. Periodic limb movement disorder (PLMD is characterized by periodic episodes of repetitive, highly stereotyped, limb movement during sleep, which results in disturbed sleep. Its pathophysiology is unclear. It is associated with many conditions, but we were unable to find a previous report regarding WFS accompanied by PLMD. We therefore report, for the first time, about a patient with WFS presenting with PLMD and discuss its pathomechanism with a literature review.

  6. Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

    Directory of Open Access Journals (Sweden)

    Lian Duan

    2018-02-01

    Full Text Available ObjectiveWolfram syndrome (WS is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM and optic atrophy (OA. We aim to characterize clinical features in Chinese patients who had been poorly studied until now.MethodsWe performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described.ResultsSix patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10–19 years. Blood glucose impairment, OA, and diabetes insipidus were present in all (100%, hearing impairment in four (66.7%, urological abnormalities in four (66.7%, neurological abnormalities in one (16.7%, and endocrine disorder in one (16.7%. Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93 was identified in exon 4 of WFS1.ConclusionOur series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

  7. Retinal thickness as a marker of disease progression in longitudinal observation of patients with Wolfram syndrome.

    Science.gov (United States)

    Zmyslowska, Agnieszka; Fendler, Wojciech; Waszczykowska, Arleta; Niwald, Anna; Borowiec, Maciej; Jurowski, Piotr; Mlynarski, Wojciech

    2017-11-01

    Wolfram syndrome (WFS) is a recessively inherited monogenic form of diabetes coexisting with optic atrophy and neurodegenerative disorders with no currently recognized markers of disease progression. The aim of the study was to evaluate retinal parameters by using optical coherence tomography (OCT) in WFS patients after 2 years of follow-up and analysis of the parameters in relation to visual acuity. OCT parameters and visual acuity were measured in 12 WFS patients and 31 individuals with type 1 diabetes. Total thickness of the retinal nerve fiber layer (RNFL), average retinal thickness and total retinal volume decreased in comparison with previous OCT examination. Significant decreases were noted for RNFL (average difference -17.92 µm 95% CI -30.74 to -0.10; p = 0.0157), macular average thickness (average difference -5.38 µm 95% CI -10.63 to -2.36; p = 0.0067) and total retinal volume (average difference -0.15 mm 3 95% CI -0.30 to -0.07; p = 0.0070). Central thickness remained unchanged (average difference 1.5 µm 95% CI -7.61 to 10.61; p = 0.71). Visual acuity of WFS patients showed a strong negative correlation with diabetes duration (R = -0.82; p = 0.0010). After division of WFS patients into two groups (with low-vision and blind patients), all OCT parameters except for the RNFL value were lower in blind WFS patients. OCT measures structural parameters and can precede visual acuity loss. The OCT study in WFS patients should be performed longitudinally, and serial retinal examinations may be helpful as a potential end point for future clinical trials.

  8. Visual pathway function and structure in Wolfram syndrome: patient age, variation and progression.

    Science.gov (United States)

    Hoekel, James; Narayanan, Anagha; Rutlin, Jerrel; Lugar, Heather; Al-Lozi, Amal; Hershey, Tamara; Tychsen, Lawrence

    2018-01-01

    To report alterations in visual acuity and visual pathway structure over an interval of 1-3 years in a cohort of children, adolescents and young adults who have Wolfram syndrome (WFS) and to describe the range of disease severity evident in patients with WFS whose ages differed by as much as 20 years at first examination. Annual, prospective ophthalmological examinations were performed in conjunction with retinal nerve fibre layer (RNFL) analysis. Diffusion tensor MRI-derived fractional anisotropy was used to assess the microstructural integrity of the optic radiations (OR FA). Mean age of the 23 patients with WFS in the study was 13.8 years (range 5-25 years). Mean log minimum angle resolution visual acuity was 0.66 (20/91). RNFL thickness was subnormal in even the youngest patients with WFS. Average RNFL thickness in patients with WFS was 57±8 µ or ~40% thinner than that measured in normal (94±10 µ) children and adolescents (P<0.01). Lower OR FA correlated with worse visual acuity (P=0.006). Subsequent examinations showed declines (P<0.05) in visual acuity, RNFL thickness and OR FA at follow-up intervals of 12-36 months. However, a wide range of disease severity was evident across ages: some of the youngest patients at their first examination had deficits more severe than the oldest patients. The genetic mutation of WFS causes damage to both pregeniculate and postgeniculate regions of the visual pathway. The damage is progressive. The decline in visual pathway structure is accompanied by declines of visual function. Disease severity differs widely in individual patients and cannot be predicted from their age.

  9. Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications.

    Science.gov (United States)

    Zmyslowska, A; Borowiec, M; Fichna, P; Iwaniszewska, B; Majkowska, L; Pietrzak, I; Szalecki, M; Szypowska, A; Mlynarski, W

    2014-01-01

    Improvements in diagnostic methods and greater genetic awareness have brought remarkable progress in the recognition of monogenic forms of diabetes, including Wolfram syndrome (WFS). WFS is diagnosed based on clinical criteria of coexistence of diabetes mellitus and optic atrophy, and confirmed by molecular analysis; however, the condition is still sometimes misdiagnosed. To begin to understand the reasons for misdiagnosis, we conducted a retrospective analysis of WFS patients who were originally misdiagnosed. The medical histories of 13 pediatric patients with clinical misdiagnosis of type 1 diabetes and early chronic complications made in the years 1995-2010 and who were subsequently correctly diagnosed with WFS based on genetic testing in 2008-2011 were analyzed. The average age of the patients at diabetes onset was 5 (4.4-6.3) years, and the mean HbA1c level at diagnosis was 9.1±2.3%. Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). Diagnosis of optic atrophy was made at an average age of 9 (5.9-11.5) years, which corresponds to 4 years after diabetes recognition (p=0.002). At the time of genetic analysis, the average age of the patients was 16 (12-18.7) years, which corresponds to 7 years after recognition of coexistence of diabetes mellitus and optic atrophy (p=0.007). Delays of at least 7 years occurred before recognition of WFS among a cohort of pediatric patients with diabetes. All patients with WFS were primarily misdiagnosed as having type 1 diabetes. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  10. False diagnosis of type 1 diabetes mellitus and its complications in Wolfram syndrome--is it the reason for the low number of reported cases of this abnormality?

    Science.gov (United States)

    Homa, Katarzyna; Stefański, Adam; Zmysłowska, Agnieszka; Molęda, Piotr; Bryśkiewicz, Marta Ewa; Majkowska, Liliana

    2014-01-01

    Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive syndrome (1/770,000 in the United Kingdom), characterised by juvenile onset of diabetes mellitus, optic nerve atrophy, diabetes insipidus, sensorineural deafness, renal tract and neurological abnormalities, and primary gonadal atrophy. WS is caused mainly by biallelic mutations in the WFS1 gene, which encodes wolframin. Wide tissue distribution of wolframin and many mutations in the wolframin gene resulting in Wolfram syndrome may contribute to different phenotypes and the unusual combinations of clinical features. We describe a female patient with Wolfram syndrome diagnosed at the age of 25, with a previous false diagnosis of type 1 diabetes mellitus and misdiagnosed diabetic complications. The patient was found to be a compound heterozygote for two novel mutations in exon 8 of WFS1 gene: a 2-bp deletion AT at nt 1539 leading to a frameshift (Y513fs) and a single-base substitution 1174C > T resulting in a stop codon (Q392X). A detailed analysis of the patient's medical history and a review of the literature suggest that many cases of Wolfram syndrome may remain undiagnosed due to misdiagnosis as type 1 diabetes mellitus and incorrect interpretation of clinical symptoms of neurodegenerative abnormalities, especially in their early stages.

  11. The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2

    NARCIS (Netherlands)

    Gabreëls, B. A.; Swaab, D. F.; de Kleijn, D. P.; Dean, A.; Seidah, N. G.; van de Loo, J. W.; van de Ven, W. J.; Martens, G. J.; van Leeuwen, F. W.

    1998-01-01

    Wolfram syndrome (WS) is characterized by optic atrophy, insulin-dependent diabetes mellitus, vasopressin (VP)-sensitive diabetes insipidus, and neurosensory hearing loss. Here we report a disturbance in VP precursor processing in the supraoptic and paraventricular nuclei of WS patients. In these

  12. A clinical case study of a Wolfram syndrome-affected family: pattern-reversal visual evoked potentials and electroretinography analysis.

    Science.gov (United States)

    Langwińska-Wośko, Ewa; Broniek-Kowalik, Karina; Szulborski, Kamil

    2012-04-01

    Wolfram syndrome (WFS), or DIDMOAD, is a rare (1/100 000 to 1/770 000), progressive neurodegenerative disorder. In its early stages, it is characterized by insulin-dependent diabetes mellitus, optic atrophy and loss of sensorineural hearing-this is followed by diabetes insipidus, progressive neurological abnormalities and other endocrine abnormalities, which occur in later years. The aim of this study was to report on the clinical and electrophysiological findings from a family with the WFS1 mutation. The five family members were subjected to a complete ophthalmic examination, which included a flash full-field electroretinogram and pattern-reversal visual evoked potentials (PVEPs) performed according to ISCEV standards. Optic atrophy was confirmed in two homozygotic patients, where P100 latencies were significantly delayed-up to 146 ms in PVEP. P100 latencies were normal in the three heterozygotic patients we examined. Curve morphology abnormalities were observed in all five patients we examined. No literature describing the morphology of PVEP in Wolfram syndrome patients was found. In flash electroretinography, scotopic and photopic responses appeared in normal morphology and value. Diabetic retinopathy was not observed in the diabetes mellitus patients.

  13. Central nervous system PET-CT imaging reveals regional impairments in pediatric patients with Wolfram syndrome.

    Directory of Open Access Journals (Sweden)

    Agnieszka Zmyslowska

    Full Text Available Wolfram syndrome (WFS is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography and MRI (magnetic resonance imaging in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs based on images of (18F fluorodeoxyglucose (FDG uptake in 7 WFS patients aged 10.1-16.0 years (mean 12.9±2.4 and in 20 healthy children aged 3-17.9 years (mean 12.8±4.1. In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups 13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (-1.24±1.20 vs. -0.13±1.05; p = 0.028 and cerebellum (-1.11±0.69 vs. -0.204±1.00; p = 0.036 were observed and the same tendency for cingulate (-1.13±1.05 vs. -0.15±1.12; p = 0.056, temporal lobe (-1.10±0.98 vs. -0.15±1.10; p = 0.057, parietal lobe (-1.06±1.20 vs. -0.08±1.08; p = 0.058, central region (-1.01±1.04 vs. -0.09±1.06; p = 0.060, basal ganglia (-1.05±0.74 vs. -0.20±1.07; p = 0.066 and mesial temporal lobe (-1.06±0.82 vs. -0.26±1.08; p = 0.087 was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging.

  14. A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype.

    Science.gov (United States)

    Elli, Francesca M; Ghirardello, Stefano; Giavoli, Claudia; Gangi, Silvana; Dioni, Laura; Crippa, Milena; Finelli, Palma; Bergamaschi, Silvia; Mosca, Fabio; Spada, Anna; Beck-Peccoz, Paolo

    2012-11-01

    Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus (DI), insulin-dependent diabetes mellitus (DM), optic atrophy (OA) and deafness caused by mutations in WFS1 gene (4p16.1), which encodes an endoplasmic reticulum protein, called Wolframin. We describe the case of an infant who presented hypernatremia and severe hypoplasia of the left eyeball with alteration of visual evoked potentials. Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output. Brain magnetic resonance imaging showed absence of the neurohypophysis hyperintense signal, normal adenohypophysis and optic tracts hypoplasia. The concomitant presence of DI and OA, even in the absence of DM and deafness, prompted the suspicion of WS and complete genetic analysis was performed. Genomic DNA sequencing of WFS1 showed no inactivating mutations described to date, but suggested a structural mutation as markers genotyping revealed a segmental paternal heterodisomy involving the upstream regulatory region (promoter and 5'UTR). cDNA sequencing revealed the coexistence of the wild-type transcript and two splice variants; one variant, probably benign, is known in literature and the other one causes the loss of exon 2, containing the translation initiation site. Western blot confirmed a marked protein reduction. During the clinical follow-up child's condition remained stable and glucose metabolism is still in the standard. In conclusion, the phenotype associated with this structural rearrangement, which substantially reduces the synthesis of Wolframin, confirms a tissue-specific pattern of expression of WFS1, suggests the presence of a different protein dosage sensitivity in different tissues and could be causative of DI and OA in our patient. The "incomplete" phenotype here described, usually

  15. Glycemic variability in patients with Wolfram syndrome is lower than in type 1 diabetes.

    Science.gov (United States)

    Zmyslowska, A; Fendler, W; Szadkowska, A; Borowiec, M; Mysliwiec, M; Baranowska-Jazwiecka, A; Buraczewska, M; Fulmanska-Anders, M; Mianowska, B; Pietrzak, I; Rzeznik, D; Mlynarski, W

    2015-12-01

    Wolfram syndrome (WFS) is diagnosed as coexistence of diabetes mellitus and optic atrophy, where pancreatic beta cell destruction is associated with neurodegeneration. Typically, WFS necessitates insulin treatment similar to type 1 diabetes (T1D), but the mechanism of beta cell mass reduction leading to hyperglycemia is different. The aim of the study was to assess glycemic variability using the continuous glucose monitoring (CGM) system in seven pediatric patients with genetically confirmed WFS and compare the results with data obtained from 21 propensity score-matched patients with T1D. The "GlyCulator" application was used for the calculation of glycemic variability indices. CGM recordings showed similarities in glycemic variability among WFS patients, but differing from those of the T1D group. Coefficient of variation (%CV), CONGA4h, and GONGA6h were significantly (p < 0.05) lower in WFS patients (28.08 ± 7.37, 54.96 ± 11.92, and 55.99 ± 10.58) than in T1D patients (37.87 ± 14.24, 74.12 ± 28.74, p = 0.02, and 80.26 ± 35.05, respectively). In WFS patients, the percentage of values above 126 mg/dL was 69.79 (52.08-77.43), whereas in patients with T1D, the percentage was significantly lower-47.22 (35.07-62.85, p = 0.018). Curiously, a tendency toward a lower percentage of measurements below 70 mg/dL was noted in the WFS group [0 (0-7.29)] in comparison with the T1D group [6.25 (0-18.06), p = 0.122]. WFS patients had a significantly higher C-peptide level (0.31 ± 0.2 ng/mL) than T1D patients (0.04 ± 0.04 ng/mL; p = 0.006). Patients with WFS show smaller glycemic variability than individuals with T1D, and this may be associated with persistent residual insulin secretion.

  16. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product.

    Science.gov (United States)

    Hofmann, Sabine; Philbrook, Christine; Gerbitz, Klaus-Dieter; Bauer, Matthias F

    2003-08-15

    Mutations of the WFS1 gene are responsible for Wolfram syndrome, a rare, recessive disorder characterized by early-onset, non-autoimmune diabetes mellitus, optic atrophy and further neurological and endocrinological abnormalities. The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum. The function of wolframin is completely unknown. In order to characterize wolframin, we have generated polyclonal antibodies against both hydrophilic termini of the protein. Wolframin was found to be ubiquitously expressed with highest levels in brain, pancreas, heart and insulinoma beta-cell lines. Analysis of the structural features provides experimental evidence that wolframin contains nine transmembrane segments and is embedded in the membrane in an N(cyt)/C(lum) topology. Wolframin assembles into higher molecular weight complexes of approximately 400 kDa in the membrane. Pulse-chase experiments demonstrate that during maturation wolframin is N-glycosylated but lacks proteolytical processing. Moreover, N-glycosylation appears to be essential for the biogenesis and stability of wolframin. Here we investigate, for the first time, the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. In patients harboring nonsense mutations complete absence of the mutated wolframin is caused by instability and rapid decay of WFS1 nonsense transcripts. In a patient carrying a compound heterozygous missense mutation, R629W, we found markedly reduced steady-state levels of wolframin. Pulse-chase experiments of mutant wolframin expressed in COS-7 cells indicated that the R629W mutation leads to instability and strongly reduced half-life of wolframin. Thus, the Wolfram syndrome in patients investigated here is caused by reduced protein dosage rather than dysfunction of the mutant wolframin.

  17. Identification of unsuspected Wolfram syndrome cases through clinical assessment and WFS1 gene screening in type 1 diabetes mellitus patients.

    Science.gov (United States)

    Blanco-Aguirre, Maria E; la Parra, David Rivera-De; Tapia-Garcia, Hugo; Gonzalez-Rodriguez, Johanna; Welschen, Daniela; Welskin, Daniela; Arroyo-Yllanes, Maria Estela; Escudero, Irineo; Nuñez-Hernandez, Jorge A; Medina-Bravo, Patricia; Zenteno, Juan C

    2015-07-15

    Wolfram syndrome (WS) is a severe autosomal recessive pleiotropic disease primarily characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. Earlier reports have shown that a proportion of WS cases may remain unrecognized due to misdiagnosis as type 1 diabetes mellitus (T1DM). The objectives of this work were to estimate the prevalence of patients fulfilling clinical criteria for WS in a cohort of subjects diagnosed as T1DM and to identify causal WFS1 gene mutations in those individuals meeting clinical criteria for the disease. A cohort of 131 unrelated Mexican T1DM patients was collected, including 77 females and 54 males. Additional clinical anomalies suggesting WS were identified through review of medical files, detailed physical examination and/or specialized tests. WFS1 gene analysis was performed using exon-by-exon PCR amplification and direct Sanger sequencing on genomic DNA from patients reaching WS clinical criteria. Clinical criteria for a WS diagnosis were reached in 6 probands, corresponding to a 4.58% frequency of the disease. WFS1 mutations were identified in 4 out of 5 (80%) individuals fulfilling WS clinical criteria, including two homozygous, one compound heterozygous, and one patient with a single allele mutation. No WFS1 mutations were identified in the remaining subject. In our cohort, approximately 6% of cases diagnosed as T1DM were in fact patients with Wolfram syndrome. WFS1 mutations were identified in 4 out of 5 individuals (80%) fulfilling clinical criteria for WS. Clinical and genetic analyses of large cohorts of T1DM patients from different ethnic origins would help to better estimate the occurrence of WS and will lead to a better management of such patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic beta-cells.

    Science.gov (United States)

    Hatanaka, Masayuki; Tanabe, Katsuya; Yanai, Akie; Ohta, Yasuharu; Kondo, Manabu; Akiyama, Masaru; Shinoda, Koh; Oka, Yoshitomo; Tanizawa, Yukio

    2011-04-01

    Wolfram syndrome is an autosomal recessive disorder characterized by juvenile-onset insulin-dependent diabetes mellitus and optic atrophy. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER) resident transmembrane protein. The Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes. Previous work suggested that the function of the WFS1 protein is connected to unfolded protein response and to intracellular Ca(2+) homeostasis. However, its precise molecular function in pancreatic β-cells remains elusive. In our present study, immunofluorescent and electron-microscopic analyses revealed that WFS1 localizes not only to ER but also to secretory granules in pancreatic β-cells. Intragranular acidification was assessed by measuring intracellular fluorescence intensity raised by the acidotrophic agent, 3-[2,4-dinitroanilino]-3'-amino-N-methyldipropyramine. Compared with wild-type β-cells, there was a 32% reduction in the intensity in WFS1-deficient β-cells, indicating the impairment of granular acidification. This phenotype may, at least partly, account for the evidence that Wfs1-null islets have impaired proinsulin processing, resulting in an increased circulating proinsulin level. Morphometric analysis using electron microscopy evidenced that the density of secretory granules attached to the plasma membrane was significantly reduced in Wfs1-null β-cells relative to that in wild-type β-cells. This may be relevant to the recent finding that granular acidification is required for the priming of secretory granules preceding exocytosis and may partly explain the fact that glucose-induced insulin secretion is profoundly impaired in young prediabetic Wfs1-null mice. These results thus provide new insights into the molecular mechanisms of β-cell dysfunction in patients with Wolfram syndrome.

  19. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

    Science.gov (United States)

    Matsunaga, Kimie; Tanabe, Katsuya; Inoue, Hiroshi; Okuya, Shigeru; Ohta, Yasuharu; Akiyama, Masaru; Taguchi, Akihiko; Kora, Yukari; Okayama, Naoko; Yamada, Yuichiro; Wada, Yasuhiko; Amemiya, Shin; Sugihara, Shigetaka; Nakao, Yuzo; Oka, Yoshitomo; Tanizawa, Yukio

    2014-01-01

    Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

  20. [Research progress of mutational spectrum and pathophysiology of WFS1 gene in Wolfram syndrome and nonsyndromic low frequency sensorineural hearing loss].

    Science.gov (United States)

    Shi, S M; Han, Y H; Wang, H B

    2016-09-07

    Compound homozygous or heterozygous mutations in WFS 1 can lead to autosomal recessive Wolfram syndrome (WS), and heterozygous mutations in WFS 1 can lead to autosomal dominant non-syndromic low frequency sensorineural hearing loss (LFSNHL). In addition, mutations in the WFS region has relationship with diabetes and psychiatric diseases. In this paper, we provide an overview of genetic research with different phenotypes, including WS and LFSNHL.

  1. Identification and characterization of wolframin, the product of the wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein.

    Science.gov (United States)

    Yurimoto, Saki; Hatano, Naoya; Tsuchiya, Mitsumasa; Kato, Kiyohito; Fujimoto, Tomohito; Masaki, Tsutomu; Kobayashi, Ryoji; Tokumitsu, Hiroshi

    2009-05-12

    To search for calmodulin (CaM) targets, we performed affinity chromatography purification of a rat brain extract using CaM fused with GST as the affinity ligand. Proteomic analysis was then carried out to identify CaM-binding proteins. In addition to identifying 36 known CaM-binding proteins, including CaM kinases, calcineurin, nNOS, the IP(3) receptor, and Ca(2+)-ATPase, we identified an ER transmembrane protein, wolframin [the product of the Wolfram syndrome gene (WFS1)] as interacting. A CaM overlay and an immunoprecipitation assay revealed that wolframin is capable of binding the Ca(2+)/CaM complex in vitro and in transfected cells. Surface plasmon resonance analysis and zero-length cross-linking showed that the N-terminal cytoplasmic domain (residues 2-285) of wolframin binds to an equimolar unit of CaM in a Ca(2+)-dependent manner with a K(D) for CaM of 0.15 muM. Various truncation and deletion mutants showed that the Ca(2+)/CaM binding region in wolframin is located from Glu90 to Trp186. Furthermore, we demonstrated that three mutations (Ala127Thr, Ala134Thr, and Arg178Pro) associated with Wolfram syndrome completely abolished CaM binding of wolframin. This observation may indicate that CaM binding is important for wolframin function and that impairment of this interaction by mutation contributes to the pathology seen in Wolfram syndrome.

  2. Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro).

    Science.gov (United States)

    Yuca, Sevil Ari; Rendtorff, Nanna Dahl; Boulahbel, Houda; Lodahl, Marianne; Tranebjærg, Lisbeth; Cesur, Yasar; Dogan, Murat; Yilmaz, Cahide; Akgun, Cihangir; Acikgoz, Mehmet

    2012-01-01

    Wolfram syndrome, also named "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an inherited association of juvenile-onset diabetes mellitus and optic atrophy as key diagnostic criteria. Renal tract abnormalities and neurodegenerative disorder may occur in the third and fourth decade. The wolframin gene, WFS1, associated with this syndrome, is located on chromosome 4p16.1. Many mutations have been described since the identification of WFS1 as the cause of Wolfram syndrome. We identified a new homozygous WFS1 mutation (c.1532T>C; p.Leu511Pro) causing Wolfram syndrome in a large inbred Turkish family. The patients showed early onset of IDDM, diabetes insipidus, optic atrophy, sensorineural hearing impairment and very rapid progression to renal failure before age 12 in three females. Ectopic expression of the wolframin mutant in HEK cells results in greatly reduced levels of protein expression compared to wild-type wolframin, strongly supporting that this mutation is disease-causing. The mutation showed perfect segregation with disease in the family, characterized by early and severe clinical manifestations. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  3. A new mutation in WFS1 gene (C.1522-1523delTA, Y508fsX421) may be responsible for early appearance of clinical features of Wolfram syndrome and suicidal behaviour.

    Science.gov (United States)

    Aluclu, Mehmet Ufuk; Bahceci, Mithat; Tuzcu, Alpaslan; Arikan, Senay; Gokalp, Deniz

    2006-12-01

    Wolfram syndrome (WS) is an autosomal recessive disorder characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. It is also known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We diagnosed Wolfram syndrome in 2 male siblings and determined a new mutation (c. 1522-1523delTA, Y508fsX421). Both affected siblings were homozygous, other family members were heterozygous. Dilated renal outflow tracts in the third decade, and neuropsychiatric disorders including bipolar disorder and neurosensorial deafness appear in the fourth decade in ordinary WS, whereas these features appeared in second decade in our patients. This mutation may be responsible for early appearance of dilated renal outflow tracts and multiple neurological abnormalities. Psychiatric disturbances such as suicide were reported at increased frequency in Wolfram patients and in heterozygous carriers. Suicidal behaviour occurred in our patients when they were yet 11 and 13 years old. Therefore, our findings may indicate that there may be a relationship between this WFS1 mutation and mood disorder such as suicidal behaviour. We determined a new mutation (c. 1522-1523delTA, Y508fsX421) in WS1 gene in 2 siblings with Wolfram syndrome. This mutation may be responsible for early appearance of clinical features of Wolfram syndrome, and there may be a relationship between this mutation and suicidal behaviour.

  4. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

    Directory of Open Access Journals (Sweden)

    Kimie Matsunaga

    Full Text Available BACKGROUND: Wolfram syndrome (WFS is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1. However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. METHODOLOGY: The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. PRINCIPAL FINDINGS: Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49% having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5% had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5% had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. CONCLUSION/SIGNIFICANCE: This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may

  5. Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells.

    Science.gov (United States)

    Philbrook, Christine; Fritz, Eberhard; Weiher, Hans

    2005-01-01

    Wolfram Syndrome is an autosomal recessive degenerative disorder of the neuroendocrine system. Diabetes mellitus is its lead symptom. Patients show mutations in the wolframin (WFS1) gene coding for a hydrophobic transmembrane protein of 890 amino acids. This protein was preliminarily localised in the endoplasmatic reticulum (ER) in cells of mice and rats. Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress. We here used antibodies against substructures of the wolframin protein in order to analyse its expression and localisation. Expression was detected in both pancreatic beta-cells and the limbic system of mice. Using the rat insulinoma cell line RIN 5AH and fractionated mouse brain tissue, we confirmed wolframin localisation to the endoplasmic reticulum. Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence. However, cell proliferation was indistinguishable from non-mutated cells. In contrast to data obtained on murine pancreatic islets, we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death.

  6. Clinical and molecular genetic analysis of a new mutation in children with Wolfram syndrome: a case report.

    Science.gov (United States)

    Xu, Qianqian; Qu, Huaiyu; Wei, Shihui

    2013-03-01

    A 12‑year‑old Chinese girl presented with gradual vision loss and insulin‑dependent diabetes mellitus and was suspected to suffer from Wolfram syndrome (WFS). A series of clinical examinations were performed, as well as direct DNA sequencing to screen the entire coding region of the WFS1 gene in the patient's family, including her parents and a brother. Ophthalmological examination revealed counting fingers/10 cm in the right eye and hand motions/10 cm in the left eye. Ophthalmoscopical examination identified bilateral optic atrophy without any signs of diabetic retinopathy. A hearing test was performed and revealed that the hearing ability for high frequency sounds was decreased. Urinary output in 24 h was >5,000 ml. In addition, a base substitution at c.2411T>C (Leu804Pro) in exon 8 was identified which was homozygous with the patient and heterozygous with the healthy parents and the brother. In the present case, a neuroophthalmology consult performed in the early stages of the disease was crucial for early diagnosis. In addition, this case study highlights the importance of performing a hearing test as well as collecting and analyzing 24‑h urine output in patients presenting with juvenile diabetes mellitus patients and optic atrophy without any signs of diabetic retinopathy.

  7. Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration.

    Science.gov (United States)

    Plaas, Mario; Seppa, Kadri; Reimets, Riin; Jagomäe, Toomas; Toots, Maarja; Koppel, Tuuliki; Vallisoo, Tuuli; Nigul, Mait; Heinla, Indrek; Meier, Riho; Kaasik, Allen; Piirsoo, Andres; Hickey, Miriam A; Terasmaa, Anton; Vasar, Eero

    2017-08-31

    Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.

  8. Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis.

    Science.gov (United States)

    Wiley, Sandra E; Andreyev, Alexander Y; Divakaruni, Ajit S; Karisch, Robert; Perkins, Guy; Wall, Estelle A; van der Geer, Peter; Chen, Yi-Fan; Tsai, Ting-Fen; Simon, Melvin I; Neel, Benjamin G; Dixon, Jack E; Murphy, Anne N

    2013-06-01

    Miner1 is a redox-active 2Fe2S cluster protein. Mutations in Miner1 result in Wolfram Syndrome, a metabolic disease associated with diabetes, blindness, deafness, and a shortened lifespan. Embryonic fibroblasts from Miner1(-/-) mice displayed ER stress and showed hallmarks of the unfolded protein response. In addition, loss of Miner1 caused a depletion of ER Ca(2+) stores, a dramatic increase in mitochondrial Ca(2+) load, increased reactive oxygen and nitrogen species, an increase in the GSSG/GSH and NAD(+)/NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Furthermore, mitochondria in fibroblasts lacking Miner1 displayed ultrastructural alterations, such as increased cristae density and punctate morphology, and an increase in O2 consumption. Treatment with the sulphydryl anti-oxidant N-acetylcysteine reversed the abnormalities in the Miner1 deficient cells, suggesting that sulphydryl reducing agents should be explored as a treatment for this rare genetic disease. Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  9. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions.

    Science.gov (United States)

    Rouzier, Cécile; Moore, David; Delorme, Cécile; Lacas-Gervais, Sandra; Ait-El-Mkadem, Samira; Fragaki, Konstantina; Burté, Florence; Serre, Valérie; Bannwarth, Sylvie; Chaussenot, Annabelle; Catala, Martin; Yu-Wai-Man, Patrick; Paquis-Flucklinger, Véronique

    2017-05-01

    Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease. © The Author 2017. Published by Oxford University Press.

  10. QUANTUM: A Wolfram Mathematica add-on for Dirac Bra-Ket Notation, Non-Commutative Algebra, and Simulation of Quantum Computing Circuits

    Science.gov (United States)

    Gómez Muñoz, J. L.; Delgado, F.

    2016-03-01

    This paper introduces QUANTUM, a free library of commands of Wolfram Mathematica that can be used to perform calculations directly in Dirac braket and operator notation. Its development started several years ago, in order to study quantum random walks. Later, many other features were included, like operator and commutator algebra, simulation and graphing of quantum computing circuits, generation and solution of Heisenberg equations of motion, among others. To the best of our knowledge, QUANTUM remains a unique tool in its use of Dirac notation, because it is used both in the input and output of the calculations. This work depicts its usage and features in Quantum Computing and Quantum Hamilton Dynamics.

  11. QUANTUM: A Wolfram Mathematica add-on for Dirac Bra-Ket Notation, Non-Commutative Algebra, and Simulation of Quantum Computing Circuits

    International Nuclear Information System (INIS)

    Muñoz, J L Gómez; Delgado, F

    2016-01-01

    This paper introduces QUANTUM, a free library of commands of Wolfram Mathematica that can be used to perform calculations directly in Dirac braket and operator notation. Its development started several years ago, in order to study quantum random walks. Later, many other features were included, like operator and commutator algebra, simulation and graphing of quantum computing circuits, generation and solution of Heisenberg equations of motion, among others. To the best of our knowledge, QUANTUM remains a unique tool in its use of Dirac notation, because it is used both in the input and output of the calculations. This work depicts its usage and features in Quantum Computing and Quantum Hamilton Dynamics. (paper)

  12. Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.

    Science.gov (United States)

    Raud, Sirli; Reimets, Riin; Loomets, Maarja; Sütt, Silva; Altpere, Alina; Visnapuu, Tanel; Innos, Jürgen; Luuk, Hendrik; Plaas, Mario; Volke, Vallo; Vasar, Eero

    2015-08-01

    Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.

    Science.gov (United States)

    Danielpur, Liron; Sohn, Yang-Sung; Karmi, Ola; Fogel, Chen; Zinger, Adar; Abu-Libdeh, Abdulsalam; Israeli, Tal; Riahi, Yael; Pappo, Orit; Birk, Ruth; Zangen, David H; Mittler, Ron; Cabantchik, Zvi-Ioav; Cerasi, Erol; Nechushtai, Rachel; Leibowitz, Gil

    2016-10-01

    Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). A case report and in vitro mechanistic studies. We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of β-cell dysfunction and the effects of GLP-1-RA. Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

  14. Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

    Science.gov (United States)

    Haghighi, Amirreza; Haghighi, Alireza; Setoodeh, Aria; Saleh-Gohari, Nasrollah; Astuti, Dewi; Barrett, Timothy G

    2013-01-01

    Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families. PMID:22781099

  15. Tungsten/wolfram: A little-known connection between the 18th century Basque Country and SOFT 2014 in Donostia/San Sebastián

    Energy Technology Data Exchange (ETDEWEB)

    Román, Pascual [Departamento de Química Inorgánica, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Apartado 644, E-48080 Bilbao (Spain); Ascasíbar, Enrique, E-mail: enrique.ascasibar@ciemat.es [Laboratorio Nacional de Fusión, CIEMAT, Avda. Complutense 40, 28040 Madrid (Spain)

    2015-10-15

    Highlights: • SOFT 2014 has taken place in Donostia/San Sebastián. • Tungsten/wolfram (W) is a strategic material for the development of fusion. • W was isolated very close to Donostia in the late 18th century as a result of a combination of fortunate circumstances. • This fact is largely unknown even to the fusion materials experts working with W. • We describe this story with some detail. - Abstract: This paper is intended as a preface of the special issue that Fusion Engineering and Design will devote to the best papers presented in the Symposium on Fusion Technology, 2014 (SOFT 2014) that took place in Donostia/San Sebastián. It is a historical note dwelling on the largely unknown story of the isolation of tungsten/wolfram in Spain, more precisely, in the Basque Country, very close to Donostia/San Sebastián, in the late 18th century. Given the current strategic importance of tungsten in the development of fusion as a viable energy source we think it is timely to recall the protagonists and the circumstances involved in the isolation of this metal.

  16. Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2014-11-01

    Wolfram syndrome also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare neurodegenerative autosomal recessive disorder. There is evidence of variable expressivity both in patients and heterozygous carriers. In this study, we describe three Persian Wolfram syndrome families with differences in the age of onset, signs and symptoms of the disease. We clinically evaluated affected families for verifying WS clinical diagnosis. After linkage analysis via 5 STR markers, molecular analysis for WFS1 was performed by direct sequencing for patients and available family members. Three homozygous mutations were identified including c.1885 C>T, c.2205C>A both in exon 8 and c.460+1G>A in intron 4. The mutation c.2205C>A was found to be novel. We report interesting phenotype-genotype correlations: homozygous c.1885C>T and c.2205C>A variants were correlated with quite different disease severity and onset in the siblings. We report a rare case of WS with homozygous c.1885C>T who is married and has a healthy child. c.460+1G>A showed a possible partial dominant inheritance put forth by a heterozygous parent showing partial WS symptoms while her daughter displayed typical WS symptoms. Due to variable expressivity, detailed clinical examination and molecular diagnostics should be used to confirm WS and a more exact recurrence risk data.

  17. Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility.

    Science.gov (United States)

    Haghighi, Amirreza; Haghighi, Alireza; Setoodeh, Aria; Saleh-Gohari, Nasrollah; Astuti, Dewi; Barrett, Timothy G

    2013-03-01

    Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families.

  18. A p.(Glu809Lys) Mutation in the WFS1 Gene Associated with Wolfram-like Syndrome: A Case Report.

    Science.gov (United States)

    Prochazkova, Dagmar; Hruba, Zuzana; Konecna, Petra; Skotakova, Jarmila; Fajkusova, Lenka

    2016-12-01

    Wolfram-like syndrome (WFSL) is a rare autosomal dominant disease characterised by congenital progressive hearing loss, diabetes mellitus, and optic atrophy. The patient was a boy with the juvenile form of diabetes mellitus and findings which clinically matched the symptoms of Wolfram syndrome. At the age of 3 1/4 years, diabetes mellitus was diagnosed in this boy who also had severe psychomotor retardation, failure to thrive, a dysmorphic face with Peters anomaly type 3 (i.e. posterior central defect with stromal opacity of the cornea, adhering stripes of the iris, and cataract with corneolenticular adhesion), congenital glaucoma, megalocornea, severe hearing impairment, a one-sided deformity of the auricle with atresia of the bony and soft external auditory canal, non-differentiable eardrum, missing os incus, hypothyreosis, and nephrocalcinosis. Molecular-genetic examinations revealed a de novo mutation p.(Glu809Lys) in the WFS1 gene. No mutations were detected in the biological parents. The mutation p.(Glu809Lys) in the WFS1 gene is associated with WFSL.

  19. Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A).

    Science.gov (United States)

    Çelmeli, Gamze; Türkkahraman, Doğa; Çürek, Yusuf; Houghton, Jayne; Akçurin, Sema; Bircan, İffet

    2017-03-01

    Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in WFS1 gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis.

  20. Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2013-10-10

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS. © 2013 Elsevier B.V. All rights reserved.

  1. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome.

    Science.gov (United States)

    Morikawa, Shuntaro; Tajima, Toshihiro; Nakamura, Akie; Ishizu, Katsura; Ariga, Tadashi

    2017-12-01

    Wolfram syndrome (WS) is a disorder characterized by the association of insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as "ER stress". This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract and severe bilateral hearing loss. Analyze the WFS1 and functional consequence of the patient WFS1 in vitro. The patient WFS1 contained a heterozygous 4 amino acid in-frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6α promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T-cell reporter activity, reflecting elevated cytosolic Ca 2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca 2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca 2+ homeostasis, decreased SERCA2b expression might affect ER Ca 2+ efflux, causing cell apoptosis. A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca 2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome.

    Science.gov (United States)

    Farmer, Amy; Aymé, Ségolène; de Heredia, Miguel Lopez; Maffei, Pietro; McCafferty, Susan; Młynarski, Wojciech; Nunes, Virginia; Parkinson, Kay; Paquis-Flucklinger, Véronique; Rohayem, Julia; Sinnott, Richard; Tillmann, Vallo; Tranebjaerg, Lisbeth; Barrett, Timothy G

    2013-08-27

    Wolfram, Alström and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well characterized cohorts of patients, and limited information on the natural history of the diseases. We aim to establish a Europe-wide registry for these diseases to inform patient care and research. EURO-WABB is an international multicenter large-scale observational study capturing longitudinal clinical and outcome data for patients with WABB diagnoses. Three hundred participants will be recruited over 3 years from different sites throughout Europe. Comprehensive clinical, genetic and patient experience data will be collated into an anonymized disease registry. Data collection will be web-based, and forms part of the project's Virtual Research and Information Environment (VRIE). Participants who haven't undergone genetic diagnostic testing for their condition will be able to do so via the project. The registry data will be used to increase the understanding of the natural history of WABB diseases, to serve as an evidence base for clinical management, and to aid the identification of opportunities for intervention to stop or delay the progress of the disease. The detailed clinical characterisation will allow inclusion of patients into studies of novel treatment interventions, including targeted interventions in small scale open label studies; and enrolment into multi-national clinical trials. The registry will also support wider access to genetic testing, and encourage international collaborations for patient benefit.

  3. Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected.

    Science.gov (United States)

    Lombardo, F; Salzano, G; Di Bella, C; Aversa, T; Pugliatti, F; Cara, S; Valenzise, M; De Luca, F; Rigoli, L

    2014-02-01

    Since the original description, there have been only few epidemiological studies of Wolfram syndrome (WS). Aims of the present paper are to ascertain WS prevalence and expression in a district of North-eastern Sicily, i.e. a geographic area where consanguineous unions are not very unusual. Prevalence rates of WS in the Messina district were calculated by taking into consideration both the total population (653,737) and the populations included within the 0-30 year age range (202,681). We estimated the relative prevalence of WS among patients with youth-onset insulin-dependent diabetes mellitus (DM) who are currently aged under 30 years (256). Global WS prevalence in our district is 1:54,478, whereas prevalence among individuals under 30 is 1:16,890 and relative prevalence among patients with juvenile-onset insulin-dependent DM is 1:22.3. When compared with the patients with insulin-dependent DM of Messina district, WS patients did not exhibit significant differences in terms of biochemical features at DM onset, whereas age at DM diagnosis was significantly earlier in WS group. (a) WS prevalence is not so infrequent as generally expected; (b) in our series, DM presented before 10 years in 11/12 patients and ten cases have already developed all the four peculiar manifestations of WS by 26 years; (c) 9/12 patients exhibited a homozygous frameshift/truncation mutation (Y454_L459del_fsX454), which is the one most frequently found also in patients from other Italian regions; (d) age at DM diagnosis was significantly earlier in WS group than in the patients with insulin-dependent DM of Messina district.

  4. A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients.

    Science.gov (United States)

    Cattaneo, Monica; La Sala, Lucia; Rondinelli, Maurizio; Errichiello, Edoardo; Zuffardi, Orsetta; Puca, Annibale Alessandro; Genovese, Stefano; Ceriello, Antonio

    2017-12-13

    Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients.

  5. Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila.

    Science.gov (United States)

    Sakakibara, Yasufumi; Sekiya, Michiko; Fujisaki, Naoki; Quan, Xiuming; Iijima, Koichi M

    2018-01-01

    Wolfram syndrome (WS), caused by loss-of-function mutations in the Wolfram syndrome 1 gene (WFS1), is characterized by juvenile-onset diabetes mellitus, bilateral optic atrophy, and a wide spectrum of neurological and psychiatric manifestations. WFS1 encodes an endoplasmic reticulum (ER)-resident transmembrane protein, and mutations in this gene lead to pancreatic β-cell death induced by high levels of ER stress. However, the mechanisms underlying neurodegeneration caused by WFS1 deficiency remain elusive. Here, we investigated the role of WFS1 in the maintenance of neuronal integrity in vivo by knocking down the expression of wfs1, the Drosophila homolog of WFS1, in the central nervous system. Neuronal knockdown of wfs1 caused age-dependent behavioral deficits and neurodegeneration in the fly brain. Knockdown of wfs1 in neurons and glial cells resulted in premature death and significantly exacerbated behavioral deficits in flies, suggesting that wfs1 has important functions in both cell types. Although wfs1 knockdown alone did not promote ER stress, it increased the susceptibility to oxidative stress-, excitotoxicity- or tauopathy-induced behavioral deficits, and neurodegeneration. The glutamate release inhibitor riluzole significantly suppressed premature death phenotypes induced by neuronal and glial knockdown of wfs1. This study highlights the protective role of wfs1 against age-associated neurodegeneration and furthers our understanding of potential disease-modifying factors that determine susceptibility and resilience to age-associated neurodegenerative diseases.

  6. Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila.

    Directory of Open Access Journals (Sweden)

    Yasufumi Sakakibara

    2018-01-01

    Full Text Available Wolfram syndrome (WS, caused by loss-of-function mutations in the Wolfram syndrome 1 gene (WFS1, is characterized by juvenile-onset diabetes mellitus, bilateral optic atrophy, and a wide spectrum of neurological and psychiatric manifestations. WFS1 encodes an endoplasmic reticulum (ER-resident transmembrane protein, and mutations in this gene lead to pancreatic β-cell death induced by high levels of ER stress. However, the mechanisms underlying neurodegeneration caused by WFS1 deficiency remain elusive. Here, we investigated the role of WFS1 in the maintenance of neuronal integrity in vivo by knocking down the expression of wfs1, the Drosophila homolog of WFS1, in the central nervous system. Neuronal knockdown of wfs1 caused age-dependent behavioral deficits and neurodegeneration in the fly brain. Knockdown of wfs1 in neurons and glial cells resulted in premature death and significantly exacerbated behavioral deficits in flies, suggesting that wfs1 has important functions in both cell types. Although wfs1 knockdown alone did not promote ER stress, it increased the susceptibility to oxidative stress-, excitotoxicity- or tauopathy-induced behavioral deficits, and neurodegeneration. The glutamate release inhibitor riluzole significantly suppressed premature death phenotypes induced by neuronal and glial knockdown of wfs1. This study highlights the protective role of wfs1 against age-associated neurodegeneration and furthers our understanding of potential disease-modifying factors that determine susceptibility and resilience to age-associated neurodegenerative diseases.

  7. Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis.

    Science.gov (United States)

    Awata, T; Inoue, K; Kurihara, S; Ohkubo, T; Inoue, I; Abe, T; Takino, H; Kanazawa, Y; Katayama, S

    2000-02-16

    Recently, a novel gene for a putative transmembrane protein (WFS1/wolframin) was found to be mutated in patients with Wolfram syndrome or DI-DM-OA-D (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. It is suggested that the WFS1 protein is important in the survival of islet beta-cells. We studied the WFS1 gene in a Japanese population to assess its possible role in common type 1 diabetes. Mutation screening revealed four missense mutations; R456H, G576S, H611R, and I720V. By genetic association studies of 185 type 1 diabetes patients and 380 control subjects, we found that R456H was significantly increased in the type 1 diabetes group compared to the control group (P = 0.0005); H611R and I720V were also significantly increased with weaker significance. Furthermore, in patients with the R456H mutation, type 1 diabetes-resistant HLA-DRB1 alleles (DRB1*0406, 1501, and 1502) were significantly increased compared to mutation-negative patients while susceptible DRB1*0901 was significantly decreased. Frequencies of autoimmunity characteristics (ICA or GAD-Ab positiveness and combination of autoimmune thyroid disease) were decreased in the R456H-positive patients compared to the R456H-negative patients. These data suggest that the WFS1 gene may have a role in the development of common type 1 diabetes as a nonautoimmune genetic basis. Copyright 2000 Academic Press.

  8. Generation of Human-Induced Pluripotent Stem Cells from Wolfram Syndrome Type 2 Patients Bearing the c.103 + 1G>A CISD2 Mutation for Disease Modeling.

    Science.gov (United States)

    La Spada, Alberto; Ntai, Aikaterini; Genovese, Stefano; Rondinelli, Maurizio; De Blasio, Pasquale; Biunno, Ida

    2018-02-15

    Wolfram syndrome (WFS) is a rare autosomal premature aging syndrome that shows signs of diabetes mellitus, optic atrophy, and deafness in addition to central nervous system and endocrine complications. The frequent form of WFS type 1 (WFS1) harbors causative mutations in the WFS1 gene, whereas the rare form or WFS type 2 (WFS2) involves CISD2. Mutations in these two genes are recognized by a subset of variable clinical symptoms and a set of overlapping features. In this study, we report on the generation of stable human-induced pluripotent stem cells (hiPSCs) derived from primary fibroblasts of a previously reported Italian family with CISD2 mutation (c.103 + 1G>A), occurring in the consensus intron 1 splicing site in two sisters, deleting the first exon of the transcript. The generated hiPSCs provide a cell model system to study the mutation's role in the multisystemic clinical disorders previously described and test eventual drug effects on the specific and associated clinical phenotype.

  9. Investigation of the local fracture toughness and the elastic-plastic fracture behavior of NiAl and tungsten by means of micro-cantilever tests; Untersuchung der lokalen Bruchzaehigkeit und des elastisch-plastischen Bruchverhaltens von NiAl und Wolfram mittels Mikrobiegebalkenversuchen

    Energy Technology Data Exchange (ETDEWEB)

    Ast, Johannes

    2016-07-01

    . This is linked to the thermally activated dislocation mobility which is more constrained in those samples. Investigations on plastically predeformed samples were performed in order to study the influence of the dislocation density on the fracture behavior. It was found that the fracture toughness was again not affected but that the predeformed samples failed at an earlier stage at lower J-integrals. This is due to the lower mobility of the dislocations emitted from the crack tip in consequence of the high amount of strain hardening and the higher flow stress in those samples. Experiments in ultrafine-grained tungsten revealed a fracture behavior which was more brittle than expected. A single grain at the crack front with its crystallographic orientation being prone to cleavage failure can decisively influence the fracture behavior at the micro scale. [German] Das Ziel dieser Arbeit war es, ein verbessertes Verstaendnis fuer die Groessenabhaengigkeit der Bruchzaehigkeit zu gewinnen. Hierfuer wurden mittels fokussierter Ionenstrahlen gekerbte Mikrobiegebalken in verschiedenen Groessen vom Submikrometerbereich bis hin zu einigen 10 μm in B2-NiAl und Wolfram praepariert. Diese beiden Materialien besitzen charakteristische Sproed-Duktil-Uebergange, die oberhalb der Raumtemperatur liegen. Dies erlaubte es, Bruchvorgaenge, welche von begrenzter plastischer Verformung um die Rissspitze begleitet werden, auf der Mikroskala zu untersuchen. Neue Methoden zur Beschreibung und Bestimmung des lokalen elastisch-plastischen Bruchverhaltens bzw. der Bruchzaehigkeit wurden hierfuer erarbeitet. Im Speziellen wurde das J-Integral-Konzept zur Ermittlung von Rissfortschritt ueber Steifigkeitsmessungen auf die Mikroskala uebertragen. Dies ermoeglichte eine praezise Analyse des fuer die Bruchzaehigkeit charakteristischen Uebergangs von Rissabstumpfung zu stabilem Rissfortschritt. Die Versuche an einkristallinem NiAl fuer die beiden untersuchten Risssysteme der harten und weichen Orientierung

  10. METHOD FOR ELECTRO-NICKEL PLATING WOLFRAM CARBIDE

    Science.gov (United States)

    Slatin, H.L.

    1959-05-01

    A WC body can be electroplated with Ni after anodic etching in Na/sub 4/ P/sub 2/O/sub 7/ solution (200 g/l) with a Pb cathode. A current density of 2 amp/in./sup 2/ for 10 min is sufficient. This allows Ni to be electrodeposited in an adherent coating which is weldable. (T.R.H.)

  11. An efficient image cryptosystem based on wolfram sequence and RNS

    African Journals Online (AJOL)

    Journal of Computer Science and Its Application. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 20, No 2 (2013) >. Log in or Register to get access to full text downloads.

  12. Lieutenant General Pete Quesada and Generalfeldmarschall Wolfram Von Richthofen: What Made Them Great

    Science.gov (United States)

    2009-06-01

    separated only by a hedgerow “so a single bomb could not kill both of us.”170 “We spent an awfully [sic] lot of time together in Normandy, and...K239.0512-838, 9. 191 Stephen Hart and Leo Daugherty, Battle of the Hedgerows : Bradley’s First Army in Normandy, Jun-July 1944 (Osceola, WI: Zenith...fighters with forward-firing rockets against troops and tanks hiding in hedgerow country as well as 100-pound bombs against soft targets such as troops

  13. Micro-powder injection moulding of tungsten; Prozessentwicklung fuer das Mikro-Pulverspritzgiessen von Wolfram

    Energy Technology Data Exchange (ETDEWEB)

    Zeep, B.

    2007-12-15

    For He-cooled Divertors as integral components of future fusion power plants, about 300000 complex shaped tungsten components are to be fabricated. Tungsten is the favoured material because of its excellent properties (high melting point, high hardness, high sputtering resistance, high thermal conductivity). However, the material's properties cause major problems for large scale production of complex shaped components. Due to the resistance of tungsten to mechanical machining, new fabrication technologies have to be developed. Powder injection moulding as a well established shaping technology for a large scale production of complex or even micro structured parts might be a suitable method to produce tungsten components for fusion applications but is not yet commercially available. The present thesis is dealing with the development of a powder injection moulding process for micro structured tungsten components. To develop a suitable feedstock, the powder particle properties, the binder formulation and the solid load were optimised. To meet the requirements for a replication of micro patterned cavities, a special target was to define the smallest powder particle size applicable for micro-powder injection moulding. To investigate the injection moulding performance of the developed feedstocks, experiments were successfully carried out applying diverse cavities with structural details in micro dimension. For debinding of the green bodies, a combination of solvent debinding and thermal debinding has been adopted for injection moulded tungsten components. To develop a suitable debinding strategy, a variation of the solvent debinding time, the heating rate and the binder formulation was performed. For investigating the thermal consolidation behaviour of tungsten components, sinter experiments were carried out applying tungsten powders suitable for micro-powder injection moulding. First mechanical tests of the sintered samples showed promising material properties such as a high hardness comparable to recrystalized material as well as a tensile strength of 290 N/mm{sup 2} and an elongation of break at 35 %. Nevertheless, by conventional sintering extensive grain growth up to 68 {mu}m was observed for samples with a sintered density of 99% theoretical density. To avoid extensive grain growth a HIP-process was developed for injection moulded tungsten samples, achieving a grain size of 5,5 {mu}m. In addition to tungsten, a wide range of tungsten alloys are of industrial interest for e.g. electrodes, thermal shielding, microelectronics and automotive applications. Accordingly the process developments for micro injection moulding has successfully been extended to oxide disperse strengthened tungsten and tungsten heavy alloys. (orig.)

  14. Diabetes mellitus, diabetes insipidus, optic atrophy, and deafness: A case of Wolfram (DIDMOAD syndrome

    Directory of Open Access Journals (Sweden)

    Nasrollah Maleki

    2015-09-01

    Conclusion: WS should be considered a differential diagnosis in patients with diabetes mellitus who present with optic atrophy, and it is necessary to perform a hearing test as well as collecting 24-h urine output.

  15. Studien zur Reaktivität der Vinylcarben-Komplexe in der Metathese Reaktion : Darstellung des Wolfram-Allenylidenkomplexes

    OpenAIRE

    Rooshenas, Parham

    2005-01-01

    Als Modellreaktion für die homogen katalysierte Olefin-Metathese wurde im Rahmen der vorliegenden Dissertation die Umsetzung der Vinylcarben-Komplexe 16a und 16b mit Enaminen 14a und 14b, als Beispiele für elektronreiche Alkene, untersucht. Als Produkt der Reaktion wurden die η1-Acyl-Komplexe 18-20 in hoher Ausbeute isoliert und mit Hilfe der spektroskopischen Daten identifiziert. Die Struktur der Verbindung 18 wurde zusätzlich mit Hilfe der Einkristallstrukturanalyse belegt. Mechanistis...

  16. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

    NARCIS (Netherlands)

    Bespalova, I.N.; Camp, G. van; Bom, S.J.H.; Brown, D.J.; Cryns, K.; Wan, A.T. de; Erson, A.E.; Flothmann, K.; Kunst, H.P.M.; Kurnool, P.; Sivakumaran, T.A.; Cremers, C.W.R.J.; Leal, S.M.; Burmeister, M.; Lesperance, M.M.

    2001-01-01

    Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have

  17. A novel compound heterozygous mutation in an adolescent with insulin-dependent diabetes: The challenge of characterizing Wolfram syndrome.

    Science.gov (United States)

    Maltoni, Giulio; Minardi, Raffaella; Cristalli, Carlotta Pia; Nardi, Laura; D'Alberton, Franco; Mantovani, Vilma; Zucchini, Stefano

    2016-11-01

    WS diagnosis is often delayed since misdiagnosed as autoimmune diabetes. The rarity of the condition and the absence of other diseases at diabetes diagnosis might make extremely challenging the recognition of WS. However the novel compound heterozygosity for the here reported mutations, seems to confer a mild phenotype among the spectrum of WS manifestations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Class and Homework Problems: The Break-Even Radius of Insulation Computed Using Excel Solver and WolframAlpha

    Science.gov (United States)

    Foley, Greg

    2014-01-01

    A problem that illustrates two ways of computing the break-even radius of insulation is outlined. The problem is suitable for students who are taking an introductory module in heat transfer or transport phenomena and who have some previous knowledge of the numerical solution of non- linear algebraic equations. The potential for computer algebra,…

  19. Pages 259 - 267.pmd

    African Journals Online (AJOL)

    Administrator

    Peltier CA, Omes C, Ndimubanzi PC et al. Validation of 2006 WHO Prediction Scores for. True HIV Infection in Children less than 18 months with a positive serological HIV test. PLoS ONE I www.plosone.org April 2009; 4. (4): I e5312. 28. Mayaux MJ, Burgard M, Teglas JP,et al. Neonatal characteristics in rapidly progressive ...

  20. Implementation of extended Kalman filter-based simultaneous ...

    Indian Academy of Sciences (India)

    Manigandan Nagarajan Santhanakrishnan

    2017-07-03

    2012-2013) to carry out this work. References. [1] Beinhofer M, MЭller J and Burgard W 2013 Effective landmark placement for accurate and reliable mobile robot navigation. Robot. Auton. Syst. 61(10): 1060–1069. doi:10.

  1. Mission Planning for Heterogeneous UxVs Operating in a Post-Disaster Urban Environment

    Science.gov (United States)

    2017-09-01

    wife, Nicole, who took the time off work to support me as well as to nurture our two wonderful kids , Kate and Matthew, during this one-year eventful...described in the book Probabilistic Robotics (Thrun and Burgard 2005). The Chapman-Kolmogorov equation, specifically the discrete analog component

  2. Application Of Waterloo Maple 9.5 And Wolfram Mathematica 5.1 Software For Analytic Solving Of Certain Nonlinear Partial Differential Equations Of Physics

    Directory of Open Access Journals (Sweden)

    Łukasz T. Stępień

    2008-01-01

    Full Text Available In the current paper some applications of the packet MAPLE (v. 9.5 for analytic solving ofcertain nonline partial differential equations have been presented. Additionally, for graphicpresentation of the found solutions packet MATHEMATICA (v. 5.1 has been applied.

  3. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

    DEFF Research Database (Denmark)

    Luuk, H.; Koks, S.; Plaas, M.

    2008-01-01

    , and central auditory pathway. Wf1 expression was also detected in numerous brainstem nuclei and in laminae VIII and IX of the spinal cord. Wfs1-positive nerve fibers were found in the medial forebrain bundle, reticular part of the substantia nigra, globus pallidus, posterior caudate putamen, lateral lemniscus...

  4. Genetic Testing for Wolfram Syndrome Mutations in a Sample of 71 Patients with Hereditary Optic Neuropathy and Negative Genetic Test Results for OPA1/OPA3/LHON.

    Science.gov (United States)

    Galvez-Ruiz, Alberto; Galindo-Ferreiro, Alicia; Schatz, Patrik

    2018-04-01

    In this study, the authors present a sample of 71 patients with hereditary optic neuropathy and negative genetic test results for OPA1/OPA3/LHON. All of these patients later underwent genetic testing to rule out WFS. As a result, 53 patients (74.7%) were negative and 18 patients (25.3%) were positive for some type of mutation or variation in the WFS gene. The authors believe that this study is interesting because it shows that a sizeable percentage (25.3%) of patients with hereditary optic 25 neuropathy and negative genetic test results for OPA1/OPA3/LHON had WFS mutations or variants.

  5. On the existence of additional solutions of the equations in the (1/2,0)0,1/2) representation space.

    Science.gov (United States)

    Dvoeglazov, Valeri V.

    We analyze dispersion relations of the equations recently proposed by Ahluwalia for describing the neutrino. Equations for type-II spinors are deduced on the basis of the Wigner rules for left- and right- 2-spinors and the Ryder-Burgard relation. It is shown that the equations contain acausal solutions which are similar to those of the Dirac-like second-order equation. The latter is obtained in a similar way, provided that we do not apply any constraints in the calculation.

  6. Efficient Option Pricing under Levy Processes, with CVA and FVA

    Directory of Open Access Journals (Sweden)

    Jimmy eLaw

    2015-07-01

    Full Text Available We generalize the Piterbarg (2010 model to include 1 bilateral default risk as in Burgard and Kjaer (2012, and 2 jumps in the dynamics of the underlying asset using general classes of L'evy processes of exponential type. We develop an efficient explicit-implicit scheme for European options and barrier options taking CVA-FVA into account. We highlight the importance of this work in the context of trading, pricing and management a derivative portfolio given the trajectory of regulations.

  7. Investigations of the ternary system beryllium-carbon-tungsten and analyses of beryllium on carbon surfaces; Untersuchung des ternaeren Systems Beryllium-Kohlenstoff-Wolfram und Betrachtungen von Beryllium auf Kohlenstoffoberflaechen

    Energy Technology Data Exchange (ETDEWEB)

    Kost, Florian

    2009-05-25

    Beryllium, carbon and tungsten are planned to be used as first wall materials in the future fusion reactor ITER. The aim of this work is a characterization of mixed material formation induced by thermal load. To this end, model systems (layers) were prepared and investigated, which give insight into the basic physical and chemical concepts. Before investigating ternary systems, the first step was to analyze the binary systems Be/C and Be/W (bottom-up approach), where the differences between the substrates PG (pyrolytic graphite) and HOPG (highly oriented pyrolytic graphite) were of special interest. Particularly X-ray photoelectron spectroscopy (XPS), low energy ion scattering (ISS) and Rutherford backscattering spectroscopy (RBS) were used as analysis methods. Beryllium evaporated on carbon shows an island growth mode, whereas a closed layer can be assumed for layer thicknesses above 0.7 nm. Annealing of the Be/C system induces Be{sub 2}C island formation for T{>=}770 K. At high temperatures (T{>=}1170 K), beryllium carbide dissociates, resulting in (metallic) beryllium desorption. For HOPG, carbide formation starts at higher temperatures compared to PG. Activation energies for the diffusion processes were determined by analyzing the decreasing beryllium amount versus annealing time. Surface morphologies were characterized using angle-resolved XPS (ARXPS) and atomic force microscopy (AFM). Experiments were performed to study processes in the Be/W system in the temperature range from 570 to 1270 K. Be{sub 2}W formation starts at 670 K, a complete loss of Be{sub 2}W is observed at 1170 K due to dissociation (and subsequent beryllium desorption). Regarding ternary systems, particularly Be/C/W and C/Be/W were investigated, attaching importance to layer thickness (reservoir) variations. At room temperature, Be{sub 2}C, W{sub 2}C, WC and Be{sub 2}W formation at the respective interfaces was observed. Further Be{sub 2}C is forming with increasing annealing temperatures. Depending on the layer sequence, carbide formation is complete in the temperature range between 570 and 770 K. Be{sub 2}W alloy formation only takes place if further metallic beryllium is available after carbide formation. Be{sub 2}C and Be{sub 2}W dissociate at temperatures T>1170 K. Based on RBS analysis of C/Be/W systems of several 100 nm thickness, the concentration dependent diffusion coefficient for Be in W was determined. Only Be{sub 12}W formation was observed due to the large beryllium reservoir. Carbide formation (Be{sub 2}C) is not observed until the alloy formation is completed. Furthermore, the first successful depth-resolved XPS measurements were performed on ternary layer systems using synchrotron radiation. The reactions in the ternary system are restricted to compounds that are already known from binary system investigations. No further Be, C, W-containing species are detected. Beryllium carbide is dominant in the system as long as it does not dissociate. (orig.)

  8. Monogenic diabetes syndromes

    DEFF Research Database (Denmark)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers

    2017-01-01

    (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations...

  9. A mixed-integer linear programming approach to the reduction of genome-scale metabolic networks.

    Science.gov (United States)

    Röhl, Annika; Bockmayr, Alexander

    2017-01-03

    Constraint-based analysis has become a widely used method to study metabolic networks. While some of the associated algorithms can be applied to genome-scale network reconstructions with several thousands of reactions, others are limited to small or medium-sized models. In 2015, Erdrich et al. introduced a method called NetworkReducer, which reduces large metabolic networks to smaller subnetworks, while preserving a set of biological requirements that can be specified by the user. Already in 2001, Burgard et al. developed a mixed-integer linear programming (MILP) approach for computing minimal reaction sets under a given growth requirement. Here we present an MILP approach for computing minimum subnetworks with the given properties. The minimality (with respect to the number of active reactions) is not guaranteed by NetworkReducer, while the method by Burgard et al. does not allow specifying the different biological requirements. Our procedure is about 5-10 times faster than NetworkReducer and can enumerate all minimum subnetworks in case there exist several ones. This allows identifying common reactions that are present in all subnetworks, and reactions appearing in alternative pathways. Applying complex analysis methods to genome-scale metabolic networks is often not possible in practice. Thus it may become necessary to reduce the size of the network while keeping important functionalities. We propose a MILP solution to this problem. Compared to previous work, our approach is more efficient and allows computing not only one, but even all minimum subnetworks satisfying the required properties.

  10. Bringing education to your virtual doorstep

    Science.gov (United States)

    Kaurov, Vitaliy

    2013-03-01

    We currently witness significant migration of academic resources towards online CMS, social networking, and high-end computerized education. This happens for traditional academic programs as well as for outreach initiatives. The talk will go over a set of innovative integrated technologies, many of which are free. These were developed by Wolfram Research in order to facilitate and enhance the learning process in mathematical and physical sciences. Topics include: cloud computing with Mathematica Online; natural language programming; interactive educational resources and web publishing at the Wolfram Demonstrations Project; the computational knowledge engine Wolfram Alpha; Computable Document Format (CDF) and self-publishing with interactive e-books; course assistant apps for mobile platforms. We will also discuss outreach programs where such technologies are extensively used, such as the Wolfram Science Summer School and the Mathematica Summer Camp.

  11. Hochstift und Domkapitel Augsburg in Tirol

    OpenAIRE

    Wüst, Wolfgang

    1989-01-01

    Hochstift und Domkapitel Augsburg in Tirol : Herrschaftsgeschichte, Verwaltungsorganisation u. wirtschaftl. Bedeutung. - In: Schwaben - Tirol / [Hrsg.: Wolfram Baer ...] - Rosenheim : Rosenheimer Verlagshaus. - Beiträge. - 1989. - S. 103-116

  12. Education through the prism of computation

    Science.gov (United States)

    Kaurov, Vitaliy

    2014-03-01

    With the rapid development of technology, computation claims its irrevocable place among research components of modern science. Thus to foster a successful future scientist, engineer or educator we need to add computation to the foundations of scientific education. We will discuss what type of paradigm shifts it brings to these foundations on the example of Wolfram Science Summer School. It is one of the most advanced computational outreach programs run by Wolfram Foundation, welcoming participants of almost all ages and backgrounds. Centered on complexity science and physics, it also covers numerous adjacent and interdisciplinary fields such as finance, biology, medicine and even music. We will talk about educational and research experiences in this program during the 12 years of its existence. We will review statistics and outputs the program has produced. Among these are interactive electronic publications at the Wolfram Demonstrations Project and contributions to the computational knowledge engine Wolfram|Alpa.

  13. Antioxidants: Protecting Healthy Cells

    Science.gov (United States)

    ... and Nutrients Antioxidants - Protecting Healthy Cells Print Email Antioxidants - Protecting Healthy Cells Reviewed by Taylor Wolfram, MS, ... to cardiovascular disease and certain types of cancers. Antioxidants — such as vitamins C and E and carotenoids, ...

  14. Disease: H00854 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy...i I, Loiselet J, Permutt A, Halaby G ... TITLE ... Diabetes mellitus and optic atrophy: a study of Wolfram syn

  15. A New Kind of Finance

    OpenAIRE

    Maymin, Philip Z.

    2012-01-01

    Finance has benefited from the Wolfram's NKS approach but it can and will benefit even more in the future, and the gains from the influence may actually be concentrated among practitioners who unintentionally employ those principles as a group.

  16. Nutrition for Young Men

    Science.gov (United States)

    ... Healthy Aging Nutrition for Young Men Print Email Nutrition for Young Men Reviewed by Taylor Wolfram, MS, ... 2017 XiXinXing/iStock/Thinkstock For many young men, nutrition isn't always a focus. There are many ...

  17. Thiamine– Responsive Megaloblastic Anemia Syndrome

    Directory of Open Access Journals (Sweden)

    F Motavaselian

    2009-01-01

    Full Text Available Thiamine Responsive megaloblastic anemia in DIDMOA (Wolfram syndrome has an autosomal- recessive mode of inheritance . Megaloblastic anemia and sideroblastic anemia is accompanied by diabetes insipidus (DI, diabetes mellitus (DM ,optic atrophy (OA and deafness (D. Neutropenia and thrombocytopenia are also present. We report a 7 month old girl with congenital macrocytic anemia; a rare clinical feature of Wolfram,s syndrome with increased plasma levels of blood glucose, both of which dramatically responded to administration of thiamine in large doses . The patient also had neurosensorial deafness, but no improvement was observed in the deafness. We presented the case because thiamine-responsive megaloblastic anemia is a rare clinical presentation of Wolfram syndrome and after institution of treatment with thiamine, the anemia and hyperglycemia returned to normal.

  18. A new kind of science - or a not-so-new kind of computer program?

    CERN Multimedia

    Naiditch, D

    2003-01-01

    Critical discussion of Stephen Wolfram's theory that "scientists give up their unwieldy equations and instead employ the types of computational rules used in cellular automata (CA) and related computer programs" (2 pages).

  19. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

    DEFF Research Database (Denmark)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda

    2011-01-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare...... that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome....

  20. Characterization of one-dimensional cellular automata rules through topological network features

    Science.gov (United States)

    D'Alotto, Lou; Pizzuti, Clara

    2016-10-01

    The paper investigates the relationship between the classification schemes, defined by Wolfram and Gilman, of one-dimensional cellular automata through concepts coming from network theory. An automaton is represented with a network, generated from the elementary rule defining its behavior. Characteristic features of this graph are computed and machine learning classification models are built. Such models allow to classify automaton rules and to compare Wolfram's and Gilman's classes by comparing the classes predicted by these models.

  1. Quantitative plant ecology

    DEFF Research Database (Denmark)

    Damgaard, Christian

    2014-01-01

    This e-book is written in the Wolfram' CDF format (download free CDF player from Wolfram.com) The objective of this e-book is to introduce the population ecological concepts for measuring and predicting the ecological success of plant species. This will be done by focusing on the measurement...... and statistical modelling of plant species abundance and the relevant ecological processes that control species abundance. The focus on statistical modelling and likelihood function based methods also means that more algorithm based methods, e.g. ordination techniques and boosted regression tress...

  2. A young diabetic with suicidal risk: Rare disease with a rarer presentation

    Directory of Open Access Journals (Sweden)

    Rajeev Philip

    2013-01-01

    Full Text Available Rare genetic or inherited forms of diabetes can mimic immune mediated type 1 diabetes. Early age of onset and associated features help to differentiate these diseases from type 1 diabetes. Wolfram syndrome, an inherited neuro degenerative disorder, presents as insulin dependent diabetes mellitus, diabetes insipidus, optic atrophy and deafness. But less well described features like psychiatric manifestations can be the presentation of this disease. We present such a case. Wolfram syndrome should be considered as a differential diagnosis in insulin dependent diabetic children who present with neuropsychiatric problems.

  3. Uuemat kirjandusteadust Saksast (4) : Böhlau esitleb Austriat / Jaan Undusk

    Index Scriptorium Estoniae

    Undusk, Jaan, 1958-

    1996-01-01

    Arvustus: Hall, Murray G.; Renner, Gerhard. Handbuch der Nachlässe und Sammlungen österreichischer Autoren. 2., neu bearbeitete und erweiterte Auflage. Wien - Köln - Weimar : Böhlau Verlag, 1995 ; Kontinent Bernhard : Zur Thomas - Bernhard - Rezeption in Europa / Hrsg. Wolfram Bayer, Claude Porcell. Wien - Köln - Weimar : Böhlau Verlag, 1995

  4. Dělení wolframového monokrystalického drátku při výrobě hrotových katod

    Czech Academy of Sciences Publication Activity Database

    Konečný, Pavel; Vlček, Ivan

    2001-01-01

    Roč. 46, č. 6 (2001), s. 195-197 ISSN 0447-6441 R&D Projects: GA AV ČR IAA1065804 Institutional research plan: CEZ:AV0Z2065902 Keywords : wolfram single crystal wire Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering

  5. A man who would shake up science; physicist says he's explained the way nature operates

    CERN Multimedia

    Rothstein, E

    2002-01-01

    Stephen Wolfram is finally publishing his long-awaited book "A New Kind of Science". In it he claims he has discovered underlying principles that affect the development of everything from the human brain to the workings of the universe, requiring a revolutionary rethinking of physics, mathematics, biology and other sciences (1 page).

  6. WOLFRAMALPHA use when training in the solution of tasks with parameters

    Directory of Open Access Journals (Sweden)

    Дмитрий Анатольевич Власов

    2014-12-01

    Full Text Available In the center of attention of this article WolframAlpha — quality of mathematical and methodical preparation of future mathematics teacher and informatics in bachelor degree and magistracy system is essential to raise the new mathematical online-processor allowing on condition of methodically expedient use in educational process.

  7. Revisiting Mathematical Problem Solving and Posing in the Digital Era: Toward Pedagogically Sound Uses of Modern Technology

    Science.gov (United States)

    Abramovich, S.

    2014-01-01

    The availability of sophisticated computer programs such as "Wolfram Alpha" has made many problems found in the secondary mathematics curriculum somewhat obsolete for they can be easily solved by the software. Against this background, an interplay between the power of a modern tool of technology and educational constraints it presents is…

  8. 36 Etude de l'effet de l'amodiaquine sur les globules rouges infectés ...

    African Journals Online (AJOL)

    BAGUI

    techniques d'analyse multivariée telles que la classification hiérarchique, la méthode des k-moyennes et l'analyse en ... techniques such as hierarchical classification, k-means method and principal component analysis techniques. The ..... [7] - ERIC W. WEISSTEIN,''K-means Clustering Algorithm'' from Wolfram Mathworld.

  9. An Essay on Interactive Investigations of the Zeeman Effect in the Interstellar Medium

    Science.gov (United States)

    Woolsey, Lauren

    2015-01-01

    The paper presents an interactive module created through the Wolfram Demonstrations Project that visualizes the Zeeman effect for the small magnetic field strengths present in the interstellar medium. The paper provides an overview of spectral lines and a few examples of strong and weak Zeeman splitting before discussing the module in depth.…

  10. International Journal of Herbs and Pharmacological Research

    African Journals Online (AJOL)

    2015-07-31

    Jul 31, 2015 ... those from nonsmoking control groups (Pasupathi et al., 2009; Wolfram et al., 2008; Gremmel et al., 2009). Nevertheless, tobacco has been implicated in the acute ..... Diabetes and Metabolic Syndrome: Clinical Research and Reviews; 3: 120-127. Peyvandi, F., Haertel, S., Knaub, S. and Mannucci, P.M. ...

  11. Association of the WFS1 gene with disease progression in children with new onset T1D. Results from the Hvidoere study group on childhood diabetes

    DEFF Research Database (Denmark)

    Nielsen, L.B.; Andersen, M.L.M.; Svensson, Jannete

    2010-01-01

    variants the Wolfram syndrome. The aim of this study was to investigate the impact of a common genetic variant (rs10010131) of the WFS1 gene on disease progression in a group of children newly diagnosed with T1D. Methods: The study is a multicenter longitudinal investigation with 18 participating...

  12. EURO-WABB

    DEFF Research Database (Denmark)

    Farmer, Amy; Aymé, Ségolène; de Heredia, Miguel Lopez

    2013-01-01

    Wolfram, Alström and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well...

  13. Sequences for Student Investigation

    Science.gov (United States)

    Barton, Jeffrey; Feil, David; Lartigue, David; Mullins, Bernadette

    2004-01-01

    We describe two classes of sequences that give rise to accessible problems for undergraduate research. These problems may be understood with virtually no prerequisites and are well suited for computer-aided investigation. The first sequence is a variation of one introduced by Stephen Wolfram in connection with his study of cellular automata. The…

  14. Classroom

    Indian Academy of Sciences (India)

    mathworld. wolfram.com. TwinPythagoreanTriple.html. [5] Difference Equations, from. Wikipedia, the free encyclo- pedia. [6] A I Markushevich, pp.18–27 in Recursion Sequences, Mir. Publishers, Moscow, 1975. Now this must be the same as (i + 1)2.

  15. Usable Human Authentication: A Quantitative Treatment

    Science.gov (United States)

    2014-06-30

    Symposium on, pages 40–49. IEEE, 2013. 6.5, 11 [81] Paolo Gasti and KasperB. Rasmussen. On the security of password manager database formats. In Sara ...blot. http://demonstrations.wolfram.com/ RandomInkBlot/. 6.5 [130] Blake Ross, Collin Jackson, Nick Miyake, Dan Boneh, and John C Mitchell. Stronger

  16. A generalized cellular automata approach to modeling first order ...

    Indian Academy of Sciences (India)

    lar Automata (CA) is a discrete representation of natural systems (Wolfram 1984). It deals with ..... 120. 140. 160. 180. 200. 220. 240. 260. 280. 300. 320. 340 final product concentration parameter value. (a). (b). (c). (d). (e). (f). Figure 6. Variation of final product concentration P with (a) Join (ES); (b) Break (ES); (c) Join (EI);.

  17. Universal map for cellular automata

    International Nuclear Information System (INIS)

    García-Morales, V.

    2012-01-01

    A universal map is derived for all deterministic 1D cellular automata (CAs) containing no freely adjustable parameters and valid for any alphabet size and any neighborhood range (including non-symmetrical neighborhoods). The map can be extended to an arbitrary number of dimensions and topologies and to arbitrary order in time. Specific CA maps for the famous Conway's Game of Life and Wolfram's 256 elementary CAs are given. An induction method for CAs, based in the universal map, allows mathematical expressions for the orbits of a wide variety of elementary CAs to be systematically derived. -- Highlights: ► A universal map is derived for all deterministic 1D cellular automata (CA). ► The map is generalized to 2D for Von Neumann, Moore and hexagonal neighborhoods. ► A map for all Wolfram's 256 elementary CAs is derived. ► A map for Conway's “Game of Life” is obtained.

  18. Diabetes mellitus and optic atrophy in two siblings: a report on a new association and a review of the literature.

    Science.gov (United States)

    Khardori, R; Stephens, J W; Page, O C; Dow, R S

    1983-01-01

    Two siblings with diabetes mellitus and optic atrophy (Wolfram syndrome) are described. As often noted, they also had atonic urinary bladders. Only one of the siblings had some impairment of hearing. Other findings not previously reported that appeared in each subject were esophageal dysphagia and vertigo. An autopsy in one revealed brain stem hypoplasia and thinning and flattening of the optic nerves with atrophy of the lateral geniculate bodies.

  19. New complex exact travelling wave solutions for the generalized-Zakharov equation with complex structures

    Directory of Open Access Journals (Sweden)

    Haci Mehmet Baskonus

    2016-07-01

    Full Text Available In this paper, we apply the sine-Gordon expansion method which is one of the powerful methods to the generalized-Zakharov equation with complex structure. This algorithm yields new complex hyperbolic function solutions to the generalized-Zakharov equation with complex structure. Wolfram Mathematica 9 has been used throughout the paper for plotting two- and three-dimensional surface of travelling wave solutions obtained.

  20. Giessener Universitätsblätter 33 (2000)

    OpenAIRE

    2000-01-01

    Geoffrey P Wilson: Was bedeutet es, Europäer zu sein. Angelika Hartmann: Islam und Europa. Von der Notwendigkeit eines kritischen Dialogs. Wolfram Kurz: Leopold Cordier. Der Vertreter der Praktischen Theologie an der Universität Gießen von 1926 bis 1938. Erwin Leibfried: Goethe. Trotz der Denkmäler ein Verborgener. Ulrich Karthaus: Thomas Manns Sprachkunst Sprache und Kunst. Jost Benedum: Die Frühgeschichte der künstlichen Niere. Manfred Landfester: Geistiger Wiederaufbau De...

  1. Expression of the diabetes risk gene wolframin (WFS1) in the human retina

    OpenAIRE

    Schmidt-Kastner, Rainald; Kreczmanski, Pawel; Preising, Markus; Diederen, Roselie; Schmitz, Christoph; Reis, Danielle; Blanks, Janet; Dorey, C. Kathleen

    2009-01-01

    Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolfra...

  2. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice

    OpenAIRE

    Tein, Karin; Kasvandik, Sergo; Kõks, Sulev; Vasar, Eero; Terasmaa, Anton

    2015-01-01

    BackgroundMutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness (DIDMOAD). The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala ...

  3. Association Study of the Effect of WFS1 Polymorphisms on Risk of Type 2 Diabetes in Japanese Population

    OpenAIRE

    Mita,Masaki; Miyake,Kazuaki; Zenibayashi,Masako; Hirota,Yushi; Teranishi,Tetsuya; Kouyama,Kunichi; Sakaguchi,Kazuhiko; Kasuga,Masato

    2008-01-01

    Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomalrecessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafnessand diabetes insipidus. The product encoded by WFS1 gene, wolframin, could beinvolved in ER stress response causing β-cell loss through impaired cell cycleprogression and increased apoptosis. Recently, polymorphisms in the WFS1 gene werestrongly associated with type 2 diabetes in Caucasians. The aim of the present studywas to examine wh...

  4. Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

    OpenAIRE

    Noormets, Klari; K?ks, Sulev; Kavak, Ants; Arend, Andres; Aunapuu, Marina; Keldrimaa, Aivi; Vasar, Eero; Tillmann, Vallo

    2009-01-01

    Abstract Background Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Methods Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) ...

  5. Complacency: A Threat to Homeland Security

    Science.gov (United States)

    2014-06-01

    employ vast numbers of men and women made it impractical to select individuals for specific jobs. Thus, the focus shifted to designing for people’s...research scientist, academician, businessman, and philanthropist, started the Santa Fe Institute in Los Alamos, New Mexico ; Stephen Wolfram began the...symptoms of groupthink, including illusions of invulnerability and a sense of superiority, collective rationalization, and stereotyping of outsiders

  6. Flavor-Oscillation Clocks, Continuous Quantum Measurements and a Violation of Einstein Equivalence Principle

    Science.gov (United States)

    Camacho, A.

    The relation between Einstein equivalence principle and a continuous quantum measurement is analyzed in the context of the recently proposed flavor-oscillation clocks, an idea pioneered by Ahluwalia and Burgard (Gen. Rel. Grav. 29, 681(E) (1997)). We will calculate the measurement outputs if a flavor-oscillation clock, which is immersed in a gravitational field, is subject to a continuous quantum measurement. Afterwards, resorting to the weak equivalence principle, we obtain the corresponding quantities in a freely falling reference frame. Finally, comparing this last result with the measurement outputs that would appear in a Minkowskian space-time it will be found that they do not coincide, in other words, we have a violation of Einstein equivalence principle. This violation appears in two different forms, namely: (i) the oscillation frequency in a freely falling reference frame does not match with the case predicted by general relativity, a feature previously obtained by Ahluwalia; (ii) the probability distribution of the measurement outputs, obtained by an observer in a freely falling reference frame, does not coincide with the results that would appear in the case of a Minkowskian space-time. Concerning this last difference, the probability distribution differs in two directions. Firstly, the maximum, as function of the energy of the system (that emerges if we calculate first the probability distribution in the original curved manifold and then, resorting to the weak equivalence principle, we find the corresponding expression in a freely falling reference frame) is shifted with respect to the case in which the system is in a Minkowskian space-time. Secondly, the magnitude of this maximum is not equal to the respective quantity predicted by general relativity. In other words, we obtain two new theoretical results that predict a violation of Einstein equivalence principle, and that could be measured.

  7. Expression of the diabetes risk gene wolframin (WFS1) in the human retina.

    Science.gov (United States)

    Schmidt-Kastner, Rainald; Kreczmanski, Pawel; Preising, Markus; Diederen, Roselie; Schmitz, Christoph; Reis, Danielle; Blanks, Janet; Dorey, C Kathleen

    2009-10-01

    Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1-23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1.

  8. Gluon fragmentation in T(1S) decays

    International Nuclear Information System (INIS)

    Bienlein, J.K.

    1983-05-01

    In T(1S) decays most observables (sphericity, charged multiplicity, photonic energy fraction, inclusive spectra) can be understood assuming that gluons fragment like quarks. New results from LENA use the (axis-independent) Fox-Wolfram moments for the photonic energy deposition. Continuum reactions show 'standard' Field-Feynman fragmentation. T(1S) decays show a significant difference in the photonic energy topology. It is more isotropic than with the Field-Feynman fragmentation scheme. Gluon fragmentation into isoscalar mesons (a la Peterson and Walsh) is excluded. But if one forces the leading particle to be isoscalar, one gets good agreement with the data. (orig.)

  9. Autoimmune Disease in a DFNA6/14/38 Family carrying a Novel Missense Mutation in WFS1

    OpenAIRE

    Hildebrand, Michael S.; Sorensen, Jessica L.; Jensen, Maren; Kimberling, William J.; Smith, Richard J.H.

    2008-01-01

    Most familial cases of autosomal dominant low frequency sensorineural hearing loss (LFSNHL) are attributable to mutations in the Wolframin syndrome 1 (WFS1) gene at the DFNA6/14/38 locus. WFS1 mutations at this locus were first described in 2001 in six families segregating LFSNHL that was non-progressive below 2000 Hz; the causative mutations all clustered in the C-terminal domain of the wolframin protein. Mutations in WFS1 also cause Wolfram syndrome (WS), an autosomal recessive neurodegener...

  10. A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

    OpenAIRE

    Chistiakov, Dimitry A; Khodyrev, Dmitry S.; Smetanina, Svetlana A.; Bel'chikova, Larisa N.; Suplotova, Lyudmila A.; Nosikov, Valery V.

    2010-01-01

    BACKGROUND: Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. AIM: In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. METHODS: The p...

  11. Novel Targets for the Diagnosis and Treatment of Breast Cancer Identified by Genomic Analysis

    Science.gov (United States)

    2006-12-01

    containing 3 5q15 2.24 3419 202069_s_at IDH3A isocitrate dehydrogenase 3 (NAD+) alpha 15q25.1-q25.2 2.21 7466 202908_at WFS1 Wolfram syndrome 1 ( wolframin ...protein 15q21.1 3.11 27236 218230_at ARFIP1 ADP-ribosylation factor interacting protein 1 (arfaptin 1) 4q31.3 3.06 9236 221511_x_at CPR8 cell cycle...of genetic interactions . In addition, we Table 2 Tentative subcellular annotation for probe sets with predicted localization Predicted location Total

  12. AHP 45: REVIEW: TIBETAN LITERARY GENRES, TEXTS, AND TEXT TYPES

    Directory of Open Access Journals (Sweden)

    Zoe Tribur

    2017-03-01

    Full Text Available Following the quantitative tradition of sociolinguistic research pioneered by such scholars as William Labov, Walt Wolfram, and Penelope Eckert, Reynolds presents a detailed, coherent analysis of the social parameters behind a specific on-going sound change, the merger of syllable final bilabial nasal (m with aveolar coronal nasal (n, in one small farming community in Qinghai Province. His is certainly not the first such study on Tibetan sound change. It is also not the first study to investigate the merger of (m into (n, which is a prominent feature of so-called "farmer" dialects of Amdo Tibetan (Hua 2005. ...

  13. An artificial muscle computer

    Science.gov (United States)

    Marc O'Brien, Benjamin; Alexander Anderson, Iain

    2013-03-01

    We have built an artificial muscle computer based on Wolfram's "2, 3" Turing machine architecture, the simplest known universal Turing machine. Our computer uses artificial muscles for its instruction set, output buffers, and memory write and addressing mechanisms. The computer is very slow and large (0.15 Hz, ˜1 m3); however by using only 13 artificial muscle relays, it is capable of solving any computable problem given sufficient memory, time, and reliability. The development of this computer shows that artificial muscles can think—paving the way for soft robots with reflexes like those seen in nature.

  14. Composición del rutilo como indicador de las condiciones de formación del greisen del distrito Mazán (Sn-W), provincia de La Rioja The rutile composition as indicator of greisen-forming conditions in the Sn-W Mazan District, La Rioja province

    OpenAIRE

    R.R. Fernández; I.B.A. Schalamuk; P. Omenetto

    2005-01-01

    El depósito mineral del antiguo distrito minero de Mazán corresponde a pequeñas vetas de cuarzo portadoras de casiterita, wolframita y, en menor proporción, scheelita. Estas vetas encajan en un granito peraluminoso asignado al Ordovícico-Silúrico, que fue intruido por un granito de probable edad carbonífera; este último estaría relacionado a la formación de greisen y a las vetas estano-wolframíferas. Sobre la base de las características de campo se han distinguido dos tipos de greisen cuarzom...

  15. Design of the Modelica Library VehProLib with Non-ideal Gas Models in Engines

    OpenAIRE

    Andersson, Conny

    2015-01-01

    This thesis covers the reconstruction and the redesign of the modeling library VehProLib,which is constructed in the modeling language Modelica with help of the modeling toolWolfram SystemModeler. The design choices are discussed and implemented. This thesisalso includes the implementation of a turbocharger package and an initial study of the justificationof the ideal gas law in vehicle modeling. The study is made with help of Van derWaals equation of states as a reference of non-ideal gas mo...

  16. Handbook of continued fractions for special functions

    CERN Document Server

    Cuyt, Annie

    2008-01-01

    Special functions are pervasive in all fields of science and industry. The most well-known application areas are in physics, engineering, chemistry, computer science and statistics. Because of their importance, several books and websites (see for instance http: functions.wolfram.com) and a large collection of papers have been devoted to these functions. Of the standard work on the subject, the Handbook of mathematical functions with formulas, graphs and mathematical tables edited by Milton Abramowitz and Irene Stegun, the American National Institute of Standards claims to have sold over 700 00

  17. The relationship of fractals in geophysics to 'the new science'

    International Nuclear Information System (INIS)

    Turcotte, Donald L.

    2004-01-01

    Many phenomena in geophysics satisfy fractal statistics, examples range from the frequency-area statistics of earthquakes to the time series of the earth's magnetic field. Solutions to classical differential equations cannot give this type of behavior. Several 'cellular automata' models have successfully reproduced the observed statistics. For example, the slider-block model for earthquakes. Stephen Wolfram's recent book A New Kind of Science sets forth a 'new science' based on cellular automata. This paper discusses the role of cellular automata in geophysics

  18. Obtained and characterization of composite materials W-Cu for electrical contact; Obtencion y caracterizacion de materiales compuestos W-Cu para contactos electricos

    Energy Technology Data Exchange (ETDEWEB)

    Krivij, N.; Alfonso-Trujillo, E.; Garcia-Sanchez, L. L.; Villalonga, J. A.; Formoso-Prego, A.; Alguacil, E. J.; Corres-Sanchez, A.

    2003-07-01

    In the Cuban Metallurgical Research Center (CIME), are manufactured by powder metallurgy, shims of adjustment of a W-Cu composite material, that are used in the electrical contacts of the panels of control of the portico derricks that operate in the port of Havana City. The base material used has a composition of 70% in mass electrolytic copper powder and wolfram powder of (30%) that is obtained by reduction from the oxide from wolfram. The powders are submitted to the stages of mixed, pressed and agglomeration and is obtained a composite material with free particles of W occluded in a counterfoil of Cu matrix, that do not interact and they provide the following properties: high melting temperature, high electro and thermo conductivity and corrosion resistance, high mechanical and electrical strengtheners, decrease weldability and stability during their development. However, when not reacting the volframio particles with the copper, the compound material will begin to fuse to the temperature of the copper, on the other hand and for the same reason the resistance to the corrosion should be similar to that of the pure copper. The shims of adjustment are fixed to the bodies of high purity copper welding with a silver alloy, the one which provides the maximum qualities of the Cu, as elasticity, breaking strength, thermal and electrical conductivities, as well corrosion resistance. (Author) 36 refs.

  19. Haplotype and linkage disequilibrium analysis of the CRMP1 and EVC genes.

    Science.gov (United States)

    Sivakumaran, Theru A; Lesperance, Marci M

    2004-11-01

    In this report, we present the haplotype and linkage disequilibrium (LD) pattern in the Collapsin Response Mediator Protein 1 (CRMP1) and Ellis-van Creveld syndrome (EVC) gene region. We genotyped eight different single nucleotide polymorphisms (SNPs) in the CRMP1 and EVC genes in 90 control individuals of diverse ethnicity. The minor allele frequencies ranged from 3.3-49.4%, with most having a frequency >25%. A total of 37 haplotypes were derived from these eight polymorphisms, with only one haplotype having a frequency >10%. Pairwise LD analysis showed a weak but significant LD between markers located about 243 kb apart in this region. The LD was significant between markers spaced about 208 kb apart in EVC, whereas no LD was found between a pair of markers located about 5 kb apart in CRMP1. However, in general, LD correlated with the distance between loci. The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL). The haplotypes obtained from these polymorphisms will be useful to track the segregation of phenotypes in families with Ellis-van Creveld syndrome, Weyers acrodental dysostosis, LFSNHL and Wolfram syndrome type 1.

  20. Tungsten in the Second World War: China, Japan, Germany, the Allies and Iberia

    Directory of Open Access Journals (Sweden)

    Joan Maria Thomàs

    2017-12-01

    Full Text Available This article studies the production, legal and illegal trade, and provisioning of strategic mineral wolfram/tungsten both by the Allies and the Axis during World War II. It analyzes the case the world’s largest producer of this mineral, China, the trade agreements signed by Chiang Kai-shek before the war with Nazi Germany, the USSR and Britain and their evolution during the global conflict. It also analyzes Japan, its difficulties in obtaining Chinese wolfram and its dependence on Korea. As for Nazi Germany, it studies its supply of Chinese ore until 1941 and later in the Iberian Peninsula, a trade made difficult by the Allied preventive purchases in Spain and Portugal. The article also studies the case of the US, its progressive auto provisioning in the Western Hemisphere, the airlift established between China and India to extract tungsten and distribution of amounts of it in Britain and the USSR. Finally, the article includes an assessment of the importance of tungsten within the set of strategic materials used by the contenders in the war and concludes that the Allied strategy hinder or prevent the provision of the enemy helped to reduce use and negatively affected the effectiveness of its machinery of war.

  1. Dominant ER Stress-InducingWFS1Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.

    Science.gov (United States)

    De Franco, Elisa; Flanagan, Sarah E; Yagi, Takuya; Abreu, Damien; Mahadevan, Jana; Johnson, Matthew B; Jones, Garan; Acosta, Fernanda; Mulaudzi, Mphele; Lek, Ngee; Oh, Vera; Petz, Oliver; Caswell, Richard; Ellard, Sian; Urano, Fumihiko; Hattersley, Andrew T

    2017-07-01

    Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome. © 2017 by the American Diabetes Association.

  2. Comparative study between NCRP-49 and NCRP-147 methodologies for shielding calculus to fluoroscopy rooms

    International Nuclear Information System (INIS)

    Ferreira, Christiano Eduardo Martins

    2011-01-01

    The walls of a fluoroscopy room must be shielded to prevent unnecessary exposures to technicians and public individuals. Thus this dissertation aims to describe the methodologies contained in two documents which are references for the calculation of shielding those rooms. They are the National Council on Radiation Protection and Measurements Report No. 49 (NCRP Report No. 49) and No. 147 (NCRP Report No. 147), the latter being more recent publication. And based on such description was made a comparative study between the two methodologies, using for this, as a benchmark, spreadsheets computer program developed by Wolfram Mathematica 6. With that we could reach the final thickness of the barriers to a Standard Plan for a fluoroscopy room (provided by Siemens) and noted that the NCRP-49 presents a methodology with results more conservative. (author)

  3. Monogenic diabetes syndromes

    DEFF Research Database (Denmark)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers

    2017-01-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1...... for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated...... diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development...

  4. Linear reversible second-order cellular automata and their first-order matrix equivalents

    Science.gov (United States)

    Macfarlane, A. J.

    2004-11-01

    Linear or one-dimensional reversible second-order cellular automata, exemplified by three cases named as RCA1-3, are introduced. Displays of their evolution in discrete time steps, &{\\in}Z_2;) as for RCA1-3. MCA1-3 are tractable because it has been possible to generalize to them the heavy duty methods already well-developed for ordinary first-order cellular automata like those of Wolfram's Rules 90 and 150. While the automata MCA1-3 are thought to be of genuine interest in their own right, with untapped further mathematical potential, their treatment has been applied here to expediting derivation of a large body of general and explicit results for N(t) for RCA1-3. Amongst explicit results obtained are formulas also for each of RCA1-3 for the total weight of the configurations of the first &2^M; times, M =0, 1, 2,\\ldots.

  5. Multi-layers castings

    Directory of Open Access Journals (Sweden)

    J. Szajnar

    2010-01-01

    Full Text Available In paper is presented the possibility of making of multi-layers cast steel castings in result of connection of casting and welding coating technologies. First layer was composite surface layer on the basis of Fe-Cr-C alloy, which was put directly in founding process of cast carbon steel 200–450 with use of preparation of mould cavity method. Second layer were padding welds, which were put with use of TIG – Tungsten Inert Gas surfacing by welding technology with filler on Ni matrix, Ni and Co matrix with wolfram carbides WC and on the basis on Fe-Cr-C alloy, which has the same chemical composition with alloy, which was used for making of composite surface layer. Usability for industrial applications of surface layers of castings were estimated by criterion of hardness and abrasive wear resistance of type metal-mineral.

  6. Rezension: Habsburgs schmutziger Krieg – Ermittlungen zur österreichisch-ungarischen Kriegsführung 1914 – 1918

    Directory of Open Access Journals (Sweden)

    Paul Winkler

    2015-06-01

    Full Text Available Ein AutorInnenkollektiv hat sich mit dieser Publikation dem schmutzigen 1. Weltkrieg der Habsburger zwischen 1914 und 1918 gewidmet und präsentiert dabei bedeutende Ergebnisse. Paul Winkler hat für die MEDIENIMPULSE rezensiert ... Beschlüssen, Kalkulationen und Kontrollverlust spüren Hannes Leidinger, Verena Moritz, Karin Moser und Wolfram Dornik in ihrer problemorientierten Untersuchung der dunkelsten Kapitel des letzten Waffengangs der Habsburger nach. Eine erschreckende Vielzahl dokumentierter Pflichtverletzungen und Gräuel erhellt Mechanismen der Gewalteskalation gegen pauschal verdächtigte Massen. Eine quellenorientierte Pionierleistung mit zweifelsohne nachhaltiger Beeinflussung einer österreichischen Erinnerungskultur – auch über das Gedenkjahr 2014 hinaus.

  7. Detection of micro- and nano-sized biocompatible particles in the blood.

    Science.gov (United States)

    Gatti, A M; Montanari, S; Monari, E; Gambarelli, A; Capitani, F; Parisini, B

    2004-04-01

    The research deals with new scanning electron microscopic evaluations of the interface between blood and explanted temporary vena cava filters from patients affected by blood disorders. The biological tissues adherent to the filter and the small thrombi formed in vivo were detached from the metallic structure of the device, fixed, dehydrated and prepared for the histological and the electron microscopy. The analyses showed that both samples (thrombus and newly formed tissue) contained foreign, in some cases nano-sized, bodies. The chemistry of these particles was different and varied, and unusual compounds containing non-biocompatible elements like bismuth, lead, wolfram, tungsten were also detected. The interaction between these debris travelling in the blood stream and the blood itself leads to suspect that the formation of the thrombus can originate from these inorganic and inert foreign bodies that act as triggering agent of the blood coagulation.

  8. On the new soliton and optical wave structures to some nonlinear evolution equations

    Science.gov (United States)

    Bulut, Hasan; Sulaiman, Tukur Abdulkadir; Baskonus, Haci Mehmet

    2017-11-01

    In this study, with the aid of the Wolfram Mathematica software, the powerful sine-Gordon expansion method is utilized to search for the solutions to some important nonlinear mathematical models arising in nonlinear sciences, namely, the (2 + 1) -dimensional Zakharov-Kuznetsov modified equal width equation, the cubic Boussinesq equation and the modified regularized long wave equation. We successfully obtain some new soliton, singular soliton, singular periodic waves and kink-type solutions with complex hyperbolic structures to these equations. We also present the two- and three-dimensional shapes of all the solutions obtained in this study. We further give the physical meaning of all the obtained solutions. We compare our results with the existing results in the literature.

  9. Computing by Temporal Order: Asynchronous Cellular Automata

    Directory of Open Access Journals (Sweden)

    Michael Vielhaber

    2012-08-01

    Full Text Available Our concern is the behaviour of the elementary cellular automata with state set 0,1 over the cell set Z/nZ (one-dimensional finite wrap-around case, under all possible update rules (asynchronicity. Over the torus Z/nZ (n<= 11,we will see that the ECA with Wolfram rule 57 maps any v in F_2^n to any w in F_2^n, varying the update rule. We furthermore show that all even (element of the alternating group bijective functions on the set F_2^n = 0,...,2^n-1, can be computed by ECA57, by iterating it a sufficient number of times with varying update rules, at least for n <= 10. We characterize the non-bijective functions computable by asynchronous rules.

  10. EDITORS’ NOTE

    Directory of Open Access Journals (Sweden)

    Heller WD

    2014-12-01

    Full Text Available In this issue of Beiträge, we publish as a Commentary the oral presentation of Wolfram Röper entitled ‘Ten Years and More of ‘Biosciences’ in CORESTA - A Brief Historic Overview’, held at the CORESTA Meeting in Sapporo, Japan, September 23-27, 2012. We chose do so because this article deviates in its structure from a regular scientific publication in Beiträge. Nevertheless, we as Editors believe that this text is of interest to many scientists involved in tobacco research, in particular the younger colleagues, since, in our view, it impressively shows the increasing importance of the ‘biosciences’ for the development, evaluation and regulation of tobacco products. It is highly likely that the ‘biosciences’ will play an equal (or perhaps an even more important role in the characterization of tobacco products in the future as did the physical and chemical sciences in the past.

  11. Association of the WFS1 gene with disease progression in children with new onset T1D. Results from the Hvidoere study group on childhood diabetes

    DEFF Research Database (Denmark)

    Nielsen, L.B.; Andersen, M.L.M.; Svensson, Jannete

    2010-01-01

    Objective: The wolframin gene, WFS1, encodes a glucoprotein involved in the calcium homeostasis of the endoplasmatic reticulum; WFS1 is critical for the function and survival of the pancreatic beta-cells. Genetic variation within the WFS1 gene is known to be associated with T2D and for rare...... variants the Wolfram syndrome. The aim of this study was to investigate the impact of a common genetic variant (rs10010131) of the WFS1 gene on disease progression in a group of children newly diagnosed with T1D. Methods: The study is a multicenter longitudinal investigation with 18 participating...... with proinsulin (est.: 1.55, P = 0.005) the first 12 month after disease onset compared to the AA genotype carriers. Conclusions: A common variant of the WFS1 gene is highly associated with better residual beta-cell function and corresponding better metabolic control during disease progression in new onset T1D...

  12. Male mice with deleted Wolframin (Wfs1) gene have reduced fertility.

    Science.gov (United States)

    Noormets, Klari; Kõks, Sulev; Kavak, Ants; Arend, Andres; Aunapuu, Marina; Keldrimaa, Aivi; Vasar, Eero; Tillmann, Vallo

    2009-08-10

    Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p Wfs1 gene influences sperm morphology needs to be clarified in further studies.

  13. No association of mutations and mRNA expression of WFS1/wolframin with bipolar disorder in humans.

    Science.gov (United States)

    Kato, Tadafumi; Iwamoto, Kazuya; Washizuka, Shinsuke; Mori, Kanako; Tajima, Osamu; Akiyama, Tsuyoshi; Nanko, Shinichiro; Kunugi, Hiroshi; Kato, Nobumasa

    2003-02-20

    Association of WFS1 (wolframin) and bipolar disorder has been suggested by psychiatric manifestations in patients or non-symptomatic carriers of Wolfram disease and linkage of bipolar disorder with 4p16, the locus of WFS1. Five studies of WFS1 in bipolar disorder did not support this association, although possible association of several missense mutations has not been excluded yet. In this study, four such mutations were genotyped in 184 patients with bipolar disorder and 207 controls. None had the A559T and A602V mutations, and no association of G576S and H611R with bipolar disorder was found. We also quantified the expression levels of WFS1 mRNA in the postmortem brains of patients with bipolar disorder, depression, schizophrenia, and controls. There was no significant difference of the expression levels. These results did not support the pathophysiological significance of WFS1 in bipolar disorder. Copyright 2002 Elsevier Science Ireland Ltd.

  14. Practical skills of the future innovator

    Science.gov (United States)

    Kaurov, Vitaliy

    2015-03-01

    Physics graduates face and often are disoriented by the complex and turbulent world of startups, incubators, emergent technologies, big data, social network engineering, and so on. In order to build the curricula that foster the skills necessary to navigate this world, we will look at the experiences at the Wolfram Science Summer School that gathers annually international students for already more than a decade. We will look at the examples of projects and see the development of such skills as innovative thinking, data mining, machine learning, cloud technologies, device connectivity and the Internet of things, network analytics, geo-information systems, formalized computable knowledge, and the adjacent applied research skills from graph theory to image processing and beyond. This should give solid ideas to educators who will build standard curricula adapted for innovation and entrepreneurship education.

  15. Shear banding in large strain plasticity - Influence of specimen dimensions

    Science.gov (United States)

    Mucha, Marzena; Wcisło, Balbina; Pamin, Jerzy

    2018-01-01

    The paper deals with numerical analysis of shear banding which occurs in an elongated rectangular plate for a large strain elastic-plastic material model. It is focused on the influence of plate size proportions and finite element mesh density on numerical results. The discussion is limited to isothermal conditions and ideal plasticity. First a plain strain case is computed for different lengths of the plate, then simulations are repeated for plane stress for which different thicknesses of the plate are considered. Most of the computations are performed for three finite element meshes to verify discretization sensitivity of the results. The simulations are performed using AceGen and AceFEM packages for Wolfram Mathematica.

  16. The Universe as Automaton From Simplicity and Symmetry to Complexity

    CERN Document Server

    Mainzer, Klaus

    2012-01-01

    This booklet is an essay at the interface of philosophy and complexity research, trying to inspire the reader with new ideas and new conceptual developments of cellular automata.  Going beyond the numerical experiments of Steven Wolfram, it is argued that cellular automata must be considered complex dynamical systems in their own right, requiring appropriate analytical models in order to find precise answers and predictions in the universe of cellular automata.  Indeed, eventually we have to ask whether cellular automata can be considered models of the real world and, conversely, whether there are limits to our modern approach of attributing the world, and the universe for that matter, essentially a digital reality.

  17. Success in the pipeline for CMS

    CERN Multimedia

    2008-01-01

    The very heart of any LHC experiment is not a pixel detector, nor a vertex locator but a beam pipe. It is the site of each collision and the boundary where the accelerator and experiment meet. As an element of complex design and manufacture the CMS beam pipe was fifteen years in the making and finally fully installed on Tuesday 10 June. Watch the video! End cap beam pipe installation in the CMS detector. Central beam pipe installation.The compensation modules were the final pieces to take their places in the cavern at Point 5: "These are like bellows," says Wolfram Zeuner, Deputy Technical Co-ordinator for CMS. "They allow us to compensate for the change in length when we heat or cool the beam pipe. And they are the very last elements; beam pipe installation, which began last year, is now complete." The beam pipe is neither too fragile nor too bulky, but just right to satisfy the conflicting n...

  18. Tribological Behaviour of OA-Capped WO3 Nanoparticles as an Additive to Base Oils

    International Nuclear Information System (INIS)

    Siti Fazlili Abdullah

    2008-01-01

    Oleic acid (OA) capped wolfram (VI) oxide, WO 3 nanoparticles were chemically synthesized and characterized by means of Fourier Transform-Infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). The tribological properties of the capped WO 3 nanoparticles as an additive in base oils were investigated using a four-ball machine. Results show that OA-capped WO 3 nanoparticles are able to prevent water adsorption and capable of being dispersed stable in organic solvents which is base oils. The as-prepared capped WO 3 nanoparticles have an average size of 15 nm. In addition, OA-capped WO 3 nanoparticles as an additive in base oils perform good anti-wear (AW) and anti-friction (AF) properties owing to the formation of a boundary film. (author)

  19. 1943: Franco Vs. Naciones Unidas. La guerra silenciosa de los servicios de inteligencia norteamericanos y británicos en España

    Directory of Open Access Journals (Sweden)

    Emilio Grandío Seoane

    2016-12-01

    Full Text Available 1943 was a decisive year for the Franco regime. Redirect the course of Spanish politics was key for the Allies. The pressures occurred: external – wolfram, rumors of Allied invasion and coup d’état… –, and internal – letter of Procuradores; threats from the Generals… –. August marked a turning point after the interview between Hayes and Franco and the urgent visit by Samuel Hoare at his summer residence in Meirás. The battle between neutrality and non-interference had the support of information networks deployed by the Allies, but the positions of the British and US Embassy not always pulled in the same direction. A relationship of forced cooperation and permanent competition that would be decisive for the future of Europe.

  20. The writing and the voice in three Grail novels

    Directory of Open Access Journals (Sweden)

    Demétrio Alves Paz

    2014-07-01

    Full Text Available The objetive of this paper is to analyse the narrator and the characters in the romances of chivalry about the Grail: Perceval, by Chrétien de Troyes; Parsifal, by Wolfram von Eschenbach and A Demanda do Santo Graal, an anonymous portuguese text. After analysing the prodution context of these works, it is used the ideas of Paul Zumthor and Walter Benjamim about the relation of orality and writing to discuss the narrator of the novels. Then, the characters are investigated according to the typology proposed by Antonio Prieto. The first two romances of chivalry about the Grail are closer not only to the orality as well as the myth, whereas in the portuguese text there is a greater control of the narrative due to its religious characteristic.

  1. Flexible Automatic Discretization for Finite Differences: Eliminating the Human Factor

    Science.gov (United States)

    Pranger, Casper

    2017-04-01

    In the geophysical numerical modelling community, finite differences are (in part due to their small footprint) a popular spatial discretization method for PDEs in the regular-shaped continuum that is the earth. However, they rapidly become prone to programming mistakes when physics increase in complexity. To eliminate opportunities for human error, we have designed an automatic discretization algorithm using Wolfram Mathematica, in which the user supplies symbolic PDEs, the number of spatial dimensions, and a choice of symbolic boundary conditions, and the script transforms this information into matrix- and right-hand-side rules ready for use in a C++ code that will accept them. The symbolic PDEs are further used to automatically develop and perform manufactured solution benchmarks, ensuring at all stages physical fidelity while providing pragmatic targets for numerical accuracy. We find that this procedure greatly accelerates code development and provides a great deal of flexibility in ones choice of physics.

  2. Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment

    Energy Technology Data Exchange (ETDEWEB)

    Kunz, Juergen; Marquez-Klaka, Ben; Uebe, Steffen; Volz-Peters, Anja; Berger, Roswitha; Rausch, Peter

    2003-04-09

    Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM no. 606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein.

  3. Genetics of monegenic forms of diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Tamara Leonidovna Kuraeva

    2011-03-01

    Full Text Available It is universally recognized that autoimmune type 1 diabetes mellitus (DM is not the only form of this disease in children. Increasingly more children and adolescents present with DM2, MODY, and rarer syndromal forms of DM. The actual prevalence of DM other than DM1 in children and adolescents is unknown but may be estimated at 10%. Despite rare occurrence of genetic syndromes, they collectively account for almost 5% of DM cases among children. The rapid upgrowth of molecular biology opens up a wide range of possibilities for designating various symptom complexes as nosologically selfconsistent forms. New genetic syndromes associated with DM are annually described. It is important both to adequately identify and treat manifestations and complications of these syndromes in children and to provide relevant medico-genetic counseling and recommendations to the parents. Key words: non-immune diabetes mellitus, MODY, Wolfram syndrome, neonatal, syndromal forms

  4. Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment

    International Nuclear Information System (INIS)

    Kunz, Juergen; Marquez-Klaka, Ben; Uebe, Steffen; Volz-Peters, Anja; Berger, Roswitha; Rausch, Peter

    2003-01-01

    Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM no. 606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein

  5. Endoplasmic Reticulum (ER Stress and Endocrine Disorders

    Directory of Open Access Journals (Sweden)

    Daisuke Ariyasu

    2017-02-01

    Full Text Available The endoplasmic reticulum (ER is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR, which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI, Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2 are discussed in this article.

  6. Stochastic properties of disturbed Elementary Cellular Automata

    International Nuclear Information System (INIS)

    Posiewnik, M.

    2005-01-01

    Cellular automata are class of simple mathematical systems that generate diverse, often complicated behaviour. Evolution of such a system is given by set of local and deterministic rules. However, in spite of simplicity of 'interactions' it's global behaviour can't be, in general, simply predicted or even can not be predicted in time shorter that time of it's strict evolution. We get as, a systems well known 1-dimensional, Wolfram class automata, and connect it into the reservoir consists of some random source (noise). In our experiment we are interested in: a) numeric verification of ergodicity for such a coupled system. b) finding it's probability distribution and evolution. c) finding some analogous for 'real' quantities and behaviour. d) using the dynamical systems and Markov chains theory to describe the system, and to make any predictions of it's behaviour. (author)

  7. Dynamical systems with applications using Mathematica

    CERN Document Server

    Lynch, Stephen

    2017-01-01

    This textbook, now in its second edition, provides a broad introduction to the theory and practice of both continuous and discrete dynamical systems with the aid of the Mathematica software suite. Taking a hands-on approach, the reader is guided from basic concepts to modern research topics. Emphasized throughout are numerous applications to biology, chemical kinetics, economics, electronics, epidemiology, nonlinear optics, mechanics, population dynamics, and neural networks. The book begins with an efficient tutorial introduction to Mathematica, enabling new users to become familiar with the program, while providing a good reference source for experts. Working Mathematica notebooks will be available at: http://library.wolfram.com/infocenter/Books/9563/ The author has focused on breadth of coverage rather than fine detail, with theorems and proofs being kept to a minimum, though references are included for the inquisitive reader. The book is intended for senior undergraduate and graduate students as well as w...

  8. Computational complexity of symbolic dynamics at the onset of chaos

    Science.gov (United States)

    Lakdawala, Porus

    1996-05-01

    In a variety of studies of dynamical systems, the edge of order and chaos has been singled out as a region of complexity. It was suggested by Wolfram, on the basis of qualitative behavior of cellular automata, that the computational basis for modeling this region is the universal Turing machine. In this paper, following a suggestion of Crutchfield, we try to show that the Turing machine model may often be too powerful as a computational model to describe the boundary of order and chaos. In particular we study the region of the first accumulation of period doubling in unimodal and bimodal maps of the interval, from the point of view of language theory. We show that in relation to the ``extended'' Chomsky hierarchy, the relevant computational model in the unimodal case is the nested stack automaton or the related indexed languages, while the bimodal case is modeled by the linear bounded automaton or the related context-sensitive languages.

  9. The Latest from CMS

    CERN Multimedia

    2009-01-01

    CMS is on track to be ready for physics one month in advance of the LHC restart. The final installations are being completed and tests are being run to ensure that the experiment is as well prepared as possible to exploit sustained LHC operation throughout 2010. Physics week in Bologna, Italy, was a valuable time for CMS collaborators to discuss preparations for numerous physics analyses, as well as the performance of the detector during the recent data-taking period with cosmics (CRAFT 09). During this five-week exercise, more than 300 million cosmic events were recorded with the magnetic field on. This large data-set is being used to further improve the sub-detector alignment, calibration and performance whilst awaiting p-p collisions. Meanwhile, in the experimental cavern, Wolfram Zeuner, Deputy Technical Coordinator of CMS, reports "We are now very nearly closed up again. We are just doing the final clean-up work and are ready t...

  10. High energy physics. Progress report, March 1, 1985-February 28, 1986

    International Nuclear Information System (INIS)

    Phillips, G.C.; Roberts, J.B. Jr.

    1985-01-01

    Analysis was completed on comparison of pion and proton induced large p/sub T/ di-jet events, which revealed a new, unique structure, possibly evidence for higher twist scattering in QCD. QCD Monte Carlo studies using both the Feynman-Field and Field-Fox Wolfram models have continued. Data have been analyzed on the collisions of protons with targets of He, Be, C, Al, Sn, and Pb. The use of a 200 MeV polarimeter in polarized beam studies is reported. A large value of the spin asymmetry parameter was measured at high p/sub T/. Detailed design of the equipment has been completed and construction has begun on facilities for a polarized beam experiment. Work is reported in quantum field theory and perturbative QCD

  11. Removing obstacles for African American English-speaking children through greater understanding of language difference.

    Science.gov (United States)

    Pearson, Barbara Zurer; Conner, Tracy; Jackson, Janice E

    2013-01-01

    Language difference among speakers of African American English (AAE) has often been considered language deficit, based on a lack of understanding about the AAE variety. Following Labov (1972), Wolfram (1969), Green (2002, 2011), and others, we define AAE as a complex rule-governed linguistic system and briefly discuss language structures that it shares with general American English (GAE) and others that are unique to AAE. We suggest ways in which mistaken ideas about the language variety add to children's difficulties in learning the mainstream dialect and, in effect, deny them the benefits of their educational programs. We propose that a linguistically informed approach that highlights correspondences between AAE and the mainstream dialect and trains students and teachers to understand language varieties at a metalinguistic level creates environments that support the academic achievement of AAE-speaking students. Finally, we present 3 program types that are recommended for helping students achieve the skills they need to be successful in multiple linguistic environments.

  12. Archaea: Evolution, Physiology, and Molecular Biology

    DEFF Research Database (Denmark)

    Introduced by Crafoord Prize winner Carl Woese, this volume combines reviews of the major developments in archaeal research over the past 10-15 years with more specialized articles dealing with important recent breakthroughs. Drawing on major themes presented at the June 2005 meeting held in Muni...... and technological context, and include accounts of cutting-edge research developments. The book spans archaeal evolution, physiology, and molecular and cellular biology and will be an essential reference for both graduate students and researchers....... to honor the archaea pioneers Wolfram Zillig and Karl O. Stetter, the book provides a thorough survey of the field from its controversial beginnings to its ongoing expansion to include aspects of eukaryotic biology. The editors have assembled articles from the premier researchers in this rapidly burgeoning...

  13. Functional approaches in translation studies in Germany Functional approaches in translation studies in Germany

    Directory of Open Access Journals (Sweden)

    Paul Kussmaul

    2008-04-01

    Full Text Available In the early phase of translation studies in Germany, contrastive linguistics played a major role. I shall briefly describe this approach so that the functional approach will become clearer by contrast. Influenced by the representatives of stylistique comparée, Vinay/Darbelnet (1968 Wolfram Wilss, for instance, in his early work (1971, 1977 makes frequent use of the notion transposition (German “Ausdrucksverschiebung“, cf. also Catford’s (1965 term shift. As a whole, of course, Wilss’ work has a much broader scope. More recently, he has investigated the role of cognition (1988 and the various factors in translator behaviour (1996. Nevertheless, transposition is still a very important and useful notion in describing the translation process. The need for transpositions arises when there is no possibility of formal one-to-one correspondence between source and target-language structures. The basic idea is that whenever there is a need for transposition, we are faced with a translation problem. In the early phase of translation studies in Germany, contrastive linguistics played a major role. I shall briefly describe this approach so that the functional approach will become clearer by contrast. Influenced by the representatives of stylistique comparée, Vinay/Darbelnet (1968 Wolfram Wilss, for instance, in his early work (1971, 1977 makes frequent use of the notion transposition (German “Ausdrucksverschiebung“, cf. also Catford’s (1965 term shift. As a whole, of course, Wilss’ work has a much broader scope. More recently, he has investigated the role of cognition (1988 and the various factors in translator behaviour (1996. Nevertheless, transposition is still a very important and useful notion in describing the translation process. The need for transpositions arises when there is no possibility of formal one-to-one correspondence between source and target-language structures. The basic idea is that whenever there is a need for

  14. Screening of mitochondrial mutations in Tunisian patients with mitochondrial disorders: an overview study.

    Science.gov (United States)

    Mkaouar-Rebai, Emna; Chamkha, Imen; Mezghani, Najla; Ben Ayed, Imen; Fakhfakh, Faiza

    2013-06-01

    To investigate the spectrum of common mitochondrial mutations in Tunisia during the years of 2002-2012, 226 patients with mitochondrial disorders were clinically diagnosed with hearing loss, Leigh syndrome (LS), diabetes, cardiomyopathy, Kearns-Sayre syndrome (KSS), Pearson syndrome (PS), myopathy, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) and Wolfram syndrome. Restriction fragment length polymorphism (PCR-RFLP), radioactive PCR, single specific primer-PCR (SSP-PCR) analysis and PCR-sequencing methods were used to identify the mutations. Two cases with m.1555A>G mutation and two families with the novel 12S rRNA m.735A>G transition were detected in patients with hearing loss. Three cases with m.8993T>G mutation, two patients with the novel m.5523T>G and m.5559A>G mutations in the tRNA(Trp) gene, and two individuals with the undescribed m.9478T>C mutation in the cytochrome c oxidase subunit III (COXIII) gene were found with LS. In addition, one case with hypertrophic cardiomyopathy and deafness presented the ND1 m.3395A>G mutation and the tRNA(Ile) m.4316A>G variation. Besides, multiple mitochondrial deletions were detected in patients with KSS, PS, and Wolfram syndrome. The m.14709T>C mutation in the tRNA(Glu) was reported in four maternally inherited diabetes and deafness patients and a novel tRNA(Val) m.1640A>G mutation was detected in a MELAS patient.

  15. Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress.

    Science.gov (United States)

    Zatyka, Malgorzata; Ricketts, Christopher; da Silva Xavier, Gabriela; Minton, Jayne; Fenton, Sarah; Hofmann-Thiel, Sabine; Rutter, Guy A; Barrett, Timothy G

    2008-01-15

    Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein, Wolframin. Although its precise functions are unknown, Wolframin deficiency increases ER stress, impairs cell cycle progression and affects calcium homeostasis. To gain further insight into its function and identify molecular partners, we used the WFS1-C-terminal domain as bait in a yeast two-hybrid screen with a human brain cDNA library. Na+/K+ ATPase beta1 subunit was identified as an interacting clone. We mapped the interaction to the WFS1 C-terminal and transmembrane domains, but not the N-terminal domain. Our mapping data suggest that the interaction most likely occurs in the ER. We confirmed the interaction by co-immunoprecipitation in mammalian cells and with endogenous proteins in JEG3 placental cells, neuroblastoma SKNAS and pancreatic MIN6 beta cells. Na+/K+ ATPase beta1 subunit expression was reduced in plasma membrane fractions of human WFS1 mutant fibroblasts and WFS1 knockdown MIN6 pancreatic beta-cells compared with wild-type cells; Na+/K+ ATPase alpha1 subunit expression was also reduced in WFS-depleted MIN6 beta cells. Induction of ER stress in wild-type cells only partly accounted for the reduced Na+/K+ ATPase beta1 subunit expression observed. We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation; loss of this interaction may contribute to the pathology seen in Wolfram syndrome via reductions in sodium pump alpha1 and beta1 subunit expression in pancreatic beta-cells.

  16. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

    Science.gov (United States)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda; Johansen, Ida R; Pandya, Arti; Welch, Katherine O; Norris, Virginia W; Arnos, Kathleen S; Bitner-Glindzicz, Maria; Emery, Sarah B; Mets, Marilyn B; Fagerheim, Toril; Eriksson, Kristina; Hansen, Lars; Bruhn, Helene; Möller, Claes; Lindholm, Sture; Ensgaard, Stefan; Lesperance, Marci M; Tranebjaerg, Lisbeth

    2011-06-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. Copyright © 2011 Wiley-Liss, Inc.

  17. Mejoramiento de la eficiencia energética en los procesos de extrusión de tuberías plásticas; Improve of the energy efficiency in the processes of plastic pipe extrusion

    Directory of Open Access Journals (Sweden)

    Antonio Jiménez Ramos

    2015-06-01

    Full Text Available El presente trabajo, muestra el desarrollo de una herramienta, para el mejoramiento energético, de los procesos de extrusión de tuberías plásticas, mediante la modelación del proceso de transferencia de calor, en estado transitorio, empleando para la solución el software Wolfram Mathematica 8.0. La herramienta desarrollada, posibilita en breve tiempo, la toma de decisiones para mantener un proceso optimizado, en función de las propiedades físicas, de las materias primas utilizadas, aumentando las producciones, con la consiguiente reducción de los índices de consumo, sin afectar la calidad del producto terminado. Esta herramienta posibilita además, conocer el comportamiento del equipamiento que procesa estas producciones ya que se definen los tiempos óptimos de enfriamiento, a partir de la temperatura, lo que posibilita ajustes rápidos y eficaces, por lo cual, se ahorran materias primas y puede actuarse, sobre posibles defectos técnicos del equipamiento, en los cuales intervienen las distintas especialidades destinadas a estas misiones.This paper shows the development of a tool for energetic improve of plastic pipes extrusion processes by heat transference processes transients using the Wolfram Mathematica7 software. With this tool may take decisions quickly to keep an optimized process in function of the material properties used to increasing the productions and to reduce the consumption without quality affectations of end product. Further, with this tool is possible to know the equipment behavior because it is defined that the optimal cooling time from temperature what enables rapid adjustment and effective, saving materials and enable the actions before technical faults of the equipment, in which there are interventions of different technicians.

  18. Automatic lithofacies segmentation from well-logs data. A comparative study between the Self-Organizing Map (SOM) and Walsh transform

    Science.gov (United States)

    Aliouane, Leila; Ouadfeul, Sid-Ali; Rabhi, Abdessalem; Rouina, Fouzi; Benaissa, Zahia; Boudella, Amar

    2013-04-01

    The main goal of this work is to realize a comparison between two lithofacies segmentation techniques of reservoir interval. The first one is based on the Kohonen's Self-Organizing Map neural network machine. The second technique is based on the Walsh transform decomposition. Application to real well-logs data of two boreholes located in the Algerian Sahara shows that the Self-organizing map is able to provide more lithological details that the obtained lithofacies model given by the Walsh decomposition. Keywords: Comparison, Lithofacies, SOM, Walsh References: 1)Aliouane, L., Ouadfeul, S., Boudella, A., 2011, Fractal analysis based on the continuous wavelet transform and lithofacies classification from well-logs data using the self-organizing map neural network, Arabian Journal of geosciences, doi: 10.1007/s12517-011-0459-4 2) Aliouane, L., Ouadfeul, S., Djarfour, N., Boudella, A., 2012, Petrophysical Parameters Estimation from Well-Logs Data Using Multilayer Perceptron and Radial Basis Function Neural Networks, Lecture Notes in Computer Science Volume 7667, 2012, pp 730-736, doi : 10.1007/978-3-642-34500-5_86 3)Ouadfeul, S. and Aliouane., L., 2011, Multifractal analysis revisited by the continuous wavelet transform applied in lithofacies segmentation from well-logs data, International journal of applied physics and mathematics, Vol01 N01. 4) Ouadfeul, S., Aliouane, L., 2012, Lithofacies Classification Using the Multilayer Perceptron and the Self-organizing Neural Networks, Lecture Notes in Computer Science Volume 7667, 2012, pp 737-744, doi : 10.1007/978-3-642-34500-5_87 5) Weisstein, Eric W. "Fast Walsh Transform." From MathWorld--A Wolfram Web Resource. http://mathworld.wolfram.com/FastWalshTransform.html

  19. Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease

    Directory of Open Access Journals (Sweden)

    Melanie A. Jones

    2014-04-01

    Full Text Available Wolfram syndrome (WFS is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1 and CDGSH iron sulfur domain 2 (CISD2, respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies, on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on

  20. Hidroquímica de las aguas del Altiplano de Bolivia

    Directory of Open Access Journals (Sweden)

    1995-01-01

    Full Text Available HYDROCHIMIE DES EAUX DE L’ALTIPLANO BOLIVIEN. Les eaux de surface ont été échantillonnées sur 36 points de mesure du bassin endoreïque qui inclut le lac Titicaca, le rio Desaguadero et les lacs Uru-Uru et Poopó (bassin TDPS. Pour les eaux souterraines, des échantillons ont été prélevés dans 37 puits du bassin TDPS et dans 33 puits de la province Aroma. La présente étude concerne la période de 1989 à 1993 qui est déficitaire en précipitation. La salinité augmente du nord au sud c’est un problème grave pour les lacs Uru-Uru et Poopó. Au sud du bassin versant, il y a une pollution naturelle par arsenic, silice, chlorures, sulfates, sodium, calcium et bore. L’influence anthropique est à l’origine d’une pollution bactériologique dans la région d’Oruro et aussi d’une pollution par le wolfram, l’étain, le cobalt, le cadmium, le nickel, l’antimoine et le plomb dans les zones rurales. En général, les eaux de surface présentent un risque pour les populations ainsi que pour les animaux et l’irrigation. En revanche les eaux souterraines montrent de meilleures caractéristiques physico-chimiques. Se muestrearon 36 lugares de agua superficial en la cuenca que incluye el lago Titicaca, río Desaguadero y los lagos Uru Uru y Poopó (Sistema TDPS. En agua subterránea se analizaron 37 pozos del sistema TDPS y 33 pozos en la provincia Aroma. La presente evaluación se refiere a un período de déficit pluviométrico entre 1989 y 1993. El contenido en sales aumenta de norte a sur y es grave en los lagos Uru-Uru y Poopó. Al sur de la cuenca, se nota una contaminación natural por arsénico, sílice, cloruros, sulfatos, sodio, calcio y boro. La contaminación antrópica está al origen de una polución de tipo bacteriológico en el área de Oruro y con wolfram, estaño, cobalto, cadmio, níquel, antimonio y plomo en el área rural. En general, las aguas superficiales presentan riesgos para el consumo humano, animal y para riego

  1. Package-X 2.0: A Mathematica package for the analytic calculation of one-loop integrals

    Science.gov (United States)

    Patel, Hiren H.

    2017-09-01

    This article summarizes new features and enhancements of the first major update of Package-X. Package-X 2.0 can now generate analytic expressions for arbitrarily high rank dimensionally regulated tensor integrals with up to four distinct propagators, each with arbitrary integer weight, near an arbitrary even number of spacetime dimensions, giving UV divergent, IR divergent, and finite parts at (almost) any real-valued kinematic point. Additionally, it can generate multivariable Taylor series expansions of these integrals around any non-singular kinematic point to arbitrary order. All special functions and abbreviations output by Package-X 2.0 support Mathematica's arbitrary precision evaluation capabilities to deal with issues of numerical stability. Finally, tensor algebraic routines of Package-X have been polished and extended to support open fermion chains both on and off shell. The documentation (equivalent to over 100 printed pages) is accessed through Mathematica's Wolfram Documentation Center and contains information on all Package-X symbols, with over 300 basic usage examples, 3 project-scale tutorials, and instructions on linking to FEYNCALC and LOOPTOOLS. Program files doi:http://dx.doi.org/10.17632/yfkwrd4d5t.1 Licensing provisions: CC by 4.0 Programming language: Mathematica (Wolfram Language) Journal reference of previous version: H. H. Patel, Comput. Phys. Commun 197, 276 (2015) Does the new version supersede the previous version?: Yes Summary of revisions: Extension to four point one-loop integrals with higher powers of denominator factors, separate extraction of UV and IR divergent parts, testing for power IR divergences, construction of Taylor series expansions of one-loop integrals, numerical evaluation with arbitrary precision arithmetic, manipulation of fermion chains, improved tensor algebraic routines, and much expanded documentation. Nature of problem: Analytic calculation of one-loop integrals in relativistic quantum field theory. Solution

  2. Radon exposure in abandoned metalliferous mines of South America

    International Nuclear Information System (INIS)

    Silva, A.A.R. da; Umisedo, N.; Yoshimura, E.M.; Anjos, R.M.; Valladares, D.L.; Velasco, H.; Rizzotto, M.

    2011-01-01

    Since the days of the Spanish and Portuguese conquerors, South America has been closely associated with the metalliferous ore mining. Gold, silver, tin, lead, tungsten, nickel, copper, and palladium ores have been explored over the last centuries. In addition, there has also been the development and promotion of other economic activities related to mining, as the underground mine tourism. A few works have been published on radon levels in the South American mining. In this study, we investigated the radon transport process and its health hazard in two exhausted and abandoned mines in San Luis Province, Argentina. These mines were chosen because they have different physical configurations in their cavities, features which can affect the air flow patterns and radon concentrations. La Carolina gold mine (32 deg 48' 0'' S, 66 deg 60' 0'' W) is currently a blind end system, corresponding to a horizontal excavation into the side of a mountain, with only a main adit. Los Condores wolfram mine (32 deg 33' 25'' S, 65 deg 15' 20'' W) is also a horizontal excavation into the side of a mountain, but has a vertical output (a shaft) at the end of the main gallery. Three different experimental methodologies were used. Radon concentration measurements were performed by CR-39 nuclear track detectors. The distribution of natural radionuclide activities ( 40 K, 232 Th and 238 U) was determined from rock samples collected along their main adits, using in laboratory gamma-ray spectrometry. The external gamma dose rate was evaluated using thermoluminescent dosimeters and a portable survey meter. The values for the 222 Rn concentration ranged from 0.43 ± 0.04 to 1.48 ± 0.12 kBq/m 3 in the Los Condores wolfram mine and from 1.8 ± 0.1 to 6.0±0.5 kBq/m 3 in the La Carolina gold mine, indicating that, in this mine, the radon levels exceed up to four times the action level of 1.5 kBq/m 3 recommended by the ICRP. The patterns of the radon transport process revealed that the La Carolina

  3. Sex differences in the development of diabetes in mice with deleted wolframin (Wfs1) gene.

    Science.gov (United States)

    Noormets, K; Kõks, S; Muldmaa, M; Mauring, L; Vasar, E; Tillmann, V

    2011-05-01

    Wolfram syndrome, caused by mutations in the wolframin (Wfs1) gene, is characterised by juvenile-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus and deafness. Diabetes tend to start earlier in boys. This study investigated sex differences in longitudinal changes in blood glucose concentration (BGC) in wolframin-deficient mice (Wfs1KO) and compared their plasma proinsulin and insulin levels with those of wild-type (wt) mice. Non-fasting BGC was measured weekly in 42 (21 males) mice from both groups at nine weeks of age. An intraperitoneal glucose tolerance test (IPGTT) was conducted at the 30 (th) week and plasma insulin, c-peptide and proinsulin levels were measured at the 32 (nd) week. At the 32 (nd) week, Wfs1KO males had increased BGC compared to wt males (9.40±0.60 mmol/l vs. 7.91±0.20 mmol/l; p<0.05). The opposite tendency was seen in females. Both male and female Wfs1KO mice had impaired glucose tolerance on IPGTT. Wfs1KO males had significantly lower mean plasma insulin levels than wt males (57.78±1.80 ng/ml vs. 69.42±3.06 ng/ml; p<0.01) and Wfs1KO females (70.30±4.42 ng/ml; p<0.05). Wfs1KO males had a higher proinsulin/insulin ratio than wt males (0.09±0.02 vs. 0.05±0.01; p=0.05) and Wfs1KO females (0.04±0.01; p<0.05). Plasma c-peptide levels in males were lower in Wfs1KO males (mean 55.3±14.0 pg/ml vs. 112.7±21.9 pg/ml; p<0.05). Male Wfs1KO mice had a greater risk of developing diabetes than female Wfs1KO mice. Low plasma insulin concentration with an increased proinsulin/insulin ratio in Wfs1KO males indicates possible disturbances in converting proinsulin to insulin which in long-term may lead to insulin deficiency. Further investigation is needed to clarify the mechanism for the sex differences in the development of diabetes in Wolfram syndrome. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  4. Особенности подготовки и использования электронных ресурсов при преподавании компьютерной графики

    OpenAIRE

    Таранчук, В. Б.; Кулинкович, В. А.

    2014-01-01

    Описаны новые возможности и рекомендации по применению технологий Wolfram, демонстрационных модулей коллекций Wolfram Demonstrations Project для создания и сопровождения интерактивных электронных образовательных ресурсов. Приведены примеры решений в учебном процессе дисциплины «Компьютерная графика», преподаваемой студентам 3 курса специальности «Прикладная информатика». Сovers new features and recommendations for creating and maintaining interactive electronic educational resources using ...

  5. Factors influencing the renal arterial Doppler waveform: a simulation study using an electrical circuit model (secondary publication)

    International Nuclear Information System (INIS)

    Sung, Chang Kyu; Han, Bong Soo; Kim, Seung Hyup

    2016-01-01

    The goal of this study was to evaluate the effect of vascular compliance, resistance, and pulse rate on the resistive index (RI) by using an electrical circuit model to simulate renal blood flow. In order to analyze the renal arterial Doppler waveform, we modeled the renal blood-flow circuit with an equivalent simple electrical circuit containing resistance, inductance, and capacitance. The relationships among the impedance, resistance, and compliance of the circuit were derived from well-known equations, including Kirchhoff’s current law for alternating current circuits. Simulated velocity-time profiles for pulsatile flow were generated using Mathematica (Wolfram Research) and the influence of resistance, compliance, and pulse rate on waveforms and the RI was evaluated. Resistance and compliance were found to alter the waveforms independently. The impedance of the circuit increased with increasing proximal compliance, proximal resistance, and distal resistance. The impedance decreased with increasing distal compliance. The RI of the circuit decreased with increasing proximal compliance and resistance. The RI increased with increasing distal compliance and resistance. No positive correlation between impedance and the RI was found. Pulse rate was found to be an extrinsic factor that also influenced the RI. This simulation study using an electrical circuit model led to a better understanding of the renal arterial Doppler waveform and the RI, which may be useful for interpreting Doppler findings in various clinical settings

  6. Using collider event topology in the search for the six-jet decay of top quark-antiquark pairs

    International Nuclear Information System (INIS)

    Field, R.D.; Kanev, Y.A.

    1997-11-01

    The authors investigate the use of the event topology as a tool in the search for the six-jet decay of top-pair production in proton-antiproton collisions at 1.8 TeV. Modified-Fox-Wolfram shape variables, H ell , are employed to help distinguish the top-pair signal from the ordinary QCD multi-jet background. The h ell 's can be constructed directly from the calorimeter cells or from jets. Events are required to lie in a region of H ell -space defined by L ell ell ell for ell = 1, ..., 6, where the Left, L ell , and right, R ell , cuts are determined by a genetic algorithm (GA) procedure to maximize the signal over the square root of the background. They are able to reduce the background over the signal to less than a factor of 100 using purely topological methods without using jet multiplicity cuts and without the aid of b-quark tagging

  7. Vibration analysis on compact car shock absorber

    Science.gov (United States)

    Tan, W. H.; Cheah, J. X.; Lam, C. K.; Lim, E. A.; Chuah, H. G.; Khor, C. Y.

    2017-10-01

    Shock absorber is a part of the suspension system which provides comfort experience while driving. Resonance, a phenomenon where forced frequency is coinciding with the natural frequency has significant effect on the shock absorber itself. Thus, in this study, natural frequencies of the shock absorber in a 2 degree-of-freedom system were investigated using Wolfram Mathematica 11, CATIA, and ANSYS. Both theoretical and simulation study how will the resonance affect the car shock absorber. The parametric study on the performance of shock absorber also had been conducted. It is found that the failure tends to occur on coil sprung of the shock absorber before the body of the shock absorber is fail. From mathematical modelling, it can also be seen that higher vibration level occurred on un-sprung mass compare to spring mass. This is due to the weight of sprung mass which could stabilize as compared with the weight of un-sprung mass. Besides that, two natural frequencies had been obtained which are 1.0 Hz and 9.1 Hz for sprung mass and un-sprung mass respectively where the acceleration is recorded as maximum. In conclusion, ANSYS can be used to validate with theoretical results with complete model in order to match with mathematical modelling.

  8. APPS en el rendimiento académico y autoconcepto de estudiantes de ingeniería

    Directory of Open Access Journals (Sweden)

    Mawency Vergel Ortega

    2015-11-01

    Full Text Available La investigación fue realizada en la Universidad Francisco de Paula Santander de la ciudad de Cúcuta, Colombia, durante el I-2014, comparó dos métodos de enseñanza, a través de un grupo prueba donde estudiantes de ecuaciones diferenciales utilizan aplicativos móviles como la calculadora HD, wolfram alpha-powered apps, y un grupo control que recibió clases sin ayuda de aplicativos. Su objeto fue determinar la influencia del uso de apps en el rendimiento académico de estudiantes de ecuaciones diferenciales en ingeniería. A través de un enfoque cuantitativo, de tipo campo, una entrevista, un diario de observación y test de autoconcepto y ansiedad como instrumentos junto a resultados en evaluaciones, permitieron observar mejora en el rendimiento académico de los estudiantes, percepción positiva hacia las ecuaciones diferenciales, mejora en niveles de autoconcepto y disminución en puntuaciones de ansiedad. Palabras claves: Aprendizaje, tecnología de la información, Ecuaciones diferenciales, Educación superior, rendimiento académico          

  9. Reaction-diffusion systems in natural sciences and new technology transfer

    Science.gov (United States)

    Keller, André A.

    2012-12-01

    Diffusion mechanisms in natural sciences and innovation management involve partial differential equations (PDEs). This is due to their spatio-temporal dimensions. Functional semi-discretized PDEs (with lattice spatial structures or time delays) may be even more adapted to real world problems. In the modeling process, PDEs can also formalize behaviors, such as the logistic growth of populations with migration, and the adopters’ dynamics of new products in innovation models. In biology, these events are related to variations in the environment, population densities and overcrowding, migration and spreading of humans, animals, plants and other cells and organisms. In chemical reactions, molecules of different species interact locally and diffuse. In the management of new technologies, the diffusion processes of innovations in the marketplace (e.g., the mobile phone) are a major subject. These innovation diffusion models refer mainly to epidemic models. This contribution introduces that modeling process by using PDEs and reviews the essential features of the dynamics and control in biological, chemical and new technology transfer. This paper is essentially user-oriented with basic nonlinear evolution equations, delay PDEs, several analytical and numerical methods for solving, different solutions, and with the use of mathematical packages, notebooks and codes. The computations are carried out by using the software Wolfram Mathematica®7, and C++ codes.

  10. Using collider event topology in the search for the six-jet decay of top quark-antiquark pairs

    Energy Technology Data Exchange (ETDEWEB)

    Field, R.D.; Kanev, Y.A.

    1997-11-01

    The authors investigate the use of the event topology as a tool in the search for the six-jet decay of top-pair production in proton-antiproton collisions at 1.8 TeV. Modified-Fox-Wolfram shape variables, {cflx H}{sub {ell}}, are employed to help distinguish the top-pair signal from the ordinary QCD multi-jet background. The {cflx h}{sub {ell}}`s can be constructed directly from the calorimeter cells or from jets. Events are required to lie in a region of {cflx H}{sub {ell}}-space defined by L{sub {ell}} < {cflx h}{sub {ell}} < R{sub {ell}} for {ell} = 1, ..., 6, where the Left, L{sub {ell}}, and right, R{sub {ell}}, cuts are determined by a genetic algorithm (GA) procedure to maximize the signal over the square root of the background. They are able to reduce the background over the signal to less than a factor of 100 using purely topological methods without using jet multiplicity cuts and without the aid of b-quark tagging.

  11. Conference on support mechanisms evolution and renewable energies integration in France and in Germany markets

    International Nuclear Information System (INIS)

    Praetorius, Barbara; Cruciani, Michel; Schwarz, Virginie; Nabe, Christian; Mayer, Joerg; Vogel, Wolfram; Abegg, Janosch; Lioret, Sonia; Avedissian, Franck; Cosse, Julien; Woodhouse, Stephen; Bradbury, Simon; Mollard, Matthieu; Solal, Lucie; Nodari, Antonio

    2015-01-01

    The French-German office for Renewable energies (OFAEnR) organised a conference on the support mechanisms evolution and the renewable energies integration in France and in Germany markets. In the framework of this French-German exchange of experience, participants exchanged views on the current support mechanisms in both countries and on their forthcoming legal modifications. The legal framework of direct renewable energy selling in the German market and the impacts and challenges of this model were addressed as well. Technical aspects of auction sales of electricity were approached too and illustrated with experience feedbacks from direct selling operators. This document brings together the available presentations (slides) made during this event: 1 - Tenders for Renewable energy and the German Energiewende - Perspectives, challenges, debates (Barbara Praetorius); 2 - Promotion of energy from renewable sources - A short analysis of the French public policy 2000 -2014 (Michel Cruciani); 3 - Support schemes for renewables in France and their evolution as foreseen in the energy transition law (Virginie Schwarz); 4 - Direct electricity selling on the wholesale market: legal framework and perspective - a French-German comparison (Christian Nabe); 5 - Self-consumption and power purchase Business framework in Germany (Joerg Mayer); 6 - Successful Integration of Renewable energies in the Market: the Role of the Power exchange (Wolfram Vogel); 7 - Earn money and do good by marketing renewables (Janosch Abegg); 8 - Proposals for a new electricity market design (Sonia Lioret)

  12. Genetic forms of neurohypophyseal diabetes insipidus.

    Science.gov (United States)

    Rutishauser, Jonas; Spiess, Martin; Kopp, Peter

    2016-03-01

    Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro. In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II (AVP) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin (WFS 1) gene. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf-Hirschhorn syndrome.

    Science.gov (United States)

    Flipsen-ten Berg, Klara; van Hasselt, Peter M; Eleveld, Marc J; van der Wijst, Suzanne E; Hol, Frans A; de Vroede, Monique A M; Beemer, Frits A; Hochstenbach, P F Ron; Poot, Martin

    2007-11-01

    The Wolf-Hirschhorn syndrome (WHS (MIM 194190)), which is characterized by growth delay, mental retardation, epilepsy, facial dysmorphisms, and midline fusion defects, shows extensive phenotypic variability. Several of the proposed mutational and epigenetic mechanisms in this and other chromosomal deletion syndromes fail to explain the observed phenotypic variability. To explain the complex phenotype of a patient with WHS and features reminiscent of Wolfram syndrome (WFS (MIM 222300)), we performed extensive clinical evaluation and classical and molecular cytogenetic (GTG banding, FISH and array-CGH) and WFS1 gene mutation analyses. We detected an 8.3 Mb terminal deletion and an adjacent 2.6 Mb inverted duplication in the short arm of chromosome 4, which encompasses a gene associated with WFS (WFS1). In addition, a nonsense mutation in exon 8 of the WFS1 gene was found on the structurally normal chromosome 4. The combination of the 4p deletion with the WFS1 point mutation explains the complex phenotype presented by our patient. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletions represents an additional explanation for the phenotypic variability observed in chromosomal deletion disorders.

  14. Simulation of root forms using cellular automata model

    Energy Technology Data Exchange (ETDEWEB)

    Winarno, Nanang, E-mail: nanang-winarno@upi.edu; Prima, Eka Cahya [International Program on Science Education, Universitas Pendidikan Indonesia, Jl. Dr. Setiabudi no 229, Bandung40154 (Indonesia); Afifah, Ratih Mega Ayu [Department of Physics Education, Post Graduate School, Universitas Pendidikan Indonesia, Jl. Dr. Setiabudi no 229, Bandung40154 (Indonesia)

    2016-02-08

    This research aims to produce a simulation program for root forms using cellular automata model. Stephen Wolfram in his book entitled “A New Kind of Science” discusses the formation rules based on the statistical analysis. In accordance with Stephen Wolfram’s investigation, the research will develop a basic idea of computer program using Delphi 7 programming language. To best of our knowledge, there is no previous research developing a simulation describing root forms using the cellular automata model compared to the natural root form with the presence of stone addition as the disturbance. The result shows that (1) the simulation used four rules comparing results of the program towards the natural photographs and each rule had shown different root forms; (2) the stone disturbances prevent the root growth and the multiplication of root forms had been successfully modeled. Therefore, this research had added some stones, which have size of 120 cells placed randomly in the soil. Like in nature, stones cannot be penetrated by plant roots. The result showed that it is very likely to further develop the program of simulating root forms by 50 variations.

  15. IBRI-CASONTO: Ontology-based semantic search engine

    Directory of Open Access Journals (Sweden)

    Awny Sayed

    2017-11-01

    Full Text Available The vast availability of information, that added in a very fast pace, in the data repositories creates a challenge in extracting correct and accurate information. Which has increased the competition among developers in order to gain access to technology that seeks to understand the intent researcher and contextual meaning of terms. While the competition for developing an Arabic Semantic Search systems are still in their infancy, and the reason could be traced back to the complexity of Arabic Language. It has a complex morphological, grammatical and semantic aspects, as it is a highly inflectional and derivational language. In this paper, we try to highlight and present an Ontological Search Engine called IBRI-CASONTO for Colleges of Applied Sciences, Oman. Our proposed engine supports both Arabic and English language. It is also employed two types of search which are a keyword-based search and a semantics-based search. IBRI-CASONTO is based on different technologies such as Resource Description Framework (RDF data and Ontological graph. The experiments represent in two sections, first it shows a comparison among Entity-Search and the Classical-Search inside the IBRI-CASONTO itself, second it compares the Entity-Search of IBRI-CASONTO with currently used search engines, such as Kngine, Wolfram Alpha and the most popular engine nowadays Google, in order to measure their performance and efficiency.

  16. Simulating shelf life determination by two simultaneous criteria.

    Science.gov (United States)

    Peleg, Micha; Normand, Mark D

    2015-12-01

    The shelf life of food and pharmaceutical products is frequently determined by a marker's concentration or quality index falling below or surpassing an assigned threshold level. Naturally, different chosen markers would indicate different shelf life for the same storage temperature history. We demonstrate that if there are two markers, such as two labile vitamins, the order in which their concentrations cross their respective thresholds may depend not only on their degradation kinetic parameters but also on the particular storage temperature profile, be it isothermal or non-isothermal. Thus, at least theoretically, the order observed in accelerated storage need not be always indicative of the actual order at colder temperatures, except where the two degradation reactions follow the same kinetic order and their temperature-dependence rate parameter is also the same. This is shown with simulated hypothetical degradation reactions that follow first or zero order kinetics and whose rate constant's temperature-dependence obeys the exponential model. It is also demonstrated with simulated hypothetical Maillard reaction's products whose synthesis rather than their degradation follows pseudo zero order kinetics. The software developed to do the simulations and calculate the thresholds crossing points has been posted on the Internet as a freely downloadable interactive Wolfram Demonstration, which can be used as a tool in storage studies and shelf life prediction. In principle, the methodology can be extended from two to any number of markers. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Studies in using a universal exchange and inference language for evidence based medicine. Semi-automated learning and reasoning for PICO methodology, systematic review, and environmental epidemiology.

    Science.gov (United States)

    Robson, Barry

    2016-12-01

    The Q-UEL language of XML-like tags and the associated software applications are providing a valuable toolkit for Evidence Based Medicine (EBM). In this paper the already existing applications, data bases, and tags are brought together with new ones. The particular Q-UEL embodiment used here is the BioIngine. The main challenge is one of bringing together the methods of symbolic reasoning and calculative probabilistic inference that underlie EBM and medical decision making. Some space is taken to review this background. The unification is greatly facilitated by Q-UEL's roots in the notation and algebra of Dirac, and by extending Q-UEL into the Wolfram programming environment. Further, the overall problem of integration is also a relatively simple one because of the nature of Q-UEL as a language for interoperability in healthcare and biomedicine, while the notion of workflow is facilitated because of the EBM best practice known as PICO. What remains difficult is achieving a high degree of overall automation because of a well-known difficulty in capturing human expertise in computers: the Feigenbaum bottleneck. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. The eye as a window to rare endocrine disorders

    Science.gov (United States)

    Chopra, Rupali; Chander, Ashish; Jacob, Jubbin J.

    2012-01-01

    The human eye, as an organ, can offer critical clues to the diagnosis of various systemic illnesses. Ocular changes are common in various endocrine disorders such as diabetes mellitus and Graves’ disease. However there exist a large number of lesser known endocrine disorders where ocular involvement is significant. Awareness of these associations is the first step in the diagnosis and management of these complex patients. The rare syndromes involving the pituitary hypothalamic axis with significant ocular involvement include Septo-optic dysplasia, Kallman's syndrome, and Empty Sella syndrome all affecting the optic nerve at the optic chiasa. The syndromes involving the thyroid and parathyroid glands that have ocular manifestations and are rare include Mc Cune Albright syndrome wherein optic nerve decompression may occur due to fibrous dysplasia, primary hyperparathyroidism that may present as red eye due to scleritis and Ascher syndrome wherein ptosis occurs. Allgrove's syndrome, Cushing's disease, and Addison's disease are the rare endocrine syndromes discussed involving the adrenals and eye. Ocular involvement is also seen in gonadal syndromes such as Bardet Biedl, Turner's, Rothmund's, and Klinefelter's syndrome. This review also highlights the ocular manifestation of miscellaneous syndromes such as Werner's, Cockayne's, Wolfram's, Kearns Sayre's, and Autoimmune polyendocrine syndrome. The knowledge of these relatively uncommon endocrine disorders and their ocular manifestations will help an endocrinologist reach a diagnosis and will alert an ophthalmologist to seek specialty consultation of an endocrinologist when encountered with such cases. PMID:22629495

  19. Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1.

    Science.gov (United States)

    Hildebrand, Michael S; Sorensen, Jessica L; Jensen, Maren; Kimberling, William J; Smith, Richard J H

    2008-09-01

    Most familial cases of autosomal dominant low frequency sensorineural hearing loss (LFSNHL) are attributable to mutations in the wolframin syndrome 1 (WFS1) gene at the DFNA6/14/38 locus. WFS1 mutations at this locus were first described in 2001 in six families segregating LFSNHL that was non-progressive below 2,000 Hz; the causative mutations all clustered in the C-terminal domain of the wolframin protein. Mutations in WFS1 also cause Wolfram syndrome (WS), an autosomal recessive neurodegenerative disorder defined by diabetes mellitus, optic atrophy and often deafness, while numerous single nucleotide polymorphisms (SNPs) in WFS1 have been associated with increased risk for diabetes mellitus, psychiatric illnesses and Parkinson disease. This study was conducted in an American family segregating autosomal dominant LFSNHL. Two hearing impaired family members also had autoimmune diseases-Graves disease (GD) and Crohn disease (CD). Based on the low frequency audioprofile, mutation screening of WFS1 was completed and a novel missense mutation (c.2576G --> A) that results in an arginine-to-glutamine substitution (p.R859Q) was identified in the C-terminal domain of the wolframin protein where most LFSNHL-causing mutations cluster. The family member with GD also carried polymorphisms in WFS1 that have been associated with other autoimmune diseases. (c) 2008 Wiley-Liss, Inc.

  20. Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders.

    Science.gov (United States)

    Koido, Kati; Kõks, Sulev; Nikopensius, Tiit; Maron, Eduard; Altmäe, Signe; Heinaste, Evelin; Vabrit, Kristel; Tammekivi, Veronika; Hallast, Pille; Kurg, Ants; Shlik, Jakov; Vasar, Veiko; Metspalu, Andres; Vasar, Eero

    2005-06-01

    Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684C/G, 1185C/T and 1832G/A, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p = 0.01) and for bipolar disorder an OR of 1.89 (p = 0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders.

  1. Modulation of wolframin expression in human placenta during pregnancy: comparison among physiological and pathological states.

    Science.gov (United States)

    Lucariello, Angela; Perna, Angelica; Sellitto, Carmine; Baldi, Alfonso; Iannaccone, Alessandro; Cobellis, Luigi; De Luca, Antonio; De Falco, Maria

    2014-01-01

    The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ.

  2. Identification of one novel causative mutation in exon 4 of WFS1 gene in two Italian siblings with classical DIDMOAD syndrome phenotype.

    Science.gov (United States)

    Rigoli, Luciana; Lombardo, Fortunato; Salzano, Giuseppina; Di Bella, Chiara; Messina, Maria Francesca; De Luca, Filippo; Iafusco, Dario

    2013-09-10

    The aim of the present paper is to describe a novel missense mutation (G107R) of WFS1 gene that was unexpectedly detected, in two siblings from Southern Italy, outside exon 8; a very unusual finding which has previously been reported only twice in Italian patients with Wolfram syndrome (WS). Although in Spanish pedigrees' WFS1 mutations are frequently located in exon 4, this finding is very infrequent in other pedigrees, particularly in Italian patients. a) our report of two siblings with one novel WSF1 mutation (G107R) expands the molecular spectrum of WS; b) this is the 3rd report of Italian patients harbouring one mutation outside exon 8 and the 2nd with one mutation in exon 4; c) on the basis of the present observations, and literature data we can infer that mutation locations outside exon 8 do not seem to be clearly associated with peculiar phenotype expressions of WFS1 gene. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

    Science.gov (United States)

    Kytövuori, Laura; Seppänen, Allan; Martikainen, Mika H; Moilanen, Jukka S; Kamppari, Seija; Särkioja, Terttu; Remes, Anne M; Räsänen, Pirkko; Rönnemaa, Tapani; Majamaa, Kari

    2013-08-01

    Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

  4. The wolframin His611Arg polymorphism influences medication overuse headache.

    Science.gov (United States)

    Di Lorenzo, C; Sances, G; Di Lorenzo, G; Rengo, C; Ghiotto, N; Guaschino, E; Perrotta, A; Santorelli, F M; Grieco, G S; Troisi, A; Siracusano, A; Pierelli, F; Nappi, G; Casali, C

    2007-09-13

    Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t=-3.504; p=0.00075) and more severe depressive symptoms on the BDI questionnaire (t=-3.048; p=0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F=12.277; d.f.=1,80; p=0.00075, adjusted R2=0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour.

  5. WFS1 mutations in hearing-impaired children.

    Science.gov (United States)

    Häkli, Sanna; Kytövuori, Laura; Luotonen, Mirja; Sorri, Martti; Majamaa, Kari

    2014-07-01

    Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. WFS1 gene mutations are a rare cause of HI among Finnish children with HI.

  6. Ultrafast haplotyping of putative microRNA-binding sites in the WFS1 gene by multiplex polymerase chain reaction and capillary gel electrophoresis.

    Science.gov (United States)

    Kerékgyártó, Márta; Németh, Nóra; Kerekes, Tamás; Rónai, Zsolt; Guttman, András

    2013-04-19

    The transmembrane protein wolframin (WSF1) plays a crucial role in cell integrity in pancreatic beta cells and maintaining ER homeostasis. Genetic variations in the WFS1 gene have been described to be associated with Wolfram syndrome or type 2 diabetes mellitus. In this paper we report on an efficient double-tube allele-specific amplification method in conjunction with ultrafast capillary gel electrophoresis for direct haplotyping analysis of the SNPs in two important miRNA-binding sites (rs1046322 and rs9457) in the WFS1 gene. An automated single-channel capillary gel electrophoresis system was utilized in the method that provided dsDNA fragment analysis in less than 240 s. The light-emitting diode induced fluorescence (LEDIF) detection system enabled excellent sensitivity for automated haplotyping of a large number of clinical samples. The detection limit was 0.002 ng/μL using field amplified injection from water diluted samples. The dynamic quantitation range was 0.08-10.00 ng/μL (R(2)=0.9997) in buffer diluted samples. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Evidence for linkage on chromosome 4p16.1 in Type 1 diabetes Danish families and complete mutation scanning of the WFS1 (Wolframin) gene.

    Science.gov (United States)

    Larsen, Z M; Johannesen, J; Kristiansen, O P; Nerup, J; Pociot, F

    2004-03-01

    To investigate whether the WFS1 gene, the gene for Wolfram syndrome, is a susceptibility gene for more common forms of diabetes in the Danish population. One hundred and fifty-two Danish Type 1 diabetes mellitus sib-pair families were genotyped for two microsatellite markers situated within 5 cM of the WFS1 gene and analysed for linkage and association using the sib-TDT. The entire coding region, the 5'UTR and 3'UTR of the WFS1 gene, were screened for mutations by direct sequencing in 29 selected Type 1 diabetes patients. Four of the identified mutations were tested for linkage and association in 255 Danish Type 1 diabetes families (including 103 simplex families). Evidence for linkage to Type 1 diabetes was found as the second most frequent allele of the marker D4S394 were transmitted 137 times (T = 61%) and not transmitted 88 times to affected offspring (Puc = 0.0011). Twelve mutations were found in the coding region and three mutations in the 3'UTR. No evidence for linkage and association to Type 1 diabetes was found testing four of the identified amino acid substitutions. Evidence of linkage to Type 1 diabetes was observed in the Danish family collection. However, no evidence of linkage and association was observed for any of the analysed polymorphisms, suggesting that other variations must be responsible for the observed evidence of linkage in the region.

  8. Differential promoter activity by nucleotide substitution at a type 2 diabetes genome-wide association study signal upstream of the wolframin gene.

    Science.gov (United States)

    Ryu, Jihye; Lee, Chaeyoung

    2016-03-01

    Functional knowledge of most genetic variants identified from genome-wide association studies (GWAS) for type 2 diabetes (T2D) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding Wolfram syndrome 1 (WFS1) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal. Promoter activity of luciferase reporter constructs was compared with haplotypes including variants composing a linkage disequilibrium block in the vicinity of rs4689388 in HEK293 and HepG2 cells. Promoter activity was highest with the most frequent haplotype (H1; ATCGT) and lowest with second most frequent haplotype (H2; GATCG), whose nucleotide alleles were all complementary to those of H1. Further analysis with artificial haplotypes revealed differential transcriptional activity by nucleotide substitution of rs4320200, rs13107806, or rs13127445 (P WFS1 by nucleotide substitution. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  9. Energy metabolism and thyroid function of mice with deleted wolframin (Wfs1) gene.

    Science.gov (United States)

    Noormets, K; Kõks, S; Ivask, M; Aunapuu, M; Arend, A; Vasar, E; Tillmann, V

    2014-05-01

    There is no data about the energy metabolism of patients with Wolfram syndrome caused by mutations in the wolframin (Wfs1) gene. The aim of this study was to investigate the role of Wfs1 in energy metabolism and thyroid function in Wfs1 deficient mice (Wfs1KO). 16 male (8 Wfs1KO, 8 wild type (wt)) and 16 female (8 Wfs1KO, 8wt) mice aged 11-13 weeks were studied alone in a specific metabolic cage for 48 h. Body weight, food, water and O2 consumption, motor activity, CO2 and heat production of mice were recorded. At the age of 14-20 weeks, plasma levels of thyroxine (T4), TSH and leptin were measured and histology of thyroid tissues examined. Mean CO2 and heat production was not different between the groups. Mean O2 consumption was higher in the Wfs1KO females compared to the Wfs1KO males (3 410.0±127.0 vs. 2 806.0±82.4 ml/kg/h; pWfs1 has a role in energy metabolism when the disease progresses further. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  10. Localization and distribution of wolframin in human tissues.

    Science.gov (United States)

    De Falco, Maria; Manente, Lucrezia; Lucariello, Angela; Baldi, Gianluca; Fiore, Paola; Laforgia, Vincenza; Baldi, Alfonso; Iannaccone, Alessandro; De Luca, Antonio

    2012-01-01

    Wolframin is a transmembrane glycoprotein of 890 aminoacids, encoded by WFS1 gene. WFS1 mutations are responsible for Wolfram syndrome, an autosomal recessive disorder. In the present paper, we first characterized the polyclonal wolframin antibody by dot blot. Secondly, we verified antibody specificity by western blotting using different human cell lines. Thirdly, we studied wolframin localization in human foetal (14-35 weeks) and adult tissues by immunohistochemistry. Wolframin expression was distributed in many organs, with different tissue and cell localization and expression levels. In foetal systems, wolframin expression was faint at 14-16 weeks and increased when development proceeded. In adult human tissues a variable positive staining was observed in both simple and stratified epithelia. A moderate wolframin expression was observed in liver and in the endocrine portion of the pancreas. In conclusion, our data suggest that this protein may have important roles in a number of different tissues, including many that are not known to be affected by WFS1-linked diseases. The immunopositivity in adult human tissues suggests that it may function maintaining physiological cellular homeostasis.

  11. Association study of the effect of WFS1 polymorphisms on risk of type 2 diabetes in Japanese population.

    Science.gov (United States)

    Mita, Masaki; Miyake, Kazuaki; Zenibayashi, Masako; Hirota, Yushi; Teranishi, Tetsuya; Kouyama, Kunichi; Sakaguchi, Kazuhiko; Kasuga, Masato

    2008-10-30

    Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafness and diabetes insipidus. The product encoded by WFS1 gene, wolframin, could be involved in ER stress response causing beta-cell loss through impaired cell cycle progression and increased apoptosis. Recently, polymorphisms in the WFS1 gene were strongly associated with type 2 diabetes in Caucasians. The aim of the present study was to examine whether the variants of WFS1 are associated with risk of type 2 diabetes in Japanese individuals. Four single nucleotide polymorphisms, rs6446482, rs12511742, rs1801208 (R456H) and rs734312 (H611R) were genotyped in a total of 536 diabetic patients and 398 nondiabetic control subjects. Among the four variants, rs12511742 showed a marginal association with susceptibility to type 2 diabetes (odds ratio = 1.32, 95% confidence interval = 1.02-1.71, P = 0.033). Carriers of the risk allele at rs12511742 exhibited lower pancreas beta-cell function (P = 0.017). However, this association disappeared after adjustment for sex, age and BMI (Adjusted P = 0.24). Although we found no evidence for a substantial effect of WFS1 polymorphisms on risk of type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population, this gene is still a good candidate for a type 2 diabetes susceptibility gene, potentially, through impaired insulin secretion.

  12. Study of selective oxidation of methane catalyzed by solid superacid in unique reaction field; Tokushu hannoba no kotai chokyosan wo mochiiru methane no sentaku sanka hanno ni kansuru kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Misonoo, M.; Tatsumi, T.; Mizuno, T.; Inumaru, T. [The University of Tokyo, Tokyo (Japan)

    1997-02-01

    Selective oxidation of lower alkanes by use of heteropolymeric compounds is studied. Alkanes are activated on Cs2.5H0.5PW12O40 serving as catalyst, and their activity and selectivity improve when the catalyst is developed into a dual function catalyst in which Cs and Pt are combined. A success is reported of the synthesis of a heteropolymeric acid in which two molecules of the coordination element wolfram are replaced with a transition metal of the first period, on which acid the oxidation of cyclohexane is enhanced. Cs2.5Ni0.08H1.34PVMo11O40 as a metal/heteropolymeric acid dual function catalyst enables the direct oxidation (9% recovered at 340{degree}C) of isobutane into a methacrylic acid, which is attributed to the harmonious coordination of the oxidizing work of the catalyst and acidity. It is possible to oxidize propane into the acrylic acid, but not ethane into the acetic acid. In the case of Pd/Cs2.5H1.5PVMo11O40, the formic acid, methanol, etc., are produced upon addition of hydrogen to the system. This reaction in the hydrogen/oxygen system is supposed to take place via activated oxygen seeds as in the case of oxidation by hydrogen peroxide. 10 refs.

  13. Lattice gas simulations of dynamical geometry in two dimensions.

    Science.gov (United States)

    Klales, Anna; Cianci, Donato; Needell, Zachary; Meyer, David A; Love, Peter J

    2010-10-01

    We present a hydrodynamic lattice gas model for two-dimensional flows on curved surfaces with dynamical geometry. This model is an extension to two dimensions of the dynamical geometry lattice gas model previously studied in one dimension. We expand upon a variation of the two-dimensional flat space Frisch-Hasslacher-Pomeau (FHP) model created by Frisch [Phys. Rev. Lett. 56, 1505 (1986)] and independently by Wolfram, and modified by Boghosian [Philos. Trans. R. Soc. London, Ser. A 360, 333 (2002)]. We define a hydrodynamic lattice gas model on an arbitrary triangulation whose flat space limit is the FHP model. Rules that change the geometry are constructed using the Pachner moves, which alter the triangulation but not the topology. We present results on the growth of the number of triangles as a function of time. Simulations show that the number of triangles grows with time as t(1/3), in agreement with a mean-field prediction. We also present preliminary results on the distribution of curvature for a typical triangulation in these simulations.

  14. The Computable Catchment: An executable document for model-data software sharing, reproducibility and interactive visualization

    Science.gov (United States)

    Gil, Y.; Duffy, C.

    2015-12-01

    This paper proposes the concept of a "Computable Catchment" which is used to develop a collaborative platform for watershed modeling and data analysis. The object of the research is a sharable, executable document similar to a pdf, but one that includes documentation of the underlying theoretical concepts, interactive computational/numerical resources, linkage to essential data repositories and the ability for interactive model-data visualization and analysis. The executable document for each catchment is stored in the cloud with automatic provisioning and a unique identifier allowing collaborative model and data enhancements for historical hydroclimatic reconstruction and/or future landuse or climate change scenarios to be easily reconstructed or extended. The Computable Catchment adopts metadata standards for naming all variables in the model and the data. The a-priori or initial data is derived from national data sources for soils, hydrogeology, climate, and land cover available from the www.hydroterre.psu.edu data service (Leonard and Duffy, 2015). The executable document is based on Wolfram CDF or Computable Document Format with an interactive open-source reader accessible by any modern computing platform. The CDF file and contents can be uploaded to a website or simply shared as a normal document maintaining all interactive features of the model and data. The Computable Catchment concept represents one application for Geoscience Papers of the Future representing an extensible document that combines theory, models, data and analysis that are digitally shared, documented and reused among research collaborators, students, educators and decision makers.

  15. SIMULATION MODEL BASED ON REGIONAL DEVELOPMENT AND VIRTUAL CHANGES

    Directory of Open Access Journals (Sweden)

    Petr Dlask

    2015-10-01

    Full Text Available This paper reports on change as an indicator that can be provide more focused goals in studies of development. The paper offers an answer to the question: How might management gain information from a simulation model and thus influence reality through pragmatic changes. We focus on where and when to influence, manage, and control basic technical-economic proposals. These proposals are mostly formed as simulation models. Unfortunately, however, they do not always provide an explanation of formation changes. A wide variety of simulation tools have become available, e.g. Simulink, Wolfram SystemModeler, VisSim, SystemBuild, STELLA, Adams, SIMSCRIPT, COMSOL Multiphysics, etc. However, there is only limited support for the construction of simulation models of a technical-economic nature. Mathematics has developed the concept of differentiation. Economics has developed the concept of marginality. Technical-economic design has yet to develop an equivalent methodology. This paper discusses an,alternative approach that uses the phenomenon of change, and provides a way from professional knowledge, which can be seen as a purer kind of information, to a more dynamic computing model (a simulation model that interprets changes as method. The validation of changes, as a result for use in managerial decision making, and condition for managerial decision making, can thus be improved.

  16. The application of synthetic inorganic ion exchangers to analytical chemistry, 2

    International Nuclear Information System (INIS)

    Abe, Mitsuo

    1974-01-01

    Regarding acidic salts, description is made on the general behaviour of the acidic salts of tetravalent metals and each of zirconium salts, titanium salts, stannic salts, cerium salts, thorium salts, chromium salts, and others. On heteropolyacid salts, ammonium 12-molybdophosphated and phosphorus wolframate are described. On insoluble ferrocyanides, the behaviour of various complex salts is explained. In the discussion on the general behaviour of the acidic salts of tetravalent metals, the ideality of ion exchange, the stability and solubility of the acidic salts, thermal stability and radiation resistance, the ion sieving effect of various acidic salts, and the selectivity of the acidic salts are stated. Zirconium gives a number of acidic salts, such as zirconium phosphate, crystalline zirconium phosphate, zirconium phrophosphate, various polyphosphates of zirconium, zirconium phosphate-silicate, zirconium arsenate, zirconium antimonate, zirconium molybdate, zirconium tungstate, etc. Useful titanium salts for ion exchange are titanium phosphate, titanium aresenate, titanium antimonate, titanium tungstate, titanium molybdate, titanium vanadate, and titanium selenate. The distribution coefficients of metal ions, inorganic-separation of various inorganic ion exchangers, the exchange characteristics of various elements on various ion exchangers, and the selectivity of various inorganic ion-exchangers are tabulated. (Fukutomi, T.)

  17. SIGNAL MEDIATORS AT INDUCTION OF HEAT RESISTANCE OF WHEAT PLANTLETS BY SHORT-TERM HEATING.

    Science.gov (United States)

    Karpets, Yu V; Kolupaev, Yu E; Yastreb, T O

    2015-01-01

    The effects of functional interplay of calcium ions, reactive oxygen species (ROS) and nitric oxide (NO) in the cells of wheat plantlets roots (Triticum aestivum L.) at the induction of their heat resistance by a short-term influence of hyperthermia (heating at the temperature of 42 degrees C during 1 minute) have been investigated. The transitional increase of NO and H2O2 content, invoked by heating, was suppressed by the treatment of plantlets with the antagonists of calcium EGTA (chelator of exocellular calcium), lanthanum chloride (blocker of calcium channels of various types) and neomycin (inhibitor of phosphatidylinositol-dependent phospholipase C). The rise of hydrogen peroxide content, caused by hardening, was partially suppressed by the action of inhibitors of nitrate reductase (sodium wolframate) and NO-synthase (N(G)-nitro-L-arginine methyl ester--L-NAME), and the increasing of nitric oxide content was suppressed by the treatment of plants with the antioxidant ionol and with the scavenger of hydrogen peroxide (dimethylthiourea). These compounds and antagonists of calcium also partially removed the effect of the rise of plantlets' heat resistance, invoked by hardening heating. The conclusion on calcium's role in the activation of enzymatic systems, generating reactive oxygen species and nitric oxide, and on the functional interplay of these signal mediators at the induction of heat resistance of plantlets by hardening heating is made.

  18. Pregnancy: Comparison among Physiological and Pathological States

    Directory of Open Access Journals (Sweden)

    Angela Lucariello

    2014-01-01

    Full Text Available The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ.

  19. A novel mutation in the WFS1 gene identified in a Taiwanese family with low-frequency hearing impairment

    Directory of Open Access Journals (Sweden)

    Chung Shing-Fang

    2007-05-01

    Full Text Available Abstract Background Wolfram syndrome gene 1 (WFS1 accounts for most of the familial nonsyndromic low-frequency sensorineural hearing loss (LFSNHL which is characterized by sensorineural hearing losses equal to and below 2000 Hz. The current study aimed to contribute to our understanding of the molecular basis of LFSNHL in an affected Taiwanese family. Methods The Taiwanese family with LFSNHL was phenotypically characterized using audiologic examination and pedigree analysis. Genetic characterization was performed by direct sequencing of WFS1 and mutation analysis. Results Pure tone audiometry confirmed that the family members affected with LFSNHL had a bilateral sensorineural hearing loss equal to or below 2000 Hz. The hearing loss threshold of the affected members showed no progression, a characteristic that was consistent with a mutation in the WFS1 gene located in the DFNA6/14/38 locus. Pedigree analysis showed a hereditarily autosomal dominant pattern characterized by a full penetrance. Among several polymorphisms, a missense mutation Y669H (2005T>C in exon 8 of WFS1 was identified in members of a Taiwanese family diagnosed with LFSNHL but not in any of the control subjects. Conclusion We discovered a novel heterozygous missense mutation in exon 8 of WFS1 (i.e., Y669H which is likely responsible for the LFSNHL phenotype in this particular Taiwanese family.

  20. Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Delphine Bonnet Wersinger

    Full Text Available Wolfram syndrome is an early onset genetic disease (1/180,000 featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1-/- mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP, protein disulfide isomerase (PDI and inositol-requiring enzyme 1 alpha (Ire1α markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1-/- mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1-/- mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1-/- optic pathways.

  1. Male mice with deleted Wolframin (Wfs1 gene have reduced fertility

    Directory of Open Access Journals (Sweden)

    Aunapuu Marina

    2009-08-01

    Full Text Available Abstract Background Wolfram Syndrome (WS is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO male mice have reduced fertility and, if so, to examine possible causes. Methods Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. Results The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p Conclusion The impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies.

  2. Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein

    International Nuclear Information System (INIS)

    Yamaguchi, Suguru; Ishihara, Hisamitsu; Tamura, Akira; Yamada, Takahiro; Takahashi, Rui; Takei, Daisuke; Katagiri, Hideki; Oka, Yoshitomo

    2004-01-01

    Mutations of the WFS1 gene are responsible for two hereditary diseases, Wolfram syndrome and low frequency sensorineural hearing loss. The WFS1 protein is a glycoprotein located in the endoplasmic reticulum (ER) membrane but its function is poorly understood. Herein we show WFS1 mRNA and protein levels in pancreatic islets to be increased with ER-stress inducers, thapsigargin and dithiothreitol. Another ER-stress inducer, the N-glycosylation inhibitor tunicamycin, also raised WFS1 mRNA but not protein levels. Site-directed mutagenesis showed both Asn-663 and Asn-748 to be N-glycosylated in mouse WFS1 protein. The glycosylation-defective WFS1 protein, in which Asn-663 and Asn-748 had been substituted with aspartate, exhibited an increased protein turnover rate. Consistent with this, the WFS1 protein was more rapidly degraded in the presence of tunicamycin. These data indicate that ER-stress and N-glycosylation play important roles in WFS1 expression and stability, and also suggest regulatory roles for this protein in ER-stress induced cell death

  3. Nutrient-deprivation autophagy factor-1 (NAF-1: biochemical properties of a novel cellular target for anti-diabetic drugs.

    Directory of Open Access Journals (Sweden)

    Sagi Tamir

    Full Text Available Nutrient-deprivation autophagy factor-1 (NAF-1 (synonyms: Cisd2, Eris, Miner1, and Noxp70 is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2 and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria. Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.

  4. Contributions to the 11. Geoengineering Congress in Munich. Geoengineering and energy; Beitraege zum 11. Geotechnik-Tag in Muenchen. Geotechnik und Energie

    Energy Technology Data Exchange (ETDEWEB)

    Vogt, Norbert (ed.)

    2012-11-01

    Within the eleventh geotechnics conference at 09th March, 2012 in Munich (Federal Republic of Germany), the following lectures were held: (1) New construction of the highway A44 on a new open pit dump (N. Vogt); (2) Soil liquefaction issues at mining dumps in the Lausitz (Wolfram Kudla); (3) Underfloor pumped-storage power plants in facilities of hard coal minings (Eugen Perau); (4) Geothermal energy power plant trademark (H. Haemmerle); (5) Surface settlements during the tunnel heading in the loose rock - prognosis, measurement and impact (J. Fillibeck); (6) Ring wall storages - an essential contribution to geotechnics for energy storage (M. Popp); (7) Storage basins and their geotechnical challenges (S. Messerklinger); (8) Energy from the Andes: The hydroelectric power plant La Confluencia in Chile (M. Mueller); (9) Particularities of geotechnical verifications for flat foundations of offshore wind power plants (U. Hartwig); (10) Dimensioning of piles for the foundation of offshore wind power plants (M. Achmus); (11) Offshore wind power fundaments: Practical experiences from the projects London Array and Dan Tysk (M. Horn); (12) Installation of a mono pile as a foundation structure for a tide turbine (S. Schmitz); (13) Carbon footprint - International comparison of assessment approaches at specialist foundation engineering techniques (A. Zoehrer); (14) Geotechnical assessments of upgrading power transmission lines (A. Smith).

  5. Microsoft founder opens the Windows of the micro-world

    CERN Document Server

    2009-01-01

    On Monday 8 June Bill Gates came to CERN for a short visit along with his son Rory. The Bulletin managed to grab a few words with him and discovered how much he appreciates (and supports) fundamental science. After meeting CERN Director-General Rolf Heuer, Gates and his son were given an introduction to CERN by Sergio Bertolucci, Director for Research, and then had a tour of the LHC tunnel, the Control Centre and SM18 with Mike Lamont before heading down to the CMS cavern guided by Jim Virdee, CMS Spokesperson, and Wolfram Zeuner.Millions of kids around the world dream of becoming the next Bill Gates, but Gates’ own son may well dream of becoming a physicist. "One of the reasons we wanted to come here is because Rory, my 10-year-old son, has shown a real interest in physics", explains Gates. "Rory has received some extra home-schooling in science. A lot of what we’ve been discussing has been building up to actually being able to s...

  6. FPGA Implementation of one-dimensional and two-dimensional cellular automata

    International Nuclear Information System (INIS)

    D'Antone, I.

    1999-01-01

    This report describes the hardware implementation of one-dimensional and two-dimensional cellular automata (CAs). After a general introduction to the cellular automata, we consider a one-dimensional CA used to implement pseudo-random techniques in built-in self test for VLSI. Due to the increase in digital ASIC complexity, testing is becoming one of the major costs in the VLSI production. The high electronics complexity, used in particle physics experiments, demands higher reliability than in the past time. General criterions are given to evaluate the feasibility of the circuit used for testing and some quantitative parameters are underlined to optimize the architecture of the cellular automaton. Furthermore, we propose a two-dimensional CA that performs a peak finding algorithm in a matrix of cells mapping a sub-region of a calorimeter. As in a two-dimensional filtering process, the peaks of the energy clusters are found in one evolution step. This CA belongs to Wolfram class II cellular automata. Some quantitative parameters are given to optimize the architecture of the cellular automaton implemented in a commercial field programmable gate array (FPGA)

  7. Signal mediators at induction of heat resistance of wheat plantlets by short-term heating

    Directory of Open Access Journals (Sweden)

    Yu. V. Karpets

    2015-12-01

    Full Text Available The effects of functional interplay of calcium ions, reactive oxygen species (ROS and nitric oxide (NO in the cells of wheat plantlets roots (Triticum aestivum L. at the induction of their heat resistance by a short-term influence of hyperthermia (heating at the temperature of 42 °С during 1 minute have been investigated. The transitional increase of NO and H2O2 content, invoked by heating, was suppressed by the treatment of plantlets with the antagonists of calcium EGTA (chelator of exocellular calcium, lanthanum chloride (blocker of calcium channels of various types and neomycin (inhibitor of phosphatidylinositol-dependent phospholipase C. The rise of hydrogen peroxide content, caused by hardening, was partially suppressed by the action of inhibitors of nitrate reductase (sodium wolframate and NO-synthase (NG-nitro-L-arginine methyl ester – L-NAME, and the increasing of nitric oxide content was suppressed by the treatment of plants with the antioxidant ionol and with the scavenger of hydrogen peroxide (dimethylthiourea. These compounds and antagonists of calcium also partially removed the effect of the rise of plantlets’ heat resistance, invoked by hardening heating. The conclusion on calcium’s role in the activation of enzymatic systems, generating reactive oxygen species and nitric oxide, and on the functional interplay of these signal mediators at the induction of heat resistance of plantlets by hardening heating is made.

  8. An 80th birthday celebration for the Ericsons

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    A Chinese proverb says that happiness is when friends coming from far and away meet and talk to each other. These wise words could very well be used to sum up the celebrations in honour of the 80th birthdays of Magda and Torleif Ericson, a couple in the normal sense of the word and often also in the field of physics. Torleif joined CERN's Theory Division in 1960, initially to work at the intersection of nuclear and particle physics at the Synchrocyclotron, and retired in 1995.   During the celebratory event on 17 September, speakers reviewed the depth and breadth of the contributions which both Torleif and Magda have made to theoretical physics in general and to nuclear physics in particular. José Bernabeu, Guy Chanfray, Wolfram Wiese, Achim Richter and Anthony Thomas all covered the considerable research that has been stimulated by the Ericson-Ericson correlation(s) over the past 50 years. A concert by the violinist Jean-Philippe Audoli and the pianist Blandine Eynaud and an informal...

  9. SBtab: a flexible table format for data exchange in systems biology.

    Science.gov (United States)

    Lubitz, Timo; Hahn, Jens; Bergmann, Frank T; Noor, Elad; Klipp, Edda; Liebermeister, Wolfram

    2016-08-15

    : SBtab is a table-based data format for Systems Biology, designed to support automated data integration and model building. It uses the structure of spreadsheets and defines conventions for table structure, controlled vocabularies and semantic annotations. The format comes with predefined table types for experimental data and SBML-compliant model structures and can easily be customized to cover new types of data. SBtab documents can be created and edited with any text editor or spreadsheet tool. The website www.sbtab.net provides online tools for syntax validation and conversion to SBML and HTML, as well as software for using SBtab in MS Excel, MATLAB and R. The stand-alone Python code contains functions for file parsing, validation, conversion to SBML and HTML and an interface to SQLite databases, to be integrated into Systems Biology workflows. A detailed specification of SBtab, including examples and descriptions of table types and available tools, can be found at www.sbtab.net : wolfram.liebermeister@gmail.com. © The Author 2016. Published by Oxford University Press.

  10. Navier Stokes Theorem in Hydrology

    Science.gov (United States)

    Narayanan, M.

    2005-12-01

    , more rapidly for larger acoustic speeds and smaller viscosities. This is an extremely useful paper that helps instructors to develop creative techniques for the classroom. References : Streater, R. F. Corrections to Fluid Dynamics : Open Systems and Information Dynamics, 10, 3-30, 2003. Hoff, David.: Dynamics of Singularity Surfaces for Compressible Navier-Stokes Flows in Two Space Dimensions. Journees Equations aux derivees partielles, Art. No. 7, 9 p. 2001. Arfken, G. "Gauss's Theorem." 1.11 in Mathematical Methods for Physicists, 3rd ed. Orlando, FL: Academic Press, pp. 57-61, 1985. Morse, P. M. and Feshbach, H. "Gauss's Theorem." In Methods of Theoretical Physics, Part I. New York: McGraw-Hill, pp. 37-38, 1953. Eric W. Weisstein. "Divergence Theorem." From MathWorld--A Wolfram Web Resource. http://mathworld.wolfram.com/DivergenceTheorem.html

  11. FIESTA 2: Parallelizeable multiloop numerical calculations

    Science.gov (United States)

    Smirnov, A. V.; Smirnov, V. A.; Tentyukov, M.

    2011-03-01

    The program FIESTA has been completely rewritten. Now it can be used not only as a tool to evaluate Feynman integrals numerically, but also to expand Feynman integrals automatically in limits of momenta and masses with the use of sector decompositions and Mellin-Barnes representations. Other important improvements to the code are complete parallelization (even to multiple computers), high-precision arithmetics (allowing to calculate integrals which were undoable before), new integrators, Speer sectors as a strategy, the possibility to evaluate more general parametric integrals. Program summaryProgram title:FIESTA 2 Catalogue identifier: AECP_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AECP_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU GPL version 2 No. of lines in distributed program, including test data, etc.: 39 783 No. of bytes in distributed program, including test data, etc.: 6 154 515 Distribution format: tar.gz Programming language: Wolfram Mathematica 6.0 (or higher) and C Computer: From a desktop PC to a supercomputer Operating system: Unix, Linux, Windows, Mac OS X Has the code been vectorised or parallelized?: Yes, the code has been parallelized for use on multi-kernel computers as well as clusters via Mathlink over the TCP/IP protocol. The program can work successfully with a single processor, however, it is ready to work in a parallel environment and the use of multi-kernel processor and multi-processor computers significantly speeds up the calculation; on clusters the calculation speed can be improved even further. RAM: Depends on the complexity of the problem Classification: 4.4, 4.12, 5, 6.5 Catalogue identifier of previous version: AECP_v1_0 Journal reference of previous version: Comput. Phys. Comm. 180 (2009) 735 External routines: QLink [1], Cuba library [2], MPFR [3] Does the new version supersede the previous version?: Yes Nature of problem: The sector

  12. Obtención y caracterización de materiales compuestos W-Cu para contactos eléctricos

    Directory of Open Access Journals (Sweden)

    Krivij, N.

    2003-08-01

    Full Text Available In the Cuban Metallurgical Research Center (CIME, are manufactured by powder metallurgy, shims of adjustment of a W-Cu composite material, that are used in the electrical contacts of the panels of control of the portico derricks that operate in the port of Havana City. The base material used has a composition of 70 % in mass electrolytic copper powder and wolfram powder of (30 % that is obtained by reduction from the oxide from wolfram. The powders are submitted to the stages of mixed, pressed and agglomeration and is obtained a composite material with free particles of W occluded in a counterfoil of Cu matrix, that do not interact and they provide the following properties: high melting temperature, high electro and thermo conductivity and corrosion resistance, high mechanical and electrical strengtheners, decrease weldability and stability during their development. However, when not reacting the volframio particles with the copper, the compound material will begin to fuse to the temperature of the copper, on the other hand and for the same reason the resistance to the corrosion should be similar to that of the pure copper. The shims of adjustment are fixed to the bodies of high purity copper welding with a silver alloy, the one which provides the maximum qualities of the Cu, as elasticity, breaking strength, thermal and electrical conductivities, as well corrosion resistance.

    En el Centro de Investigaciones Metalúrgicas (CIME, cubano, se fabrican por pulvimetalurgia, calzos de material compuesto volframio-cobre, que se utilizan en los contactos eléctricos de los paneles de control de las grúas pórtico que operan en el puerto de Ciudad de La Habana. El material base que se utiliza contiene un 70 % en masa de polvo de cobre electrolítico y polvo de volframio (30 %, que se obtiene por reducción del óxido de volframio. Los polvos se someten a las etapas de mezclado, prensado y sinterización obteniéndose un material compuesto con las

  13. Wfs1-deficient mice display altered function of serotonergic system and increased behavioural response to antidepressants

    Directory of Open Access Journals (Sweden)

    Tanel eVisnapuu

    2013-07-01

    Full Text Available It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT and noradrenaline (NA reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioural despair. The tail suspension test (TST and forced swimming test (FST were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 minutes tobrightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.

  14. Coupled circuit numerical analysis of eddy currents in an open MRI system

    Science.gov (United States)

    Akram, Md. Shahadat Hossain; Terada, Yasuhiko; Keiichiro, Ishi; Kose, Katsumi

    2014-08-01

    We performed a new coupled circuit numerical simulation of eddy currents in an open compact magnetic resonance imaging (MRI) system. Following the coupled circuit approach, the conducting structures were divided into subdomains along the length (or width) and the thickness, and by implementing coupled circuit concepts we have simulated transient responses of eddy currents for subdomains in different locations. We implemented the Eigen matrix technique to solve the network of coupled differential equations to speed up our simulation program. On the other hand, to compute the coupling relations between the biplanar gradient coil and any other conducting structure, we implemented the solid angle form of Ampere’s law. We have also calculated the solid angle for three dimensions to compute inductive couplings in any subdomain of the conducting structures. Details of the temporal and spatial distribution of the eddy currents were then implemented in the secondary magnetic field calculation by the Biot-Savart law. In a desktop computer (Programming platform: Wolfram Mathematica 8.0®, Processor: Intel(R) Core(TM)2 Duo E7500 @ 2.93 GHz; OS: Windows 7 Professional; Memory (RAM): 4.00 GB), it took less than 3 min to simulate the entire calculation of eddy currents and fields, and approximately 6 min for X-gradient coil. The results are given in the time-space domain for both the direct and the cross-terms of the eddy current magnetic fields generated by the Z-gradient coil. We have also conducted free induction decay (FID) experiments of eddy fields using a nuclear magnetic resonance (NMR) probe to verify our simulation results. The simulation results were found to be in good agreement with the experimental results. In this study we have also conducted simulations for transient and spatial responses of secondary magnetic field induced by X-gradient coil. Our approach is fast and has much less computational complexity than the conventional electromagnetic numerical

  15. A microwave resonator for limiting depth sensitivity for electron paramagnetic resonance spectroscopy of surfaces.

    Science.gov (United States)

    Sidabras, Jason W; Varanasi, Shiv K; Mett, Richard R; Swarts, Steven G; Swartz, Harold M; Hyde, James S

    2014-10-01

    A microwave Surface Resonator Array (SRA) structure is described for use in Electron Paramagnetic Resonance (EPR) spectroscopy. The SRA has a series of anti-parallel transmission line modes that provides a region of sensitivity equal to the cross-sectional area times its depth sensitivity, which is approximately half the distance between the transmission line centers. It is shown that the quarter-wave twin-lead transmission line can be a useful element for design of microwave resonators at frequencies as high as 10 GHz. The SRA geometry is presented as a novel resonator for use in surface spectroscopy where the region of interest is either surrounded by lossy material, or the spectroscopist wishes to minimize signal from surrounding materials. One such application is in vivo spectroscopy of human finger-nails at X-band (9.5 GHz) to measure ionizing radiation dosages. In order to reduce losses associated with tissues beneath the nail that yield no EPR signal, the SRA structure is designed to limit depth sensitivity to the thickness of the fingernail. Another application, due to the resonator geometry and limited depth penetration, is surface spectroscopy in coating or material science. To test this application, a spectrum of 1.44 μM of Mg(2+) doped polystyrene 1.1 mm thick on an aluminum surface is obtained. Modeling, design, and simulations were performed using Wolfram Mathematica (Champaign, IL; v. 9.0) and Ansys High Frequency Structure Simulator (HFSS; Canonsburg, PA; v. 15.0). A micro-strip coupling circuit is designed to suppress unwanted modes and provide a balanced impedance transformation to a 50 Ω coaxial input. Agreement between simulated and experimental results is shown.

  16. Visualization and Interaction in Research, Teaching, and Scientific Communication

    Science.gov (United States)

    Ammon, C. J.

    2017-12-01

    Modern computing provides many tools for exploring observations, numerical calculations, and theoretical relationships. The number of options is, in fact, almost overwhelming. But the choices provide those with modest programming skills opportunities to create unique views of scientific information and to develop deeper insights into their data, their computations, and the underlying theoretical data-model relationships. I present simple examples of using animation and human-computer interaction to explore scientific data and scientific-analysis approaches. I illustrate how valuable a little programming ability can free scientists from the constraints of existing tools and can facilitate the development of deeper appreciation data and models. I present examples from a suite of programming languages ranging from C to JavaScript including the Wolfram Language. JavaScript is valuable for sharing tools and insight (hopefully) with others because it is integrated into one of the most powerful communication tools in human history, the web browser. Although too much of that power is often spent on distracting advertisements, the underlying computation and graphics engines are efficient, flexible, and almost universally available in desktop and mobile computing platforms. Many are working to fulfill the browser's potential to become the most effective tool for interactive study. Open-source frameworks for visualizing everything from algorithms to data are available, but advance rapidly. One strategy for dealing with swiftly changing tools is to adopt common, open data formats that are easily adapted (often by framework or tool developers). I illustrate the use of animation and interaction in research and teaching with examples from earthquake seismology.

  17. The Quest for High Luminosity in Hadron Colliders (413th Brookhaven Lecture)

    International Nuclear Information System (INIS)

    Fischer, Wolfram

    2006-01-01

    In 1909, by bombarding a gold foil with alpha particles from a radioactive source, Ernest Rutherford and coworkers learned that the atom is made of a nucleus surrounded by an electron cloud. Ever since, scientists have been probing deeper and deeper into the structure of matter using the same technique. With increasingly powerful machines, they accelerate beams of particles to higher and higher energies, to penetrate more forcefully into the matter being investigated and reveal more about the contents and behavior of the unknown particle world. To achieve the highest collision energies, projectile particles must be as heavy as possible, and collide not with a fixed target but another beam traveling in the opposite direction. These experiments are done in machines called hadron colliders, which are some of the largest and most complex research tools in science. Five such machines have been built and operated, with Brookhaven's Relativistic Heavy Ion Collider (RHIC) currently the record holder for the total collision energy. One more such machine is under construction. Colliders have two vital performance parameters on which their success depends: one is their collision energy, and the other, the number of particle collisions they can produce, which is proportional to a quantity known as the luminosity. One of the tremendous achievements in the world's latest collider, RHIC, is the amazing luminosity that it produces in addition to its high energy. To learn about the performance evolution of these colliders and the way almost insurmountable difficulties can be overcome, especially in RHIC, join Wolfram Fischer, a physicist in the Collider-Accelerator (C-A) Department, who will give the next Brookhaven Lecture, on 'The Quest for High Luminosity in Hadron Colliders.'

  18. Theoretical study of aerobic vitamin C loss kinetics during commercial heat preservation and storage.

    Science.gov (United States)

    Peleg, Micha

    2017-12-01

    The non-isothermal aerobic degradation of ascorbic acid (AA), and the formation and subsequent degradation of the dehydroascorbic acid (DHAA) are described by two simultaneous rate equations, assuming that all three underlying reactions follow first or other fixed order kinetics. Also assumed is that the temperature-dependence of these three reactions' rate-constants follows the exponential model, a simpler substitute for the traditional Arrhenius equation. The effective momentary vitamin C's concentration is assumed to be the sum of the AA's and DHAA's momentary concentrations. Plots of the rate equations' numerical solutions for non-isothermal temperature histories, such as those that exist in actual heat preservation processes and commercial storage of foods, allow examining the temperature regime's role in the vitamin C's retention, at least qualitatively, and to evaluate its loss pattern when DHAA is initially absent or already present in the food. The temperature profile can be expressed algebraically or as an interpolating function constructed for digitized data. With the generalized model's version, characterization of the vitamin loss kinetics may require at least nine independent parameters, which ought to be known a priori, assumed on the basis of literature reports or determined experimentally. However, for many practical applications the number of kinetic parameters can be reduced to six. Isothermal loss is a special case, which can be used to test the calculation procedure by comparing the numerical solutions for quasi-isothermal temperature histories with the analytical solutions for truly isothermal temperature profiles. A version of the calculation and simulation procedure has been posted on the Internet as a freely downloadable interactive Wolfram Demonstration, which can be used as a tool to examine the effect of actual and hypothetical temperature histories on the vitamin's retention during heat processing and storage. It can also be used to

  19. Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain.

    Science.gov (United States)

    Tekko, Triin; Lilleväli, Kersti; Luuk, Hendrik; Sütt, Silva; Truu, Laura; Örd, Tiit; Möls, Märt; Vasar, Eero

    2014-06-01

    Wolframin (Wfs1) is a membrane glycoprotein that resides in the endoplasmic reticulum (ER) and regulates cellular Ca(2+) homeostasis. In pancreas Wfs1 attenuates unfolded protein response (UPR) and protects cells from apoptosis. Loss of Wfs1 function results in Wolfram syndrome (OMIM 222300) characterized by early-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus, deafness, and psychiatric disorders. Similarly, Wfs1-/- mice exhibit diabetes and increased basal anxiety. In the adult central nervous system Wfs1 is prominent in central extended amygdala, striatum and hippocampus, brain structures largely involved in behavioral adaptation of the organism. Here, we describe the initiation pattern of Wfs1 expression in mouse forebrain using mRNA in situ hybridization and compare it with Synaptophysin (Syp1), a gene encoding synaptic vesicle protein widely used as neuronal differentiation marker. We show that the expression of Wfs1 starts during late embryonic development in the dorsal striatum and amygdala, then expands broadly at birth, possessing several transitory regions during maturation. Syp1 expression precedes Wfs1 and it is remarkably upregulated during the period of Wfs1 expression initiation and maturation, suggesting relationship between neural activation and Wfs1 expression. Using in situ hybridization and quantitative real-time PCR we show that UPR-related genes (Grp78, Grp94, and Chop) display dynamic expression in the perinatal brain when Wfs1 is initiated and their expression pattern is not altered in the brain lacking functional Wfs1. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  20. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice.

    Science.gov (United States)

    Tein, Karin; Kasvandik, Sergo; Kõks, Sulev; Vasar, Eero; Terasmaa, Anton

    2015-01-01

    Mutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness. The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala, and limbic structures. The aim of this study was to investigate the effect of Wfs1 knockout (KO) on peptide processing in mouse hippocampus. A peptidomic approach was used to characterize individual peptides in the hippocampus of wild-type and Wfs1 KO mice. We identified 126 peptides in hippocampal extracts and the levels of 10 peptides differed between Wfs1 KO and wild-type mice at P Wfs1 KO mice compared to wild-type mice. Processing (cleavage) of little-LEN from the Pcsk1n gene product proSAAS involves prohormone convertase 2 (PC2). Thus, PC2 activity was measured in extracts prepared from the hippocampus of Wfs1 KO mice. The activity of PC2 in Wfs1 mutant mice was significantly higher (149.9 ± 2.3%, p Wfs1-KO mice, which is caused by increased activity of PC2. Increased activity of PC2 in Wfs1 KO mice is not caused by alteration in the levels of PC2 protein. Our results suggest a functional link between Wfs1 and PC2. Thus, the detailed molecular mechanism of the role of Wfs1 in the regulation of PC2 activity needs further investigation.

  1. Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations.

    Science.gov (United States)

    Franks, P W; Rolandsson, O; Debenham, S L; Fawcett, K A; Payne, F; Dina, C; Froguel, P; Mohlke, K L; Willer, C; Olsson, T; Wareham, N J; Hallmans, G; Barroso, I; Sandhu, M S

    2008-03-01

    Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p=0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p=4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p=4.9 x 10(-11)). In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.

  2. Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene.

    Science.gov (United States)

    Kovacs-Nagy, Reka; Elek, Zsuzsanna; Szekely, Anna; Nanasi, Tibor; Sasvari-Szekely, Maria; Ronai, Zsolt

    2013-06-01

    Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life-threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non-clinical spectrum has not been studied yet. Self-report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non-psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter-gene assay of the cloned 3' untranslated region with coexpression of miR-668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR-668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss-Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co-expressed with miR-668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non-clinical sample. Copyright © 2013 Wiley Periodicals, Inc.

  3. A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 diabetes in Russian patients.

    Science.gov (United States)

    Chistiakov, Dimitry A; Khodyrev, Dmitry S; Smetanina, Svetlana A; Bel'chikova, Larisa N; Suplotova, Lyudmila A; Nosikov, Valery V

    2010-01-01

    Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10(-7)). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (p(adjusted) = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (p(adjusted) = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (p(adjusted) = 0.029) and HOMA-β = 0.011. Disease-associated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function.

  4. Interrelationships between information and energy using knowledge management tools

    Energy Technology Data Exchange (ETDEWEB)

    Lizcano, D., E-mail: david.lizcano@udima.es, E-mail: mariaaurora.martinez@udima.es; Martínez, A. María, E-mail: david.lizcano@udima.es, E-mail: mariaaurora.martinez@udima.es [Madrid Open University, Carretera de la Coruña, km 38,5. 28400. Collado-Villalba, Madrid (Spain)

    2014-10-06

    Edward Fredkin was an enthusiastic advocate of information-based theoretical physics, who, in the early 1980s, proposed a new theory of physics based on the idea that the universe is ultimately composed of software. According to Fredkin, reality should be considered as being composed not of particles, matter and forces or energy but of bits of data or information modified according to computational rules. Fredkin went on to demonstrate that, while energy is necessary for storing and retrieving information, it can be arbitrarily reduced in order to carry out any particular instance of information processing, and this operation does not have a lower bound. This implies that it is information rather than matter or energy that should be considered at the ultimate fundamental constituent of reality. This possibility had already been suggested by other scientists. Norbert Wiener heralded a fundamental shift from energy to information and suggested that the universe was founded essentially on the transformation of information, not energy. However, Konrad Zuse was the first, back in 1967, to defend the idea that a digital computer is computing the universe. Richard P. Feynman showed this possibility in a similar light in his reflections on how information related to matter and energy. Other pioneering research on the theory of digital physics was published by Kantor in 1977 and more recently by Stephen Wolfram in 2002, who thereby joined the host of voices upholding that it is patterns of information, not matter and energy, that constitute the cornerstones of reality. In this paper, we introduce the use of knowledge management tools for the purpose of analysing this topic.

  5. Interrelationships between information and energy using knowledge management tools

    Science.gov (United States)

    Lizcano, D.; Martínez, A. María

    2014-10-01

    Edward Fredkin was an enthusiastic advocate of information-based theoretical physics, who, in the early 1980s, proposed a new theory of physics based on the idea that the universe is ultimately composed of software. According to Fredkin, reality should be considered as being composed not of particles, matter and forces or energy but of bits of data or information modified according to computational rules. Fredkin went on to demonstrate that, while energy is necessary for storing and retrieving information, it can be arbitrarily reduced in order to carry out any particular instance of information processing, and this operation does not have a lower bound. This implies that it is information rather than matter or energy that should be considered at the ultimate fundamental constituent of reality. This possibility had already been suggested by other scientists. Norbert Wiener heralded a fundamental shift from energy to information and suggested that the universe was founded essentially on the transformation of information, not energy. However, Konrad Zuse was the first, back in 1967, to defend the idea that a digital computer is computing the universe. Richard P. Feynman showed this possibility in a similar light in his reflections on how information related to matter and energy. Other pioneering research on the theory of digital physics was published by Kantor in 1977 and more recently by Stephen Wolfram in 2002, who thereby joined the host of voices upholding that it is patterns of information, not matter and energy, that constitute the cornerstones of reality. In this paper, we introduce the use of knowledge management tools for the purpose of analysing this topic.

  6. Interrelationships between information and energy using knowledge management tools

    International Nuclear Information System (INIS)

    Lizcano, D.; Martínez, A. María

    2014-01-01

    Edward Fredkin was an enthusiastic advocate of information-based theoretical physics, who, in the early 1980s, proposed a new theory of physics based on the idea that the universe is ultimately composed of software. According to Fredkin, reality should be considered as being composed not of particles, matter and forces or energy but of bits of data or information modified according to computational rules. Fredkin went on to demonstrate that, while energy is necessary for storing and retrieving information, it can be arbitrarily reduced in order to carry out any particular instance of information processing, and this operation does not have a lower bound. This implies that it is information rather than matter or energy that should be considered at the ultimate fundamental constituent of reality. This possibility had already been suggested by other scientists. Norbert Wiener heralded a fundamental shift from energy to information and suggested that the universe was founded essentially on the transformation of information, not energy. However, Konrad Zuse was the first, back in 1967, to defend the idea that a digital computer is computing the universe. Richard P. Feynman showed this possibility in a similar light in his reflections on how information related to matter and energy. Other pioneering research on the theory of digital physics was published by Kantor in 1977 and more recently by Stephen Wolfram in 2002, who thereby joined the host of voices upholding that it is patterns of information, not matter and energy, that constitute the cornerstones of reality. In this paper, we introduce the use of knowledge management tools for the purpose of analysing this topic

  7. TNF-related apoptosis-inducing ligand deficiency enhances survival in murine colon ascendens stent peritonitis

    Directory of Open Access Journals (Sweden)

    Beyer K

    2016-06-01

    Full Text Available Katharina Beyer,1 Laura Stollhof,1 Christian Poetschke,2 Wolfram von Bernstorff,1 Lars Ivo Partecke,1 Stephan Diedrich,1 Stefan Maier,1 Barbara M Bröker,2 Claus-Dieter Heidecke1 1Department of General, Visceral, Thoracic, and Vascular Surgery, 2Institute of Immunology, University of Greifswald, Greifswald, GermanyBackground: Apart from inducing apoptosis in tumor cells, tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL influences inflammatory reactions. Murine colon ascendens stent peritonitis (CASP represents a model of diffuse peritonitis. Recently, it has been demonstrated that administration of exogenous TRAIL not only induces apoptosis in neutrophils but also enhances survival in this model. The aim of this study was to examine the impact of genetic TRAIL deficiency on the course of CASP.Methods: Peritonitis was induced in 6- to 8-week-old female TRAIL−/− mice as well as in wild-type mice. The sepsis severity score and survival of mice were monitored. Bacterial loads in blood as well as in the lymphoid organs were examined. Additionally, the number of apoptotic cells within the lymphoid organs was determined.Results: As early as 8 hours postinduction of CASP, TRAIL−/− mice were significantly more affected by sepsis than wild-type mice, as measured by the sepsis severity score. However, during the further course of sepsis, TRAIL deficiency led to significantly decreased sepsis severity scores, resulting in an enhanced overall survival in TRAIL−/− mice. The better survival of TRAIL−/− mice was accompanied by a decreased bacterial load within the blood. In marked contrast, the number of apoptotic cells within the lymphoid organs was highly increased in TRAIL−/− mice 20 hours after induction of CASP.Conclusion: Hence, exogenous and endogenous TRAIL is protective during the early phase of sepsis, while endogenous TRAIL appears to be detrimental in the later course of this disease.Keywords: CASP, mice

  8. Woody crops conference 2013; Agrarholz-Kongress 2013

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-06-01

    Within the Guelzow expert discussions at 19th and 20th February 2013 in Berlin (Federal Republic of Germany) the following lectures were held: (1) Research funding of the BMELV in the field of the production of woody crops (Andreas Schuette); (2) ELKE - Development of extensive concepts of land use for the production of renewable raw materials as possible compensatory measures and substitute measures (Frank Wegener); (3) Knowledge transfer to the realm of practice, experiences of the DLG (Frank Setzer); (4) Results of the tests with fast growing tree species after 18 years of cultivation in Guelzow (Andreas Gurgel); (5) Latest findings on the production of woody crops in Brandenburg (D. Murach); (6) Phytosanitary situation in short-rotation coppices in Germany - Current state of knowledge and prognoses for the future (Christiane Helbig); (7) Evaluation of alternative delivery procedures in short-rotation coppices (Janine Schweier); (8) With a short-rotation coppice shredder through Germany (Wolfram Kudlich); (9) Changes of land-use of traditional crops rotation systems to short-rotation coppices consisting of poplar trees and willow trees, which sites are suitable? - Selected results from the ProLoc association (Martin Hofmann); (10) Cultivation of populus tremula for short-rotation coppices at agricultural areas (Mirko Liesebach); (11) Investigations of the resistance behaviour of newly developed black poplar clones and balsam poplar clones against the poplar leave rust Melampsora larici-populina (Christina Fey-Wagner); (12) A agri-forestry system for ligneous energy production in the organic farming - First results from cultivation experiments in Bavaria (Klaus Wiesinger); (13) Implementation of agri-forestry systems with energy wood in the rural area - the project AgroForstEnergie (Armin Vetter); (14) Impact of agroforestry land utilization on microclimate, soil fertility and quality of water (Christian Boehm).

  9. Optimizing an analytical dose calculation algorithm for fast 2D calculations

    International Nuclear Information System (INIS)

    Lorenz, Friedlieb; Richter, Henning; Zygmanski, Piotr

    2010-01-01

    Previously, an analytical dose calculation algorithm for MLC-based radiotherapy was developed and commissioned, which includes a detailed model of various MLC effects as a unique feature [1]. The algorithm was originally developed as an independent verification of the treatment planning system's dose calculation and it explicitly modeled spatial and depth dependent MLC effects such as interleaf transmission, the tongue-and-groove effect, rounded leaf ends, MLC scatter, beam hardening, and gradual MLC transmission fall-off with increasing off-axis distance. Originally the algorithm was implemented in Mathematica trademark (Wolfram). To speed up the calculation time and to be able to calculate high resolution 2D dose distributions within a reasonable time frame (<2 s) the algorithm needs to be optimized and to be embedded in a user friendly environment. To achieve this goal, the dose calculation model is implemented in Visual Basic 6.0, which decreases the calculation time moderately. More importantly, the numerical algorithm for dose calculation is changed at two levels: the dose contributions are split into their x- and y-contributions and the calculation is aperture- rather than as originally point-based. Implementing these three major changes, the calculation time is reduced considerably without loosing accuracy. The time for a typical IMRT field with about 2500 calculation points decreased from 2387 seconds to 0.624 seconds (a factor of about 3800). The mean agreement of the optimized and the not optimized calculation algorithm at the isocenter for a fairly complex IMRT plan with 23 fields is better than 1% relative to the local dose at the measuring point. (orig.)

  10. 17. Kassel symposium energy systems technology. Structures and grids for the future energy supply; 17. Kasseler Symposium Energie-Systemtechnik. Strukturen und Netze fuer die Energieversorgung von Morgen

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-07-01

    Within the 17th Kassel symposium from 11th to 12th October, 2012, in Kassel (Federal Republic of Germany), the following lectures were held: (1) E-Energy - the art of flexibilization between market and regulation (Michael Wedler); (2) The model region Harz (Florian Schloegl); (3) The role of IKT at the transformation of the energy supply - Chances for new business ideas (Arnold Picot); (4) Standardized connection of plants to IEC 61850 (Martin Winter); (5) Implementation of a IKT infrastructure for a virtual power plant in the model region Harz (Manuel Wickert); (6) OGEMA2.0 - Smart grid meets smart home (David Nestle); (7) Evaluation of the grid stability of a purely regenerative power supply (Kaspar Knorr); (8) Biogas plants and storage for the integration of renewable energies (Patrick Hochloff); (9) moma Architecture and functions in the intelligent energy system (Andreas Kiessling); (10) Power hub - showing the full potential of the VPP technology (Andreas Bjerre); (11) Implementation of electricity grids, heat grids and traffic grids - Potentials, requirements and efficiencies (Wolfram Wellssow); (12) Exploration of the regional distribution grid as a basis for the implementation of smart grids using the RegModHarz project as an example (Christian Roehrig); (13) New design and works management of distribution grids in decentralized supply structures (Martin Braun); (14) Advantages and challenges of the coupling of natural gas distribution systems and power distribution systems (Herbert Bauer); (15) Acceptance of renewable energies in the region Harz (Amelie Fechner); (16) Business models for a future 100 per cent supply of renewable energies (Peer Ritter).

  11. Density- and wavefunction-normalized Cartesian spherical harmonics for l ≤ 20.

    Science.gov (United States)

    Michael, J Robert; Volkov, Anatoliy

    2015-03-01

    The widely used pseudoatom formalism [Stewart (1976). Acta Cryst. A32, 565-574; Hansen & Coppens (1978). Acta Cryst. A34, 909-921] in experimental X-ray charge-density studies makes use of real spherical harmonics when describing the angular component of aspherical deformations of the atomic electron density in molecules and crystals. The analytical form of the density-normalized Cartesian spherical harmonic functions for up to l ≤ 7 and the corresponding normalization coefficients were reported previously by Paturle & Coppens [Acta Cryst. (1988), A44, 6-7]. It was shown that the analytical form for normalization coefficients is available primarily for l ≤ 4 [Hansen & Coppens, 1978; Paturle & Coppens, 1988; Coppens (1992). International Tables for Crystallography, Vol. B, Reciprocal space, 1st ed., edited by U. Shmueli, ch. 1.2. Dordrecht: Kluwer Academic Publishers; Coppens (1997). X-ray Charge Densities and Chemical Bonding. New York: Oxford University Press]. Only in very special cases it is possible to derive an analytical representation of the normalization coefficients for 4 4 the density normalization coefficients were calculated numerically to within seven significant figures. In this study we review the literature on the density-normalized spherical harmonics, clarify the existing notations, use the Paturle-Coppens (Paturle & Coppens, 1988) method in the Wolfram Mathematica software to derive the Cartesian spherical harmonics for l ≤ 20 and determine the density normalization coefficients to 35 significant figures, and computer-generate a Fortran90 code. The article primarily targets researchers who work in the field of experimental X-ray electron density, but may be of some use to all who are interested in Cartesian spherical harmonics.

  12. A point mutation in the [2Fe–2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties

    Energy Technology Data Exchange (ETDEWEB)

    Tamir, Sagi; Eisenberg-Domovich, Yael [The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904 (Israel); Conlan, Andrea R.; Stofleth, Jason T.; Lipper, Colin H.; Paddock, Mark L. [University of California at San Diego, La Jolla, CA 92093 (United States); Mittler, Ron [University of North Texas, Denton, TX 76203 (United States); Jennings, Patricia A. [University of California at San Diego, La Jolla, CA 92093 (United States); Livnah, Oded, E-mail: oded.livnah@huji.ac.il; Nechushtai, Rachel, E-mail: oded.livnah@huji.ac.il [The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904 (Israel)

    2014-06-01

    NAF-1 has been shown to be related with human health and disease, is upregulated in epithelial breast cancer and suppression of its expression significantly suppresses tumor growth. It is shown that replacement of the single His ligand with Cys resulted in dramatic changes to the properties of its 2Fe-2S clusters without any global crystal structural changes. NAF-1 is an important [2Fe–2S] NEET protein associated with human health and disease. A mis-splicing mutation in NAF-1 results in Wolfram Syndrome type 2, a lethal childhood disease. Upregulation of NAF-1 is found in epithelial breast cancer cells, and suppression of NAF-1 expression by knockdown significantly suppresses tumor growth. Key to NAF-1 function is the NEET fold with its [2Fe–2S] cluster. In this work, the high-resolution structure of native NAF-1 was determined to 1.65 Å resolution (R factor = 13.5%) together with that of a mutant in which the single His ligand of its [2Fe–2S] cluster, His114, was replaced by Cys. The NAF-1 H114C mutant structure was determined to 1.58 Å resolution (R factor = 16.0%). All structural differences were localized to the cluster binding site. Compared with native NAF-1, the [2Fe–2S] clusters of the H114C mutant were found to (i) be 25-fold more stable, (ii) have a redox potential that is 300 mV more negative and (iii) have their cluster donation/transfer function abolished. Because no global structural differences were found between the mutant and the native (wild-type) NAF-1 proteins, yet significant functional differences exist between them, the NAF-1 H114C mutant is an excellent tool to decipher the underlying biological importance of the [2Fe–2S] cluster of NAF-1 in vivo.

  13. Type 1 diabetes in a patient with Ellis-van Creveld syndrome

    Directory of Open Access Journals (Sweden)

    Carla Graziadio

    Full Text Available CONTEXT: Ellis-van Creveld (EVC syndrome is a rare autosomal recessive disease characterized by disproportionate short stature, narrow thorax, postaxial polydactyly, nail and tooth abnormalities and congenital heart disease. CASE REPORT: The patient was a 22-year-old Caucasian man, the third child of consanguineous parents. He received the diagnosis of insulin-dependent diabetes mellitus (DM at 16 years of age, and around one year later, he underwent surgery to correct a partial atrioventricular septal defect. Upon physical examination, at 22 years of age, he presented stature of 145.5 cm (P3, weight of 49 kg (P3, head circumference of 54 cm (P2-50, high palate, absence of one of the lower lateral incisor teeth, narrow shoulders, narrowing of the upper thorax, scoliosis, rhizomelic shortening of the upper limbs, brachydactyly, postaxial polydactyly and clinodactyly of the second and third fingers. The lower limbs showed rhizomelic shortening with significant genu valgum (knock-knee deformity, small feet with postaxial polydactyly, syndactyly between the second and third toes and hallux valgus. Multiple melanocytic nevi were evident on the face, thorax and limbs. At that time, he was using neutral protamine Hagedorn (NPH insulin, with poorly controlled DM. The clinical findings presented led to the diagnosis of EVC syndrome. Only one case of this syndrome has been described with DM so far. Attention is drawn to the fact that the genes associated with this syndrome are located close to those of the Wolfram syndrome, a condition that leads to early-onset diabetes.

  14. A point mutation in the [2Fe–2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties

    International Nuclear Information System (INIS)

    Tamir, Sagi; Eisenberg-Domovich, Yael; Conlan, Andrea R.; Stofleth, Jason T.; Lipper, Colin H.; Paddock, Mark L.; Mittler, Ron; Jennings, Patricia A.; Livnah, Oded; Nechushtai, Rachel

    2014-01-01

    NAF-1 has been shown to be related with human health and disease, is upregulated in epithelial breast cancer and suppression of its expression significantly suppresses tumor growth. It is shown that replacement of the single His ligand with Cys resulted in dramatic changes to the properties of its 2Fe-2S clusters without any global crystal structural changes. NAF-1 is an important [2Fe–2S] NEET protein associated with human health and disease. A mis-splicing mutation in NAF-1 results in Wolfram Syndrome type 2, a lethal childhood disease. Upregulation of NAF-1 is found in epithelial breast cancer cells, and suppression of NAF-1 expression by knockdown significantly suppresses tumor growth. Key to NAF-1 function is the NEET fold with its [2Fe–2S] cluster. In this work, the high-resolution structure of native NAF-1 was determined to 1.65 Å resolution (R factor = 13.5%) together with that of a mutant in which the single His ligand of its [2Fe–2S] cluster, His114, was replaced by Cys. The NAF-1 H114C mutant structure was determined to 1.58 Å resolution (R factor = 16.0%). All structural differences were localized to the cluster binding site. Compared with native NAF-1, the [2Fe–2S] clusters of the H114C mutant were found to (i) be 25-fold more stable, (ii) have a redox potential that is 300 mV more negative and (iii) have their cluster donation/transfer function abolished. Because no global structural differences were found between the mutant and the native (wild-type) NAF-1 proteins, yet significant functional differences exist between them, the NAF-1 H114C mutant is an excellent tool to decipher the underlying biological importance of the [2Fe–2S] cluster of NAF-1 in vivo

  15. Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors

    Directory of Open Access Journals (Sweden)

    Hui eHan

    2013-10-01

    Full Text Available Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER stress response in liver cancer development was investigated using an animal model with a liver knockout of the chaperone BiP and under constitutive hepatic ER stress. Long-term alcohol and high fat diet (HFD feeding resulted in higher levels of serum alanine aminotransferase (ALT, impaired ER stress response, and higher incidence of liver tumor in older (aged 16 months knockout females than in either middle-aged (6 months knockouts or older (aged 16 months wild type females. In the older knockout females, stronger effects of the alcohol on methylation of CpG islands at promoter regions of genes involved in the ER associated degradation (ERAD were also detected. Altered expression of ERAD factors including derlin 3, Creld2 (cysteine-rich with EGF-like domains 2, Herpud1 (ubiquitin-like domain member, Wfs1 (wolfram syndrome gene, and Yod1 (deubiquinating enzyme 1 was co-present with decreased proteasome activities, increased estrogen receptor alpha variant (ERa36, and enhanced phosphorylations of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2 and STAT3 (the signal transducers and activators of transcription in the older knockout female fed alcohol. Our results suggest that long-term alcohol consumption and ageing may promote liver tumorigenesis in females through interfering with DNA methylation and expression of genes involved in the ER associated degradation.

  16. Linear reversible second-order cellular automata and their first-order matrix equivalents

    International Nuclear Information System (INIS)

    Macfarlane, A J

    2004-01-01

    Linear or one-dimensional reversible second-order cellular automata, exemplified by three cases named as RCA1-3, are introduced. Displays of their evolution in discrete time steps, t=0, 1, 2, ..., from their simplest initial states and on the basis of updating rules in modulo 2 arithmetic, are presented. In these, shaded and unshaded squares denote cells whose cell variables are equal to one and zero respectively. This paper is devoted to finding general formulas for, and explicit numerical evaluations of, the weights N(t) of the states or configurations of RCA1-3, i.e. the total number of shaded cells in tth line of their displays. This is achieved by means of the replacement of RCA1-3 by the equivalent linear first-order matrix automata MCA1-3, for which the cell variables are 2x2 matrices, instead of just numbers (element of Z 2 ) as for RCA1-3. MCA1-3 are tractable because it has been possible to generalize to them the heavy duty methods already well-developed for ordinary first-order cellular automata like those of Wolfram's Rules 90 and 150. While the automata MCA1-3 are thought to be of genuine interest in their own right, with untapped further mathematical potential, their treatment has been applied here to expediting derivation of a large body of general and explicit results for N(t) for RCA1-3. Amongst explicit results obtained are formulas also for each of RCA1-3 for the total weight of the configurations of the first 2 M times, M=0, 1, 2, ..

  17. Modelado y análisis de datos procedentes de sistemas de imagen para diagnóstico médico mediante Mathematica

    Directory of Open Access Journals (Sweden)

    Nuria Ortigosa

    2017-01-01

    Full Text Available Los sistemas de imagen para diagnóstico médico son una de las tecnologías que han despertado gran interés en los últimos años. Precisamente por presentar un marcado carácter multidisciplinar, aunando matemáticas, física e ingeniería biomédica y electrónica, este área suscita un gran interés en el alumnado de secundaria y bachillerato. En este trabajo se presenta el contenido de una de las sesiones desarrolladas en la Universitat Politècnica de València, enmarcada dentro de los Campus Científicos de Verano CAMPUS-VLC, bajo el título "Tecnología y física médicas''. En ella, a partir de la base y el conocimiento previo del funcionamiento del Tomógrafo por Emisión de Positrones, los alumnos aprenden a procesar la información registrada por estos equipos utilizando el popular software Wolfram Mathematica. Gracias a él, por ejemplo, serán capaces de ubicar el punto de emisión de radioactividad mediante la utilización de histogramas. Además, también se les presentan los algoritmos para la manipulación y procesado de este tipo de imágenes, como la detección de bordes.

  18. Linking myometrial physiology to intrauterine pressure; how tissue-level contractions create uterine contractions of labor.

    Directory of Open Access Journals (Sweden)

    Roger C Young

    2014-10-01

    the 4-class system of Wolfram. However, instead of classifying the rules, biological CAs should classify the set of input values for the rules that describe the relevant biology.

  19. RNA-sequencing of WFS1-deficient pancreatic islets.

    Science.gov (United States)

    Ivask, Marilin; Hugill, Alison; Kõks, Sulev

    2016-04-01

    Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in theWFS1gene.WFS1encodes an endoplasmic reticulum resident transmembrane protein. TheWfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets inWFS1-deficient mice.WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KOpancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared toWTand Wfs1HZislets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KOhad an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KOwas significantly higher than that ofWTand Wfs1HZRNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated inWFS1-deficient mice. Functional annotation ofRNAsequencing results showed thatWFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  20. Interfaces and ventilator settings for long-term noninvasive ventilation in COPD patients

    Directory of Open Access Journals (Sweden)

    Callegari J

    2017-06-01

    Full Text Available Jens Callegari,1 Friederike Sophie Magnet,1 Steven Taubner,1 Melanie Berger,2 Sarah Bettina Schwarz,1 Wolfram Windisch,1 Jan Hendrik Storre3,4 1Department of Pneumology, Cologne-Merheim Hospital, Kliniken der Stadt Koeln, Witten/Herdecke University Hospital, 2Department of Pneumology, Malteser Hospital St Hildegardis, Cologne, 3Department of Pneumology, University Medical Hospital, Freiburg, 4Department of Intensive Care, Sleep Medicine and Mechanical Ventilation, Asklepios Fachkliniken Munich-Gauting, Gauting, Germany Introduction: The establishment of high-intensity (HI noninvasive ventilation (NIV that targets elevated PaCO2 has led to an increase in the use of long-term NIV to treat patients with chronic hypercapnic COPD. However, the role of the ventilation interface, especially in more aggressive ventilation strategies, has not been systematically assessed.Methods: Ventilator settings and NIV compliance were assessed in this prospective cross-sectional monocentric cohort study of COPD patients with pre-existing NIV. Daytime ­arterialized blood gas analyses and lung function testing were also performed. The primary end point was the distribution among study patients of interfaces (full-face masks [FFMs] vs nasal masks [NMs] in a real-life setting.Results: The majority of the 123 patients studied used an FFM (77%, while 23% used an NM. Ventilation settings were as follows: mean ± standard deviation (SD inspiratory positive airway pressure (IPAP was 23.2±4.6 mbar and mean ± SD breathing rate was 16.7±2.4/minute. Pressure support ventilation (PSV mode was used in 52.8% of patients, while assisted pressure-controlled ventilation (aPCV was used in 47.2% of patients. Higher IPAP levels were associated with an increased use of FFMs (IPAP <21 mbar: 73% vs IPAP >25 mbar: 84%. Mean compliance was 6.5 hours/day, with no differences between FFM (6.4 hours/day and NM (6.7 hours/day users. PaCO2 assessment of ventilation quality revealed

  1. A Strategic Analysis of Information Sharing Among Cyber Attackers

    Directory of Open Access Journals (Sweden)

    Kjell Hausken

    2015-10-01

    our analysis to endogenize the firm’s asset and this analysis largely confirms the preceding analysis with a fixed asset. We use the software Mathematica 10.1 (www.wolfram.com to program the model mathematically with equilibrium constraints, and perform numerical analysis illustrated graphically.

  2. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice

    Directory of Open Access Journals (Sweden)

    Karin eTein

    2015-08-01

    Full Text Available BackgroundMutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness (DIDMOAD. The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala and limbic structures. The aim of this study was to investigate the effect of Wfs1 knockout on peptide processing in mouse hippocampus. A peptidomic approach was used to characterize individual peptides in the hippocampus of wild-type and Wfs1 knockout mice. ResultsWe identified 126 peptides in hippocampal extracts and the levels of 10 peptides differed between Wfs1 KO and wild-type mice at P<0.05. The peptide with the largest alteration was little-LEN, which level was 25 times higher in the hippocampus of Wfs1 KO mice compared to wild-type mice. Processing (cleavage of little-LEN from the Pcsk1n gene product proSAAS involves prohormone convertase 2 (PC2. Thus, PC2 activity was measured in extracts prepared from the hippocampus of Wfs1 knockout mice. The activity of PC2 in Wfs1 mutant mice was significantly higher (149.9±2.3%, p<0.0001, n=8 than in wild-type mice (100.0±7.0%, n=8. However, Western blot analysis showed that protein levels of 7B2, proPC2 and PC2 were same in both groups, and so were gene expression levels.ConclusionsProcessing of proSAAS is altered in the hippocampus of Wfs1-KO mice, which is caused by increased activity of PC2. Increased activity of PC2 in Wfs1 knockout mice is not caused by alteration in the levels of PC2 protein. Our results suggest a functional link between Wfs1 and PC2. Thus, the detailed molecular mechanism of the role of Wfs1 in the regulation of PC2 activity needs further investigation.

  3. Machine-learning the string landscape

    Science.gov (United States)

    He, Yang-Hui

    2017-11-01

    We propose a paradigm to apply machine learning various databases which have emerged in the study of the string landscape. In particular, we establish neural networks as both classifiers and predictors and train them with a host of available data ranging from Calabi-Yau manifolds and vector bundles, to quiver representations for gauge theories, using a novel framework of recasting geometrical and physical data as pixelated images. We find that even a relatively simple neural network can learn many significant quantities to astounding accuracy in a matter of minutes and can also predict hithertofore unencountered results, whereby rendering the paradigm a valuable tool in physics as well as pure mathematics. Of course, this paradigm is useful not only to physicists but to also to mathematicians; for instance, could our NN be trained well enough to approximate bundle cohomology calculations? This, and a host of other examples, we will now examine.Methodology  Neural networks are known for their complexity, involving usually a complicated directed graph each node of which is a ;perceptron; (an activation function imitating a neuron) and amongst the multitude of which there are many arrows encoding input/output. Throughout this letter, we will use a rather simple multi-layer perceptron (MLP) consisting of 5 layers, three of which are hidden, with activation functions typically of the form of a logistic sigmoid or a hyperbolic tangent. The input layer is a linear layer of 100 to 1000 nodes, recognizing a tensor (as we will soon see, algebro-geometric objects such as Calabi-Yau manifolds or polytopes are generically configurations of integer tensors) and the output layer is a summation layer giving a number corresponding to a Hodge number, or to rank of a cohomology group, etc. Such an MLP can be implemented, for instance, on the latest versions of Wolfram Mathematica. With 500-1000 training rounds, the running time is merely about 5-20 minutes on an ordinary laptop. It

  4. MEGAS - multi-electrode gas sensor system. Micromechanical high-temperature sensor system on a Si basis for measurements of nitrogen monoxide concentrations in motor car exhaust. Final report; MEGAS - Multi-Elektroden-Gassensorsystem. Mikromechanisches Hochtemperatur-Sensorsystem aus Silizium-Basis zur Ermittlung von Stickstoffmonoxid-Konzentrationen im Kfz-Abgas. Abschlussbericht

    Energy Technology Data Exchange (ETDEWEB)

    Junge, S.

    2002-07-01

    The IMSAS is working on an actively heated Si substrate with interdigital structures fo working temperatures up to 550 C and for aggressive working media. The following tasks were achieved: Gas sensor design; Process development and optimisation; Processing of the Si substrate; Optimisation of the sensor substrate. The following problems were encountered: Minimisation of intrinsic stress of the stratified packages; Optimisation of the adhesive strength; Development of a stable sensor heating up to 550 C; Development and optimisation of structuring methods; Combination of thin film and thick film technologies. Resistive gas sensors with titanium-tungsten mixed oxides must be heated to 500 C for fast and sensitive response to a NO atmosphere. The gas sensitivity is strongly temperature-dependent, i.e. gas sensor temperature contro is required. In the case of diesel engine catalytic converters, ambient temperatures are high and vary with the mode of operation and operating time. The sensor temperature must be at least as high as the maximum ambient temperature and must be kept stable at this level. (orig.) [German] Am IMSAS liegt der Schwerpunkt im Bereich der Entwicklung eines aktiv beheizten Siliziumsubstrates mit Interdigitalstrukturen, das Arbeitstemperaturen bis zu 550 C und aggressiven Umgebungsbedingungen standhaelt. Die Arbeitspakete lassen sich grob zusammenfassen: - Designerstellung des Gassensors - Prozessentwicklung und -optimierung - Prozessierung des Siliziumsubstrates - Optimierung des Sensorsubstrates. Aus diesen Schwerpunkten ergeben sich Schwierigkeiten, die im Projektverlauf geloest werden muessen: - Minimierung des intrinsischen Stresses der Schichtpakete - Optimierung der Haftfestigkeit der Schichten/Schichtpakete - Entwicklung einer stabilen Sensorheizung bis 550 C - Entwicklung und Optimierung der Strukturierungsmethoden - Kombination von Duenn- und Dickschichttechnik (Si-Technologie und Siebdruck). Resistive Gassensoren mit Titan-Wolfram

  5. Topographic effect in marine magnetotelluric data and implications to the electrical conductivity structure of the mantle beneath the Tristan da Cunha hotspot area in southern Atlantic

    Science.gov (United States)

    Baba, K.; Chen, J.; Jegen, M. D.; Utada, H.; Kammann, J.; Geissler, W. H.

    2015-12-01

    Kiyoshi Baba1,2, Jin Chen2, Marion Jegen2, Hisashi Utada1, Janina Kammann3, and Wolfram H. Geissler4 1. Earthquake Research Institute, The University of Tokyo2. GEOMAR, Helmholtz Centre for Ocean Research Kiel3. University of Hamburg4. Alfred Wegener Institute Helmholtz Centre for Polar and Marine ResearchTristan da Cunha Island is one of the hot spots in the Atlantic Ocean. The discussion about its source have not reached consensus yet whether it is in shallow asthenosphere or deeper mantle, because of lack of the geophysical observations in the area. A marine magnetotelluric (MT) experiment was conducted together with seismological observations in the area in 2012-2013 by collaboration between Germany and Japan, in order to give further constraints on the physical state of the mantle beneath the area. A total of 26 seafloor stations were deployed around the Tristan da Cunha islands and available data were retrieved from 23 stations. The MT responses were estimated for those available sites. The detailed data processing will be presented by Chen et al. in this meeting. In this study, we report on the topographic effect on the observed MT responses. During the cruises for seafloor instruments deployment and recovery, detailed bathymetry data were collected around the stations by onboard multi-narrow beam echo sounding (MBES) system. We compiled the MBES data and ETOPO1 data to incorporate the local and regional topography. Then, we applied iterative topographic effect correction and one-dimensional (1-D) conductivity structure inversion. The MT responses of each station were simulated by three-dimensional (3-D) forward modeling. Preliminary results show the overall feature of the observed MT responses at some stations were qualitatively well explained by the seafloor topography included in the conductivity structure model over the 1-D mantle structure. An extreme example is the station near the Tristan da Cunha Island. The impedance phases varies ~300 degrees in

  6. New applications of natural oils and fats II. Subproject 2.1 and 2.3. Olefin metathesis and selective oxidation of unsaturated fatty compounds. Final report; Neue Einsatzmoeglichkeiten natuerlicher Oele und Fette II. Teilprojekt 2.1 und 2.3. Industriechemikalien durch Olefin-Metathese oleochemischer Verbindungen und Selektivoxidationen ungesaettigter Fettstoffe durch Metallkomplexkatalyse. Abschlussbericht

    Energy Technology Data Exchange (ETDEWEB)

    Warwel, S.; Ercklentz, B.; Fischer, S.; Hoffmann, A.; Kaiser, W.; Tillack, J.; Thomas, S.; Bavaj, P.; Deckwirth, E.A.; Ruesch genannt Klaas, M.; Wolff, B.

    1994-07-01

    Metathesis: New high effective catalysts (B{sub 2}O{sub 3}-Re{sub 2}O{sub 7}/Al{sub 2}O{sub 3}-SiO{sub 2} + SnBu{sub 4} and MeReO{sub 3} + B{sub 2}O{sub 3}-Al{sub 2}O{sub 3}-SiO{sub 2}) were developed for the metathesis of unsaturated fatty acid esters. They were used for the synthesis of {omega} unsaturated esters, middle-chained esters, branched esters, dicarboxylic acid esters and pre-pheromones. The metathesis of unsaturated esters with ethylene was tested successfully in a continuous miniplant. Selective oxidations: unsaturated fatty acid esters were converted to keto fatty acid esters catalysed by PdSO{sub 4}/heteropoly acid using O{sub 2} or H{sub 2}O{sub 2}. By Ruthenium catalysis/peracetic acid or Re{sub 2}O{sub 7}/H{sub 2}O{sub 2} the oxidative C=C-cleavage to dicarboxylic acids was achieved. Oleochemical di- and polyols were produced by tungsten- and rhenium-catalysis and H{sub 2}O{sub 2}. (orig.) [Deutsch] Olefin-Metathese: Fuer die Metathese ungesaettigter Fettsaeureester wurden mit B{sub 2}O{sub 3}-Re{sub 2}O{sub 7}/Al{sub 2}O{sub 3}-SiO{sub 2} + SnBu{sub 4} und MeReO{sub 3} + B{sub 2}O{sub 3}-Al{sub 2}O{sub 3}-SiO{sub 2} neue hochaktive Katalysatoren entwickelt und fuer Synthesen von {omega}-ungesaettigten Estern, mittelkettigen Estern, verzweigten Estern sowie fuer Dicarbonsaeuren und Pheromonvorstufen genutzt. Die Metathese ungesaettigter Ester mit Ethylen wurde erfolgreich in kontinuierlicher Fahrweise in einer Miniplant erprobt. Selektivoxidationen: ungesaettigte Fettsaeureester wurden unter Katalyse von PdSO{sub 4}/Heteropolysaeure mit O{sub 2} oder H{sub 2}O{sub 2} in Ketofettsaeuren ueberfuehrt. Mit Ru.-Kat./Peressigsaeure bzw. Re{sub 2}O{sub 7}/H{sub 2}O{sub 2} gelang die oxidative C=C-Spaltung zu Dicarbonsaeuren. Fettchemische Di- und Polyole wurden wolfram- und rheniumkatalysiert mittels H{sub 2}O{sub 2} erhalten. (orig.)

  7. A structured review of health utility measures and elicitation in advanced/metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Hao Y

    2016-06-01

    Full Text Available Yanni Hao,1 Verena Wolfram,2 Jennifer Cook2 1Novartis Pharmaceuticals, East Hanover, NJ, USA; 2Adelphi Values, Bollington, UK Background: Health utilities are increasingly incorporated in health economic evaluations. Different elicitation methods, direct and indirect, have been established in the past. This study examined the evidence on health utility elicitation previously reported in advanced/metastatic breast cancer and aimed to link these results to requirements of reimbursement bodies. Methods: Searches were conducted using a detailed search strategy across several electronic databases (MEDLINE, EMBASE, Cochrane Library, and EconLit databases, online sources (Cost-effectiveness Analysis Registry and the Health Economics Research Center, and web sites of health technology assessment (HTA bodies. Publications were selected based on the search strategy and the overall study objectives. Results: A total of 768 publications were identified in the searches, and 26 publications, comprising 18 journal articles and eight submissions to HTA bodies, were included in the evidence review. Most journal articles derived utilities from the European Quality of Life Five-Dimensions questionnaire (EQ-5D. Other utility measures, such as the direct methods standard gamble (SG, time trade-off (TTO, and visual analog scale (VAS, were less frequently used. Several studies described mapping algorithms to generate utilities from disease-specific health-related quality of life (HRQOL instruments such as European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Breast Cancer 23 (EORTC QLQ-BR23, Functional Assessment of Cancer Therapy – General questionnaire (FACT-G, and Utility-Based Questionnaire-Cancer (UBQ-C; most used EQ-5D as the reference. Sociodemographic factors that affect health utilities, such as age, sex

  8. Replication of the association between variants in the WFS1 gene and risk of type 2 diabetes in European populations

    Science.gov (United States)

    Franks, P.W.; Rolandsson, O.; Debenham, S.L.; Fawcett, K.A.; Payne, F.; Dina, C.; Froguel, P.; Mohlke, K.L.; Willer, C.; Olsson, T.; Wareham, N.J.; Hallmans, G.; Barroso, I; Sandhu, M.S.

    2009-01-01

    Aims/hypothesis: Mutations at the Wolframin encoding gene, WFS1, cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. In the present study, we sought to replicate those associations in a northern Swedish case-control study for type 2 diabetes. We also meta-analyzed published and previously unpublished data from Sweden, Finland and France to obtain updated summary effect estimates. Methods: Four WFS1 SNPs (rs10010131, rs6446482, rs752854, rs734312 [R611H]) were genotyped in a type 2 diabetes case-control study (N=1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex, and body mass index. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 cases and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. Results: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk (OR=0.85; 95% CI=0.75-0.96; p=0.010). Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131, or its proxy variants, showed evidence for statistical association (OR=0.87; 95% CI=0.82-0.93; p=4.5×10−5). In an updated meta-analysis of all 11 studies, comprising 14,139 cases and 16,109 controls, strong evidence for statistical association was also observed (OR=0.89; 95% CI=0.86-0.92; p=4.9×10−11). Conclusion: In this study of WFS1 gene variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and risk of type 2 diabetes. PMID:18040659

  9. Atenção à saúde ocular de crianças com alterações no desenvolvimento em serviços de intervenção precoce: barreiras e facilitadores

    Directory of Open Access Journals (Sweden)

    Gabriela Cordeiro Corrêa do Nascimento

    Full Text Available RESUMO Objetivo: Identificar fatores que influenciam na detecção precoce de deficiência visual e o início da intervenção precoce de crianças com alterações no desenvolvimento. Métodos: O estudo constituiu-se de levantamento, exploratório e descritivo, que contou com a aplicação de questionários com representantes institucionais, profissionais da equipe dos serviços de intervenção precoce e mães ou cuidadores das crianças atendidas. Os dados receberam tratamento estatístico através dos softwares Sistema de Análise Estatística SAS 9.3, Wolfram Mathematica e Microsoft Excel.A amostra constituiu-se de 434 sujeitos (19 representantes institucionais, 142 profissionais dos serviços e 273 mães/cuidadores das crianças atendidas. Resultados: A análise dos resultados revelou valores estatísticos de p-valor=0,0119 para a realização do teste do olhinho no que se refere ao início da intervenção precoce. A mãe recebe orientação quanto ao desenvolvimento da visão que obteve valores de p-valor=0,0106 para início da intervenção oportuna e valores de p-valor=0,0061 para primeira consulta ao oftalmologista. Conclusão: Realizar o teste do olhinho constituiu-se fator facilitador para o início da intervenção precoce e ter uma deficiência exclusivamente visual e frequentar instituição privada como barreira.A entrada tardia em serviço de intervenção precoce afeta negativamente a idade da primeira consulta oftalmológica. A mãe recebe orientação quanto ao desenvolvimento da visão que revelou-se fator facilitador para a primeira consulta ao oftalmologista e para início da intervenção oportuna. O campo da saúde ocular constitui-se demanda da saúde pública e requer ações e programas educativos direcionados aos familiares, profissionais e gestores institucionais.

  10. Theory of synergistic effects: Hill-type response surfaces as 'null-interaction' models for mixtures.

    Science.gov (United States)

    Schindler, Michael

    2017-08-02

    The classification of effects caused by mixtures of agents as synergistic, antagonistic or additive depends critically on the reference model of 'null interaction'. Two main approaches are currently in use, the Additive Dose (ADM) or concentration addition (CA) and the Multiplicative Survival (MSM) or independent action (IA) models. We compare several response surface models to a newly developed Hill response surface, obtained by solving a logistic partial differential equation (PDE). Assuming that a mixture of chemicals with individual Hill-type dose-response curves can be described by an n-dimensional logistic function, Hill's differential equation for pure agents is replaced by a PDE for mixtures whose solution provides Hill surfaces as 'null-interaction' models and relies neither on Bliss independence or Loewe additivity nor uses Chou's unified general theory. An n-dimensional logistic PDE decribing the Hill-type response of n-component mixtures is solved. Appropriate boundary conditions ensure the correct asymptotic behaviour. Mathematica 11 (Wolfram, Mathematica Version 11.0, 2016) is used for the mathematics and graphics presented in this article. The Hill response surface ansatz can be applied to mixtures of compounds with arbitrary Hill parameters. Restrictions which are required when deriving analytical expressions for response surfaces from other principles, are unnecessary. Many approaches based on Loewe additivity turn out be special cases of the Hill approach whose increased flexibility permits a better description of 'null-effect' responses. Missing sham-compliance of Bliss IA, known as Colby's model in agrochemistry, leads to incompatibility with the Hill surface ansatz. Examples of binary and ternary mixtures illustrate the differences between the approaches. For Hill-slopes close to one and doses below the half-maximum effect doses MSM (Colby, Bliss, Finney, Abbott) predicts synergistic effects where the Hill model indicates 'null

  11. Lixiviación ácida de concentrados de scheelita

    Directory of Open Access Journals (Sweden)

    Navarro, P.

    2005-04-01

    Full Text Available The acid leaching in hydrochloric media of a tungsten concentrate (scheelite, CaWO4 was studied. Of the above-mentioned, an insoluble solid (H2WO4 was obtained which were treated with an alkaline solution of sodium hydroxide, achieving the complete solubilization of the tungsten as wolframate ion (WO4-2 . The transformed fraction of tungsten increases with the temperature, as well as with a finer grain. A maximum dissolution of 88.5 % (400 g/1 HCl, 363 K and 20 µm of particle size was achieved for a 3 h process, of the disolution process was interpreted by the recessive core model with formation of a layer of solid product for the whole range of variation of the parameters in study. The activation energy value was found to be 28.0 kj/mol

    Se estudió la lixiviación acida, en medio clorhídrico, de un concentrado de wolframio (scheelita, CaWO4. De lo anterior, se obtuvo un sólido insoluble (H2WO4, que se trató con una solución alcalina de hidróxido de sodio, lográndose la completa solubilización del wolframio como ion wolframato (WO4-2 . La fracción transformada de wolframio aumenta con la temperatura, como también con una granulometría más fina. Se logró una disolución máxima de 88,5 % (400 g/1 HCl, 363 K y 20 µm de tamaño de partícula para 3 h de proceso, disolución que se interpretó a través del modelo de núcleo recesivo con formación de capa de producto sólido para todo el rango de variación de los parámetros en estudio. El valor de energía de activación encontrado fue de 28,0 kj/mol

  12. Investigation of corrosion and wear mechanisms in hard material-reinforced duplex steel coatings; Untersuchungen zum Korrosions- und Verschleissverhalten von hartstoffverstaerkten `Duplex`-Schutzschichten. Schlussbericht

    Energy Technology Data Exchange (ETDEWEB)

    Bouaifi, B. [Technische Univ. Clausthal, Clausthal-Zellerfeld (Germany). Inst. fuer Schweisstechnik und Trennende Fertigungsverfahren; Goellner, J. [Technische Univ. Magdeburg (Germany). Inst. fuer Werkstofftechnik und Werkstoffpruefung

    1998-09-30

    werden konnten. Mikrostrukturuntersuchungen zeigten, dass sich durch die Einlagerung von Hartstoffen nicht mehr das typische ferritisch-austenitische Gefuege von Duplexstahl einstellt. Durch Aufloesung und Diffusion reichert sich das Matrixgefuege mit Kohlenstoff und je nach Karbid mit Chrom bzw. Wolfram an, was zu einer Erhoehung der austenitischen Gefuegebestandteile fuehrt. Das Verschleissverhalten der Auftragschweissungen ist sehr gut. Der Abtrag verringert sich unabhaengig von der Karbidart um den Faktor 6. Die Reibflaechen zeigen keine Ausloesungen oder Rissbildung. Das Korrosionsverhalten in Schwefelsaeure ist ebenfalls gut. Die Schweissungen zeigen das typische Verhalten eines passiven Werkstoffes. Die Bestaendigkeit sinkt etwas nach Verschleissbeanspruchung. In kuenstlichem Meerwasser ist eine gute Differenzierung einzelner Proben moeglich. Kleine Kornfraktionen und Vorwaermtemperaturen von 100 C wirken sich positiv auf die Korrosionsbestaendigkeit aus. Anwendungsmoeglichkeiten ergeben sich bei der Beschichtung von Prallblechen in REA-Becken, Rohrleitungen, Pumpenteilen, Flanschen oder Stutzen, aber auch generell fuer die Regeneration korrosiv/abrasiv beanspruchter Anlagenkomponenten. (orig.)

  13. Who is Responsible for Instability in the Democratic Republic of Congo?

    Directory of Open Access Journals (Sweden)

    G. M. Sidorova

    2014-01-01

    Full Text Available The research focuses on the problem of military-political instability in the Democratic Republic of the Congo experiencing continued armed conflict for a long time. Dozens of illegal armed groups both Congolese and foreign origin continue to destabilize situation in the eastern part of the country causing humanitarian disasters. Due to governmental weakness, economic backwardness, chronical lack of finance resources, interethnic conflicts, all-round and widely spread corruption of the authorities, the Congolese government at the moment is not able to overcome scores of problems including the problem of security. Assistanceprovided to the DRC by itspartnerssuch as, first of all, the former metropolitan country Belgium, as well as the USA, Great Britain, the Europe Union and China works only in favourof these country-donors. They are attracted by rich Congolese natural resources which the DRC remaining one of the poorest countries in the world cannot turn to advantage to the full extent because of its economic backwardness. In exchange for so-calleddevelopment programmes, expensive strategic raw material (such as coltan, wolfram, casseterit, cooper, gold, niobium, and other is being extracted and exported from the country, in addition, often on the inequivalent basis. This is taking place for the reason that numerous mines and open-cast mines are being controlled by different illegal armed groups and not by the central government. Therefore, it turns out that in the context of a military-political crisis, for so-called partners it is more beneficial to pursue their own interests. Furthermore, western ideologists arouse "separatism-oriented" theories similar to "balkanization", in other words, a breakdown of this giant country into several independent states. The Congolese are tremulous to this issue, they try to counter such approachs and defend the territorial integrity of the DRC. However, it is not an easy task. The impediment is unsettled

  14. High temperature facility TS-3000 K

    International Nuclear Information System (INIS)

    Ion, M.; Padureanu, I.; Mateescu, G.; Radulescu, G.

    1998-01-01

    The high temperature facility TS-3000 K is designed for inelastic and quasielastic slow neutron scattering and neutron diffraction experiments in condensed matter studies over a very large temperature range. A large class of materials is proposed for such kind of investigations: 1. Investigation of oxygen disorder, thermal parameters, lattice vibrations and elastic constants of nuclear fuel oxides as UO 2 , ThO 2 , PuO 2 at temperatures up to 3000 K; 2. Large and small angle neutron scattering experiments on disordered materials; 3. Investigation of the fast ion conductor lattice dynamics (superionic) using neutron scattering techniques; 4. Structure and dynamics of the liquid metals and alloys both in high purity state and with various impurities; 5. Investigation of the materials for fusion reactors at temperatures up to 3000 K; 6. Neutron - dynamics studies of the carbon lattice, its modifications, as well as fullerenes, at high temperature; 7. High temperature mass spectrometric measurements; 8. High purity materials. The facility TS-3000 is running under high internal vacuum conditions (under 10 -6 mbar), water cooled, automatically controlled and stabilized within a very large temperature range (Tmax = 3000 K) for samples of 80 x 80 mm size for inelastic neutron scattering or of a smaller size for diffraction investigation. The temperature is measured either by a wolfram - 5% Rh thermocouple or by direct viewing IR electronic thermometer. First investigations are planned at high intensity and resolution spectrometric complex DIN-2PI setup at the fast pulsed reactor IBR-2 of the Joint Institute for Nuclear Research, Dubna. The main parts of the TS-3000 K facility are: - The furnace with tungsten heater, tungsten, niobium or tantalum shields positioned in an accurate geometry depending of the temperature range and neutron optics (Tmax=3000 K); - The power supply assembly, data acquisition and storage, automatic or manual control; - The power three

  15. Chromatographic 188W →188Re generator

    International Nuclear Information System (INIS)

    Khujaev, S.

    2005-01-01

    Full text: The main purpose of the generator - reception of daughter radioisotope Rhenium-188 from it by periodic elution for a long period of time (more than half-year). It is generally known that Rhenium-188, in the form of its complex connections, is applied in nuclear medicine in treatment and removal of painful syndromes. The generator possesses convenient nuclear-physical characteristics of a daughter radioisotope Rhenium-188. It is a source of (Irradiation with energy 2.12 MeV (98 %) with small contribution soft γ-radiation with energy 0.155 MeV (15 %). The Period of half-life destruction of radioisotope is 17 hours. The 188 W parent radioisotope for the generator is formed by irradiation of 186 W neutrons based on the following reaction: 186 W (n,γ) 187 W (n,γ) 188 W (69 days) → 188 Re (17 hours) + β The following were used as targets for irradiation: 1) Metal Tungsten (powder) of natural structure; 2) Metal Tungsten (plate) of natural structure; 3) Metal Tungsten (wire) of natural structure, d = 12 mm; 4) Metal Tungsten (powder) with enrichment on isotope 186 W - 99.79 %. The irradiated material was exposed to chemical processing with reception of radioactive solution of tungsten-188, from which sorption Tungsten was carried out onto sorbent as poly-wolframate-ions. It is established that Tungsten sorption depends on many factors as there are various chemical forms of Tungsten (VI) in water solutions, ratio of which depends on pH of the solution, concentration of Tungsten in the solution and presence of foreign ions. Tungsten sorption was carried out in static and in dynamic regimes. At dynamic regime the sorbent was placed directly in the generating column. The generator consisted of chromatographic columns with sorbent and radioisotope 188 W, eluting system and radiation protection. Rhenium-188 was taken from the generator as perrhenate sodium by elution of 0.9 % solution of chloride sodium in 10 ml. Technical characteristics of the generator

  16. Random generation of RNA secondary structures according to native distributions

    Directory of Open Access Journals (Sweden)

    Nebel Markus E

    2011-10-01

    logarithmized probabilities. Conclusion A number of experimental results shows that our random generation method produces realistic output, at least with respect to the appearance of the different structural motifs. The algorithm is available as a webservice at http://wwwagak.cs.uni-kl.de/NonUniRandGen and can be used for generating random secondary structures of any specified RNA type. A link to download an implementation of our method (in Wolfram Mathematica can be found there, too.

  17. A Flow-Channel Analysis for the Mars Hopper

    Energy Technology Data Exchange (ETDEWEB)

    W. Spencer Cooley

    2013-02-01

    The Mars Hopper is an exploratory vehicle designed to fly on Mars using carbon dioxide from the Martian atmosphere as a rocket propellant. The propellent gasses are thermally heated while traversing a radioisotope ther- mal rocket (RTR) engine’s core. This core is comprised of a radioisotope surrounded by a heat capacitive material interspersed with tubes for the propellant to travel through. These tubes, or flow channels, can be manu- factured in various cross-sectional shapes such as a special four-point star or the traditional circle. Analytical heat transfer and computational fluid dynamics (CFD) anal- yses were performed using flow channels with either a circle or a star cross- sectional shape. The nominal total inlet pressure was specified at 2,805,000 Pa; and the outlet pressure was set to 2,785,000 Pa. The CO2 inlet tem- perature was 300 K; and the channel wall was 1200 K. The steady-state CFD simulations computed the smooth-walled star shape’s outlet temper- ature to be 959 K on the finest mesh. The smooth-walled circle’s outlet temperature was 902 K. A circle with a surface roughness specification at 0.01 mm gave 946 K and at 0.1 mm yielded 989 K. The The effects of a slightly varied inlet pressure were also examined. The analytical calculations were based on the mass flow rates computed in the CFD simulations and provided significantly higher outlet temperature results while displaying the same comparison trends. Research relating to the flow channel heat transfer studies was also done. Mathematical methods to geometrically match the cross-sectional areas of the circle and star, along with a square and equilateral triangle, were derived. A Wolfram Mathematica 8 module was programmed to analyze CFD results using Richardson Extrapolation and calculate the grid convergence index (GCI). A Mathematica notebook, also composed, computes and graphs the bulk mean temperature along a flow channel’s length while the user dynam- ically provides the input

  18. The G3 Experience with Electronic Publishing: An Editor's Perspective

    Science.gov (United States)

    White, W. M.

    2003-12-01

    and immediately imported into programs such as Excel. Numerous animations and movies have been published in animated GIF, Apple Quicktime, Macromedia Flash, and Wolfram Research Mathreader formats. Computer models and tools have been published as Excel Macros and MATLAB Scripts. Full color, high resolution images allow superior publication of detailed maps and photographs. While G3 is a success by most measures, the process of pioneering electronic publication has at times been painful and frustrating. Early on, there were problems and delays in converting files, particularly graphics, to pdf format for both review and final publication. Costs have been higher than anticipated - primarily due to the cost of file conversion and formatting. The time from acceptance to publication (currently 10 weeks), although improving, it still longer than the goal, again because of the time required for copy-editing and formatting. Automation of this process in the future is the primary opportunity to both reduce cost and further speed publication. Authors have been slow to take advantage of the new illustration formats, with most relying on tradition figures instead. This will likely change slowly in the future, as these new formats, and the software tools to create them, become more familiar.

  19. The potential for ore, industrial minerals and commercial stones in the Simpevarp area

    Energy Technology Data Exchange (ETDEWEB)

    Lindroos, Hardy [MIRAB Mineral Resurser AB, Uppsla (Sweden)

    2004-10-01

    On behalf of SKB (the Swedish Nuclear Fuel and Waste Management Company), a survey has been made of existing information concerning the potential for ore, industrial minerals and commercial stones in and around the two candidate areas for a deep repository in Oskarshamn. A deep repository for spent nuclear fuel should not be located in a rock type or in an area where mineral extraction might be considered in the future, since this would make it difficult or impossible to exploit this natural resource. Avoiding such areas reduces the risk that people in the future will come into contact with the deep repository through mineral prospecting or mining activities.The survey has made use of the geoscientific information compiled in the more regional investigations in Oskarshamn Municipality in 1998-99. The new information after the municipal study includes extensive geophysical measurements from both the air and the ground. The results of the recently completed geophysical helicopter survey of the Simpevarp area are presented in a special chapter. The judgement of an area's ore potential is in part based on the evaluation of these geophysical measurements. In order to be better able to judge the ore potential, a geochemical investigation of soil samples, including reanalysing of older samples collected by the Geological Survey of Sweden (SGU), has been carried out. The report also discusses prospecting efforts in the area as well as relevant Swedish mining legislation. In cooperation with SGU a mineral resource map of the Simpevarp area has been prepared. The map shows two areas with a potential for commercial stones, namely the granites at Goetemar and Uthammar, situated in the northernmost respectively the southernmost part of the study area. Furthermore, the Goetemar granite has probably a small potential for ores containing tin (Sn) and/or wolfram (W). Although no mineralizations of this type have so far been found, the Goetemar granite area may be unsuitable or

  20. Synthesis, Crystal Structures, Magnetic Properties, and Theoretical Investigation of a New Series of NiII-LnIII-WVHeterotrimetallics: Understanding the SMM Behavior of Mixed Polynuclear Complexes.

    Science.gov (United States)

    Vieru, Veacheslav; Pasatoiu, Traian D; Ungur, Liviu; Suturina, Elizaveta; Madalan, Augustin M; Duhayon, Carine; Sutter, Jean-Pascal; Andruh, Marius; Chibotaru, Liviu F

    2016-12-05

    The polynuclear compounds containing anisotropic metal ions often exhibit efficient barriers for blocking of magnetization at fairly arbitrary geometries. However, at variance with mononuclear complexes, which usually become single-molecule magnets (SMM) under the sole requirement of a highly axial crystal field at the metal ion, the factors influencing the SMM behavior in polynuclear complexes, especially, with weakly axial magnetic ions, still remain largely unrevealed. As an attempt to clarify these conditions, we present here the synthesis, crystal structures, magnetic behavior, and ab initio calculations for a new series of Ni II -Ln III -W V trimetallics, [(CN) 7 W(CN)Ni(H 2 O)(valpn)Ln(H 2 O) 4 ]·H 2 O (Ln = Y 1, Eu 2, Gd 3, Tb 4, Dy 5, Lu 6). The surprising finding is the absence of the magnetic blockage even for compounds involving strongly anisotropic Dy III and Tb III metal ions. This is well explained by ab initio calculations showing relatively large transversal components of the g-tensor in the ground exchange Kramers doublets of 1 and 4 and large intrinsic tunneling gaps in the ground exchange doublets of 3 and 5. In order to get more insight into this behavior, another series of earlier reported compounds with the same trinuclear [W V Ni II Ln III ] core structure, [(CN) 7 W(CN)Ni(dmf)(valdmpn)Ln(dmf) 4 ]·H 2 O (Ln = Gd III 7, Tb III 8a, Dy III 9, Ho III 10), [(CN) 7 W(CN)Ni(H 2 O)(valdmpn)Tb(dmf) 2.5 (H 2 O) 1.5 ]·H 2 O·0.5dmf 8b, and [(CN) 7 W(CN)Ni(H 2 O)(valdmpn)Er(dmf) 3 (H 2 O) 1 ]·H 2 O·0.5dmf 11, has been also investigated theoretically. In this series, only 8b exhibits SMM behavior which is confirmed by the present ab initio calculations. An important feature for the entire series is the strong ferromagnetic coupling between Ni(II) and W(V), which is due to an almost perfect trigonal dodecahedron geometry of the octacyano wolframate fragment. The reason why only 8b is an SMM is explained by positive zero-field splitting on the nickel

  1. PREFACE: The International Conference on Highly Frustrated Magnetism HFM2008

    Science.gov (United States)

    Eremin, Ilya; Brenig, Wolfram; Kremer, Reinhard; Litterst, Jochen

    2009-01-01

    The International Conference on Highly Frustrated Magnetism 2008 (HFM2008) took place on 7-12 September 2008 at the Technische Universität Carolo-Wilhelmina zu Braunschweig, Germany. This conference was the fourth event in a series of meetings, which started in Waterloo, Canada (HFM 2000), followed by the second one in Grenoble, France (HFM 2003), and the third meeting in Osaka, Japan (HFM 2006). HFM2008 attracted more than 220 participants from all over the world. The number of participants of the HFM conference series has been increasing steadily, from about 80 participants at HFM 2000, to 120 participants at HFM 2003, and 190 participants at HFM 2006, demonstrating that highly frustrated magnetism remains a rapidly growing area of research in condensed matter physics. At the end of HFM2008 it was decided that the next International Conference on Highly Frustrated Magnetism will be held in Baltimore, USA in 2010. HFM2008 saw four plenary talks by R Moessner, S Nakatsuji, S-W Cheong, and S Sachdev, 18 invited presentations, 30 contributed talks and about 160 poster presentations from all areas of frustrated magnetism. The subjects covered by the conference included: Kagome systems Itinerant frustrated systems Spinels and pyrochlore materials Triangular systems Unconventional order and spin liquids Chain systems Chain systems Novel frustrated systems This volume of Journal of Physics: Conference Series contains the proceedings of HFM2008 with 83 papers that provide a scientific record of the scientific topics covered by the conference. All articles have been refereed by experts in the field. It is our hope that the reader will enjoy and profit from the HFM2008 Proceedings. Ilya Eremin Proceedings Editor Wolfram Brenig, Reinhard Kremer, and Jochen Litterst Co-Editors International Advisory Board L Balents (USA) F Becca (Italy) S Bramwell (UK) P Fulde (Germany) B D Gaulin (Canada) J E Greedan (Canada) A Harrison (France) Z Hiroi (Japan) H Kawamura (Japan) A Keren

  2. Biogas in the agriculture. State of the art. Proceedings; Biogas in der Landwirtschaft. Stand und Perspektiven. Tagungsband

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-07-01

    fermentation of renewable raw materials effect organic soil carbon? (Peter Dominik et al.); (20) Efficiency of composting of residues of fermentation (Helmut Doehler et al.); (21) Feeding biogas in the natural gas grid: actual market developments in the area of gas processing and line feeding (Wolfgang Urban); (22) Practical experiences in the substitution of natural gas by bio methane in Germany (Michael Beil); (23) Biogas plants - the technical view of the network access (Uwe Klaus, Andreas Schrader); (24) Optimized cultivation of energy plants for biogas plants (Christoph Strauss); (25) Deintegration procedure - Expenditure and utility for the generation of biogas (Bjoern Schwarz et al.); (26) Biogas substrate - Which exotics have the potential for the future? (Armin Vetter); (27) The step of hydrolyse in the fermentation of renewable raw materials - Does it enhance the efficiency? (Hans Oechsner et al.); (28) Quality silage for the production of biogas (Christiane Herrmann et al.); (29) Possibilities of the optimization of mixtures of raw materials (Thomas Amon); (30) Ignition jet cogeneration plant - State of the art and perspectives using the effective post power generation of waste gas (Wolfram Dreier, Kai Liesendahl); (31) Gas-fuelled spark ignition engine - state of the art and perspectives (Thomas Elsenbruch); (32) Power generation from biogas in a fuel cell (Peter Landgraf); (33) Micro gas turbine - state of the art (Tobias Panne, Axel Widenhorn); (34) Possibilities of the reduction of the energy demand of biogas plants (Andreas Lehner, Matthias Effenberger); (35) EEG conform utilization of waste heat of agricultural biogas plants (Wolfgang Schulz). Beside these lectures twenty six poster contributions were exhibited.

  3. 2nd International Open and Distance Learning (IODL Symposium

    Directory of Open Access Journals (Sweden)

    Reviewed by Murat BARKAN

    2006-10-01

    Full Text Available This closing remarks prepared and presented by Prof. Dr. Murat BARKAN Anadolu University, Eskisehir, TURKEY DEAR GUESTS, As the 2nd International Open and Distance Learning (IODL Symposium is now drawing to end, I would like to thank you all for your outstanding speeches, distinguished presentations, constructive roundtable and session discussions, and active participation during the last five days. I hope you all share my view that the whole symposium has been a very stimulating and successful experience. Also, on behalf of all the participants, I would like to take this opportunity to thank and congratulate the symposium organization committee for their excellent job in organizing and hosting our 2nd meeting. Throughout the symposium, five workshops, six keynote speeches and 66 papers, which were prepared by more than 150 academicians and practitioners from 23 different countries, reflected remarkable and various views and approaches about open and flexible learning. Besides, all these academic endeavors, 13 educational films were displayed during the symposium. The technology exhibition, hosted by seven companies, was very effective to showcase the current level of the technology and the success of applications of theory into practice. Now I would like to go over what our scholar workshop and keynote presenters shared with us: Prof. Marina McIsaac form Arizona State University dwelled on how to determine research topics worthwhile to be examined and how to choose appropriate research design and methods. She gave us clues on how to get articles published in professional journals. Prof. Colin Latchem from Australia and Prof. Dr. Ali Ekrem Ozkul from Anadolu University pointed to the importance of strategic planning for distance and flexible learning. They highlighted the advantages of strategic planning for policy-makers, planners, managers and staff. Dr. Wolfram Laaser from Fern University of Hagen, presented different multimedia clips and

  4. EDITORIAL: Focus on Plasma Medicine

    Science.gov (United States)

    Morfill, G. E.; Kong, M. G.; Zimmermann, J. L.

    2009-11-01

    -pressure microwave plasmas in an N2 and O2 gas mixture M K Singh, A Ogino and M Nagatsu Degradation of adhesion molecules of G361 melanoma cells by a non-thermal atmospheric pressure microplasma H J Lee, C H Shon, Y S Kim, S Kim, G C Kim and M G Kong The acidification of lipid film surfaces by non-thermal DBD at atmospheric pressure in air A Helmke, D Hoffmeister, N Mertens, S Emmert, J Schuette and W Vioel Reduction and degradation of amyloid aggregates by a pulsed radio-frequency cold atmospheric plasma jet D L Bayliss, J L Walsh, G Shama, F Iza and M G Kong The effect of low-temperature plasma on bacteria as observed by repeated AFM imaging René Pompl, Ferdinand Jamitzky, Tetsuji Shimizu, Bernd Steffes, Wolfram Bunk, Hans-Ulrich Schmidt, Matthias Georgi, Katrin Ramrath, Wilhelm Stolz, Robert W Stark, Takuya Urayama, Shuitsu Fujii and Gregor Eugen Morfill Removal and sterilization of biofilms and planktonic bacteria by microwave-induced argon plasma at atmospheric pressure Mi Hee Lee, Bong Joo Park, Soo Chang Jin, Dohyun Kim, Inho Han, Jungsung Kim, Soon O Hyun, Kie-Hyung Chung and Jong-Chul Park Cell permeabilization using a non-thermal plasma M Leduc, D Guay, R L Leask and S Coulombe Physical and biological mechanisms of direct plasma interaction with living tissue Danil Dobrynin, Gregory Fridman, Gary Friedman and Alexander Fridman Nosocomial infections-a new approach towards preventive medicine using plasmas G E Morfill, T Shimizu, B Steffes and H-U Schmidt Generation and transport mechanisms of chemical species by a post-discharge flow for inactivation of bacteria Takehiko Sato, Shiroh Ochiai and Takuya Urayama Low pressure plasma discharges for the sterilization and decontamination of surfaces F Rossi, O Kylián, H Rauscher, M Hasiwa and D Gilliland Contribution of a portable air plasma torch to rapid blood coagulation as a method of preventing bleeding S P Kuo, O Tarasenko, J Chang, S Popovic, C Y Chen, H W Fan, A Scott, M Lahiani, P Alusta, J D Drake and M Nikolic A two

  5. Automated evaluation of matrix elements between contracted wavefunctions: A Mathematica version of the FRODO program

    Science.gov (United States)

    Angeli, C.; Cimiraglia, R.

    2013-02-01

    .1080/00268976.2012.689872 [10] http://www.wolfram.com/Mathematica. Mathematica version 8 for Linux

  6. PREFACE New developments in nanopore research—from fundamentals to applications New developments in nanopore research—from fundamentals to applications

    Science.gov (United States)

    Albrecht, Tim; Edel, Joshua B.; Winterhalter, Mathias

    2010-11-01

    refereeing process, and Ms Natalia Goehring for the beautiful cover artwork. Finally, to the readers, we hope you find this special issue a valuable source of information and insight into the field of nanopores. New developments in nanopore research—from fundamentals to applications contents Mathematical modeling and simulation of nanopore blocking by precipitation M-T Wolfram, M Burger and Z S Siwy Protein conducting nanopores Anke Harsman, Vivien Krüger, Philipp Bartsch, Alf Honigmann, Oliver Schmidt, Sanjana Rao, Christof Meisinger and Richard Wagner Electrically sensing protease activity with nanopores Mikiembo Kukwikila and Stefan Howorka Electrical characterization of DNA-functionalized solid state nanopores for bio-sensing V Mussi, P Fanzio, L Repetto, G Firpo, P Scaruffi, S Stigliani, M Menotta, M Magnani, G P Tonini and U Valbusa Automatable lipid bilayer formation and ion channel measurement using sessile droplets J L Poulos, S A Portonovo, H Bang and J J Schmidt Critical assessment of OmpF channel selectivity: merging information from different experimental protocols M L López, E García-Giménez, V M Aguilella and A Alcaraz Chemically modified solid state nanopores for high throughput nanoparticle separation Anmiv S Prabhu, Talukder Zaki N Jubery, Kevin J Freedman, Rafael Mulero, Prashanta Dutta and Min Jun Kim Changes in ion channel geometry resolved to sub-ångström precision via single molecule mass spectrometry Joseph W F Robertson, John J Kasianowicz and Joseph E Reiner Entropic transport of finite size particles W Riefler, G Schmid, P S Burada and P Hänggi Osmotic stress regulates the strength and kinetics of sugar binding to the maltoporin channel Philip A Gurnev, Daniel Harries, V Adrian Parsegian and Sergey M Bezrukov Detection of urea-induced internal denaturation of dsDNA using solid-state nanoporesn Alon Singer, Heiko Kuhn, Maxim Frank-Kamenetskii and Amit Meller Translocation events in a single-walled carbon nanotube Jin He, Hao Liu, Pei Pang

  7. NARRATIVE: A short history of my life in science A short history of my life in science

    Science.gov (United States)

    Manson, Joseph R.

    2010-08-01

    institute directed by Professor Wolfgang Ernst. The story of how this particular collaboration developed is interesting because it illustrates again how important personal contacts and social interactions are in the progress of science. In 2007 I was contacted by Bodil Holst, then of the TU-Graz and now at the Technical University of Bergen in Norway, about the possibility of having one of her very bright graduate students visit Clemson for a few months as a part of his work in analyzing some He atom scattering data that they had taken on silica glass surfaces. A decade earlier Holst had been a postdoctoral research associate at the Toennies laboratory in Göttingen during several of the summers I was also there and, although we never worked directly together at that time, we had many interesting discussions about science and other subjects. The student, Wolfram Steurer, arrived in Clemson in the middle of the fall semester with his belongings in a bag that was smaller than the guitar he carried strapped over his back. He immediately created for himself a place in our department, and by the time he left three months later we had developed some rudimentary ideas of how to analyze the data he had, and we also suspected that this data might reveal some new aspects of the dynamics of glass surfaces that had not been realized before. Wolfram delved into this problem with a vengeance, and shortly afterwards we began a series of papers involving Holst, Ernst and Steurer and the Graz graduate students, Andreas Apfolter and Mattias Koch, as well as Elin Søndergård of the French CNRS laboratory located at the St Gobain Corporation's research facilities in Paris. It was this initial contact with Holst a decade earlier that eventually led to a productive period of research on glass surfaces, something that I would have never predicted beforehand, but a collaboration that shows every sign of continuing into the future to produce new and interesting results. So, this brings the history

  8. editorial

    Directory of Open Access Journals (Sweden)

    Ugur Demiray

    2008-07-01

    University, Islamabad, PAKISTAN. This paper presents and concluded No strong relationship was found between Learning from TV and academic achievement in the AIOU situation. Use of television in the AIOU Situation will be more effective if transmission day, time and duration are adjusted according to the students’ demand and when students’ assignments are based on both textbook and TV programs. Next and the ninth article article is written by Selahattin GONEN and Bulent BASARAN from Diyarbakir University, Turkey. Their paper is entitled as “The New Method Of Problem Solving in Physics Education By Using Scorm-Compliant Content Package”. Their study two basic purposes are presented. First, taking effective feedbacks in the electronic learning environment about the learning level of students at the problem solving which are told in physics lessons and laboratories. Second, providing a possibility for students to repeat the subjects and solved problems by watching and listening, which are told in lessons and laboratories, whenever or wherever they want. For this purpose, in the first step, the problems solved in classroom and laboratories about physics and subject expressions are transferred to digital environment and e-learning materials are developed. In the second step, these materials are converted to standard SCORM (Sharable Content Object Reference Model package and integrated to Course Management System (CMS. The tenth article is also from Germany and written by Wolfram LAASER, FernUniversität in Hagen. Paper is titled as “Economics of Distance Education Reconsidered”. The economic viability of e-learning projects will be questioned with more scrutiny than in earlier periods. Therefore it seems to be a good opportunity to see what can be learned from past experience in costing distance learning projects and what aspects are added by current attempts to measure economic efficiency. After reviewing early research about costing distance learning some more recent

  9. Editorial

    Directory of Open Access Journals (Sweden)

    Ugur Demiray

    2012-08-01

    communication in open and distance learning were investigated. In the study, affects of the students’ gender and computer experience on their attitudes were also examined. Article 24 written by Nilton Cesar LIMA, Antonio Sergio Torres PENEDO, Marcio Mattos Borges de OLIVEIRA, Sonia Valle Walter Borges de OLIVEIRA and Jamerson Viegas QUEIROZ from on “The Systemic Vision Of The Educational Learning” Brazil. The purpose of this study is aim to discuss some implications of trying to use the systems management as modern teaching methodology. The 25th article written by Lalit Lalitav Mohakud, Rajiba Lochan Mohapatra and Sikshana MANDIRA and Santosh Kumar BEHERA on “Encouraging Higher Education Through Open And Distance Learning (Odl: Some Aspects. Their paper deals with the role of ODL in the promotion of higher education in India. A reviewed book was Harmonizing Global Education-From Genghis Khan To Facebook, written by Jon BAGGALEY which is reviewed by Wolfram LAASER,from Germany. on Baggaley’s book is an exiting and profound piece of academic literature. It also includes personal anecdotes and flash backs about topics he came across during his long academic career as professor at Athabasca University, Concordia University and Memorial University of New Foundland.Then the last article from Anadolu, written by Gulfem GURSES, on Providing Efficient Active Learning On E-Television: Case of “Open Class”. This study was undertaken with an aim to understand whether the effective use of the blackboard, one of the teaching aids utilized by Anadolu University's distance learning program in the e-television Open Classroom, has a positive effect on focus and concentration. Gagné's Theory of Instruction was utilized during this research. Knowledge of the efficient use of the blackboard and the efficient viewing on the television screen is required. Dear readers, you can reach us online either directly at http://tojde.anadolu.edu.tr or by visiting Anadolu University homepage at

  10. From the Editor

    Directory of Open Access Journals (Sweden)

    Ugur DEMIRAY

    2011-08-01

    collected and the research-suggested case study data analysis approaches, the following themes were emerged; realty, learning by discovering, learning by design, scaffolding and chunking information, and real life desires.After using Whyville virtual platform, the aim of this study was expected to start new discussion on young children using more complex virtual worlds such as Second Life. Thus, the results of this study could be guidance for transmission process of children toward Second Life type of virtual worlds. Even though a further discussion may need about the nature of using the virtual worlds, the primary findings of these case studies suggest some practical implications for children’s education.The sixteenth aricle arrived from Germany on SEMINAR ABOUT SERIOUS GAMES AND VIRTUAL WORLDS: An Experience of International Collaboration And Reflection”, written by Wolfram LAASER, from GERMANY and Julio Gonzalo BRITO, from ARGENTINA. They evaluated a seminar about serious games and virtual worldsas an experience of international collaboration and reflection for the educational possibilities of ICT, dizzying and exponentially growing every day, offer multiple alternatives of mediation for teaching, learning and communication. The inclusion of video games and virtual worlds into educational context represents a qualitative leap that claims to significantly boost ways of communication and knowledge representation of the scenarios involvedThe paper describes didactic design and technical solutions of the seminar format. The last but not least the 17th article is on a Finnish project experience which is written by Heidi HEIKKILÄ who is the project coordinator of the Finnish Language and Literature, Sotunki Distance Learning Center, FINLAND, on “SOTUNKI: An Island Of Education and Adventure”. It serves that the information points to reflect the stylistic periods they presented so it would be easy to learn something of a stylistic period by just looking around: it

  11. From the Editor

    Directory of Open Access Journals (Sweden)

    Ugur Demiray

    2006-10-01

    pioneer countries in e-learning and distance learning. Next article is which numbered 12, from Turkey. Article is entitled as “COMPUTER SIMULATIONS IN SCIENCE EDUCATION: Implications for Distance Education”, and written by Dr. Sami SAHIN, Gazi University, Ankara. This paper is akind of review of the literature about the use of computer simulations in science education. This review examines the types and good examples of computer simulations. Author says that literature review indicated that although computer simulations cannot replace science classroom and laboratory activities completely, they offer various advantages both for classroom and distance education. Hiis paper consists of four parts. The first part describes computer simulations; the second part reviews the benefits in science education; the third part looks for the relation with science process skills; and the last part makes connections with the distance education. The literature suggests that the success of computer simulations use in science education depends on how they incorporated into curriculum and how teacher use it. The most appropriate use of computer simulations seems that use them for a supplementary tools for classroom instruction and laboratory. Multimedia supported, highly interactive, collaborative computer simulations appealing growing interest because of their potentials to supplement constructivist learning. They offer inquiry environments and cognitive tools to scaffold learning and apply problem-solving skills. Computer simulations are good tools to improve students’ hypothesis construction, graphic interpretation and prediction skills. The literature review also implied that computer simulations have potential for distance education laboratories. Yet this area is elusive and needs to be researched further. The thirteenth and the las article is from GERMANY which written by Dr. Wolfram LAASER, FernUniversität in Hagen/ZFE. His article is entitled as “Virtual Universities for