Group IIIA-metal hydroxides indirectly neutralize the voltage sensor of the voltage-dependent mitochondrial channel, VDAC, by interacting with a dynamic binding site.

The voltage-dependent, anion-selective mitochondrial channel, VDAC, undergoes two different conformational changes from the open to a closed state under positive and negative applied electric fields. Micromolar quantities of aluminum hydroxide and other metal trihydroxides have recently been shown to be able to inhibit this voltage-dependent closure (Dill et al. (1987) J. Membr. Biol. 99, 187-196; Zhang and Colombini (1989) Biochim. Biophys. Acta 991, 68-78). It was suggested that the inhibition results from the neutralization of the positively charged voltage sensors by the metal species. In the present study, the dynamics of the metal-binding site accompanying channel closure was investigated by adding In(OH)3 to only one side of the membrane and examining its effect on the channel's gating processes. Indium added to open channels inhibited channel closure only when the metal-containing side was on the lower potential side of the applied field. If indium was added only to the higher-potential side, the channels closed and tended to remain closed after the field was abolished. The addition of metal hydroxide after closing the channels with a negative potential on the metal side did not result in channel re-opening as would be expected for sensor neutralization. Inhibition occurred immediately, however, if the channels were first allowed to open briefly. The closed-state selectivity seemed to be very similar in the absence or presence of the metal, indicating that the metal-binding sites are not located within the pore of the channel in the closed conformation. The results are consistent with a voltage-dependent translocation across the membrane of each of two metal-binding sites on VDAC. This translocation is tightly coupled with channel opening and closing.     

乳粉中嗜热菌污染研究进展

嗜热菌是乳粉中的常见污染菌,是影响乳粉品质的一个重要因素。本文综述乳粉中嗜热菌的种类、污染源对乳品工业的危害及其控制手段的研究进展,为国内相关领域研究提供参考。     

Single-cell transcriptomic atlas of primate cardiopulmonary aging

Aging is a major risk factor for many diseases,especially in highly prevalent cardiopulmonary comorbidities and infectious diseases including Coronavirus Diseas...     

Genetic Polymorphisms of Pneumocystis Jirovecii in HIV-Positive and HIV-Negative Patients in Northern China

Pneumocystis jirovecii is an opportunistic fungus that can cause severe and potentially fatal Pneumocystis pneumonia (PCP) in immunodeficient patients. In this study, we investigated the genetic polymorphisms of P. jirovecii at eight different loci, including six nuclear genes (ITS, 26S rRNA, sod, dhps, dhfr and β-Tub) and two mitochondrial genes (mtLSU-rRNA and cyb) in three PCP cases, including two patients with HIV infection and one without HIV infection in Shanxi Province, P.R. China. The gene targets were amplified by PCR followed by sequencing of plasmid clones. The HIV-negative patient showed a coinfection with two genotypes of P. jirovecii at six of the eight loci sequenced. Of the two HIV-positive patients, one showed a coinfection with two genotypes of P. jirovecii at the same two of the six loci as in the HIV-negative patient, while the other showed a single infection at all eight loci sequenced. None of the three drug target genes (dhfr, dhps and cyb) showed mutations known to be potentially associated with drug resistance. This is the first report of genetic polymorphisms of P. jirovecii in PCP patients in Shanxi Province, China. Our findings expand our understanding of the genetic diversity of P. jirovecii in China. Open in a separate window     

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.Subject terms: Cell death, Molecular biology     

Discovery and SAR analysis of 5-chloro-4-((substituted phenyl)amino)pyrimidine bearing histone deacetylase inhibitors

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC₅₀ values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC₅₀ value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells.