Productive infection of the retinal pigment epithelium by SARS-CoV-2: Initial effects and consideration of long-term consequences.

As the SARS-CoV-2 coronavirus continues to evolve and infect the global population, many individuals are likely to suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Manifestations of PASC include vision symptoms, but little is known about the ability of SARS-CoV-2 to infect and impact the retinal cells. Here, we demonstrate that SARS-CoV-2 can infect and perturb the retinal pigment epithelium (RPE) in vivo, after intranasal inoculation of a transgenic mouse model of SARS-CoV-2 infection, and in cell culture.

Isolation and Enrichment of Major Primary Neuroglial Cells from Neonatal Mouse Brain.

The central nervous system (CNS) relies on the complex interaction of neuroglial cells to carry out vital physiological functions. To comprehensively understand the structural and functional interplay between these neuroglial cells, it is essential to establish an appropriate in vitro system that can be utilized for thorough investigation. Traditional protocols for establishing primary neuronal and mixed glial cultures from prenatal mice or neural stem cells require sacrificing pregnant mice and have the drawback of yielding only specific types of cells.

Single-Cell Profiling of the Differential In Vivo Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Lung Tissue Cell Subtypes at the Protein Level.

The complexity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its variants in lung cells can truly be characterized only at the tissue and protein levels among unique cell subtypes. However, in vivo data are limited due to lack of accessible human tissues. Using a transgenic mouse model of SARS-CoV-2 infection and flow cytometry, we provide in vivo novel insight at the protein level that the differential impact of SARS-CoV-2 (Wuhan strain) and its B.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection Alters Mediators of Lung Tissue Remodeling In Vitro and In Vivo.

Background: Altered mediators of airway tissue remodeling such as matrix metalloproteinases (MMPs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may contribute to morbidity in coronavirus disease 2019 (COVID-19); however, the differential impact of SARS-CoV-2 variants of concern (VOCs) on MMPs is unknown.

Methods: Using both in vitro human airway cell culture model and in vivo transgenic mouse model of SARS-CoV-2 infection, we studied the differential effect of SARS-CoV-2 VOCs on expression of key MMPs and inflammatory mediators in airway cells and tissues.

Results: The most consistent findings with all SARS-CoV-2 variants in infected compared to uninfected human bronchial epithelial cell air-liquid interface cultures were the SARS-CoV-2-induced increases in MMP-12 and tissue inhibitor of MMPs.

Connexin 43 mediated collective cell migration is independent of Golgi orientation.

Cell migration is vital for multiple physiological functions and is involved in the metastatic dissemination of tumour cells in various cancers. For effective directional migration, cells often reorient their Golgi apparatus and, therefore, the secretory traffic towards the leading edge. However, not much is understood about the regulation of Golgi's reorientation.

Ifit2 restricts murine coronavirus spread to the spinal cord white matter and its associated myelin pathology.

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection.

Chronic Electronic Cigarette Use and Atherosclerosis Risk in Young People: A Cross-Sectional Study-Brief Report.

Background: Little is known whether electronic cigarettes (ECIG) increase vulnerability to future atherosclerotic cardiovascular disease. We determined, using an ex vivo mechanistic atherogenesis assay, whether proatherogenic changes including monocyte transendothelial migration and monocyte-derived foam cell formation are increased in people who use ECIGs.

Methods: In a cross-sectional single-center study using plasma and peripheral blood mononuclear cells from healthy participants who are nonsmokers or with exclusive use of ECIGs or tobacco cigarettes (TCIGs), autologous peripheral blood mononuclear cells with patient plasma and pooled peripheral blood mononuclear cells from healthy nonsmokers with patient plasma were utilized to dissect patient-specific ex vivo proatherogenic circulating factors present in plasma and cellular factors present in monocytes.

Mitoquinone Mesylate and Mitochondrial DNA in End Organs in Humanized Mouse Model of Chronic Treated Human Immunodeficiency Virus Infection.

No treatment exists for mitochondrial dysfunction, a contributor to end-organ disease in human immunodeficiency virus (HIV). The mitochondrial antioxidant mitoquinone mesylate (MitoQ) attenuates mitochondrial dysfunction in preclinical mouse models of various diseases but has not been used in HIV. We used a humanized murine model of chronic HIV infection and polymerase chain reaction to show that HIV-1-infected mice treated with antiretroviral therapy and MitoQ for 90 days had higher ratios of human and murine mitochondrial to nuclear DNA in end organs compared with HIV-1-infected mice on antiretroviral therapy.

Blood immune cells from people with HIV on antiviral regimens that contain tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) have differential metabolic signatures.

Background: Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) may alter mitochondrial function and energy production in immune cells in HIV patients.

Methods: Cellular bioenergetics were determined in PBMCs from HIV-1 participants exposed to TAF versus TDF in vitro, at a comparable concentration to a clinically relevant plasma exposure.

Ectodomain shedding of proteins important for SARS-CoV-2 pathogenesis in plasma of tobacco cigarette smokers compared to electronic cigarette vapers: a cross-sectional study.

The impact of tobacco cigarette (TCIG) smoking and electronic cigarette (ECIG) vaping on the risk of development of severe COVID-19 is controversial. The present study investigated levels of proteins important for SARS-CoV-2 pathogenesis present in plasma because of ectodomain shedding in smokers, ECIG vapers, and non-smokers (NSs). Protein levels of soluble angiotensin-converting enzyme 2 (ACE2), angiotensin (Ang) II (the ligand of ACE2), Ang 1-7 (the main peptide generated from Ang II by ACE2 activity), furin (a protease that increases the affinity of the SARS-CoV-2 spike protein for ACE2), and products of ADAM17 shedding activity that predict morbidity in COVID-19 (IL-6/IL-6R alpha (IL-6/IL-6Rα) complex, soluble CD163 (sCD163), L-selectin) were determined in plasma from 45 NSs, 30 ECIG vapers, and 29 TCIG smokers using ELISA.

Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models.

Unlabelled: To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern and . Mito-MES had nanomolar antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59).

ApoA-I mimetics reduce systemic and gut inflammation in chronic treated HIV.

Novel therapeutic strategies are needed to attenuate increased systemic and gut inflammation that contribute to morbidity and mortality in chronic HIV infection despite potent antiretroviral therapy (ART). The goal of this study is to use preclinical models of chronic treated HIV to determine whether the antioxidant and anti-inflammatory apoA-I mimetic peptides 6F and 4F attenuate systemic and gut inflammation in chronic HIV. We used two humanized murine models of HIV infection and gut explants from 10 uninfected and 10 HIV infected persons on potent ART, to determine the in vivo and ex vivo impact of apoA-I mimetics on systemic and intestinal inflammation in HIV.

Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity.

Monocytic-lineage inflammatory Ly6cCD103 dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6cCD103 DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth.

Imatinib-Resistant Gastrointestinal Stromal Tumor Presenting as a Large Abdominal Mass.

Gastrointestinal stromal tumors (GISTs) are the stromal or mesenchymal neoplasms affecting the gastrointestinal tract. Although they constitute 1% of primary gastrointestinal tumors, they are the most common nonepithelial tumors involving the gastrointestinal tract. They mostly present as overt or occult gastrointestinal bleeding.

The ApoA-I mimetic peptide 4F attenuates in vitro replication of SARS-CoV-2, associated apoptosis, oxidative stress and inflammation in epithelial cells.

An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry.

The structurally conserved TELR region on shelterin protein TPP1 is essential for telomerase processivity but not recruitment.

The shelterin protein TPP1 is involved in both recruiting telomerase and stimulating telomerase processivity in human cells. Assessing the in vivo significance of the latter role of TPP1 has been difficult, because TPP1 mutations that perturb telomerase function tend to abolish both telomerase recruitment and processivity. The telomerase-associated Est3 protein adopts a protein fold similar to the N-terminal region of TPP1.

Apolipoprotein A-I mimetics attenuate macrophage activation in chronic treated HIV.

Objectives: Despite antiretroviral therapy (ART), there is an unmet need for therapies to mitigate immune activation in HIV infection. The goal of this study is to determine whether the apoA-I mimetics 6F and 4F attenuate macrophage activation in chronic HIV.

Design: Preclinical assessment of the in-vivo impact of Tg6F and the ex-vivo impact of apoA-I mimetics on biomarkers of immune activation and gut barrier dysfunction in treated HIV.

Superior Mesenteric Artery Syndrome: A Forgotten Cause of Duodenal Obstruction.

Superior mesenteric artery (SMA) syndrome has been described in medical literature as a rare cause of duodenal occlusion. It has a varied presentation, with distressing gastrointestinal symptoms such as nausea, abdominal pain, and further weight loss. Several conditions contribute to duodenal obstruction in SMA syndrome.

An N-terminal Flag-tag impairs TPP1 regulation of telomerase function.

The shelterin protein complex protects natural chromosome ends from being recognized as DNA damage sites and also regulates the synthesis of telomeric repeats by telomerase. TPP1, a shelterin subunit that is essential for telomerase extension of telomeres, has been studied intensively in recent years. Many such studies utilize epitope tagged TPP1, but it is unclear how the tags may affect the multiple cellular functions of TPP1.

Calculated Serum Osmolality, Acute Kidney Injury, and Relationship to Mortality after Percutaneous Coronary Intervention.

Background: Data on the associations between serum osmolality (sOsmo) and acute kidney injury (AKI) as well as short- and long-term mortality in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) are limited.

Objectives: To investigate the association between sOsmo and development of AKI and clinical outcomes in patients undergoing PCI.

Methods: We investigated 1,927 consecutive patients undergoing PCI from the registry of a single center.

Impact of Discharge Location After Transcatheter Aortic Valve Replacement on 1-Year Outcomes in Women: Results From the WIN-TAVI Registry.

Background: Several clinical and procedural factors determine outcomes after transcatheter aortic valve replacement (TAVR), but data are scarce on the impact of post-TAVR discharge disposition on long-term outcomes. We sought to analyse whether discharge location after TAVR is associated with 1-year outcomes in women undergoing contemporary TAVR.

Methods: The Women's INternational Transcatheter Aortic Valve Implantation (WIN-TAVI) registry is the first all-female TAVR registry to study the safety and performance of contemporary TAVR in women (n = 1019).

Dual Antiplatelet Therapy Cessation and Adverse Events After Drug-Eluting Stent Implantation in Patients at High Risk for Atherothrombosis (from the PARIS Registry).

The impact of dual antiplatelet therapy (DAPT) cessation after percutaneous coronary intervention with drug eluting stent implantation in patients at high atherothrombotic risk remains unclear. We aimed to characterize the risk for adverse events, and its relation with the mode of DAPT cessation in patients at high atherothrombotic risk (HATR). Considering patients treated with drug-eluting stents among those enrolled in the Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients registry, we defined subjects with prior myocardial infarction (MI), prior stroke or peripheral vascular disease at HATR, while patients without any of these conditions were classified as atherothrombotic risk (LATR).

Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy.

Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proinflammatory signals such as IL6 and IFNγ.