Atomic structures of a bacteriocin targeting Gram-positive bacteria.

Due to envelope differences between Gram-positive and Gram-negative bacteria, engineering precision bactericidal contractile nanomachines requires atomic-level understanding of their structures; however, only those killing Gram-negative bacteria are currently known. Here, we report the atomic structures of an engineered diffocin, a contractile syringe-like molecular machine that kills the Gram-positive bacterium Clostridioides difficile. Captured in one pre-contraction and two post-contraction states, each structure fashions six proteins in the bacteria-targeting baseplate, two proteins in the energy-storing trunk, and a collar linking the sheath with the membrane-penetrating tube.

Redisposition of acremonium-like fungi in .

is acknowledged as a highly ubiquitous genus including saprobic, parasitic, or endophytic fungi that inhabit a variety of environments. Species of this genus are extensively exploited in industrial, commercial, pharmaceutical, and biocontrol applications, and proved to be a rich source of novel and bioactive secondary metabolites. has been recognised as a taxonomically difficult group of ascomycetes, due to the reduced and high plasticity of morphological characters, wide ecological distribution and substrate range.

Hearing Impairment and Physical Activity and Physical Functioning in Older Adults: Baseline Results From the ACHIEVE Trial.

Background: Hearing loss is associated with restricted physical activity (PA) and impaired physical functioning, yet the relationship between severity of hearing impairment (HI) and novel PA measures in older adults with untreated HI is not well understood.

Methods: Analyses included 845 participants aged ≥70 years (mean = 76.6 years) with a better-hearing ear pure-tone average (PTA) ≥30 and <70 dB in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study who wore an ActiGraph accelerometer for 7 days.

Atomic structures of a bacteriocin targeting Gram-positive bacteria.

Due to envelope differences between Gram-positive and Gram-negative bacteria, engineering precision bactericidal contractile nanomachines requires atomic-level understanding of their structures; however, only those killing a Gram-negative bacterium are currently known. Here, we report the atomic structures of an engineered diffocin, a contractile syringe-like molecular machine that kills the Gram-positive bacterium . Captured in one pre-contraction and two post-contraction states, each structure fashions six proteins in the bacteria-targeting baseplate, two proteins in the energy-storing trunk, and a collar protein linking the sheath with the membrane-penetrating tube.

Keystone taxa enhance the stability of soil bacterial communities and multifunctionality under steelworks disturbance.

Continuous discharge of wastewater, emissions, and solid wastes from steelworks poses environmental risks to ecosystems. However, the role of keystone taxa in maintaining multifunctional stability during environmental disturbances remains poorly understood. To address this, we investigated the community diversity, assembly mechanisms, and soil multifunctionality of soils collected from within the steelworks (I), within 2.

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin.

Two-photon synthetic aperture microscopy for minimally invasive fast 3D imaging of native subcellular behaviors in deep tissue.

Holistic understanding of physio-pathological processes requires noninvasive 3D imaging in deep tissue across multiple spatial and temporal scales to link diverse transient subcellular behaviors with long-term physiogenesis. Despite broad applications of two-photon microscopy (TPM), there remains an inevitable tradeoff among spatiotemporal resolution, imaging volumes, and durations due to the point-scanning scheme, accumulated phototoxicity, and optical aberrations. Here, we harnessed the concept of synthetic aperture radar in TPM to achieve aberration-corrected 3D imaging of subcellular dynamics at a millisecond scale for over 100,000 large volumes in deep tissue, with three orders of magnitude reduction in photobleaching.

Intranasal Boosting with Spike Fc-RBD of Wild-Type SARS-CoV-2 Induces Neutralizing Antibodies against Omicron Subvariants and Reduces Viral Load in the Nasal Turbinate of Mice.

The emergence of new immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and subvariants outpaces the development of vaccines specific against the dominant circulating strains. In terms of the only accepted immune correlate of protection, the inactivated whole-virion vaccine using wild-type SARS-CoV-2 spike induces a much lower serum neutralizing antibody titre against the Omicron subvariants. Since the inactivated vaccine given intramuscularly is one of the most commonly used coronavirus disease 2019 (COVID-19) vaccines in developing regions, we tested the hypothesis that intranasal boosting after intramuscular priming would provide a broader level of protection.

COVID-19 mRNA vaccine protects against SARS-CoV-2 Omicron BA.1 infection in diet-induced obese mice through boosting host innate antiviral responses.

Background: Obesity is a worldwide epidemic and is considered a risk factor of severe manifestation of Coronavirus Disease 2019 (COVID-19). The pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host responses to infection, re-infection, and vaccination in individuals with obesity remain incompletely understood.

Methods: Using the diet-induced obese (DIO) mouse model, we studied SARS-CoV-2 Alpha- and Omicron BA.

Trial of Endovascular Thrombectomy for Large Ischemic Strokes.

Background: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations.

Methods: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging.

A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo.

"Pan-coronavirus" antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo.

Cost-Effectiveness of Intensive Versus Standard Blood Pressure Treatment in Older Patients With Hypertension in China.

Background: In the STEP trial (Strategy of Blood Pressure Intervention in older Hypertensive Patients), the risk of cardiovascular events is significantly lower in patients who received intensive systolic blood psressure (BP) treatment than in those who received standard treatment. This study compared the lifetime health benefits and medical costs of intensive BP treatment with those of standard BP treatment.

Methods: A microsimulation model included 10 000 hypothetical samples of Chinese adults aged 60 to 80 years old with baseline systolic BP higher than 140 mm Hg.

Vemurafenib Inhibits Enterovirus A71 Genome Replication and Virus Assembly.

Enterovirus A71 (EV-A71) infection is a major cause of hand, foot, and mouth disease (HFMD), which may be occasionally associated with severe neurological complications. There is currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its critical importance in the regulation of cell growth, differentiation, and survival, has been shown to be essential for virus replication.

Targeting ACLY efficiently inhibits SARS-CoV-2 replication.

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets.

Climate and health: An evolving relationship.

Understanding and addressing the complex effects of climate change on planetary health requires a multidisciplinary approach. Here, experts share their experience working at the intersection of health and climate. Their Voices advocate for cooperation, rethinking the concept of sustainability,and urge for immediate action to preserve global health.

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

Background: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings.

Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection.

hnRNP C modulates MERS-CoV and SARS-CoV-2 replication by governing the expression of a subset of circRNAs and cognitive mRNAs.

Host circular RNAs (circRNAs) play critical roles in the pathogenesis of viral infections. However, how viruses modulate the biogenesis of host proviral circRNAs to facilitate their replication remains unclear. We have recently shown that Middle East respiratory syndrome coronavirus (MERS-CoV) infection increases co-expression of circRNAs and their cognate messenger RNAs (mRNAs), possibly by hijacking specific host RNA binding proteins (RBPs).

SARS-CoV-2 exploits host DGAT and ADRP for efficient replication.

Coronavirus Disease 2019 (COVID-19) is predominantly a respiratory tract infection that significantly rewires the host metabolism. Here, we monitored a cohort of COVID-19 patients' plasma lipidome over the disease course and identified triacylglycerol (TG) as the dominant lipid class present in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced metabolic dysregulation. In particular, we pinpointed the lipid droplet (LD)-formation enzyme diacylglycerol acyltransferase (DGAT) and the LD stabilizer adipocyte differentiation-related protein (ADRP) to be essential host factors for SARS-CoV-2 replication.

In Silico Structure-Based Design of Antiviral Peptides Targeting the Severe Fever with Thrombocytopenia Syndrome Virus Glycoprotein Gn.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target.

Iterative tomography with digital adaptive optics permits hour-long intravital observation of 3D subcellular dynamics at millisecond scale.

Long-term subcellular intravital imaging in mammals is vital to study diverse intercellular behaviors and organelle functions during native physiological processes. However, optical heterogeneity, tissue opacity, and phototoxicity pose great challenges. Here, we propose a computational imaging framework, termed digital adaptive optics scanning light-field mutual iterative tomography (DAOSLIMIT), featuring high-speed, high-resolution 3D imaging, tiled wavefront correction, and low phototoxicity with a compact system.

Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line-HK-2-that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screen and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection.

Beneficial effect of combinational methylprednisolone and remdesivir in hamster model of SARS-CoV-2 infection.

Effective treatments for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Dexamethasone has been shown to confer survival benefits to certain groups of hospitalized patients, but whether glucocorticoids such as dexamethasone and methylprednisolone should be used together with antivirals to prevent a boost of SARS-CoV-2 replication remains to be determined. Here, we show the beneficial effect of methylprednisolone alone and in combination with remdesivir in the hamster model of SARS-CoV-2 infection.

Oral SARS-CoV-2 Inoculation Establishes Subclinical Respiratory Infection with Virus Shedding in Golden Syrian Hamsters.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is transmitted largely by respiratory droplets or airborne aerosols. Despite being frequently found in the immediate environment and feces of patients, evidence supporting the oral acquisition of SARS-CoV-2 is unavailable. Using the Syrian hamster model, we demonstrate that the severity of pneumonia induced by the intranasal inhalation of SARS-CoV-2 increases with virus inoculum.