The Lick-Carnegie Survey: Four New Exoplanet Candidates

We present new precise HIRES radial velocity (RV) data sets of five nearby stars obtained at Keck Observatory. HD 31253, HD 218566, HD 177830, HD 99492 and HD 74156 are host stars of spectral classes F through K and show radial velocity variations consistent with new or additional planetary companions in Keplerian motion. The orbital parameters of the candidate planets in the five planetary systems span minimum masses of M sin i = 27.43 M_{earth} to M sin i = 8.28 M_{jup}, periods of 17.05 to 4696.95 days and eccentricities ranging from circular to extremely eccentric (e ~ 0.63). The 5th star, HD 74156, was known to have both a 52-day and a 2500-day planet, and was claimed to also harbor a 3rd planet at 336d, in apparent support of the "Packed Planetary System" hypothesis. Our greatly expanded data set for HD 74156 provides strong confirmation of both the 52-day and 2500-d planets, but strongly contradicts the existence of a 336-day planet, and offers no significant evidence for any other planets in the system.Comment: 13 pages, 15 figures. Accepted for publication in ApJ. Fixed typos in Table 2. Additional material at http://www.ucolick.org/~smeschia/4planet.ph

Debris Disks of Members of the Blanco 1 Open Cluster

We have used the Spitzer Space Telescope to obtain Multiband Imaging Photometer for Spitzer (MIPS) 24 um photometry for 37 members of the ~100 Myr old open cluster Blanco 1. For the brightest 25 of these stars (where we have 3sigma uncertainties less than 15%), we find significant mid-IR excesses for eight stars, corresponding to a debris disk detection frequency of about 32%. The stars with excesses include two A stars, four F dwarfs and two G dwarfs. The most significant linkage between 24 um excess and any other stellar property for our Blanco 1 sample of stars is with binarity. Blanco 1 members that are photometric binaries show few or no detected 24 um excesses whereas a quarter of the apparently single Blanco 1 members do have excesses. We have examined the MIPS data for two other clusters of similar age to Blanco 1 -- NGC 2547 and the Pleiades. The AFGK photometric binary star members of both of these clusters also show a much lower frequency of 24 um excesses compared to stars that lie near the single-star main sequence. We provide a new determination of the relation between V-Ks color and Ks-[24] color for main sequence photospheres based on Hyades members observed with MIPS. As a result of our analysis of the Hyades data, we identify three low mass Hyades members as candidates for having debris disks near the MIPS detection limit.Comment: Accepted to Ap

Mosquito saliva enhances virus infection through sialokinin-dependent vascular leakage

Viruses transmitted by Aedes mosquitoes are an increasingly important global cause of disease. Defining common determinants of host susceptibility to this large group of het-erogenous pathogens is key for informing the rational design of panviral medicines. Infection of the vertebrate host with these viruses is enhanced by mosquito saliva, a complex mixture of salivary-gland-derived factors and microbiota. We show that the enhancement of infection by saliva was dependent on vascular function and was independent of most antisaliva immune responses, including salivary microbiota. Instead, the Aedes gene product sialokinin mediated the enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having a vertebrate-like tachykinin sequence and is absent from Anopheles mosquitoes, which are incompetent for most arthropod-borne viruses, whose saliva was not proviral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have the potential to limit disease severity following infection with Aedes mosquito-borne viruses.</p

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy.

Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative disease seen in two closely related giant dog breeds, the Leonberger and Saint Bernard. Neuropathology of an affected dog from each breed showed variable nerve fiber loss and scattered inappropriately thin myelinated fibers. Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. CNTNAP1 encodes a contactin-associated protein important for organization of myelinated axons. The herein described likely pathogenic CNTNAP1 variant occurs in unrelated breeds at variable frequencies. Individual homozygous mutant LPPN-affected Labrador retrievers that were on average four years younger than dogs affected by geriatric onset laryngeal paralysis polyneuropathy could be explained by this variant. Pathologic changes in a Labrador retriever nerve biopsy from a homozygous mutant dog were similar to those of the Leonberger and Saint Bernard. The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear. Pathogenic variants in CNTNAP1 have previously been reported in human patients with lethal congenital contracture syndrome and hypomyelinating neuropathy, including vocal cord palsy and severe respiratory distress. This is the first report of contactin-associated LPPN in dogs characterized by a deleterious variant that most likely predates modern breed establishment

Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model

Dabie bandavirus (previously severe fever with thrombocytopenia syndrome virus; SFTSV) is an emerging tick-borne bunyavirus responsible for severe fever with thrombocytopenia syndrome (SFTS), a disease with high case fatality that is characterised by high fever, thrombocytopenia, and potentially lethal haemorrhagic manifestations. Currently, neither effective therapeutic strategies nor approved vaccines exist for SFTS. Therefore, there remains a pressing need to better understand the pathogenesis of the disease and to identify therapeutic strategies to ameliorate SFTS outcomes. Using a type I interferon (IFN)-deficient mouse model, we investigated the viral tropism, disease kinetics and the role of the virulence factor non-structural protein (NSs) in SFTS. Ly6C+ MHCII+ cells in the lymphatic tissues were identified as an important target cell for SFTSV. Advanced SFTS was characterised by significant migration of inflammatory leukocytes, notably neutrophils, into the lymph node and spleen, however, these cells were not required to orchestrate the disease phenotype. The development of SFTS was associated with significant upregulation of pro-inflammatory cytokines, including high levels of IFN-γ and IL-6 in the serum, lymph node and spleen. Humoral immunity generated by inoculation with delNSs SFTSV was 100% protective. Importantly, NSs was critical to the inhibition of the host IFNɣ response or downstream interferon stimulated gene production and allowed for the establishment of severe disease. Finally, therapeutic but not prophylactic use of anti-IL-6 antibodies significantly increased the survival of mice following SFTSV infection and therefore this treatment modality presents a novel therapeutic strategy for treating severe SFTS

Eddy–Mean Flow Interaction in the Kuroshio Extension Region

The authors use data collected by a line of tall current meter moorings deployed across the axis of the Kuroshio Extension (KE) jet at the location of maximum time-mean eddy kinetic energy to characterize the mean jet structure, the eddy variability, and the nature of eddy–mean flow interactions observed during the Kuroshio Extension System Study (KESS). A picture of the 2-yr record mean jet structure is presented in both geographical and stream coordinates, revealing important contrasts in jet strength, width, vertical structure, and flanking recirculation structure. Eddy variability observed is discussed in the context of some of its various sources: jet meandering, rings, waves, and jet instability. Finally, various scenarios for eddy–mean flow interaction consistent with the observations are explored. It is shown that the observed cross-jet distributions of Reynolds stresses at the KESS location are consistent with wave radiation away from the jet, with the sense of the eddy feedback effect on the mean consistent with eddy driving of the observed recirculations. The authors consider these results in the context of a broader description of eddy–mean flow interactions in the larger KE region using KESS data in combination with in situ measurements from past programs in the region and satellite altimetry. This demonstrates important consistencies in the along-stream development of time-mean and eddy properties in the KE with features of an idealized model of a western boundary current (WBC) jet used to understand the nature and importance of eddy–mean flow interactions in WBC jet systems

Mosquito saliva enhances virus infection through sialokinin-dependent vascular leakage

Viruses transmitted by Aedes mosquitoes are an increasingly important global cause of disease. Defining common determinants of host susceptibility to this large group of heterogenous pathogens is key for informing the rational design of panviral medicines. Infection of the vertebrate host with these viruses is enhanced by mosquito saliva, a complex mixture of salivary-gland-derived factors and microbiota. We show that the enhancement of infection by saliva was dependent on vascular function and was independent of most antisaliva immune responses, including salivary microbiota. Instead, the Aedes gene product sialokinin mediated the enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having a vertebrate-like tachykinin sequence and is absent from Anopheles mosquitoes, which are incompetent for most arthropod-borne viruses, whose saliva was not proviral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have the potential to limit disease severity following infection with Aedes-mosquito-borne viruses