Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions

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Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML

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Historical Ecology on Sandoy, Faroe Islands: Palaeoenvironmental and Archaeological Perspectives

We present palaeoenvironmental, geomorphological, archaeological, and place-name data which allow a holistic assessment of the history of landscape change on Sandoy, Faroe Islands, especially in terms of the changes that occurred in response to the colonization of the island by humans. In contrast to other situations in the North Atlantic region, there is considerable continuity in the patterns and processes of landscape evolution across the initial settlement horizon. Many of the characteristic features of post-settlement North Atlantic landscapes—absence of trees, widespread blanket mires, high rates of soil erosion—were already in place when the first people arrived. Although human impact on Sandoy appears to have been light, conversely, the unusual environment forced major alterations of the subsistence economy imported by the colonists. Settlement-era archaeological records suggest that, from the start, patterns of resource use differed substantially from the regional norm, and these differences became amplified over time as the Faroese economy created a locally sustainable cultural landscape.     

Niche construction,human behavior,and the adaptive‐lag hypothesis

Niche construction is the process whereby organisms modify selective environments, thereby affecting evolution. The niche‐construction perspective is particularly relevant to researchers using evolutionary methods to interpret human behavior and society. On the basis of niche‐construction theory, we argue against the hypothesis that modern humans experience an atypically large adaptive lag. We stress that humans construct their world largely to suit themselves and frequently buffer adaptive lag through cultural niche construction. Where they are unable to do that, natural selection of genes rapidly ensues. Our argument has implications for evolutionary psychology and human behavioral ecology, and suggests that the methods of the latter are potentially applicable to all human societies, even postindustrial ones.     

Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo

Monocyte chemoattractant protein-1 (MCP-1)-induced monocyte chemotaxis is a major event in inflammatory disease. Our prior studies have demonstrated that MCP-1-dependent chemotaxis requires release of arachidonic acid (AA) by activated cytosolic phospholipase A₂ (cPLA₂). Here we investigated the involvement of AA metabolites in chemotaxis. Neither cyclooxygenase nor lipoxygenase pathways were required, whereas pharmacologic inhibitors of both the cytochrome-P450 (CYP) and the soluble epoxide hydrolase (sEH) pathways blocked monocyte chemotaxis to MCP-1. To verify specificity, we demonstrated that the CYP and sEH products epoxyeiscosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs), respectively, restored chemotaxis in the presence of the inhibitors, indicating that sEH-derived products are essential for MCP-1-driven chemotaxis. Importantly, DHETs also rescued chemotaxis in cPLA₂-deficient monocytes and monocytes with blocked Erk1/2 activity, because Erk controls cPLA₂ activation. The in vitro findings regarding the involvement of CYP/sEH pathways were further validated in vivo using two complementary approaches measuring MCP-1-dependent chemotaxis in mice. These observations reveal the importance of sEH in MCP-1-regulated monocyte chemotaxis and may explain the observed therapeutic value of sEH inhibitors in treatment of inflammatory diseases, cardiovascular diseases, pain, and even carcinogenesis. Their effectiveness, often attributed to increasing EET levels, is probably influenced by the impairment of DHET formation and inhibition of chemotaxis.     

Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.