Co-Localization of Basal and Proliferative Cells in the Murine Main Olfactory Epithelium and Vomeronasal Organ after Injury with Cyclophosphamide

ABSTRACT In humans, advanced malignancies are often targeted with broad-spectrum cytotoxic drugs that engender several detrimental side effects, in addition to their primary usage for eradicating cancerous cells. One of the lesser-researched of these effects, histological distortion of the olfactory system impedes a patient\u27s ability to smell, perceive flavor, and ultimately may interfere with their nutritional intake and recovery from chemotherapy. Recent studies have indicated that cytotoxic drugs can damage gustatory epithelia immediately following administration (Mukherjee & Delay, 2011, 2013). We sought to observe the histological effects that cyclophosphamide (CYP), one of the oldest and most popular alkylating antineoplastic agents, may have on the murine main olfactory epithelium (MOE) and vomeronasal organ (VNO). We utilized two immunohistochemical antibodies to label cells in the olfactory epithelia: anti-Ki67, a marker strictly associated with cell proliferation; and, anti-Keratin 5, a marker for the cytoskeleton of horizontal basal cells. Twenty-eight C57BL/6 mice were administered a single intraperitoneal injection of CYP (75 mg/kg), while 20 control mice were administered saline, all at approximately seven weeks of age. Mice were euthanized at days one, two, six, 14, 30, and 45 post injection; subsequently, they were perfused with 4% paraformaldehyde, decalcified, cryoprotected, cryosectioned, and incubated with anti-Ki67 and anti-Keratin 5 antibodies, sequentially. Quantification results by fluorescent imaging of labeled sections revealed a significant decrease in the number of proliferative cells in the MOE and VNO of CYP-injected mice within the first 10 days post injection, followed by a compensatory period of increased cell proliferation through day 45 post injection, compared to saline-injected mice. Co-localization of horizontal basal cells and proliferative cells in the MOE and VNO of CYP-injected mice was significantly amplified at approximately 14 and 45 days post injection, respectively, compared to saline-injected mice. Our results suggest that administration of CYP can rapidly depress the populations of proliferative cells in the murine MOE and VNO; consequently, horizontal basal cells may afford restoration of the proliferative cell populations in the murine MOE and VNO, 14 to 45 days post injection, respectively

History of Galaxy Interactions and their Impact on Star Formation over the Last 7 Gyr from GEMS

We perform a comprehensive estimate of the frequency of galaxy mergers and their impact on star formation over z~0.24--0.80 (lookback time T_b~3--7 Gyr) using 3698 (M*>=1e9 Msun) galaxies with GEMS HST, COMBO-17, and Spitzer data. Our results are: (1) Among 790 high mass (M*>=2.5e10 Msun) galaxies, the visually-based merger fraction over z~0.24--0.80, ranges from 9%+-5% to 8%+-2%. Lower limits on the major and minor merger fractions over this interval range from 1.1% to 3.5%, and 3.6% to 7.5%, respectively. This is the first approximate empirical estimate of the frequency of minor mergers at z<1. For a visibility timescale of ~0.5 Gyr, it follows that over T_b~3--7 Gyr, ~68% of high mass systems have undergone a merger of mass ratio >1/10, with ~16%, 45%, and 7% of these corresponding respectively to major, minor, and ambiguous `major or minor' mergers. The mean merger rate is a few x 1e-4 Gyr-1 Mpc-3. (2) We compare the empirical merger fraction and rate for high mass galaxies to a suite of Lambda CDM-based models: halo occupation distribution models, semi-analytic models, and hydrodynamic SPH simulations. We find qualitative agreement between observations and models such that the (major+minor) merger fraction or rate from different models bracket the observations, and show a factor of five dispersion. Near-future improvements can now start to rule out certain merger scenarios. (3) Among ~3698 M*>=1e9 Msun galaxies, we find that the mean SFR of visibly merging systems is only modestly enhanced compared to non-interacting galaxies over z~0.24--0.80. Visibly merging systems only account for less than 30% of the cosmic SFR density over T_b~3--7 Gyr. This suggests that the behavior of the cosmic SFR density over the last 7 Gyr is predominantly shaped by non-interacting galaxies.Comment: Accepted for Publication in the Astrophysical Journal. 17 pages of text, 21 figures, 3 tables. Uses emulateapj5.st

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

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

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe

Search for Physics beyond the Standard Model in Events with Overlapping Photons and Jets

Results are reported from a search for new particles that decay into a photon and two gluons, in events with jets. Novel jet substructure techniques are developed that allow photons to be identified in an environment densely populated with hadrons. The analyzed proton-proton collision data were collected by the CMS experiment at the LHC, in 2016 at root s = 13 TeV, and correspond to an integrated luminosity of 35.9 fb(-1). The spectra of total transverse hadronic energy of candidate events are examined for deviations from the standard model predictions. No statistically significant excess is observed over the expected background. The first cross section limits on new physics processes resulting in such events are set. The results are interpreted as upper limits on the rate of gluino pair production, utilizing a simplified stealth supersymmetry model. The excluded gluino masses extend up to 1.7 TeV, for a neutralino mass of 200 GeV and exceed previous mass constraints set by analyses targeting events with isolated photons.Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.

Search for dark matter in events with a leptoquark and missing transverse momentum in proton-proton collisions at 13 TeV

A search is presented for dark matter in proton-proton collisions at a center-of-mass energy of root s= 13 TeV using events with at least one high transverse momentum (p(T)) muon, at least one high-p(T) jet, and large missing transverse momentum. The data were collected with the CMS detector at the CERN LHC in 2016 and 2017, and correspond to an integrated luminosity of 77.4 fb(-1). In the examined scenario, a pair of scalar leptoquarks is assumed to be produced. One leptoquark decays to a muon and a jet while the other decays to dark matter and low-p(T) standard model particles. The signature for signal events would be significant missing transverse momentum from the dark matter in conjunction with a peak at the leptoquark mass in the invariant mass distribution of the highest p(T) muon and jet. The data are observed to be consistent with the background predicted by the standard model. For the first benchmark scenario considered, dark matter masses up to 500 GeV are excluded for leptoquark masses m(LQ) approximate to 1400 GeV, and up to 300 GeV for m(LQ) approximate to 1500 GeV. For the second benchmark scenario, dark matter masses up to 600 GeV are excluded for m(LQ) approximate to 1400 GeV. (C) 2019 The Author(s). Published by Elsevier B.V.Peer reviewe