The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein

Binding of the N terminus of Ndel1 to dynein facilitates microtubule self-organization in Ran-induced asters

KElt-18b: Puffy planet, hot host, probably perturbed

We report the discovery of KELT-18b, a transiting hot Jupiter in a 2.87-day orbit around the bright (V = 10.1), hot, F4V star BD+60 1538 (TYC 3865-1173-1). We present follow-up photometry, spectroscopy, and adaptive optics imaging that allow a detailed characterization of the system. Our preferred model fits yield a host stellar temperature of K and a mass of, situating it as one of only a handful of known transiting planets with hosts that are as hot, massive, and bright. The planet has a mass of, a radius of, and a density of, making it one of the most inflated planets known around a hot star. We argue that KELT-18b\u27s high temperature and low surface gravity, which yield an estimated ∼600 km atmospheric scale height, combined with its hot, bright host, make it an excellent candidate for observations aimed at atmospheric characterization. We also present evidence for a bound stellar companion at a projected separation of ∼1100 au, and speculate that it may have contributed to the strong misalignment we suspect between KELT-18\u27s spin axis and its planet\u27s orbital axis. The inferior conjunction time is 2457542.524998 ± 0.000416 (BJDTDB) and the orbital period is 2.8717510 ± 0.0000029 days. We encourage Rossiter-McLaughlin measurements in the near future to confirm the suspected spin-orbit misalignment of this system

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Human pharyngeal microbiota in age-related macular degeneration.

BACKGROUND: While the aetiology of age-related macular degeneration (AMD)-a major blinding disease-remains unknown, the disease is strongly associated with variants in the complement factor H (CFH) gene. CFH variants also confer susceptibility to invasive infection with several bacterial colonizers of the nasopharyngeal mucosa. This shared susceptibility locus implicates complement deregulation as a common disease mechanism, and suggests the possibility that microbial interactions with host complement may trigger AMD. In this study, we address this possibility by testing the hypothesis that AMD is associated with specific microbial colonization of the human nasopharynx. RESULTS: High-throughput Illumina sequencing of the V3-V6 region of the microbial 16S ribosomal RNA gene was used to comprehensively and accurately describe the human pharyngeal microbiome, at genus level, in 245 AMD patients and 386 controls. Based on mean and differential microbial abundance analyses, we determined an overview of the pharyngeal microbiota, as well as candidate genera (Prevotella and Gemella) suggesting an association towards AMD health and disease conditions. CONCLUSIONS: Utilizing an extensive study population from Singapore, our results provided an accurate description of the pharyngeal microbiota profiles in AMD health and disease conditions. Through identification of candidate genera that are different between conditions, we provide preliminary evidence for the existence of microbial triggers for AMD. Ethical approval for this study was obtained through the Singapore Health Clinical Institutional Review Board, reference numbers R799/63/2010 and 2010/585/A

A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants.

Background The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD. Results As early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome. Conclusions This study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development. Trial registration The study was registered in the Dutch Trial Register (Number: 2838 ) on 4th April 2011

Identification of the top TESS objects of interest for atmospheric characterization of transiting exoplanets with JWST

Funding: Funding for the TESS mission is provided by NASA's Science Mission Directorate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial support by JSPS KAKENHI (grant No. JP18H05439) and JST PRESTO (grant No. JPMJPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory. This paper makes use of data from the MEarth Project, which is a collaboration between Harvard University and the Smithsonian Astrophysical Observatory. The MEarth Project acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering, the National Science Foundation under grant Nos. AST-0807690, AST-1109468, AST-1616624 and AST-1004488 (Alan T. Waterman Award), the National Aeronautics and Space Administration under grant No. 80NSSC18K0476 issued through the XRP Program, and the John Templeton Foundation. C.M. would like to gratefully acknowledge the entire Dragonfly Telephoto Array team, and Bob Abraham in particular, for allowing their telescope bright time to be put to use observing exoplanets. B.J.H. acknowledges support from the Future Investigators in NASA Earth and Space Science and Technology (FINESST) program (grant No. 80NSSC20K1551) and support by NASA under grant No. 80GSFC21M0002. K.A.C. and C.N.W. acknowledge support from the TESS mission via subaward s3449 from MIT. D.R.C. and C.A.C. acknowledge support from NASA through the XRP grant No. 18-2XRP18_2-0007. C.A.C. acknowledges that this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). S.Z. and A.B. acknowledge support from the Israel Ministry of Science and Technology (grant No. 3-18143). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant No. PDR T.0120.21. The postdoctoral fellowship of K.B. is funded by F.R.S.-FNRS grant No. T.0109.20 and by the Francqui Foundation. H.P.O.'s contribution has been carried out within the framework of the NCCR PlanetS supported by the Swiss National Science Foundation under grant Nos. 51NF40_182901 and 51NF40_205606. F.J.P. acknowledges financial support from the grant No. CEX2021-001131-S funded by MCIN/AEI/ 10.13039/501100011033. A.J. acknowledges support from ANID—Millennium Science Initiative—ICN12_009 and from FONDECYT project 1210718. Z.L.D. acknowledges the MIT Presidential Fellowship and that this material is based upon work supported by the National Science Foundation Graduate Research Fellowship under grant No. 1745302. P.R. acknowledges support from the National Science Foundation grant No. 1952545. This work is partly supported by JSPS KAKENHI grant Nos. JP17H04574, JP18H05439, JP21K20376; JST CREST grant No. JPMJCR1761; and Astrobiology Center SATELLITE Research project AB022006. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. D.D. acknowledges support from TESS Guest Investigator Program grant Nos. 80NSSC22K1353, 80NSSC22K0185, and 80NSSC23K0769. A.B. acknowledges the support of M.V. Lomonosov Moscow State University Program of Development. T.D. was supported in part by the McDonnell Center for the Space Sciences. V.K. acknowledges support from the youth scientific laboratory project, topic FEUZ-2020-0038.JWST has ushered in an era of unprecedented ability to characterize exoplanetary atmospheres. While there are over 5000 confirmed planets, more than 4000 Transiting Exoplanet Survey Satellite (TESS) planet candidates are still unconfirmed and many of the best planets for atmospheric characterization may remain to be identified. We present a sample of TESS planets and planet candidates that we identify as “best-in-class” for transmission and emission spectroscopy with JWST. These targets are sorted into bins across equilibrium temperature Teq and planetary radius Rp and are ranked by a transmission and an emission spectroscopy metric (TSM and ESM, respectively) within each bin. We perform cuts for expected signal size and stellar brightness to remove suboptimal targets for JWST. Of the 194 targets in the resulting sample, 103 are unconfirmed TESS planet candidates, also known as TESS Objects of Interest (TOIs). We perform vetting and statistical validation analyses on these 103 targets to determine which are likely planets and which are likely false positives, incorporating ground-based follow-up from the TESS Follow-up Observation Program to aid the vetting and validation process. We statistically validate 18 TOIs, marginally validate 31 TOIs to varying levels of confidence, deem 29 TOIs likely false positives, and leave the dispositions for four TOIs as inconclusive. Twenty-one of the 103 TOIs were confirmed independently over the course of our analysis. We intend for this work to serve as a community resource and motivate formal confirmation and mass measurements of each validated planet. We encourage more detailed analysis of individual targets by the community.Peer reviewe

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

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention