Distal arthrogryposis syndrome

A 5-month-old male infant presented with weak cry, decreased body movements, tightness of whole body since birth, and one episode of generalized seizure on day 4 of life. He was born at term by elective caesarian section performed for breech presentation. The child had failure to thrive, contractures at elbow and knee joints, hypertonia, microcephaly, small mouth, retrognathia, and camptodactyly. There was global developmental delay. Abdominal examination revealed umbilical and bilateral inguinal hernia. Visual evoked response and brainstem evoked response audiometry were abnormal. Nerve conduction velocity was normal. Magnetic resonance imaging of brain revealed paucity of white matter in bilateral cerebral hemispheres with cerebellar and brain stem atrophy. The differential diagnoses considered in the index patient were distal arthrogryposis (DA) syndrome, cerebroculofacioskeletal syndrome, and Pena Shokier syndrome. The index patient most likely represents a variant of DA: Sheldon Hall syndrome

On opportunistic software reuse

The availability of open source assets for almost all imaginable domains has led the software industry toopportunistic design-an approach in which people develop new software systems in an ad hoc fashion by reusing and combining components that were not designed to be used together. In this paper we investigate this emerging approach. We demonstrate the approach with an industrial example in whichNode.jsmodules and various subsystems are used in an opportunistic way. Furthermore, to study opportunistic reuse as a phenomenon, we present the results of three contextual interviews and a survey with reuse practitioners to understand to what extent opportunistic reuse offers improvements over traditional systematic reuse approaches.Peer reviewe

Yukawa-unified natural supersymmetry

Previous work on t-b-\tau Yukawa-unified supersymmetry, as expected from SUSY GUT theories based on the gauge group SO(10), tended to have exceedingly large electroweak fine-tuning (EWFT). Here, we examine supersymmetric models where we simultaneously require low EWFT ("natural SUSY") and a high degree of Yukawa coupling unification, along with a light Higgs scalar with m_h\sim125 GeV. As Yukawa unification requires large tan\beta\sim50, while EWFT requires rather light third generation squarks and low \mu\sim100-250 GeV, B-physics constraints from BR(B\to X_s\gamma) and BR(B_s\to \mu+\mu-) can be severe. We are able to find models with EWFT \Delta\lesssim 50-100 (better than 1-2% EWFT) and with Yukawa unification as low as R_yuk\sim1.3 (30% unification) if B-physics constraints are imposed. This may be improved to R_yuk\sim1.2 if additional small flavor violating terms conspire to improve accord with B-constraints. We present several Yukawa-unified natural SUSY (YUNS) benchmark points. LHC searches will be able to access gluinos in the lower 1-2 TeV portion of their predicted mass range although much of YUNS parameter space may lie beyond LHC14 reach. If heavy Higgs bosons can be accessed at a high rate, then the rare H, A\to \mu+\mu- decay might allow a determination of tan\beta\sim50 as predicted by YUNS models. Finally, the predicted light higgsinos should be accessible to a linear e+e- collider with \sqrt{s}\sim0.5 TeV.Comment: 18 pages, 7 figures, pdflatex; 3 references adde

Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review

International audienc

5-α reductase inhibitors and prostate cancer prevention: where do we turn now?

With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research

Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia

Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke

Pdx1 Is Post-Translationally Modified In vivo and Serine 61 Is the Principal Site of Phosphorylation

Maintaining sufficient levels of Pdx1 activity is a prerequisite for proper regulation of blood glucose homeostasis and beta cell function. Mice that are haploinsufficient for Pdx1 display impaired glucose tolerance and lack the ability to increase beta cell mass in response to decreased insulin signaling. Several studies have shown that post-translational modifications are regulating Pdx1 activity through intracellular localization and binding to co-factors. Understanding the signaling cues converging on Pdx1 and modulating its activity is therefore an attractive approach in diabetes treatment. We employed a novel technique called Nanofluidic Proteomic Immunoassay to characterize the post-translational profile of Pdx1. Following isoelectric focusing in nano-capillaries, this technology relies on a pan specific antibody for detection and it therefore allows the relative abundance of differently charged protein species to be examined simultaneously. In all eukaryotic cells tested we find that the Pdx1 protein separates into four distinct peaks whereas Pdx1 protein from bacteria only produces one peak. Of the four peaks in eukaryotic cells we correlate one of them to a phosphorylation Using alanine scanning and mass spectrometry we map this phosphorylation to serine 61 in both Min6 cells and in exogenous Pdx1 over-expressed in HEK293 cells. A single phosphorylation is also present in cultured islets but it remains unaffected by changes in glucose levels. It is present during embryogenesis but is not required for pancreas development