Stereoselective synthesis of highly substituted tetrahydrofurans by diverted carbene O–H insertion reaction

Copper or rhodium catalyzed reaction of diazocarbonyl compounds with β-hydroxyketones gives highly substituted tetrahydrofurans with excellent diastereoselectivity, under mild conditions, in a single step process that starts as a carbene O–H insertion reaction but is diverted by an intramolecular aldol reaction

A phase 3 multicenter, prospective, open-label efficacy and safety study of immune globulin (human) 10% caprylate/chromatography purified in patients with myasthenia gravis exacerbations

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. Methods: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). Results: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. Conclusions: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations

Stereoselective synthesis of highly substituted tetrahydrofurans by diverted carbene O–H insertion reaction

Copper or rhodium catalyzed reaction of diazocarbonyl compounds with β-hydroxyketones gives highly substituted tetrahydrofurans with excellent diastereoselectivity, under mild conditions, in a single step process that starts as a carbene O–H insertion reaction but is diverted by an intramolecular aldol reaction

The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease

corrigéInternational audienceBACKGROUND INFORMATION: . Microvillus inclusion disease (MVID) is a genetic disorder affecting intestinal absorption. It is caused by mutations in MYO5B or syntaxin 3 (STX3) affecting apical membrane trafficking. Morphologically MVID is characterised by a depletion of apical microvilli and the formation of microvillus inclusions inside the cells, suggesting a loss of polarity. To investigate this hypothesis we examined the location of essential apical polarity determinants in five MVID patients. RESULTS: We found that the polarity determinants Cdc42, Par6B, PKCζ/ι and the structural proteins ezrin and phospho-ezrin were lost from the apical membrane and accumulated either in the cytoplasm or on the basal side of enterocytes in patients which suggests an inversion of cell polarity. Moreover microvilli-like structures were observed at the basal side in electron microscopy. We next performed Myo5B depletion in 3D-grown human Caco2 cells forming cysts and we found a direct link between the loss of Myo5B and the mislocalisation of the same apical proteins; furthermore we observed that a majority of cyst displayed an inverted polarity phenotype as seen in some patients. Finally we found that this loss of polarity was specific for MVID: tissue samples of patients with Myo5B independent absorption disorders showed normal polarity but we identified Cdc42 as a potentially essential biomarker for tricho-hepato-enteric syndrome. CONCLUSION: Our findings indicate that the loss of Myo5B induces a strong loss of enterocyte polarity, potentially leading to polarity inversion. SIGNIFICANCE: Our results show that polarity determinants could be useful markers to help establishing a diagnosis in patients. Furthermore they could be used to characterise other rare intestinal absorption diseases

Climate variability in the subarctic area for the last 2 millennia

To put recent climate change in perspective, it is necessary to extend the instrumental climate records with proxy data from paleoclimate archives. Arctic climate variability for the last 2 millennia has been investigated using statistical and signal analyses from three regionally averaged records from the North Atlantic, Siberia and Alaska based on many types of proxy data archived in the Arctic 2k database v1.1.1. In the North Atlantic and Alaska, the major climatic trend is characterized by long-term cooling interrupted by recent warming that started at the beginning of the 19th century. This cooling is visible in the Siberian region at two sites, warming at the others. The cooling of the Little Ice Age (LIA) was identified from the individual series, but it is characterized by wide-range spatial and temporal expression of climate variability, in contrary to the Medieval Climate Anomaly. The LIA started at the earliest by around AD 1200 and ended at the latest in the middle of the 20th century. The widespread temporal coverage of the LIA did not show regional consistency or particular spatial distribution and did not show a relationship with archive or proxy type either. A focus on the last 2 centuries shows a recent warming characterized by a well-marked warming trend parallel with increasing greenhouse gas emissions. It also shows a multidecadal variability likely due to natural processes acting on the internal climate system on a regional scale. A similar to 16-30-year cycle is found in Alaska and seems to be linked to the Pacific Decadal Oscillation, whereas similar to 20-30- and similar to 50-90-year periodicities characterize the North Atlantic climate variability, likely in relation with the Atlantic Multidecadal Oscillation. These regional features are probably linked to the sea ice cover fluctuations through ice-temperature positive feedback.Peer reviewe

End-stage renal disease causes skewing in the TCR Vβ-repertoire primarily within CD8+ T Cell subsets

A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR Vβ-repertoire. Here, we assessed the impact of ESRD on the TCR Vβ-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR Vβ-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR Vβ-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR Vβ-family. CD8+, but not CD4+, T cell differentiation was

GlycoDigest: a tool for the targeted use of exoglycosidase digestions in glycan structure determination

Summary: Sequencing oligosaccharides by exoglycosidases, either sequentially or in an array format, is a powerful tool to unambiguously determine the structure of complex N- and O-link glycans. Here, we introduce GlycoDigest, a tool that simulates exoglycosidase digestion, based on controlled rules acquired from expert knowledge and experimental evidence available in GlycoBase. The tool allows the targeted design of glycosidase enzyme mixtures by allowing researchers to model the action of exoglycosidases, thereby validating and improving the efficiency and accuracy of glycan analysis. Availability and implementation: http://www.glycodigest.org. Contact: [email protected] or [email protected]

UniCarb-DB: a database resource for glycomic discovery

Summary: Glycosylation is one of the most important post-translational modifications of proteins, known to be involved in pathogen recognition, innate immune response and protection of epithelial membranes. However, when compared to the tools and databases available for the processing of high-throughput proteomic data, the glycomic domain is severely lacking. While tools to assist the analysis of mass spectrometry (MS) and HPLC are continuously improving, there are few resources available to support liquid chromatography (LC)-MS/MS techniques for glycan structure profiling. Here, we present a platform for presenting oligosaccharide structures and fragment data characterized by LC-MS/MS strategies. The database is annotated with high-quality datasets and is designed to extend and reinforce those standards and ontologies developed by existing glycomics databases. Availability: http://www.unicarb-db.org Contact: [email protected]