A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models.

Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. Here we report that SARS-CoV-2 replication is restricted at a post-entry step in a number of ACE2-positive airway-derived cell lines due to tonic activation of the cGAS-STING pathway mediated by mitochondrial DNA leakage and naturally occurring cGAS and STING variants. Genetic and pharmacological inhibition of the cGAS-STING and type I/III IFN pathways as well as ACE2 overexpression overcome these blocks.

Modulation of circulating free testosterone fraction by testosterone, dihydrotestosterone, and estradiol during testosterone replacement therapy.

Background: Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction.

Objective: To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism.

A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models.

Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. Here we report that SARS-CoV-2 replication is restricted at a post-entry step in a number of ACE2-positive airway-derived cell lines due to tonic activation of the cGAS-STING pathway mediated by mitochondrial DNA leakage and naturally occurring cGAS and STING variants. Genetic and pharmacological inhibition of the cGAS-STING and type I/III IFN pathways as well as ACE2 overexpression overcome these blocks.

Vector-Borne Disease in Wild Mammals Impacted by Urban Expansion and Climate Change.

Ecologies of zoonotic vector-borne diseases may shift with climate and land use change. As many urban-adapted mammals can host ectoparasites and pathogens of human and animal health concern, our goal was to compare patterns of arthropod-borne disease among medium-sized mammals across gradients of rural to urban landscapes in multiple regions of California. DNA of Anaplasma phagocytophilum was found in 1-5% of raccoons, coyotes, and San Joaquin kit foxes; Borrelia burgdorferi in one coyote, rickettsiae in two desert kit foxes, and Yersinia pestis in two coyotes.

Predicting COVID-19 severity: Challenges in reproducibility and deployment of machine learning methods.

The increasing use of electronic health records (EHR) based computable phenotypes in clinical research is providing new opportunities for development of data-driven medical applications. Adopted widely in the United States and globally, EHRs facilitate systematic collection of patients' longitudinal information, which serves as one of the important foundations for artificial intelligence applications in medicine. Harmonization of input variables and outcome definitions is critically important for wider clinical applicability of artificial intelligence (AI) methodologies.

Effects of 2,3-DPG knockout on SCD phenotype in Townes SCD model mice.

Sickle cell disease (SCD) is a severe, multisystemic hematological disorder that impacts nearly every major organ in adults. The current approved treatments for SCD directly target mutant hemoglobin or address downstream disease pathology. Several compounds targeting reduction of 2,3-DPG by activation of Pyruvate Kinase-R are currently being evaluated in SCD patients.

Reference intervals for free testosterone in adult men measured using a standardized equilibrium dialysis procedure.

Background: Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories.

Objective: To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma.

Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen/hypoxia (SU/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle).

A deep tensor-based approach for automatic depression recognition from speech utterances.

Depression is one of the significant mental health issues affecting all age groups globally. While it has been widely recognized to be one of the major disease burdens in populations, complexities in definitive diagnosis present a major challenge. Usually, trained psychologists utilize conventional methods including individualized interview assessment and manually administered PHQ-8 scoring.

Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.

Encouraging protection results from current mRNA-based SARS-CoV-2 vaccine platforms are primarily due to the induction of SARS- CoV-2- specific B cell antibody and CD4 + T cell. Even though, current mRNA vaccine platforms are adept in inducing SARS-CoV2-specific CD8 + T cell, much less is known about CD8 T cells contribution to the overall vaccine protection. Our allogeneic cellular vaccine, based on a secreted form of the heat-shock protein gp96-Ig, achieves high frequencies of polyclonal CD8 + T cell responses to tumor and infectious antigens through antigen cross-priming .

Benefits, companion animal zoonotic disease prevalence and public perceptions of pet ownership among people experiencing homelessness in northern California.

California has the highest proportion of unhoused individuals in the country, and up to 25% of unhoused individuals own pets, providing substantial benefits but unique challenges including access to housing, transportation and unfounded grounds for social stigmatization. Unhoused individuals and pets may also be at risk for diseases due to impaired access to sanitation facilities. The purpose of this cross-sectional survey was to evaluate differences in perceived benefits, challenges and public perceptions among pet owners of varying housing security and the prevalence of diseases among their pets.

Predicting hospitalization of COVID-19 positive patients using clinician-guided machine learning methods.

Objectives: The coronavirus disease 2019 (COVID-19) is a resource-intensive global pandemic. It is important for healthcare systems to identify high-risk COVID-19-positive patients who need timely health care. This study was conducted to predict the hospitalization of older adults who have tested positive for COVID-19.

Hemostatic efficacy of marstacimab alone or in combination with bypassing agents in hemophilia plasmas and a mouse bleeding model.

Background: Patients with hemophilia have deficiencies in intrinsic coagulation factors and can develop inhibitors that limit the effectiveness of replacement coagulation factors. Marstacimab, a human monoclonal antibody, binds and inhibits the human tissue factor pathway inhibitor. Marstacimab is currently under development as a potential prophylactic treatment to prevent bleeding episodes in patients with hemophilia A and B.

Accurate Measurement and Harmonized Reference Ranges for Total and Free Testosterone Levels.

Diagnosing testosterone deficiency requires accurate and precise measurement of total testosterone levels by an accurate method, such as liquid chromatography-tandem mass spectrometry in a laboratory certified by an accuracy-based program (eg, Centers for Disease Control and Prevention's Hormone Standardization (HoST) Program), and, if needed, free testosterone level. Free testosterone level should ideally be measured by equilibrium dialysis method. Testosterone levels should be measured in 2 or more fasting samples obtained in the morning.

Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival.

Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody-mediated agonistic stimulation of the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) pathway and its potential to prolong graft survival in a mouse model of islet allotransplantation.

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious.

Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states.

Sex-hormone-binding globulin (SHBG) regulates the transport and bioavailability of estradiol. The dynamics of estradiol's binding to SHBG are incompletely understood, although it is believed that estradiol binds to each monomer of SHBG dimer with identical affinity (K ∼2 nM). Contrary to the prevalent view, we show that estradiol's binding to SHBG is nonlinear, and the "apparent" K changes with varying estradiol and SHBG concentrations.

Age Trends in Growth and Differentiation Factor-11 and Myostatin Levels in Healthy Men, and Differential Response to Testosterone, Measured Using Liquid Chromatography-Tandem Mass Spectrometry.

Background: Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an antiaging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy.

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.

Established models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2. Infection of H522 cells required the SARS-CoV-2 spike protein, though in contrast to ACE2-dependent models, spike alone was not sufficient for H522 infection.

Induction of SARS-CoV-2 Protein S-Specific CD8+ T Cells in the Lungs of gp96-Ig-S Vaccinated Mice.

Given the aggressive spread of COVID-19-related deaths, there is an urgent public health need to support the development of vaccine candidates to rapidly improve the available control measures against SARS-CoV-2. To meet this need, we are leveraging our existing vaccine platform to target SARS-CoV-2. Here, we generated cellular heat shock chaperone protein, glycoprotein 96 (gp96), to deliver SARS-CoV-2 protein S (spike) to the immune system and to induce cell-mediated immune responses.

Free testosterone and cardiometabolic parameters in men: comparison of algorithms.

Objective: Calculating the free testosterone level has gained increasing interest and different indirect algorithms have been suggested. The objective was to compare free androgen index (FAI), free testosterone estimated using the linear binding model (Vermeulen: cFTV) and the binding framework accounting for allosterically coupled SHBG monomers (Zakharov: cFTZ) in relation to cardiometabolic conditions.

Design: A prospective cohort study including 5350 men, aged 30-70 years, participating in population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with baseline and follow-up information on cardiometabolic parameters and vital status.

PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke.