Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates.

In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.

Passive Transfer of Vaccine-Elicited Antibodies Protects against SIV in Rhesus Macaques.

Several HIV-1 and SIV vaccine candidates have shown partial protection against viral challenges in rhesus macaques. However, the protective efficacy of vaccine-elicited polyclonal antibodies has not previously been demonstrated in adoptive transfer studies in nonhuman primates. In this study, we show that passive transfer of purified antibodies from vaccinated macaques can protect naive animals against SIVmac251 challenges. We vaccinated 30 rhesus macaques with Ad26-SIV Env/Gag/Pol and SIV Env gp140 protein vaccines and assessed the induction of antibody responses and a putative protective signature. This signature included multiple antibody functions and correlated with upregulation of interferon pathways in vaccinated animals. Adoptive transfer of purified immunoglobulin G (IgG) from the vaccinated animals with the most robust protective signatures provided partial protection against SIVmac251 challenges in naive recipient rhesus macaques. These data demonstrate the protective efficacy of purified vaccine-elicited antiviral antibodies in this model, even in the absence of virus neutralization.

A Functional Role for Antibodies in Tuberculosis.

While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.

Dissecting Polyclonal Vaccine-Induced Humoral Immunity against HIV Using Systems Serology.

While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive.

Structures and mechanisms of the Arabidopsis auxin transporter PIN3.

The PIN-FORMED (PIN) protein family of auxin transporters mediates polar auxin transport and has crucial roles in plant growth and development1,2. Here we present cryo-electron microscopy structures of PIN3 from Arabidopsis thaliana in the apo state and in complex with its substrate indole-3-acetic acid and the inhibitor N-1-naphthylphthalamic acid (NPA). A. thaliana PIN3 exists as a homodimer, and its transmembrane helices 1, 2 and 7 in the scaffold domain are involved in dimerization. The dimeric PIN3 forms a large, joint extracellular-facing cavity at the dimer interface while each subunit adopts an inward-facing conformation. The structural and functional analyses, along with computational studies, reveal the structural basis for the recognition of indole-3-acetic acid and NPA and elucidate the molecular mechanism of NPA inhibition on PIN-mediated auxin transport. The PIN3 structures support an elevator-like model for the transport of auxin, whereby the transport domains undergo up-down rigid-body motions and the dimerized scaffold domains remain static.

Comparative analysis of integrative classification methods for multi-omics data.

Recent advances in sequencing, mass spectrometry, and cytometry technologies have enabled researchers to collect multiple 'omics data types from a single sample. These large datasets have led to a growing consensus that a holistic approach is needed to identify new candidate biomarkers and unveil mechanisms underlying disease etiology, a key to precision medicine. While many reviews and benchmarks have been conducted on unsupervised approaches, their supervised counterparts have received less attention in the literature and no gold standard has emerged yet. In this work, we present a thorough comparison of a selection of six methods, representative of the main families of intermediate integrative approaches (matrix factorization, multiple kernel methods, ensemble learning, and graph-based methods). As non-integrative control, random forest was performed on concatenated and separated data types. Methods were evaluated for classification performance on both simulated and real-world datasets, the latter being carefully selected to cover different medical applications (infectious diseases, oncology, and vaccines) and data modalities. A total of 15 simulation scenarios were designed from the real-world datasets to explore a large and realistic parameter space (e.g. sample size, dimensionality, class imbalance, effect size). On real data, the method comparison showed that integrative approaches performed better or equally well than their non-integrative counterpart. By contrast, DIABLO and the four random forest alternatives outperform the others across the majority of simulation scenarios. The strengths and limitations of these methods are discussed in detail as well as guidelines for future applications.

Wolbachia infection-responsive immune genes suppress Plasmodium falciparum infection in Anopheles stephensi.

Wolbachia, a maternally transmitted symbiotic bacterium of insects, can suppress a variety of human pathogens in mosquitoes, including malaria-causing Plasmodium in the Anopheles vector. However, the mechanistic basis of Wolbachia-mediated Plasmodium suppression in mosquitoes is not well understood. In this study, we compared the midgut and carcass transcriptomes of stably infected Anopheles stephensi with Wolbachia wAlbB to uninfected mosquitoes in order to discover Wolbachia infection-responsive immune genes that may play a role in Wolbachia-mediated anti-Plasmodium activity. We show that wAlbB infection upregulates 10 putative immune genes and downregulates 14 in midguts, while it upregulates 31 putative immune genes and downregulates 15 in carcasses at 24 h after blood-fed feeding, the time at which the Plasmodium ookinetes are traversing the midgut tissue. Only a few of these regulated immune genes were also significantly differentially expressed between Wolbachia-infected and non-infected midguts and carcasses of sugar-fed mosquitoes. Silencing of the Wolbachia infection-responsive immune genes TEP 4, TEP 15, lysozyme C2, CLIPB2, CLIPB4, PGRP-LD and two novel genes (a peritrophin-44-like gene and a macro domain-encoding gene) resulted in a significantly greater permissiveness to P. falciparum infection. These results indicate that Wolbachia infection modulates mosquito immunity and other processes that are likely to decrease Anopheles permissiveness to Plasmodium infection.

Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults.

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4+ T helper type 1 and effector CD8+ T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405).

Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands.

The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a 'head down, tail up' configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-ß-cyclodextrin (MßCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8-3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2.

Allosteric inhibition of NMDA receptors by low dose ketamine.

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.

Hidden Charge Order and Multiple Electronic Instabilities in EuTe4.

The rare-earth telluride compound EuTe4 exhibits a charge density wave (CDW) and an unconventional thermal hysteresis transition. Herein, we report a comprehensive study of the CDW states in EuTe4 by using low-temperature scanning tunneling microscopy. Two types of charge orders are observed at 4 K, including a newly discovered spindle-shaped pattern and a typical stripe-like pattern. As an exotic charge order, the spindle-shaped CDW is off-axis and barely visible at 77 K, indicating that it is a hidden order developed at low temperature. Based on our first-principles calculations, we reveal the origins of the observed electronic instabilities. The spindle-shaped charge order stems from a subsequent transition based on the stripe-like CDW phase. Our work demonstrates that the competition and cooperation between multiple charge orders can generate exotic quantum phases.

The deficient CLEC5A ameliorates the behavioral and pathological deficits via the microglial Aß clearance in Alzheimer's disease mouse model.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive dysfunction in older adults. One of the AD pathological factors, ß-Amyloid (Aß), triggers inflammatory responses and phagocytosis of microglia. C-type lectin domain family 5 member A (CLEC5A) induces over-reactive inflammatory responses in several virus infections. Yet, the role of CLEC5A in AD progression remains unknown. This study aimed to elucidate the contribution of CLEC5A to Aß-induced microglial activation and behavioral deficits. METHODS: The AD mouse model was crossed with Clec5a knockout mice for subsequent behavioral and pathological tests. The memory deficit was revealed by the Morris water maze, while the nociception abnormalities were examined by the von Frey filament and hotplate test. The Aß deposition and microglia recruitment were identified by ELISA and immunohistochemistry. The inflammatory signals were identified by ELISA and western blotting. In the Clec5a knockdown microglial cell model and Clec5a knockout primary microglia, the microglial phagocytosis was revealed using the fluorescent-labeled Aß. RESULTS: The AD mice with Clec5a knockout improved Aß-induced memory deficit and abnormal nociception. These mice have reduced Aß deposition and increased microglia coverage surrounding the amyloid plaque, suggesting the involvement of CLEC5A in AD progression and Aß clearance. Moreover, the phagocytosis was also increased in the Aß-stressed Clec5a knockdown microglial cell lines and Clec5a knockout primary microglia. CONCLUSION: The Clec5a knockout ameliorates AD-like deficits by modulating microglial Aß clearance. This study implies that targeting microglial Clec5a could offer a promising approach to mitigate AD progression.

Vacancy Spectroscopy of Non-Abelian Kitaev Spin Liquids.

Spin vacancies in the non-Abelian Kitaev spin liquid are known to harbor Majorana zero modes, potentially enabling topological quantum computing at elevated temperatures. Here, we study the spectroscopic signatures of such Majorana zero modes in a scanning tunneling setup where a non-Abelian Kitaev spin liquid with a finite density of spin vacancies forms a tunneling barrier between a tip and a substrate. Our key result is a well-defined peak close to zero bias voltage in the derivative of the tunneling conductance whose voltage and intensity both increase with the density of vacancies. This "quasi-zero-voltage peak" is identified as the closest analog of the zero-voltage peak observed in topological superconductors that additionally reflects the fractionalized nature of spin-liquid-based Majorana zero modes. We further highlight a single-fermion Van Hove singularity at a higher voltage that reveals the energy scale of the emergent Majorana fermions in the Kitaev spin liquid. Our proposed signatures are within reach of current experiments on the candidate material α-RuCl_{3}.

Deep-Learning Density Functional Perturbation Theory.

Calculating perturbation response properties of materials from first principles provides a vital link between theory and experiment, but is bottlenecked by the high computational cost. Here, a general framework is proposed to perform density functional perturbation theory (DFPT) calculations by neural networks, greatly improving the computational efficiency. Automatic differentiation is applied on neural networks, facilitating accurate computation of derivatives. High efficiency and good accuracy of the approach are demonstrated by studying electron-phonon coupling and related physical quantities. This work brings deep-learning density functional theory and DFPT into a unified framework, creating opportunities for developing ab initio artificial intelligence.

Ionic Hyperbranched Poly(amido-amine)-Incorporated Nanofiltration Membranes for High-Efficiency Dye Desalination.

High-efficiency dye desalination is crucial in the textile industry, considering its importance for human health, safe aquatic ecological systems, and resource recovery. In order to solve the problem of effective separation of univalent salt and ionic dye under the condition of high salt, ionic hyperbranched poly(amido-amine) (HBPs) were synthesized based on a simple and scalable one-step polycondensation method and then incorporated into the polyamide (PA) selective layers to construct charged nanochannels through interfacial polymerization (IP) on the surface of a polyvinyl chloride ultrafiltration (PVC-UF) hollow fiber membrane. Both the internal nanopores of HBPs (internal nanochannels) and the interfacial voids between HBPs and the PA matrix (external nanochannels) can be regarded as a fast water molecule transport pathway, while the terminal ionic groups of ionic HBPs endow the nanochannels with charge characteristics for improving ionic dye/salt selectivities. The permeate fluxes and dye/salt selectivities of HBP-TAC/PIP (57.3 L m-2 h-1 and rhodamine B (RB)/NaCl selectivity of 224.0) and HBP-PS/PIP (63.7 L m-2 h-1 and lemon yellow (LY)/NaCl selectivity of 664.0) membranes under 0.4 MPa operation pressure are much higher than PIP-only and HBP-NH2/PIP membranes. At the same time, this project also studied the membrane desalination process in a simulated high-salinity dye/salt mixture system to provide a theoretical basis and technical support for the actual dye desalination process.

Gene signature discovery and systematic validation across diverse clinical cohorts for TB prognosis and response to treatment.

While blood gene signatures have shown promise in tuberculosis (TB) diagnosis and treatment monitoring, most signatures derived from a single cohort may be insufficient to capture TB heterogeneity in populations and individuals. Here we report a new generalized approach combining a network-based meta-analysis with machine-learning modeling to leverage the power of heterogeneity among studies. The transcriptome datasets from 57 studies (37 TB and 20 viral infections) across demographics and TB disease states were used for gene signature discovery and model training and validation. The network-based meta-analysis identified a common 45-gene signature specific to active TB disease across studies. Two optimized random forest regression models, using the full or partial 45-gene signature, were then established to model the continuum from Mycobacterium tuberculosis infection to disease and treatment response. In model validation, using pooled multi-cohort datasets to mimic the real-world setting, the model provides robust predictive performance for incipient to active TB risk over a 2.5-year period with an AUROC of 0.85, 74.2% sensitivity, and 78.3% specificity, which approximates the minimum criteria (>75% sensitivity and >75% specificity) within the WHO target product profile for prediction of progression to TB. Moreover, the model strongly discriminates active TB from viral infection (AUROC 0.93, 95% CI 0.91-0.94). For treatment monitoring, the TB scores generated by the model statistically correlate with treatment responses over time and were predictive, even before treatment initiation, of standard treatment clinical outcomes. We demonstrate an end-to-end gene signature model development scheme that considers heterogeneity for TB risk estimation and treatment monitoring.

Methylomonas defluvii sp. nov., a type I methane-oxidizing bacterium from a secondary sedimentation tank of a wastewater treatment plant.

An aerobic methanotroph was isolated from a secondary sedimentation tank of a wastewater treatment plant and designated strain OY6T. Cells of OY6T were Gram-stain-negative, pink-pigmented, motile rods and contained an intracytoplasmic membrane structure typical of type I methanotrophs. OY6T could grow at a pH range of 4.5-7.5 (optimum pH 6.5) and at temperatures ranging from 20 °C to 37 °C (optimum 30 °C). The major cellular fatty acids were C14 : 0, C16 : 1ω7c/C16 : 1ω6c and C16 : 1ω5c; the predominant respiratory quinone was MQ-8. The genome size was 5.41 Mbp with a DNA G+C content of 51.7 mol%. OY6T represents a member of the family Methylococcaceae of the class Gammaproteobacteria and displayed 95.74-99.64 % 16S rRNA gene sequence similarity to the type strains of species of the genus Methylomonas. Whole-genome comparisons based on average nucleotide identity (ANI) and digital DNA-DNA hybridisation (dDDH) confirmed that OY6T should be classified as representing a novel species. The most closely related type strain was Methylomonas fluvii EbBT, with 16S rRNA gene sequence similarity, ANI by blast (ANIb), ANI by MUMmer (ANIm) and dDDH values of 99.64, 90.46, 91.92 and 44.5 %, respectively. OY6T possessed genes encoding both the particulate methane monooxygenase enzyme and the soluble methane monooxygenase enzyme. It grew only on methane or methanol as carbon sources. On the basis of phenotypic, genetic and phylogenetic data, strain OY6T represents a novel species within the genus Methylomonas for which the name Methylomonas defluvii sp. nov. is proposed, with strain OY6T (=GDMCC 1.4114T=KCTC 8159T=LMG 33371T) as the type strain.

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Impact of the pulmonary ventilation function on the prognosis of suspected asthma patients: a retrospective observational study.

OBJECTIVE: Asthma is a common chronic respiratory diseases, and the relationship between pulmonary ventilation function and the prognosis of patients with suspected asthma is not well understood. This study aims to explore the impact of pulmonary ventilation functions on the prognosis of patients with suspected asthma. METHODS: This retrospective observational study included patients with suspected asthma who were diagnosed and treated at the Guangdong Provincial Hospital of Traditional Chinese Medicine between August 2015 and January 2020. The primary outcome of interest was improvement in asthma symptoms, as measured by bronchial provocation test (BPT) results within one year after diagnosis. The impact of pulmonary ventilation functions on prognosis was explored by multivariable logistic regression analysis. RESULTS: Seventy-two patients were included in the study. Patients with normal (OR = 0.123, p = .004) or generally normal (OR = 0.075, p = .039) pulmonary ventilation function were more likely to achieve improvement in asthma symptoms compared with patients with mild obstruction. There were no significant differences between the improvement and non-improvement groups in baseline characteristics. CONCLUSION: These results suggest that suspected asthma patients with normal or generally normal pulmonary ventilation function are more likely to achieve improvement in asthma symptoms within one year compared to patients with mild obstruction.

Publisher Correction: Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys.

In Fig. 4b of this Article, the x-axis labels 'PGT121' and 'GS-9620' were inadvertently swapped in both graphs. In Fig. 5a, b, 'TLR7' should have been 'GS-9620'. These figures have been corrected online.