Dissimilarity of the gut-lung axis and dysbiosis of the lower airways in ventilated preterm infants.

BACKGROUND: Chronic lung disease of prematurity (CLD), also called bronchopulmonary dysplasia, is a major consequence of preterm birth but the role of the microbiome in its development remains unclear. We, therefore, assessed the progression of the bacterial community in ventilated preterm infants over time in the upper and lower airways, and assessed the gut-lung axis by comparing the upper and lower airways bacterial communities with the stool findings. Finally, we assessed if the bacterial communities were associated with lung inflammation to suggest dysbiosis. METHODS: We serially sampled multiple anatomical sites including the upper airway (nasopharyngeal aspirates, NPA), lower airways (tracheal aspirate fluid, TAF, and bronchoalveolar lavage fluid, BAL) and the gut (stool) of ventilated preterm-born infants. Bacterial DNA load was measured in all samples and sequenced using the V3-V4 region of the 16S rRNA gene RESULTS: From 1102 (539 NPA, 276 TAF, 89 BAL, 198 stool) samples from 55 preterm infants, 352 (32%) amplified suitably for 16 s RNA gene sequencing. Bacterial load was low at birth, quickly increased with time but was associated with predominant operational taxonomic units (OTUs) in all sample types. There was dissimilarity in bacterial communities between the upper and lower airways and the gut with a separate dysbiotic inflammatory process occurring in the lower airways of infants. Individual OTUs were associated with increased inflammatory markers. CONCLUSIONS: Taken together, these findings suggest that targeted treatment of the predominant organisms, including those not routinely treated such as Ureaplasma spp., may decrease the development of CLD in preterm-born infants

The mating-specific Gα interacts with a kinesin-14 and regulates pheromone-induced nuclear migration in budding yeast

As a budding yeast cell elongates toward its mating partner, cytoplasmic microtubules connect the nucleus to the cell cortex at the growth tip. The Kar3 kinesin-like motor protein is then thought to stimulate plus-end depolymerization of these microtubules, thus drawing the nucleus closer to the site where cell fusion and karyogamy will occur. Here, we show that pheromone stimulates a microtubule-independent interaction between Kar3 and the mating-specific Gα protein Gpa1 and that Gpa1 affects both microtubule orientation and cortical contact. The membrane localization of Gpa1 was found to polarize early in the mating response, at about the same time that the microtubules begin to attach to the incipient growth site. In the absence of Gpa1, microtubules lose contact with the cortex upon shrinking and Kar3 is improperly localized, suggesting that Gpa1 is a cortical anchor for Kar3. We infer that Gpa1 serves as a positional determinant for Kar3-bound microtubule plus ends during mating. © 2009 by The American Society for Cell Biology

Iwasawa theory and p-adic L-functions over Zp2-extensions

We construct a two-variable analogue of Perrin-Riou’s p-adic regulator map for the Iwasawa cohomology of a crystalline representation of the absolute Galois group of Q p , over a Galois extension whose Galois group is an abelian p-adic Lie group of dimension 2. We use this regulator map to study p-adic representations of global Galois groups over certain abelian extensions of number fields whose localisation at the primes above p is an extension of the above type. In the example of the restriction to an imaginary quadratic field of the representation attached to a modular form, we formulate a conjecture on the existence of a “zeta element”, whose image under the regulator map is a p-adic L-function. We show that this conjecture implies the known properties of the 2-variable p-adic L-functions constructed by Perrin-Riou and Kim

Seamless Gene Tagging by Endonuclease-Driven Homologous Recombination

Gene tagging facilitates systematic genomic and proteomic analyses but chromosomal tagging typically disrupts gene regulatory sequences. Here we describe a seamless gene tagging approach that preserves endogenous gene regulation and is potentially applicable in any species with efficient DNA double-strand break repair by homologous recombination. We implement seamless tagging in Saccharomyces cerevisiae and demonstrate its application for protein tagging while preserving simultaneously upstream and downstream gene regulatory elements. Seamless tagging is compatible with high-throughput strain construction using synthetic genetic arrays (SGA), enables functional analysis of transcription antisense to open reading frames and should facilitate systematic and minimally-invasive analysis of gene functions

Efficacy and safety of transcranial magnetic stimulation for treating major depressive disorder: An umbrella review and re-analysis of published meta-analyses of randomised controlled trials.

OBJECTIVES: We re-analysed data from published meta-analyses testing the effects of Transcranial Magnetic Stimulation (TMS) on Major Depressive Disorder (MDD) in adults. We applied up-to-date meta-analytic techniques for handling heterogeneity including the random-effects Hartung-Knapp-Sidik-Jonkman method and estimated 95% prediction intervals. Heterogeneity practices in published meta-analyses were assessed as a secondary aim. STUDY DESIGN AND SETTING: We performed systematic searches of systematic reviews with meta-analyses that included randomised controlled trials assessing the efficacy, tolerability, and side effects of TMS on MDD. We performed risk of bias assessment using A MeaSurement Tool to Assess Reviews (AMSTAR) 2 and re-analysed meta-analyses involving 10 or more primary studies. RESULTS: We included 29 systematic reviews and re-analysed 15 meta-analyses. Authors of all meta-analyses interpreted findings to suggest TMS is safe and effective for MDD. Our re-analysis showed that in 14 out of 15 meta-analyses, the 95% prediction intervals included the null and captured values in the opposite effect direction. We also detected presence of small-study effects in some meta-analyses and 24 out of 25 systematic reviews received an AMSTAR 2 rating classed as critically low. CONCLUSION: Authors of all included meta-analyses interpreted findings to suggest TMS is safe and effective for MDD despite lack of comprehensive investigation of heterogeneity. Our re-analysis revealed the direction and magnitude of treatment effects vary widely across different settings. We also found high risk of bias in the majority of included systematic reviews and presence of small-study effects in some meta-analyses. Because of these reasons, we argue TMS for MDD may not be as effective and potentially less tolerated in some populations than current evidence suggests

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types