Integrated analysis of protein sequence and structure redefines viral diversity and the taxonomy of the Flaviviridae

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 18, 2025

Abstract The Flaviviridae are a family of non-segmented positive-sense enveloped RNA viruses containing significant pathogens including hepatitis C virus and yellow fever virus. Recent large-scale metagenomic surveys have identified many diverse related to classical orthoflaviviruses pestiviruses but quite different genome lengths configurations, with hugely expanded host range that spans multiple animal phyla, molluscs, cnidarians stramenopiles,, plants. Grouping RNA-directed polymerase (RdRP) hallmark gene sequences flavivirus ‘flavi-like’ into four divergent clades lineages within them was congruent helicase phylogeny, PPHMM profile comparisons, comparison RdRP protein structure predicted by AlphFold2. These results support their classification the established order, Amarillovirales , in three families ( Flaviviridae, Pestiviridae Hepaciviridae ), 14 genera. This taxonomic framework informed evolutionary relationships provides stable reference from which major re-organisational events can be understood.

Язык: Английский

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A Novel Heme-Degrading Enzyme that Regulates Heme and Iron Homeostasis and Promotes Virulence inEnterococcus faecalis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 20, 2025

Enterococcus faecalis , a gut commensal, is leading cause of opportunistic infections. Its virulence linked to its ability thrive in hostile environments, which includes host-imposed metal starvation. We recently showed that E. evades iron starvation using five dedicated transporters collectively scavenge from host tissues and other iron-deprived conditions. Interestingly, heme, the most abundant source human body, supported growth strain lacking all (Δ5Fe). To release many bacterial pathogens utilize heme oxygenase enzymes degrade porphyrin coordinates ion heme. Although lacks these enzymes, bioinformatics revealed potential ortholog anaerobic heme-degrading enzyme anaerobilin synthase, found Escherichia coli few Gram-negative bacteria. Here, we demonstrated deletion OG1RF_RS05575 (ΔRS05575) or Δ5Fe background (Δ5FeΔRS05575) led intracellular accumulation hypersensitivity under conditions, suggesting RS05575 encodes an first kind described Gram- positive Additionally, either alone background, impaired colonization mouse gastrointestinal tract peritonitis rabbit infective endocarditis models. These results reveal responsible for degradation identify this relatively new class as novel factor pathogenesis. Findings study are likely have broad implications, homologues Gram-positive facultative anaerobes. Heme important nutrient pathogens, mainly serve during infection. While bacteria known called oxygenases, family has been report description by bacterium, pathogen link activity their colonize infect host. also show anaerobes, implying conditions may be overlooked fitness pathogens.

Язык: Английский

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Drosophila telomeric protein Verrocchio is an ortholog of STN1

Genetica, Год журнала: 2025, Номер 153(1)

Опубликована: Янв. 22, 2025

Язык: Английский

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Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency demonstrated vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed confirmation excellent in-cell lead compound, 40, another promising analogue, 46. Evaluation the pharmacokinetic (PK) profiles these two revealed that both are well tolerated systemically orally bioavailable. Coupled its subnanomolar cellular impressive cells, long half-life 40 makes it ideal candidate evaluation consequences PIKfyve inhibition vivo. has been investigated clinically indications including rheumatoid arthritis, Crohn's disease, COVID-19, ALS using a single compound (apilimod), supporting development orthogonal inhibitors

Язык: Английский

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SUMOylation of TRIM28 is positively modulated by the BTB/POZ domain of Kaiso

Molecular Biology Reports, Год журнала: 2025, Номер 52(1)

Опубликована: Янв. 23, 2025

Язык: Английский

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Tandem repeats provide evidence for convergent evolution to similar protein structures

Genome Biology and Evolution, Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

Abstract Homology is a key concept underpinning the comparison of sequences across organisms. Sequence-level homology based on statistical framework optimized over decades work. Recently, computational protein structure prediction has enabled large-scale inference beyond limits accurate sequence alignment. In this regime it possible to observe nearly identical structures lacking detectable similarity. absence robust for comparison, largely assumed similar are homologous. However, conceivable that matching could arise through convergent evolution, resulting in analogous proteins without shared ancestry. Large databases predicted offer means determining whether analogs present among matches. Here, I find small subset (∼2.6%) Foldseek clusters lack sequence-level support homology, including ∼1% strong matches with TM-score ≥ 0.5. This result by itself does not imply these pairs non-homologous, since their have diverged recognition. Yet, enriched repeats induce spurious Some structural underpinned tandem both structures. show many repeat units genealogies inconsistent corresponding sharing common ancestor, implying highly rather than suggests caution warranted when inferring from resemblance alone homology.

Язык: Английский

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Regulating p53/PUMA pathway on Cervical Cancer C-33A and HeLa cells of Acanthus ilicifolius Linn alkaloid 2-Benzoxazolinone Derivatives

Journal of Molecular Structure, Год журнала: 2025, Номер unknown, С. 141569 - 141569

Опубликована: Янв. 1, 2025

Язык: Английский

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Exploring Marine Natural Compounds: Innovative Therapeutic Candidates Against Chagas Disease Through Virtual Screening and Molecular Dynamics

Life, Год журнала: 2025, Номер 15(2), С. 192 - 192

Опубликована: Янв. 28, 2025

Chagas disease, caused by the protozoan Trypanosoma cruzi, represents a significant public health challenge, particularly in Latin America’s endemic regions. The limited efficacy and frequent adverse effects of current treatments underscore need for novel therapeutic options. This research explores marine natural compounds as potential candidates disease treatment using virtual screening silico evaluation methods. Techniques such molecular docking, drug-likeness evaluation, pharmacokinetic analysis were employed to identify promising anti-parasitic compounds. Among candidates, chandrananimycin A, venezueline dispacamide demonstrated high binding affinities key targets T. cruzi alongside favorable docking scores compliance with essential criteria. Pharmacokinetic profiling further supported their potential, revealing desirable properties like effective absorption minimal toxicity. These findings promise marine-derived valuable source new drugs, emphasizing vitro vivo investigations elucidate mechanisms optimize development viable disease.

Язык: Английский

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Synergistic effects of distinct arabinofuranosidase specificities in lignocellulose degradation by different hemicellulases

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 140575 - 140575

Опубликована: Фев. 1, 2025

Arabinoxylan is a prevalent hemicellulose type, notably heterogeneous and resistant to biodegradation. Arabinofuranosidases (Abfs) remove arabinofuranosyl decorations of arabinoxylan, thus enabling hydrolysis by xylanases. However, variety Abf xylanase specificities have emerged in recent years, necessitating deeper understanding their role biomass degradation. This work investigates the biochemical features TtAbf43 from Thermothelomyces thermophila, which specifically removes O-3-linked arabinofuranose moieties di-substituted xylopyranoses. The enzyme also exhibited secondary hydrolytic activity on o-nitrophenyl-β-d-xylopyranoside arabinan. pretreated wheat corn bran substrates was assessed using AnAbf51, two enzymes with distinct catalytic specificities. Abfs enhanced performance endo-xylanases TmXyn10 AnXyn11, promoting release xylo-oligomers, while xylanases, turn, stimulated arabinose Abfs. Additionally, facilitated endo- exo-activities bifunctional xylobiohydrolase/glucuronoxylanase TtXyn30A for xylobiose short aldouronic acids biomass. AnAbf51 acted synergy acetyl xylan esterase OCE6 exo-deacetylase TtCE16B debranching enzymatically derived oligomers lignocellulose, whereas remained unaffected esterases. These diverse synergistic relationships among different hemicellulases could assist development new enzymatic approaches efficient valorization.

Язык: Английский

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Sweeps in space: leveraging geographic data to identify beneficial alleles inAnopheles gambiae

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 9, 2025

Abstract As organisms adapt to environmental changes, natural selection modifies the frequency of non-neutral alleles. For beneficial mutations, outcome this process may be a selective sweep, in which an allele rapidly increases and perhaps reaches fixation within population. Selective sweeps have well-studied effects on patterns local genetic variation panmictic populations, but much less is known about dynamics continuous space. In particular, because limited movement across landscape leads unique population structure, spatial influence trajectory selected mutations. Here, we use forward-in-time, individual-based simulations space study impact mutations as they sweep through show that changes joint distribution geographic range occupied by focal demonstrate signal can used identify sweeps. We then leverage in-progress malaria vector Anopheles gambiae , species under strong pressure from control measures. By considering space, multiple previously undescribed variants with potential phenotypic consequences, including im-pacting IR-associated genes altering protein structure properties. Our results novel for detecting data implications genomic surveillance understanding variation.

Язык: Английский

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