53 research outputs found
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The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand
Auf das Wasser kommt es an: Konservierte Bindungsgeometrie, enthalpiegetriebene Bindungsweise und nichtunterscheidbare Bindungsaffinitäten für fluorierte und nichtfluorierte Liganden von humaner Carbonsäureanhydrase (siehe Bild) stützen die Theorie, dass das Schlüssel-Schloss-Modell einen wichtigen Bestandteil des Bindungsvorgangs unbeachtet lässt: das Wasser, das die Bindungstasche des Proteins füllt und den Liganden umgibt.Chemistry and Chemical Biolog
Garip aileler
Fazlı Necip'in Yeni Asır'da tefrika edilen Garip Aileler adlı romanıArşivdeki eksikler nedeniyle tefrika yarım kalmıştır. Ancak tefrikanın tamamlandığı bilinmektedir
Prevalence and architecture of de novo mutations in developmental disorders.
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year
Dominância fiscal : uma investigação empÃrica sobre o caso brasileiro no perÃodo de 2003 a 2014
A estabilização econômica dos anos de 1990 e a adoção do tripé econômico, a partir de
1999, marcam o fim de um capÃtulo delicado da história brasileira; a partir de então, era
necessária a existência de certa sintonia de polÃticas monetária e fiscal para a
manutenção do controle dos diversos indicadores econômicos. Contudo, com essa
reciprocidade na polÃtica econômica, são incitadas discussões sobre a orientação do
governo na hora de definir suas prioridades nesse campo: as variáveis fiscais são
priorizadas e, por conseguinte, determinadas, forçando as monetárias a se ajustarem –
ou o contrário? A resposta para esse questionamento leva à discussão sobre a
dominância fiscal. Assim, esse trabalho visa verificar empiricamente, usando das
modelagens econométricas VAR e estudo de eventos, se há dominância fiscal ou
monetária na economia brasileira e se a eficácia da polÃtica monetária mudou na
transição do governo Lula para o governo Dilma. O resultado foi inconclusivo para o
governo Lula e indicou dominância fiscal no governo Dilma. Ainda verificou-se não
haver modificação na eficácia da polÃtica monetária.Economic stabilization, in the 1990s, and utilization of an economic tripod, after 1999,
represents the end of a delicate chapter in Brazilian history. Ever since, it was necessary
the existence of a certain agreement between monetary and fiscal politic, in order to
maintain under control a variety of economic indicators. However, this reciprocity (in
economic politic) starts discussions about the real government orientations when it
comes to define its priority on this subject: are the fiscal variables priorized, and then,
determined, forcing monetary variables to adjust themselves, or the opposite? The
answer to these questions emerge from the fiscal dominance discussion. This paper
intends to empiric verify, using econometric modeling VAR and event study, if there is
fiscal dominance or monetary in Brazilian economy and whether the effectiveness of
monetary politic has changed in the transition from Lula's government to the Dilma
government. The result was inconclusive for the Lula government and indicated fiscal
dominance in the Dilma government. There was still no change in the efficiency of the
monetary politic.CAPE
Targeting surface-layer proteins with single-domain antibodies: a potential therapeutic approach against Clostridium difficile-associated disease
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The contribution of X-linked coding variation to severe developmental disorders
Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders
Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)
Size-Based Approaches to Modeling and Managing Local Populations: A Case Study Using an Artisanal Fishery for Giant Clams, Tridacna maxima
The size of an organism is one of its most immediately obvious characteristics, and many key physiological, ecological, and evolutionary processes scale with size. Size is also relevant in the context of size-selective harvest which is common for many organisms. Using size-based approaches I report new insights into the photophysiology and demography of giant clams, to inform management of size-selective harvest. First, I found that the photosynthetic performance (photosynthetic efficiency and relative electron transport rates) of symbiotic Symbiodinium in mixotrophic giant clams (Tridacna maxima ) varied as a quadratic function of clam size. Second, I modeled a size-selective, artisanal fishery for T. maxima at a spatial scale (the island of Moorea, French Polynesia) where the amount of self-recruitment is unknown. I collected demographic data from 12 sites on Moorea annually from 2006–2010 to construct a size-based integral projection model (IPM) with a mix of self-recruitment and external recruitment. The IPM results indicated that in the worst case scenario, the population of giant clams on Moorea will exhibit a 7% decline in abundance under the present-day fishing mortality rate if it has 0% self-recruitment, but will increase exponentially if it has 100% self-recruitment. Fishing mortality decreased the projected population abundance. Finally, I evaluated the use of minimum size limits to optimize annual harvest across all possible amounts of self-recruitment in a local population of giant clams. I used the IPM to project harvest for combinations of minimum size limit and self-recruitment ranging from 0–100% of total recruitment. A single near-optimal size limit of 135 mm resulted in maximum or near-maximum harvest across the range of self-recruitment. A single near-optimum size limit can be applied for organisms with a variety of different life history characteristics unless a local population exhibits exponential decline. Overall, I found that the local population of giant clams on Moorea likely can support the present-day fishing mortality rate, and that size limits can optimize or nearly optimize harvest of local populations. My work indicates that populations can be modeled and managed at the local population scale in the face of uncertainty regarding the amount of self-recruitment
An empirical investigation of the relationship between gross domestic product and international trade, industrial employment and industrialwages in Hong Kong
published_or_final_versionStatisticsMasterMaster of Philosoph
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