Alternative splicing is critical to many cellular functions and appears to be primarily regulated through co -transcriptional mechanisms, where spliced-transcript identity is determined during transcriptional elongation. For HIV-1, alternative splicing is essential since the viral genome encodes multiple overlapping reading frames. Using quantitative single-cell imaging, we find that HIV-1 splicing is not co-transcriptionally regulated. Strikingly, HIV-1 mRNA appears to be spliced post-transcriptionally in a serial cascade. We propose a sensitive new assay to detect in vivo post-transcriptional splicing. The assay result shows that HIV-1 mRNA does not require transcription for spliceosome assembly. This serial splicing cascade appears crucial for the HIV-1 Rev negative-feedback circuit and in agreement with mathematical models. We experimentally verify the counter- intuitive prediction that Rev over-expression leads to reduced HIV-1 p24 expression. Serial post-transcriptional splicing may provide a novel target for antivirals and, more generally, an alternate gene-regulatory mechanism

Since the launch of China's Free Antiretroviral Therapy (ART) Program in 2002, more than 100,000 HIV/AIDS patients have been treated with highly actively antiretroviral therapy (HAART). However, the current evaluation system for this program mainly focused on its medical outcomes. This study aims to evaluate the medical and psychosocial needs of HIV/AIDS patients after initiating HAART. A cross-sectional study was conducted among 499 HIV/AIDS patients who were currently being treated with HAART in three designated hospitals in Luxi City, Yunnan Province. A questionnaire was used to collect information about participants' demographic characteristics, perceived HIV-related stigma, physician-patient relationship, quality of life, family functioning, etc. Patients' medical records in the National HIV Information System were linked with their questionnaire by their ART identification number. Patients on HAART who were infected with HIV through injection drug use and were current smokers typically had poorer physical health than other participants on HAART. Better financial status and better physician-patient relationship were associated with both physical and psychological well-being. Family awareness of the patient's HIV status was negatively associated with the patient's psychological well-being. Higher levels of perceived HIV-related stigma were associated with poorer psychological health and poorer family functioning. This study emphasizes the importance of assuring a caring environment in China's AIDS treatment program and re-enforces the need to combat the stigma encountered with health providers and the public.

The importance of antiretroviral therapy adherence for patients living with HIV/AIDS has been well documented. Despite this critical need, many do not follow prescribed regimens. To examine the barriers that lead to non-adherence, we used cross-sectional survey data from a randomized controlled intervention trial in northern and north-eastern Thailand. Of the 507 patients that were enrolled in the trial, we analyzed 386 patients on antiretroviral therapy in order to examine the barriers to adherence. In addition to demographic characteristics, depressive symptoms, physical health, access to care, social support, and internalized shame, HIV disclosure and family communication were examined. The correlation analysis revealed that adherence is significantly associated with internalized shame, access to care, depressive symptoms, and family communication. Based on the multiple logistic regression analysis, depressive symptoms, access to care, HIV disclosure, and family communication were significant predictors of adherence. Having depressive symptoms remains a significant barrier to adherence, while access to care, HIV disclosure, and family communication play important positive roles. Our findings underscore the critical importance of addressing these various challenges that can influence adherence to antiretroviral therapy.

Objective

To conduct a meta-analysis of randomized trials to comprehensively compare the effect of endovascular thrombectomy (EVT) versus intravenous thrombolysis (IVT) plus EVT on functional independence (modified Rankin Scale (mRS) 0-2) after acute ischemic stroke due to large vessel occlusions (AIS-LVO).

Methods

We searched Pubmed, EMBASE, CENTRAL, and clinicaltrials.gov from January 2000 to February 2021 and abstracts presented at the International Stroke Conference in March 2021 to identify trials comparing EVT alone versus IVT plus EVT in AIS-LVO. Five non-inferiority margins established in the literature were assessed: -15%, -10%, -6.5%, -5%, and -1.3% for the risk difference for functional independence at 90 days.

Results

Four trials met the selection criteria, enrolling 1633 individuals, with 817 participants randomly assigned to EVT alone and 816 to IVT plus EVT. Crude cumulative rates of 90-day functional independence were 46.0% with EVT alone versus 45.5% with IVT plus EVT. Pooled results showed the risk difference of functional independence was 1% (95% CI -4% to 5%) between EVT alone versus IVT plus EVT. The lower 95% CI bound of -4% fell within the non-inferiority margins of -15%, -10%, -6.5%, and -5%, but not -1.3%. Pooled results also showed the risk difference between EVT alone versus IVT plus EVT was 1% (95% CI -3% to 5%) for mRS 0-1, and 1% (95% CI -1% to 3%) for symptomatic intracranial hemorrhage.

Conclusions

This meta-analysis suggests that EVT alone is non-inferior to IVT plus EVT for several, but not the most stringent, non-inferiority margins.

The urea channel of Helicobacter pylori (HpUreI) is an ideal drug target for preventing gastric cancer but incomplete understanding of its gating mechanism has hampered development of inhibitors for the eradication of H. pylori. Here, we present the cryo-EM structures of HpUreI in closed and open conformations, both at a resolution of 2.7 Å. Our hexameric structures of this small membrane protein (~21 kDa/protomer) resolve its periplasmic loops and carboxyl terminus that close and open the channel, and define a gating mechanism that is pH dependent and requires cooperativity between protomers in the hexamer. Gating is further associated with well-resolved changes in the channel-lining residues that modify the shape and length of the urea pore. Site-specific mutations in the periplasmic domain and urea pore identified key residues important for channel function. Drugs blocking the urea pore based on our structures should lead to a new strategy for H. pylori eradication.

Aims

Relative bleeding risks of different antithrombotic agents in heart failure (HF) patients is an important consideration in treatment decision making, making detailed comparative analysis desirable. The aim of this study was to conduct a network meta-analysis to investigate the major bleeding risk for individual novel oral anticoagulants (NOACs) vs. aspirin among patients with HF.

Methods and results

We searched Pubmed, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, and Clinicaltrials.gov from 1966 to November 2019 to identify relevant randomized clinical trials. Studies comparing individual NOACs vs. aspirin were analysed using direct study-level meta-analysis. Studies comparing aspirin to warfarin and NOACs to warfarin were then additionally added using network (direct and indirect) study-level meta-analysis. Primary endpoint was major bleeding. Final analysis included nine trials with 34 367 participants, including one direct comparison trial (apixaban vs. aspirin) and eight indirect comparison trials against the shared warfarin comparator (four aspirin trials and one trial each of apixaban, dabigatran, rivaroxaban, and edoxaban). For apixaban, network meta-analysis combing direct and indirect comparison showed that major bleeding risk might not be different between apixaban and aspirin (odds ratio, 1.18 [95% confidence interval, 0.38 to 3.65]) in HF patients. In contrast, indirect-comparison meta-analysis showed dabigatran, rivaroxaban, and edoxaban compared with aspirin might be associated with a higher risk of major bleeding in HF patients.

Conclusions

In network meta-analysis, apixaban might be associated with a comparable risk of major bleeding compared with aspirin in patients with HF, while other NOACs might be associated with a higher risk. However, such results were not strongly convincing because of lack of direct comparison in an original trial and small sample size of trials and participants. A clinical trial directly comparing apixaban vs. aspirin in patients with HF and sinus rhythm may be worth undertaking.

Four-dimensional (4D) scanning transmission electron microscopy is used to study the electric fields at the edges of 2D semiconducting monolayer MoS₂. Sub-nanometer 1D features in the 2D electric field maps are observed at the outermost region along zigzag edges and also along nanowire MoS-terminated MoS₂ edges. Atomic-scale oscillations are detected in the magnitude of the 1D electromagnetic edge state, with spatial variations that depend on the specific periodic edge reconstructions. Electric field reconstructions, along with integrated differential phase contrast reconstructions, reveal the presence of low Z number atoms terminating many of the uniform edges, which are difficult to detect by annular dark field scanning transmission electron microscopy due to its limited dynamic range. Density functional theory calculations support the formation of periodic 1D edge states and also show that enhancement of the electric field magnitude can occur for some edge terminations. The experimentally observed electric fields at the edges are attributed to the absence of an opposing electric field from a nearest neighbor atom when the electron beam propagates through the 2D monolayer and interacts. These results show the potential of 4D-STEM to map the atomic scale structure and fluctuations of electric fields around edge atoms with different bonding states than bulk atoms in 2D materials, beyond conventional imaging.

Engineering the electronic band structure of material systems enables the unprecedented exploration of new physical properties that are absent in natural or as-synthetic materials. Half metallicity, an intriguing physical property arising from the metallic nature of electrons with singular spin polarization and insulating for oppositely polarized electrons, holds a great potential for a 100% spin-polarized current for high-efficiency spintronics. Conventionally synthesized thin films hardly sustain half metallicity inherited from their 3D counterparts. A fundamental challenge, in systems of reduced dimensions, is the almost inevitable spin-mixed edge or surface states in proximity to the Fermi level. Here, we predict electric field-induced half metallicity in bilayer A-type antiferromagnetic van der Waals crystals (i.e., intralayer ferromagnetism and interlayer antiferromagnetism), by employing density functional theory calculations on vanadium diselenide. Electric fields lift energy levels of the constituent layers in opposite directions, leading to the gradual closure of the gap of singular spin-polarized states and the opening of the gap of the others. We show that a vertical electrical field is a generic and effective way to achieve half metallicity in A-type antiferromagnetic bilayers and realize the spin field effect transistor. The electric field-induced half metallicity represents an appealing route to realize 2D half metals and opens opportunities for nanoscale highly efficient antiferromagnetic spintronics for information processing and storage.

Defects in materials give rise to fluctuations in electrostatic fields that reflect the local charge density, but imaging this with single atom sensitivity is challenging. However, if possible, this provides information about the energetics of adatom binding, localized conduction channels, molecular functionality and their relationship to individual bonds. Here, ultrastable electron-optics are combined with a high-speed 2D electron detector to map electrostatic fields around individual atoms in 2D monolayers using 4D scanning transmission electron microscopy. Simultaneous imaging of the electric field, phase, annular dark field and the total charge in 2D MoS₂ and WS₂ is demonstrated for pristine areas and regions with 1D wires. The in-gap states in sulphur line vacancies cause 1D electron-rich channels that are mapped experimentally and confirmed using density functional theory calculations. We show how electrostatic fields are sensitive in defective areas to changes of atomic bonding and structural determination beyond conventional imaging.