Genomic epidemiology of clade Ia monkeypox viruses circulating in the Central African Republic in 2022-24: a retrospective cross-sectional study.

Background: The spread of monkeypox virus (Orthopoxvirus monkeypox) clade Ib from the Democratic Republic of the Congo to neighbouring countries has raised global concerns, leading to WHO declaring mpox a public health emergency on Aug 14, 2024. We applied genomic epidemiology to investigate the causes of recurrent mpox outbreaks in the Central African Republic. We aimed to determine whether frequent zoonotic spillovers or increased human-to-human transmissions are driving mpox epidemiology.

Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics. Our endeavor involved the implementation of a bioisosterism strategy, leading to the discovery of an assemblage of halogen-containing biphenyl-diarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Notably, compound demonstrated exceptional efficacy against both WT HIV-1 (EC = 1.

Design, synthesis, and biological evaluation of dual-site HIV-1 inhibitors simultaneously targeting the NNRTI binding pocket and an adjacent site with favorable resistance profiles.

Given high mutation rate of HIV-1 and its impact on NNRTIs' efficacy, targeting novel binding pockets has emerged as a viable strategy to overcome the drug resistance. In this study, we designed and synthesized 26 novel "dual-site" HIV-1 inhibitors that simultaneously target two distinct sites on reverse transcriptase (RT): the classical non-nucleoside inhibitor binding pocket (NNIBP) and a newly identified NNRTIs-adjacent site (NNIAS). Antiviral evaluation demonstrated that all compounds possessed potent activity against the wild-type (WT) HIV-1 strain, with EC values ranging from 4.

South-to-Southeast Expansion of HIV-1 Subtype C in Brazil.

HIV-1 group M subtype C (HIV-1C) is the predominant genetic variant in southern Brazil but has been sparsely detected in other regions of the country. Our study aimed to identify HIV-1C transmission links across Brazil using phylogenetic reconstruction and to infer trends in geographical patterns and dissemination beyond the southern region. We retrieved 3693 HIV-1C (partial pol) sequences from NCBI and LANL databases and applied maximum likelihood phylogenetic reconstruction to infer transmission clusters, using clade confidence (SH-aLRT) and intracluster genetic distance as critical parameters.

-[(Thiophen-3-yl)methyl]benzamides as Fusion Inhibitors of Influenza Virus Targeting H1 and H5 Hemagglutinins.

Novel antiviral drugs are needed to prepare for infections from influenza A virus (IAV). Here, a series of -[(thiophen-3-yl)methyl]benzamides, which target the hemagglutinin (HA)-mediated fusion process, is reported. The most active compound, , displays a 50% effective concentration (EC) of ∼0.

Genomic characterization and serotype distribution of dengue virus circulating in Pakistan during 2024.

Dengue virus (DENV) remains a significant public health concern in Pakistan, with recurrent outbreaks necessitating continuous genomic surveillance. The 2024 dengue outbreak prompted an investigation into circulating serotypes and genomic diversity. The National Institute of Health (NIH), Pakistan, received 524 NS-1 confirmed dengue samples across multiple districts in 2024.

The multifaceted role of the viral 2A protease in enterovirus replication and antagonism of host antiviral responses.

Enteroviruses dramatically remodel the cellular infrastructure for efficient replication and curtailing host antiviral responses. The roles of viral proteins in these processes have been studied mostly in vitro, by ectopic overexpression, or by surrogate infection systems, all of which have shortcomings. Here, we replace the essential 2A cleavage site at the P1-P2 junction with an internal ribosome entry site (IRES), 3CD cleavage site, or T2A sequence, allowing us to catalytically inactivate 2Apro in the virus context.

Extensive cross-species transmission of pathogens and antibiotic resistance genes in mammals neglected by public health surveillance.

Non-traditional farmed and wild mammals are often neglected in pathogen surveillance. Through metagenomic and metatranscriptomic sequencing of fecal and tissue samples from 973 asymptomatic mammals, we identified 128 viruses (30 novel), including a new coronavirus genus, 10,255 bacterial species (over 7,000 undescribed), 201 fungi, and 7 parasites. Farmed and wild mammals shared 13.

Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers.

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic.

Recent advances in the inference of deep viral evolutionary history.

The rapid rate of virus evolution, while useful for outbreak investigations, poses a challenge for accurately estimating long-term viral evolutionary divergence and leaves us with little genomic traces at deep evolutionary timescales, complicating the reconstruction of deep virus evolutionary history. Recent advancements in protein structure prediction and computational biology have opened up new avenues and enabled us to peer back further in time and with greater clarity than ever before. Here, we review recent approaches to reconstructing the deep evolutionary history of viruses.

Emergence of Antiviral Drug Resistance in Congenital Cytomegalovirus Infection During Treatment: An Updated Review of Literature and Case Report.

Background: Congenital cytomegalovirus (cCMV) is the most common congenital infection worldwide and a major cause of sensorineural hearing loss. A limited number of infants present with severe symptoms, including end-organ disease, developmental delay and neurologic sequelae. Infants with severe cCMV benefit from 6 months of valganciclovir (VGCV) therapy.

Effect of five dietary emulsifiers on inflammation, permeability, and the gut microbiome: a placebo-controlled randomized trial.

Background And Aims: Dietary emulsifier consumption might promote intestinal inflammation, eventually leading to inflammatory bowel diseases. However human data are scarce and involve a limited number of emulsifiers. We studied the effects of an emulsifier-free diet (EFD) and specific emulsifier supplementation.

Antiviral activities of phenylalanine derivatives carrying carboxylic acid bioisosteres against chikungunya and parainfluenza virus type 3.

Pathogenic RNA viruses from various virus families represent substantial public health hazards. Specific antiviral drugs effective against most RNA virus infections have not yet been developed. In this study, it was aimed to investigate the broad-spectrum antiviral activities of phenylalanine derivatives designed by replacing the carboxylic acid moiety with various bioisosteres such as nitrile, hydroxamidine and 5-oxo/thioxo-1,2,4-oxadiazole.

Real-world outcomes in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia treated with ponatinib - final 6-year results from a Belgian registry.

Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in patients who fail or are intolerant to a second generation TKI or who carry the mutation.

Method: This is the final analysis of the Belgian ponatinib registry evaluating use of ponatinib in clinical practice, with data available for up to 6 years after reimbursement.

Result: Forty-eight percent of 54 CML and 28% of 29 Ph+ ALL patients had received ≥3 previous TKIs.

Halogenation-Driven Discovery of Halomethylene-Biphenyl-Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Improved Safety and PK Profiles.

To improve the safety and PK profiles of our previously established ()-, a series of halomethylene-linked biphenyl-DAPYs were developed. Enantioselectivity studies of the most promising suggested that the ()-enantiomer was more potent than its ()-counterpart and racemate. The optimal ()- exhibited remarkable antiviral activity toward wild-type HIV-1 and single mutant strains (EC = 3.

Discovery of antivirally active inhibitors of adaptor protein-2 associated kinase 1 based on various bicyclic heteroaromatic scaffolds derived from a 7-azaindole analogue.

Adaptor protein-2 associated kinase 1 (AAK1) has been proposed as a promising host target for the development of broad-spectrum antiviral agents. Different regioisomers, as well as scaffolds that were not explored before for their AAK1 affinity, were prepared that were derived from a known and potent 7-azaindole-based AAK1 inhibitor. This effort led to the discovery of various pyrrolo[2,3-b]pyridines, pyrazolo[3,4-b]pyridines and pyrazolo[3,4-d]pyrimidines with low nanomolar AAK1 binding affinity.

Infinite Mixture Models for Improved Modeling of Across-Site Evolutionary Variation.

Scientific studies in many areas of biology routinely employ evolutionary analyses based on inference of phylogenetic trees from molecular sequence data. Evolutionary processes that act at the molecular level are highly variable, and properly accounting for heterogeneity is crucial for more accurate phylogenetic inference. Nucleotide substitution rates and patterns are known to vary among sites in multiple sequence alignments, and such variation can be modeled by partitioning alignments into categories corresponding to different substitution models.

Phosphatidylethanolamine is a phagocytic ligand implicated in the binding and removal of apoptotic and bacterial extracellular vesicles.

The efficient recognition and removal of apoptotic cells and extracellular vesicles (EVs) by phagocytes is critical to prevent secondary necrosis and maintain tissue homeostasis. Such detection involves receptors and bridging molecules that recognize aminophospholipids-normally restricted to the inner leaflet of healthy cells-which become exposed on the surface of dead cells and the vesicles they produce. A majority of studies focus on phosphatidylserine (PS), for which there are well-established receptors that either bind to the lipid directly or indirectly via intermediary proteins.

An Inflammation-Associated Control Mechanism of Allergy by Proteolysis of IgE.

Background: Adaptive IgE-mediated reactions are faster than immune responses that depend on IgM, IgA, and IgG. Normal serum IgE concentrations are highly variable among individuals and extremely low in comparison with those of IgM and IgG. Omalizumab is a clinically approved monoclonal antibody that selectively binds free IgE, preventing allergy-specific IgE from binding to FcεRI expressed on mast cells and basophils, thereby inhibiting degranulation and mediator release.

Effect of whole meal yeast-leavened, sourdough-leavened and yeast-sourdough-leavened bread consumption on appetite, energy intake, and postprandial metabolic responses: A randomized, blinded, cross-over study.

Bread is a major source of carbohydrates in Europe, and whole meal varieties may offer better metabolic responses and increased satiety than white bread. We compared the effects of three types of whole meal bread: whole meal yeast bread (WYB), whole meal sourdough bread (WSB), and whole meal sourdough and yeast bread (WSYB), on appetite regulation and metabolic outcomes in healthy subjects. The sourdough contained Fructilactobacillus sanfranciscensis and Maudiozyma humilis, and the process time depended on the leavening agent.

Structure-Based Drug Design Yields Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with as the lead. All designed compounds demonstrate potent antiviral activity against the HIV-1 wild-type (WT) strain (EC = 3.

Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition.

Extracellular vesicles (EVs) are known to facilitate infection by enveloped RNA viruses including the Human T-cell leukemia virus type-1 (HTLV-1). HTLV-1-encoded proteins, like the transactivator and oncoprotein Tax-1, are loaded into EVs but their precise impact on EV cargos is not yet known. Here, we report a comprehensive interaction map between Tax-1 and the human PDZ (PSD95/DLG/ZO-1) proteins that regulate EVs formation and composition.

Synthesis, Antiproliferative Activity, ADME Profiling, and Docking Studies of Novel 1, 2, 3-Triazole Derivatives of 2-Amino and 2-Mercaptobenzoxazole.

Introduction: Benzoxazole is a privileged scaffold with diverse biological activities, and its hybridization with a 1,2,3-triazole ring can improve affinity and efficacy. This study aimed to synthesize novel 1,2,3-triazole derivatives of 2-aminobenzoxazole and 2-mercaptobenzoxazole, and to evaluate their antiproliferative activity, predicted pharmacokinetic properties, and molecular interactions with kinase targets.

Methods: 1,2,3-triazole derivatives of 2-aminobenzoxazole 3-15 and 2-mercaptobenzoxazole 18-32 were synthesized via cyclization, propargylation, and copper-catalyzed click reaction.

A pan-respiratory virus attachment inhibitor with high potency in human airway models and in vivo.

Respiratory viruses can cause severe infections, often leading to hospitalization or death, and pose a major pandemic threat. No broad-spectrum antiviral is currently available. However, most respiratory viruses use sialic acid or heparan sulfates as attachment receptors.

A key role of the PGC-1α/ERR-α pathway in regulation of angiogenic factors in proliferative diabetic retinopathy.

Background: PGC-1α is induced by hypoxia and interacts with the receptor ERR-α to stimulate angiogenic factors expression and promote angiogenesis. We investigated the possible role of the PGC-1α/ERR-α pathway in regulating angiogenic factors expression in proliferative diabetic retinopathy (PDR).

Methods: We analysed vitreous fluid samples from PDR and non-diabetic patients and epiretinal fibrovascular membranes from PDR patients.