Transactions of the American Clinical and Climatological Association最新文献

Integrins play a critical role in leukocyte recruitment and activation within inflamed tissues. These heterodimeric cell-surface receptors recognize ligands on vascular endothelium or extracellular matrix to initiate intracellular signals leading to leukocyte adhesion, migration, and activation. The best-described role for integrins is in the leukocyte adhesion cascade, which is the process by which leukocytes exit the blood vasculature and enter the tissues in response to infection or injury. During the adhesion cascade, integrin signaling is required for changes in leukocyte cytoskeletal structure required for firm adhesion to endothelial cells, followed by intravascular crawling and transmigration from the bloodstream into the tissues. During this process, integrin signaling augments leukocytes' inflammatory and antimicrobial functions. Mutations in the genes encoding integrins or their downstream signaling molecules result in immunodeficiency and altered tissue repair following injury. Many of these mutations occur in proteins involved in the reorganization of the actin cytoskeleton and have become known as actinopathies, the classic example being Wiskott-Aldrich syndrome. We describe a new actinopathy-type mutation in the integrin signaling molecule SKAP2, which is associated with autoimmunity and type 1 diabetes.

Outcomes after acute kidney injury (AKI) cover a wide spectrum ranging from full recovery to incomplete repair leading to transition to chronic kidney disease (CKD). This "AKI to CKD transition" is incompletely understood at a cellular level and there is a pressing need to identify the basic mechanisms of successful recovery from AKI and to develop therapeutic interventions to prevent the AKI to CKD transition. In recent years, single-cell transcriptomic and epigenomic technologies have substantially improved our understanding of cell types and states in homeostasis and after injury. In this paper, I will review our recent work applying single-cell technologies to better understand AKI and its transition to CKD, focusing on a proximal tubule cell state that we have termed "failed repair." Failed repair proximal tubule cells are characterized by pro-inflammatory and pro-fibrotic gene expression patterns and may drive the AKI to CKD transition.

Obesity is a risk factor for incident heart failure (HF), linked to, but also independent of, coexisting comorbidities. The association of obesity is stronger for HF with preserved versus reduced ejection fraction. Further, obesity is associated with a higher risk of HF hospitalization in patients with HF. However, multiple studies in patients with prevalent HF have suggested that higher body mass index (BMI) is associated with lower mortality-the "obesity survival paradox." This paradox was also observed with preexisting obesity prior to the development of HF. These observations had complicated the case for the routine recommendation of weight loss in patients with obesity and HF. However, recent trials with anti-obesity medications are leading to a better understanding of the benefits of weight loss in HF and thus support a reevaluation of the obesity survival paradox in HF.

Novel avian influenza viruses continue to circulate in animal species around the world and show a propensity to reassort and acquire virulence factors, which raises the concern that these viruses may adapt to humans. Pandemic preparedness has relied heavily on vaccine stockpiles. However, avian influenza strains genetically drift over time, and stockpiled vaccines often fail to elicit protective immunity for these genetic variants. Various strategies can help overcome immune imprinting and immunological hyporeactivity as well as broaden the immune response to variant viruses. Adjuvants remain a key strategy for improving the immunological response to avian influenza antigens. Today, three vaccines are approved in the United States for H5N1 influenza viruses though continued focus on surveillance and pandemic preparedness is essential to prepare for the possibility of human-to-human spread of this highly pathogenic influenza virus.

Helicobacter pylori (Hp) is the strongest known risk factor for gastric adenocarcinoma. We previously demonstrated that iron deficiency, a condition of the exposome, augments Hp-induced carcinogenesis. To define mechanisms driving this phenotype, we performed targeted metabolomics in mice which revealed that Hp significantly increased levels of deoxycholic acid (DCA), a carcinogenic secondary bile acid, exclusively under iron-deficient conditions. Further, DCA directly promoted Hp-induced dysplasia. Because bile acids and fatty acids can exert opposing effects on disease, fatty acids were also assessed within the context of iron deficiency and infection. In contrast to bile acids, long-chain fatty acids (LCFAs) were significantly downregulated by Hp under iron-deficient conditions, including levels of palmitic acid, a LCFA with therapeutic potential against gastric cancer. These data indicate that Hp increases levels of carcinogenic secondary bile acids with concordant reductions in protective LCFAs under iron-deficient conditions, suggesting an active interplay between these effectors in cancer risk.