Sec22b is a critical and nonredundant regulator of plasma cell maintenance.

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, Sec22b-deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.

Universal clinical Parkinson's disease axes identify a major influence of neuroinflammation.

BACKGROUND: There is large individual variation in both clinical presentation and progression between Parkinson's disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting. METHODS: Replicating across three large Parkinson's cohorts (Oxford Discovery cohort (n = 842)/Tracking UK Parkinson's study (n = 1807) and Parkinson's Progression Markers Initiative (n = 472)) with clinical observational measures collected longitudinally over 5-10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors ("phenotypic axes"). RESULTS: When applied to disease severity at diagnosis, the most influential of three phenotypic axes "Axis 1" was characterised by severe non-tremor motor phenotype, anxiety and depression at diagnosis, accompanied by faster progression in cognitive function measures. Axis 1 was associated with increased genetic risk of Alzheimer's disease and reduced CSF Aß1-42 levels. As observed previously for Alzheimer's disease genetic risk, and in contrast to Parkinson's disease genetic risk, the loci influencing Axis 1 were associated with microglia-expressed genes implicating neuroinflammation. When applied to measures of disease progression for each individual, integration of Alzheimer's disease genetic loci haplotypes improved the accuracy of progression modelling, while integrating Parkinson's disease genetics did not. CONCLUSIONS: We identify universal axes of Parkinson's disease phenotypic variation which reveal that Parkinson's patients with high concomitant genetic risk for Alzheimer's disease are more likely to present with severe motor and non-motor features at baseline and progress more rapidly to early dementia.

Deep phenotyping for precision medicine in Parkinson's disease.

A major challenge in medical genomics is to understand why individuals with the same disorder have different clinical symptoms and why those who carry the same mutation may be affected by different disorders. In every complex disorder, identifying the contribution of different genetic and non-genetic risk factors is a key obstacle to understanding disease mechanisms. Genetic studies rely on precise phenotypes and are unable to uncover the genetic contributions to a disorder when phenotypes are imprecise. To address this challenge, deeply phenotyped cohorts have been developed for which detailed, fine-grained data have been collected. These cohorts help us to investigate the underlying biological pathways and risk factors to identify treatment targets, and thus to advance precision medicine. The neurodegenerative disorder Parkinson's disease has a diverse phenotypical presentation and modest heritability, and its underlying disease mechanisms are still being debated. As such, considerable efforts have been made to develop deeply phenotyped cohorts for this disorder. Here, we focus on Parkinson's disease and explore how deep phenotyping can help address the challenges raised by genetic and phenotypic heterogeneity. We also discuss recent methods for data collection and computation, as well as methodological challenges that have to be overcome.

Hydrolytic Exoenzymes Produced by Bacteria Isolated and Identified From the Gastrointestinal Tract of Bombay Duck.

Bacteria producing hydrolytic exoenzymes are of great importance considering their contribution to the host metabolism as well as for their various applications in industrial bioprocesses. In this work hydrolytic capacity of bacteria isolated from the gastrointestinal tract of Bombay duck (Harpadon nehereus) was analyzed and the enzyme-producing bacteria were genetically characterized. A total of twenty gut-associated bacteria, classified into seventeen different species, were isolated and screened for the production of protease, lipase, pectinase, cellulase and amylase enzymes. It was found that thirteen of the isolates could produce at least one of these hydrolytic enzymes among which protease was the most common enzyme detected in ten isolates; lipase in nine, pectinase in four, and cellulase and amylase in one isolate each. This enzymatic array strongly correlated to the previously reported eating behavior of Bombay duck. 16S rRNA gene sequence-based taxonomic classification of the enzyme-producing isolates revealed that the thirteen isolates were grouped into three different classes of bacteria consisting of eight different genera. Staphylococcus, representing ∼46% of the isolates, was the most dominant genus. Measurement of enzyme-production via agar diffusion technique revealed that one of the isolates which belonged to the genus Exiguobacterium, secreted the highest amount of lipolytic and pectinolytic enzymes, whereas a Staphylococcus species produced highest proteolytic activity. The Exiguobacterium sp. expressing a maximum of four hydrolases, appeared to be the most promising isolate of all.