HIV envelope tail truncation confers resistance to SERINC5 restriction

SERINCs and IFITMs are potent lentiviral restriction factors that inhibit infection by blocking viral entry into cells. Specifically, SERINCs inhibit viral fusion by targeting the envelope glycoprotein (Env) by a mechanism that remains incompletely understood. Here, we report that truncation of the Env cytoplasmic tail (CT) of HIV-1 and HIV-2 confers complete resistance to SERINC and IFITM restriction. Notably, while the EnvCT of HIV-1 is necessary for viral replication in T cells, HIV-2 does not require the EnvCT. Our data suggest a mechanism by which human lentiviruses can evade restriction that is mediated by the EnvCT but reveal key differences in the likely fitness cost imposed by this on pandemic HIV-1 and nonpandemic HIV-2

The role of endocytic machinery during Vaccinia Virus egress and spread

During its egress, Vaccinia virus induces a series of events at the plasma membrane of infected cells that ultimately enhance the spread of infection. Immediately following fusion with the plasma membrane, the virus recruits the endocytic adaptor protein, AP-2 and clathrin in an A36-dependent manner. Clathrin recruitment acts to cluster the viral integral membrane protein, A36 underneath the virion to generate a robust signalling platform that recruits the adapters Nck and Grb2 downstream of phosphorylated tyrosines 112/132 respectively. This subsequently results in the recruitment of the WIP:N-WASP complex, which stimulates Arp2/3 complex dependent actin polymerization to propel the virus along the plasma membrane and onto neighbouring uninfected cells. In addition, the virus also promotes Arp2/3 driven actin polymerization via recruitment and activation of the GTPase Cdc42, facilitating its interaction with N-WASP. The ability of the virus to activate Cdc42 is dependent on the RhoGEF Intersectin-1, which is also capable of interacting with AP-2. My studies have sought to investigate the molecular mechanism and role of AP-2 and clathrin recruitment during viral egress. I found that three highly conserved Asn-Pro-Phe (NPF) motifs at the C-terminus of A36 interact directly with the Eps15 Homology (EH) domains of intersectin-1 and Eps-15. A recombinant virus lacking all three NPF motifs (∆NPF) is unable to recruit clathrin, AP-2 or intersectin-1. Besides changes in actin polymerization this virus also has defects in viral release and spread. NPF motifs are conserved endocytic interaction modules that a found in all eukaryotes, however A36 is the first viral protein containing functional NPF motifs to be identified to date

A Conserved Tryptophan in the Envelope Cytoplasmic Tail Regulates HIV-1 Assembly and Spread

The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT), but the function of the EnvCT and many conserved domains within it remain largely uncharacterised. Here, we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Alanine substitution at this position potently inhibited HIV-1 cell–cell spread (the dominant mode of HIV-1 dissemination) by preventing recruitment of Env and Gag to sites of cell–cell contact, inhibiting virological synapse (VS) formation and spreading infection. Single-molecule tracking and super-resolution imaging showed that mutation of W757 dysregulates Env diffusion in the plasma membrane and increases Env mobility. Further analysis of Env function revealed that W757 is also required for Env fusion and infectivity, which together with reduced VS formation, result in a potent defect in viral spread. Notably, W757 lies within a region of the EnvCT recently shown to act as a supporting baseplate for Env. Our data support a model in which W757 plays a key role in regulating Env biology, modulating its temporal and spatial recruitment to virus assembly sites and regulating the inherent fusogenicity of the Env ectodomain, thereby supporting efficient HIV-1 replication and spread

Fabrication, microstructure and optical characterizations of holmium oxide (Ho2O3) transparent ceramics

Ho2O3 transparent ceramics were fabricated by vacuum pre-sintering combined with hot isostatic pressing (HIP) post-treatment at relatively low temperature from high-purity Ho2O3 powder calcined at 1000 °C for 4 h. The optimal Ho2O3 ceramic sample prepared by vacuum pre-sintering at 1250 °C and HIP post-treating at 1450 °C has a dense microstructure with average grain size of 0.77 μm, and the in-line transmittances reach 80.7 % at 1550 nm and 76.7 % at 1064 nm. The effect of air annealing on the optical quality of Ho2O3 ceramics was studied, and the existence of compressed pores in the HIP-ed Ho2O3 ceramics was confirmed. The Verdet constants of Ho2O3 ceramics were measured to be -47.4 rad/(T m at 1064 nm and -15.4 rad/(T m at 1561 nm. High transmittance and large Verdet constant in the wavelength regions 1–1.07 μm, 1.3–1.5 μm make Ho2O3 transparent ceramics promising for magneto-optical devices for lasers based on Yb-, Nd-doped materials and telecom lasers. © 2020 Elsevier Ltd19-52-53014; Chinese Academy of Sciences, CAS: QYZDB-SSW-JSC022; Russian Science Foundation, RSF: 18-13-00355; National Key Research and Development Program of China, NKRDPC: 2017YFB0310500This work was supported by the National Key R&D Program of China (Grant No. 2017YFB0310500 ), the Special Exchange Program of Chinese Academy of Sciences (Plan B) , the key research project of the frontier science of the Chinese Academy of Sciences (No. QYZDB-SSW-JSC022 ), partially by the Research Project of the Russian Science Foundation (No. 18-13-00355 ) and Verdet constant measurements was done under NSFC-RFBR Cooperative Research Projects Grant 19-52-53014

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS

Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia

Aims Arachidonic acid (AA) and its metabolites, prostaglandins (PG) are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV) remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs). Methods and Results We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM) and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM), an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV. Conclusion Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca2+ channels

Normative resistance to responsibility to protect in times of emerging multipolarity: the cases of Brazil and Russia

This article assesses the normative resistance to Responsibility to Protect adopted by Brazil and Russia against the backdrop of their international identities and self-assigned roles in a changing global order. Drawing upon the framework of Bloomsfield's norm dynamics role spectrum, it argues that while the ambiguous Russian role regarding this principle represents an example of 'norm antipreneurship', particularities of Brazil's resistance are better grasped by a new category left unaccounted for by this model, which this study portrays as 'contesting entrepreneur'.- (undefined

Bronchial muscle peristaltic activity in the fetal rat

Aside for the potential for tonic contraction, the airway smooth muscle exhibits intermittent phasic rhythmic activity that may contribute to lung growth during fetal life. Therefore, we examined 4th generation rat 18-22 d gestation fetal, 4-6 d of age newborn and adult bronchial ring from Sprague Dawley rats to compare differences in smooth muscle function. We hypothesized that phasic contractions were greatest before birth. Bronchial muscle spontaneous rhythmic contractions were greatest in the fetus and absent in the adult. In response to KCl stimulation, the fetal bronchial smooth muscle only developed tonic force that was 3.5 +/- 0.6 and lower than measured in the newborn 9.0 +/- 0.3 and adult 13.7 +/- 1.4 mN/mm2. The thromboxane A2 analogue U46619 induced tonic and phasic muscle contractions and the amplitude and frequency of the phasic contractions were greater in the fetus as compared with the adult and increased with gestational age. The U46619-induced rhythmic contractions were abrogated by ryanodine, thapsigargin and reduction of extracellular Na+, suggesting intracellular Ca2+ dependence and involvement of the Na+/Ca2+ exchanger. The inward rectifier K+ blocker BaCl2 induced phasic contractions in unstimulated fetal, but not adult bronchial muscle of the same amplitude and frequency as for the spontaneous and U46619-induced ones. We conclude that the airway smooth muscle phasic activity is greatest in the fetus and tends to disappear post-natally with age suggesting an in utero role during lung development

Russia and China in global governance

Scholars studying Sino-Russian relations point at the informal division of labour between Russia and China in global governance. Russia remains active in international security governance, whereas China has increased the level of its participation in areas of economic, financial and environmental governance. These differences are ascribed to the different potential of both states as well as their related varied scope of interests in a well-functioning global governance system. However, this division of labour has evolved for the past couple of years. Beijing increased its engagement with international security governance, while Moscow lost some of its (already limited) interest in such areas as environmental or economic governance. This chapter aims at exploring this shift and its implications. Rather than analysing Sino-Russian relations in distinct areas of global governance, it proposes a different approach and identifies three patterns of interactions between the two countries: direct cooperation, parallel activities and contradictory/divergent activities