药物对hERG钾通道作用机制研究进展

人ether-a-go-go-related gene(hERG)钾通道表达了延迟整流钾电流的快激活成分,对动作电位的复极至关重要。hERG钾电流不仅是抗心律失常作用的主要靶点,也是诸多药物增加尖端扭转型室速和心源性猝死风险的关键位点,而该电流的降低和(或)升高与基因突变或药物阻滞作用密切相关。随着对药物与hERG钾通道相互作用机制研究的深入,药物与通道孔道区蛋白结合位点的作用及其对通道转运的影响逐步被揭示,但这些药物对hERG作用的临床应用仍有待评价。     

CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input

Rapid induction of CD8⁺ cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4⁺ T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naïve precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4⁺ T cells in early phases of the immune response. We show that CD4⁺ T cells help optimal CTL expansion by facilitating entry of naïve polyclonal CD8⁺ T cells into the draining lymph node (dLN) early after infection or immunization. CD4⁺ T cells also facilitate input of naïve B cells into reactive LNs. Such “help” involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen- and CD40-dependent manner, CD4⁺ T cells activate dendritic cells to support naïve lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4⁺ T-cell help, whereby they increase the input of naïve lymphocytes to the relevant LN for efficient screening of cognate CD8⁺ T cells.     

间充质干细胞来源胞外囊泡救治辐射损伤的研究进展

间充质干细胞来源胞外囊泡（MSC-EV）在保留间充质干细胞（MSC）生物学功能的同时,能够避免MSC内在缺陷;MSC-EV脂质双分子层结构能够避免其脂质、蛋白、DNA、RNA等内容物被酶类物质降解;此外,MSC-EV适合通过永生化MSC技术进行大规模制备。因此,与MSC相比,MSC-EV是一种新型高效、安全、便捷、可行的非细胞治疗方法,且在组织修复及免疫调节方面呈现出同等功效。本文仅就MSC-EV在辐射损伤救治方面的研究进展作一综述。     

Abrogation of CCL21 chemokine function by transgenic over-expression impairs T cell immunity to local infections

The CC chemokine receptor 7 (CCR7) and its two ligands, CCL21 and CCL19, play an important role in migration of immune cells to lymphoid tissue. To analyze the function of CCR7 in T cell immunity to infectious agents in vivo, transgenic (tg) mice expressing CCL21 in an ubiquitous fashion were generated. These mice contained high amounts of CCL21 in the serum ( approximately 0.3 microg/ml that resulted in CCR7 down-regulation and in a strongly impaired migration of T cells toward CCL21 in vitro. Lymph nodes in CCL21-tg mice were reduced in size but with intact microanatomy and normal distribution of T and B cells. CCL21-tg mice showed a significantly decreased CD8 T cell response to lymphocytic choriomeningitis virus after footpad infection, whereas the response after systemic infection was not altered. Likewise, the CD4 T cell response to footpad infection with Leishmania major was considerably lowered and CCL21-tg mice failed to clear parasites from infected skin. Taken together, these data demonstrate the importance of CCR7 in mediating T cell immunity to viral and parasitic pathogens after local infection.     

COVID-19 Gender Disparities and Mitigation Recommendations: A Narrative Review

The coronavirus disease 2019 (COVID-19) pandemic has rapidly created widespread impacts on global health and the economy. Data suggest that women are less susceptible to severe illness. However, sex-disaggregated data are incomplete, leaving room for misinterpretation, and focusing only on biologic sex underestimates the gendered impact of the pandemic on women. This narrative review summarizes what is known about gender disparities during the COVID-19 pandemic and the economic, domestic, and health burdens along with overlapping vulnerabilities related to the pandemic. In addition, this review outlines recommended strategies that advocacy groups, community leaders, and policymakers should implement to mitigate the widening gender disparities related to COVID-19.     

Evidence for a morphologically distinct subpopulation of striatipetal axons following injections of WGA-HRP into the ventral tegmental area in the rat

Following injections of small volumes (10-30 nl) of WGA-HRP (1-2%) into the ventral tegmental area, axonal transport of the lectin-peroxidase conjugate to ventral striatum was evaluated by light microscopy after TMB histochemistry and by electron microscopy following stabilization of the TMB reaction product with DAB and H2O2. Label was distributed more or less evenly in ventral striatum, with only slight patchiness observable in the boundary zone between the nucleus accumbens and ventromedial caudate-putamen. The electron microscope revealed that labeled axons contained markedly flattened vesicles and dense axoplasm and contacted perikarya, dendrites and dendritic spines of short (0.2-0.3 microns) symmetric appositions. Boutons with a similar triad of morphological features were observed in preparations processed for conventional electron microscopy and for tyrosine hydroxylase immunocytochemistry, suggesting that the characteristic morphological features observed are not an epiphenomenon related to histochemical processing.     

Differential degradation of PIN2 auxin efflux carrier by retromer-dependent vacuolar targeting

All eukaryotic cells present at the cell surface a specific set of plasma membrane proteins that modulate responses to internal and external cues and whose activity is also regulated by protein degradation. We characterized the lytic vacuole-dependent degradation of membrane proteins in Arabidopsis thaliana by means of in vivo visualization of vacuolar targeting combined with quantitative protein analysis. We show that the vacuolar targeting pathway is used by multiple cargos including PIN-FORMED (PIN) efflux carriers for the phytohormone auxin. In vivo visualization of PIN2 vacuolar targeting revealed its differential degradation in response to environmental signals, such as gravity. In contrast to polar PIN delivery to the basal plasma membrane, which depends on the vesicle trafficking regulator ARF-GEF GNOM, PIN sorting to the lytic vacuolar pathway requires additional brefeldin A-sensitive ARF-GEF activity. Furthermore, we identified putative retromer components SORTING NEXIN1 (SNX1) and VACUOLAR PROTEIN SORTING29 (VPS29) as important factors in this pathway and propose that the retromer complex acts to retrieve PIN proteins from a late/pre-vacuolar compartment back to the recycling pathways. Our data suggest that ARF GEF- and retromer-dependent processes regulate PIN sorting to the vacuole in an antagonistic manner and illustrate instrumentalization of this mechanism for fine-tuning the auxin fluxes during gravitropic response.     

Direct evidence for the up‐regulation of Vps34 regulated by PKCγ during short‐term treatment with morphine

In this study, we investigated whether PKCγ could be associated with functional changes of vacuolar protein sorting 34 (Vps34) during morphine treatment using primary cultures of cerebral cortical neurons from mice. The immunoprecipitation analysis showed that p‐PKCγ and Vps34 are present together in molecular complexes. The treatment with morphine increases PKCγ and Vps34 levels. Phosphorylation of PKCγ increased Vps34 level. The inhibition of morphine‐induced increase in PKCγ phosphorylation reduced Vps34 level. These results indicates that opioid receptor activation increases PKCγ phosphorylation in the neurons and, in turn, upregulates Vps34 during short‐term treatment with neurons. Synapse 63:365–368, 2009. © 2009 Wiley‐Liss, Inc.