The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and ...respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
In this issue of Cell Stem Cell, Kawakami et al. develop a SARS-CoV-2 infection-competent, progenitor-derived, human vascular organoid model and uncover a role for complement factor D (CFD) in ...mediating microvascular immunothrombosis. This model may be applied to conditions where microvascular disease plays a major pathogenic role.
In this issue of Cell Stem Cell, Kawakami et al. develop a SARS-CoV-2 infection-competent, progenitor-derived, human vascular organoid model and uncover a role for complement factor D (CFD) in mediating microvascular immunothrombosis. This model may be applied to conditions where microvascular disease plays a major pathogenic role.
Chemical mechanics: Hydrogen‐bond‐driven self‐assembly and mechanochemistry are used to facilitate supramolecular catalysis in the solid state. Mortar‐and‐pestle grinding proves to be an efficient ...means to achieve co‐crystal formation and turnover using a physical mixture composed of an olefin and catalytic amounts of a ditopic template (see scheme).
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is historically associated with Helicobacter pylori (HP) infections in more than 80% of patients. However, the incidence of HP-negative MALT ...lymphoma has been increasing. The clinicopathologic features have not been well studied, and optimal management strategies remain unclear.
The pathology database was searched for primary gastric MALT lymphomas diagnosed from 2000 to 2017. The clinical data and the slides were reviewed. The cases were divided for analysis into those with a background of chronic gastritis with HP, chronic gastritis without HP, and without either a background of chronic gastritis or HP.
Of 70 gastric MALT lymphoma cases identified, 26 (37% of total) had chronic gastritis and were positive for HP histologically (n = 23) or were HP positive by additional laboratory testing (n = 3). The remaining 44 (63% of total) cases were HP negative by histology. Within the HP-negative cases, 5 (11% of HP-negative cases) showed histologic gastritis while 39 (89% of HP-negative cases) did not have sufficient evidence of gastritis through review of slides (n = 18) or based on available pathology reports (n = 21). The HP-negative cases without gastritis had higher propensities to show a mass lesion on endoscopy compared with HP-positive cases (37.5% vs 11.1%, P = .02) at the initial diagnosis. The immunophenotype and rate of positive B-cell gene rearrangement were not significantly different between the 2 groups. While all HP-positive patients received antibiotics for HP eradication, treatment in the HP-negative group varied among antibiotics, radiation, rituximab, or chemotherapy. Among HP-negative patients with available follow-up, 13 (39%) showed disease recurrence, similar to the recurrence rate in HP-positive patients; however, no individual from either group has died of the disease thus far.
The incidence of HP-negative MALT lymphoma is increasing, and in our practice, it is currently more common than HP-associated MALT lymphomas. The pathophysiology of HP-negative MALT lymphoma without chronic gastritis remains unclear. Follow-up data in our study suggest that the prognosis of these cases is excellent despite varied management modalities.
Aging is intrinsically linked with physiologic decline and is a major risk factor for a broad range of diseases. The deleterious effects of advancing age on the vascular system are evidenced by the ...high incidence and prevalence of cardiovascular disease in the elderly. Reactive oxygen species are critical mediators of normal vascular physiology and have been shown to gradually increase in the vasculature with age. There is a growing appreciation for the complexity of oxidant and antioxidant systems at the cellular and molecular levels, and accumulating evidence indicates a causal association between oxidative stress and age-related vascular disease. Herein, we review the current understanding of mechanistic links between oxidative stress and thrombotic vascular disease and the changes that occur with aging. While several vascular cells are key contributors, we focus on oxidative changes that occur in platelets and their mediation in disease progression. Additionally, we discuss the impact of comorbid conditions (i.e., diabetes, atherosclerosis, obesity, cancer, etc.) that have been associated with platelet redox dysregulation and vascular disease pathogenesis. As we continue to unravel the fundamental redox mechanisms of the vascular system, we will be able to develop more targeted therapeutic strategies for the prevention and management of age-associated vascular disease.
Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules ...but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis.
The hemostatic response to vascular injury culminates in a fibrin clot network that forms an initial barrier to blood loss and also contributes to microbial host defense. Fibrinogen is cleaved by ...thrombin into fibrin monomers that spontaneously polymerize into protofibrils and form the extensive fiber networks characteristic of blood clots. In this issue of the JCI, Macrae and colleagues characterize an alternative fibrin structure in which fibrinogen and fibrin assemble into a continuous 2D film at the exterior face of the fibrin clot network. Fibrin films connect to the underlying fiber network through tethering fibers and provide a protective barrier to microbial infiltration. These findings shed new light on a previously overlooked mechanism of fibrin assembly at the clot surface and provide a link between hemostasis and innate immunity.
Connexins and connexin channels play important roles in cell growth/differentiation and tumorigenesis. Here, we identified a relationship between a connexin molecule and a critical cell-cycle ...regulator. Our data show that connexin (Cx) 50 regulated lens cell-cycle progression and differentiation by modulating expression of cyclin-dependent kinase inhibitor p27/p57 and E3 ubiquitin ligase Skp2. Cx50 directly interacted with and retained Skp2 in the cytosol by masking the nuclear targeting domain of Skp2, and this effect was supported by an increased nuclear localization of Skp2, disruption of Skp2 interaction with importin-7, and decreased levels of p27/p57 in mouse lenses lacking Cx50. As a result, Cx50 increased auto-ubiquitination and subsequent degradation of Skp2. A mutation (V362E) on the C terminus of Cx50 disrupted the interaction between Cx50 and Skp2 and completely abolished such effects. Therefore, this study identifies a role for connexins in regulating cell-cycle modulators and, consequently, cell growth and differentiation.
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•Connexin 50 governs cell-cycle existence and differentiation through p27/p57 and Skp2•Direct interaction with connexin 50 retains Skp2 in the cytosol•Connexin 50 promotes auto-ubiquitination and subsequent degradation of Skp2•p27/p57 protein is stabilized through downregulation of Skp2
Shi et al. examine junction/hemichannel-independent connexin function in governing cell growth and differentiation. They show that connexin 50 sequesters critical cell-cycle promoter and E3 ligase Skp2 in the cytosol. Connexin 50 promotes Skp2 degradation, resulting in stabilization of its substrate p27/p57 and thus the control of cell-cycle exit.
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