Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion.

Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence.

[Prospective, monocentric, uncontrolled study of efficacy, tolerance and adherence of cyclosporin 0.1 % for severe dry eye syndrome].

Purpose: To evaluate the efficacy, tolerability and treatment adherence of Ikervis (Santen, SAS) (ciclosporine 0.1 %) for first line therapy or following treatment with Restasis (Allergan, Inc.) (ciclosporine 0.

The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones.

Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic β cells. As PERK is generally known as a translational regulator of the unfolded protein response (UPR), the underlying cause of these β cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER. Using high-resolution imaging and standard protein fractionation and immunological methods we have examined the PERK-dependent phenotype more closely.

A Case of Type 2 Hypersensitivity to Rasburicase Diagnosed with a Natural Killer Cell Activation Assay.

Drug hypersensitivity reactions can lead to different clinical pictures depending on the underlying immunological mechanism. Diagnosis tests are already available to assess the most frequent drugs hypersensitivity reactions, which are mediated by specific IgE or T cells. However, it remains challenging to diagnose type 2 hypersensitivity reactions (T2HR), which can lead to severe cytopenia and liver failure.

Nitrate modulates stem cell dynamics in shoot meristems through cytokinins.

The shoot apical meristem (SAM) is responsible for the generation of all the aerial parts of plants. Given its critical role, dynamical changes in SAM activity should play a central role in the adaptation of plant architecture to the environment. Using quantitative microscopy, grafting experiments, and genetic perturbations, we connect the plant environment to the SAM by describing the molecular mechanism by which cytokinins signal the level of nutrient availability to the SAM.

Interplay between Selenium Levels and Replicative Senescence in WI-38 Human Fibroblasts: A Proteomic Approach.

Selenoproteins are essential components of antioxidant defense, redox homeostasis, and cell signaling in mammals, where selenium is found in the form of a rare amino acid, selenocysteine. Selenium, which is often limited both in food intake and cell culture media, is a strong regulator of selenoprotein expression and selenoenzyme activity. Aging is a slow, complex, and multifactorial process, resulting in a gradual and irreversible decline of various functions of the body.

Size-Induced Segregation in the Stepwise Microhydration of Hydantoin and Its Role in Proton-Induced Charge Transfer.

Recent photochemistry experiments provided evidence for the formation of hydantoin by irradiation of interstellar ice analogues. The significance of these results and the importance of hydantoin in prebiotic chemistry and polypeptide synthesis motivate the present theoretical investigation, in which we analyzed the effects of stepwise hydration on the electronic and thermodynamical properties of the structure of microhydrated hydantoin using a variety of computational approaches. We generally find microhydration to proceed around the hydantoin heterocycle until 5 water molecules are reached, at which stage hydration becomes segregated with a water cluster forming aside the heterocycle.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS.

Patients And Methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd.

In utero ultrasound diagnosis of corpus callosum agenesis leading to the identification of orofaciodigital type 1 syndrome in female fetuses.

Background: OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births.

Management of Sepsis-Induced Immunosuppression.

It is now well established that profound immunosuppression develops within a few days after sepsis onset in patients. This should be considered additional organ failure because it is associated with increased rate of nosocomial infections, mortality, and long-term complications, thus constituting the rationale for immunomodulation in patients. Nevertheless, the demonstration of the efficacy of such therapeutic strategy in improving deleterious outcomes in sepsis remains to be made.

TCR-stimulated changes in cell surface CD46 expression generate type 1 regulatory T cells.

A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (T1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells.

Virulence test using nematodes to prescreen species capable of inducing neurodegeneration and behavioral disorders.

Background: Parkinson's disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain-some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin. are Actinobacteria that can cause human diseases like nocardiosis.

The Prediction of Impact of a Looming Stimulus onto the Body Is Subserved by Multisensory Integration Mechanisms.

In the jungle, survival is highly correlated with the ability to detect and distinguish between an approaching predator and a putative prey. From an ecological perspective, a predator rapidly approaching its prey is a stronger cue for flight than a slowly moving predator. In the present study, we use functional magnetic resonance imaging in the nonhuman primate, to investigate the neural bases of the prediction of an impact to the body by a looming stimulus, i.

Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma.

Ossifying fibroma (OF) is a rare benign tumor of the craniofacial bones that can reach considerable and disfiguring dimensions if left untreated. Although the clinicopathological characteristics of OF are well established, the underlying etiology has remained largely unknown. Our work indicates that Men1-a tumor suppressor gene responsible of Multiple endocrine neoplasia type 1-is critical for OF formation and shows that mice with targeted disruption of Men1 in osteoblasts (Men1) develop multifocal OF in the mandible with a 100% penetrance.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

Background: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA.

Patients And Methods: Patients with CCSA received oral crizotinib 250 mg twice daily.

Spindle Misorientation of Cerebral and Cerebellar Progenitors Is a Mechanistic Cause of Megalencephaly.

Misoriented division of neuroprogenitors, by loss-of-function studies of centrosome or spindle components, has been linked to the developmental brain defects microcephaly and lissencephaly. As these approaches also affect centrosome biogenesis, spindle assembly, or cell-cycle progression, the resulting pathologies cannot be attributed solely to spindle misorientation. To address this issue, we employed a truncation of the spindle-orienting protein RHAMM.

Adaptations to different habitats in sexual and asexual populations of parasitoid wasps: a meta-analysis.

Background: Coexistence of sexual and asexual populations remains a key question in evolutionary ecology. We address the question how an asexual and a sexual form of the parasitoid can coexist in southern Europe. We test the hypothesis that both forms are adapted to different habitats within their area of distribution.

Analysis of the spotted gar genome suggests absence of causative link between ancestral genome duplication and transposable element diversification in teleost fish.

Teleost fish have been shown to contain many superfamilies of transposable elements (TEs) that are absent from most tetrapod genomes. Since theories predict an increase in TE activity following polyploidization, such diversity might be linked to the 3R whole-genome duplication that occurred approximately 300 million years ago before the teleost radiation. To test this hypothesis, we have analyzed the genome of the spotted gar Lepisosteus oculatus, which diverged from the teleost lineage before the 3R duplication.

Involvement of the specific nucleolar protein SURF6 in regulation of proliferation and ribosome biogenesis in mouse NIH/3T3 fibroblasts.

The nucleolar proteins which link cell proliferation to ribosome biogenesis are regarded to be potentially oncogenic. Here, in order to examine the involvement of an evolutionary conserved nucleolar protein SURF6/Rrp14 in proliferation and ribosome biogenesis in mammalian cells, we established stably transfected mouse NIH/3T3 fibroblasts capable of conditional overexpression of the protein. Cell proliferation was monitored in real-time, and various cell cycle parameters were quantified based on flow cytometry, Br-dU-labeling and conventional microscopy data.

Rome's urban history inferred from Pb-contaminated waters trapped in its ancient harbor basins.

Heavy metals from urban runoff preserved in sedimentary deposits record long-term economic and industrial development via the expansion and contraction of a city's infrastructure. Lead concentrations and isotopic compositions measured in the sediments of the harbor of Ostia-Rome's first harbor-show that lead pipes used in the water supply networks of Rome and Ostia were the only source of radiogenic Pb, which, in geologically young central Italy, is the hallmark of urban pollution. High-resolution geochemical, isotopic, and C analyses of a sedimentary core from Ostia harbor have allowed us to date the commissioning of Rome's lead pipe water distribution system to around the second century BC, considerably later than Rome's first aqueduct built in the late fourth century BC.

Drift, selection, or migration? Processes affecting genetic differentiation and variation along a latitudinal gradient in an amphibian.

Background: Past events like fluctuations in population size and post-glacial colonization processes may influence the relative importance of genetic drift, migration and selection when determining the present day patterns of genetic variation. We disentangle how drift, selection and migration shape neutral and adaptive genetic variation in 12 moor frog populations along a 1700 km latitudinal gradient. We studied genetic differentiation and variation at a MHC exon II locus and a set of 18 microsatellites.

Hypothermic pulsatile preservation of kidneys from uncontrolled deceased donors after cardiac arrest - a retrospective study.

Kidneys from uncontrolled donors after cardiac arrest (uDCD) suffer from a period of warm ischemia between cardiac arrest and cold flushing. Aim of the study was to evaluate renal outcomes of uDCD kidneys selected on the basis of renal Resistance Index (RI) and its influence on graft function and survival. The study included 44 kidneys procured from 26 uDCD starting 1.

Surgical versus non-surgical approach in primary desmoid-type fibromatosis patients: A nationwide prospective cohort from the French Sarcoma Group.

Purpose: The outcome of desmoid-type fibromatosis (DTF) is unpredictable. Currently, a wait-and-see approach tends to replace large en bloc resection as the first therapeutic approach. Nevertheless, there are no validated factors to guide the treatment choice.

Alder and the Golden Fleece: high diversity of and ectomycorrhizal fungi revealed from subsp. roots close to a Tertiary and glacial refugium.

Background: Recent climatic history has strongly impacted plant populations, but little is known about its effect on microbes. Alders, which host few and specific symbionts, have high genetic diversity in glacial refugia. Here, we tested the prediction that communities of root symbionts survived in refugia with their host populations.