The Role of Rab GTPases in the Endolysosomal System of S.cerevisiae

The evolution of the eucaryotic cell was accompanied by the development of an elaborate endomembrane system. Transport between intracellular compartments is mediated by vesicular carriers that constantly bud from donor membranes and fuse with target compartments. RabGTPases together with tethering factors mediate first specific contact between membranes destined fusion. This study focuses on the interplay between the endosomal RabGTPase Vps21 and the endosomal tethering complex, CORVET. The CORVET subunit Vps8 is the direct effector subunit and mediates binding to the GTP-form of Vps21, whereas the subunit Vps3 binds the GDP-form of Vps21. Vps8 and Vps21 functionally interact to mediate late endosomal tethering events. Furthermore, Vps8 and Vps21, together with the two other CORVET subunits, Vps3 and Vps16 were shown to be the minimal molecular requirement for late endosomal tethering.The results presented here indicate that the sequential recruitment of Vps8 to Vps21-positive late endosomes initiates tethering and leads to further assembly of the CORVET complex that dictates successive fusion events

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

More humid interglacials in Ecuador during the past 500 kyr linked to latitudinal shifts of the Equatorial Front and the Intertropical Convergence Zone in the eastern tropical Pacific

Studying past changes in the eastern equatorial Pacific Ocean dynamics and their impact on precipitation on land gives us insight into how the Intertropical Convergence Zone (ITCZ) movements and the El Niño‐Southern Oscillation modulate regional and global climate. In this study we present a multiproxy record of terrigenous input from marine sediments collected off the Ecuadorian coast spanning the last 500 kyr. In parallel we estimate sea surface temperatures (SST) derived from alkenone paleothermometry for the sediments off the Ecuadorian coast and complement them with alkenone‐based SST data from the Panama Basin to the north in order to investigate SST gradients across the equatorial front. Near the equator, today's river runoff is tightly linked to SST, reaching its maximum either during the austral summer when the ITCZ migrates southward or during El Niño events. Our multiproxy reconstruction of riverine runoff indicates that interglacial periods experienced more humid conditions than the glacial periods. The north‐south SST gradient is systematically steeper during glacial times, suggesting a mean background climatic state with a vigorous oceanic cold tongue, resembling modern La Niña conditions. This enhanced north‐south SST gradient would also imply a glacial northward shift of the Intertropical Convergence Zone at least in vicinity of the cold tongue: a pattern that has not yet been reproduced in climate models

helmholtz-analytics/heat: Heat 1.1.0: distributed slicing/indexing overhaul, dealing with load imbalance, and more

Highlights Slicing/indexing overhaul for a more NumPy-like user experience. Special thanks to Ben Bourgart @ben-bou and the TerrSysMP group for this one. Warning for distributed arrays: breaking change! Indexing one element along the distribution axis now implies the indexed element is communicated to all processes. More flexibility in handling non-load-balanced distributed arrays. More distributed operations, incl. meshgrid . For other details, see the CHANGELOG

helmholtz-analytics/heat: Scalable SVD, GSoC`22 contributions, Docker image, PyTorch 2 support, AMD GPUs acceleration (v1.3.0)

This release includes many important updates (see below). We particularly would like to thank our enthusiastic GSoC2022 / tentative GSoC2023 contributors @Mystic-Slice @neosunhan @Sai-Suraj-27 @shahpratham @AsRaNi1 @Ishaan-Chandak Thank you so much! Highlights #1155 Support PyTorch 2.0.1 (by @ClaudiaComito) #1152 Support AMD GPUs (by @mtar) #1126 Distributed hierarchical SVD (by @mrfh92) #1028 Introducing the sparse module: Distributed Compressed Sparse Row Matrix (by @Mystic-Slice) Performance improvements: #1125 distributed heat.reshape() speed-up (by @ClaudiaComito) #1141 heat.pow() speed-up when exponent is int (by @ClaudiaComito @coquelin77 ) #1119 heat.array() default to copy=None (e.g., only if necessary) (by @ClaudiaComito @neosunhan ) #970 Dockerfile and accompanying documentation (by @bhagemeier) Changelog Array-API compliance / Interoperability #1154 Introduce DNDarray.__array__() method for interoperability with numpy , xarray (by @ClaudiaComito) #1147 Adopt NEP29 , drop support for PyTorch 1.7, Python 3.6 (by @mtar) #1119 ht.array() default to copy=None (e.g., only if necessary) (by @ClaudiaComito) #1020 Implement broadcast_arrays , broadcast_to (by @neosunhan) #1008 API: Rename keepdim kwarg to keepdims (by @neosunhan) #788 Interface for DPPY interoperability (by @coquelin77 @fschlimb ) New Features #1126 Distributed hierarchical SVD (by @mrfh92) #1020 Implement broadcast_arrays , broadcast_to (by @neosunhan) #983 Signal processing: fully distributed 1D convolution (by @shahpratham) #1063 add eq to Device (by @mtar) Bug Fixes #1141 heat.pow() speed-up when exponent is int (by @ClaudiaComito) #1136 Fixed PyTorch version check in sparse module (by @Mystic-Slice) #1098 Validates number of dimensions in input to ht.sparse.sparse_csr_matrix (by @Ishaan-Chandak) #1095 Convolve with distributed kernel on multiple GPUs (by @shahpratham) #1094 Fix division precision error in random module (by @Mystic-Slice) #1075 Fixed initialization of DNDarrays communicator in some routines (by @AsRaNi1) #1066 Verify input object type and layout + Supporting tests (by @Mystic-Slice) #1037 Distributed weighted average() along tuple of axes: shape of weights to match shape of input (by @Mystic-Slice) Benchmarking #1137 Continous Benchmarking of runtime (by @JuanPedroGHM) Documentation #1150 Refactoring for efficiency and readability (by @Sai-Suraj-27) #1130 Reintroduce Quick Start (by @ClaudiaComito) #1079 A better README file (by @Sai-Suraj-27) Linear Algebra #1126, #1160 Distributed hierarchical SVD (by @mrfh92 @ClaudiaComito ) Contributors @AsRaNi1, @ClaudiaComito, @Ishaan-Chandak, @JuanPedroGHM, @Mystic-Slice, @Sai-Suraj-27, @bhagemeier, @coquelin77, @mrfh92, @mtar, @neosunhan, @shahpratha

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc