SARS-CoV-2, the virus that causes COVID-19, is prone to mutations and the generation of genetic variants. Since its first outbreak in 2019, SARS-CoV-2 has continually evolved, resulting in the emergence of several lineages and variants of concern (VOC) that have gained more efficient transmission, severity, and immune evasion properties. The World Health Organization has given these variants names according to the letters of the Greek Alphabet, starting with the Alpha (B.1.1.7) variant, which emerged in 2020, followed by the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. This review explores the genetic variation among different VOCs of SARS-CoV-2 and how the emergence of variants made a global impact on the pandemic.

The protein Beclin1 (BECN1, a mammalian homologue of ATG6 in yeast) plays an important role in the initiation and the normal process of autophagy in cells. Moreover, we and others have shown that Beclin1 plays an important role in viral replication and the innate immune signaling pathways. We previously used the cationic polymer polyethyleneimine (PEI) conjugated to mannose (Man) as a non-viral tool for the delivery of a small interfering (si) Beclin1-PEI-Man nanoplex, which specifically targets mannose receptor-expressing glia (microglia and astrocytes) in the brain when administered intranasally to conventional mice. To expand our previous reports, first we used C57BL/6J mice infected with EcoHIV and exposed them to combined antiretroviral therapy (cART). We show that EcoHIV enters the mouse brain, while intranasal delivery of the nanocomplex significantly reduces the secretion of HIV-induced inflammatory molecules and downregulates the expression of the transcription factor nuclear factor (NF)-kB. Since a spectrum of neurocognitive and motor problems can develop in people living with HIV (PLWH) despite suppressive antiretroviral therapy, we subsequently measured the role of Beclin1 in locomotor activities using EcoHIV-infected BECN1 knockout mice exposed to cART. Viral replication and cytokine secretion were reduced in the postmortem brains recovered from EcoHIV-infected Becn1^+/− mice when compared to EcoHIV-infected Becn1^+/+ mice, although the impairment in locomotor activities based on muscle strength were comparable. This further highlights the importance of Beclin1 in the regulation of HIV replication and in viral-induced cytokine secretion but not in HIV-induced locomotor impairments. Moreover, the cause of HIV-induced locomotor impairments remains speculative, as we show that this may not be entirely due to viral load and/or HIV-induced inflammatory cytokines.

Understanding the complexity of trauma-induced thromboinflammation necessitates data-driven approaches. We hypothesized that longitudinal plasma profiling could reveal underlying differences in patients with injury who present with similar clinical characteristics but ultimately have different outcomes. Here, we performed multiomic analyses of longitudinal plasma samples from a clinical trial of patients with traumatic injury to identify molecular endotypes and trajectories that were associated with patient outcomes. The pathophysiologic states of patients with trauma were defined by the longitudinal proteomic and metabolomic plasma profiles from a diverse cohort. Then, patients were endotyped according to their longitudinal trajectories through trauma omic states, and injury patterns and outcomes were compared. We identified endotypes associated with divergent clinical outcomes despite similar injury patterns at presentation. Organ failure and time spent in the intensive care unit (ICU) were predicted with high accuracy using omic markers. Patients who presented with evidence of elevated proteasome activation, catabolism, and superoxide formation were vulnerable to heart failure, lung failure, and acute lung injury, respectively. In addition, omic markers of increased hypoxia, RBC lysis, and hydrolase activity better fit mortality and ICU time compared with injury covariates, while providing biological insight. Injury and outcome patterns persisted in a validation trauma cohort after endotype assignment at a single, early time point. These data align with the understanding that patients with trauma may experience markedly different biological responses and outcomes despite similar clinical presentations. We suggest that mapping patient trajectories through biological injury states could provide a framework for personalized patient treatment after trauma.

It is well-established that mitochondrial dysfunction plays a critical role in the development of pulmonary hypertension (PH). However, the molecular mechanisms and how the individual electron transport complexes (ETC) may be affected are poorly understood. In this study, we identified decreased ETC Complex I activity and assembly and linked these changes to disrupted mitochondrial bioenergetics in pulmonary arterial endothelial cells (PAECs) isolated from a lamb model of PH with increased pulmonary blood flow (Shunt). These derangements were associated with decreased mitochondrial activity of the protein tyrosine kinase, pp60^Src. Treating Control PAECs with either the Src family kinase inhibitor, PP2, or the siRNA-mediated knockdown of pp60^Src was able to recapitulate the adverse effects on ETC Complex I activity and assembly and mitochondrial bioenergetics. Conversely, restoring pp60^Src activity in lamb PH PAECs re-established ETC Complex I activity, improved ETC Complex I assembly and enhanced mitochondrial bioenergetics. Phosphoprotein enrichment followed by two-dimensional gel electrophoresis and tandem mass spectrometry was used to identify three ETC Complex I subunits (NDUFS1, NDUFAF5, and NDUFV2) as pp60^Src substrates. Finally, we demonstrated that the pY levels of NDUFS1, NDUFAF5, and NDUFV2 are decreased in lamb PH PAECs. Enhancing mitochondrial pp60^Src activity could be a therapeutic strategy to reverse PH-related mitochondrial dysfunction.

Sepsis continues to overwhelm hospital systems with its high mortality rate and prevalence. A strategy to reduce the strain of sepsis on hospital systems is to develop a diagnostic/prognostic measure that identifies patients who are more susceptible to septic death. Current biomarkers fail to achieve this outcome, as they only have moderate diagnostic power and limited prognostic capabilities. Sepsis disrupts a multitude of pathways in many different organ systems, making the identification of a single powerful biomarker difficult to achieve. However, a common feature of many of these perturbed pathways is the increased generation of reactive oxygen species (ROS), which can alter gene expression, changes in which may precede the clinical manifestation of severe sepsis. Therefore, the aim of this study was to evaluate whether ROS-related circulating molecular signature can be used as a tool to predict sepsis survival. Here we created a ROS-related gene signature and used two Gene Expression Omnibus datasets from whole blood samples of septic patients to generate a 37-gene molecular signature that can predict survival of sepsis patients. Our results indicate that peripheral blood gene expression data can be used to predict the survival of sepsis patients by assessing the gene expression pattern of free radical–associated -related genes in patients, warranting further exploration.

Background: Endothelial cells (EC) dysfunction and barrier disruption are central drivers of inflammatory lung injury and adverse outcomes, yet targeted therapies remain lacking. We tested the hypothesis that a mesenchymal stem cell (MSC)–derived secretome can directly preserve EC function under inflammatory stress. We evaluated AlloEx (Vitro Biopharma), a Wharton’s Jelly MSC-derived secretome enriched in bioactive RNAs, proteins, lipids, and extracellular vesicles with pro-reparative and immunomodulatory activity. Methods: Human lung microvascular endothelial cells (HLMVEC) were exposed to TNFα (4 h) with AlloEx administered 30 min before or after TNFα stimulation. EC thromboinflammatory gene expression was quantified by qPCR. Barrier integrity was assessed by transendothelial resistance (TEER) and VE-cadherin immunofluorescence. Mitochondrial function was evaluated using MitoSOX, TMRM, and mitochondrial fission imaging. Proteomic profiling was performed using trauma patient plasma as a clinically relevant inflammatory stimulus. Results: AlloEx potently suppressed TNFα-induced EC activation, markedly reducing ICAM1 , SELE , IL6 , NOS3 , ANG2 , TEK , VEGFA , and F3 expression. Functionally, AlloEx rescued EC barrier integrity, preserving VE-cadherin localization at endothelial junctions and restoring TEER by 79% with pretreatment and 65% with post-treatment. Mechanistically, AlloEx prevented mitochondrial dysfunction, limiting reactive oxygen species generation, preserving membrane potential, and reducing fission. Proteomic profiling demonstrated that AlloEx induced coordinated remodeling of metabolic, vesicular, and inflammatory signaling pathways while suppressing cellular stress and pro-inflammatory signaling. Conclusion: These findings identify MSC-derived secretome therapy as a potent modulator of EC thromboinflammatory activation, barrier integrity, and mitochondrial function. AlloEx represents a promising, clinically translatable strategy to target EC dysfunction in inflammatory lung injury and trauma-associated endotheliopathy.