bluuebunny/crossref_metadata_2025_split huggingface dataset:
YTHDF1 and YTHDC1 m
6
A reader proteins regulate HTLV-1
tax
and
hbz
activity
Authors: King Emily M. , Midkiff Amanda , McClain Karsyn , Kim Sanggu , Panfil Amanda R. 
Published: February 2025

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Post-transcriptional chemical modification of RNA is common in eukaryotes, with N
6
-methyladenosine (m
6
A) being the most prevalent. In this study, we investigated the role of m
6
A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped the sites of m
6
A modification to the 3’ end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcripts
tax
and
hbz
, contained m
6
A modifications. m
6
A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (
Tax, Gag,
and
Env
) and increased antisense-derived
Hbz
expression.
Tax
and
hbz
transcripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found that YTHDF1 had opposing effects on viral gene expression, decreasing sense-derived viral genes and increasing antisense-derived
Hbz
. Upon further study, the YTHDF1 effects on
tax
abundance were dependent on
tax
m
6
A deposition. The nuclear m
6
A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export of
tax
transcript. Collectively, our results demonstrate global m
6
A levels and m
6
A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression.

IMPORTANCE

Human T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications that impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m
6
A) RNA chemical modifications on HTLV-1 gene expression. We found that reductions in global m
6
A levels affected viral gene expression, decreasing
Tax
and other sense-derived viral genes, whereas increasing the antisense-derived
Hbz
. Our results suggest the oncogenic viral transcripts,
tax
and
hbz
, are m
6
A-modified in cells. We found that these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated diseases.
Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development
Authors: Kuhn Ariel J. , Outlaw Victor K. , Marcink Tara C. , Yu Zhen , Mears Megan C. , Cajimat Maria N. , Kreitler Dale F. , Cleven Payton R. , Mook Jee Ching , Bente Dennis A. , Porotto Matteo , Gellman Samuel H. , Moscona Anne 
Published: February 2025

ABSTRACT

SARS-CoV-2 poses an ongoing threat to human health as variants continue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of “breakthrough” infections (i.e.
,
infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both
in vitro
and
in vivo
. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors.

IMPORTANCE
Despite the existence of vaccines for SARS-CoV-2, the constant evolution of new variants and the occurrence of breakthrough infections highlight the need for new and effective antiviral approaches. We have shown that lipopeptides designed to bind a conserved region on the SARS-CoV-2 spike protein can effectively block viral entry into cells and thereby block infection. To support the feasibility of using this approach in humans, we re-designed these lipopeptides to be more soluble, using information about the structure of the spike protein interacting with the peptides to modify the peptide chain. The new peptides are effective against both SARS-CoV-2 and MERS. The lipopeptides described here could serve as treatment for people who are unvaccinated or who experience breakthrough infections, and the approach to increasing solubility can be applied in a broad spectrum approach to treating infections with emerging viruses.
MeJA inhibits fungal growth and DON toxin production by interfering with the cAMP-PKA signaling pathway in the wheat scab fungus
Fusarium graminearum
Authors: Duan Kaili , Qin Shaozhe , Cui Fangling , Zhao Liangyuan , Huang Yongqing , Xu Jin-Rong , Wang Guanghui 
Published: February 2025

ABSTRACT

Deoxynivalenol (DON), a mycotoxin primarily produced by
Fusarium
species, is commonly found in cereal grains and poses risks to human and animal health, as well as global grain trade. This study demonstrates that methyl jasmonate (MeJA), a natural plant hormone, inhibits the growth and conidiation of
Fusarium graminearum
. Importantly, MeJA significantly reduces DON production by suppressing
TRI
gene expression and toxisome formation. To explore the molecular mechanism, we identified MeJA-tolerant mutants, including a transcription factor
MRT1
and cAMP-PKA pathway-related genes (
FgGPA1
and
FgSNT1
). MeJA treatment reduced PKA activity and intracellular cAMP levels in
F. graminearum
, suggesting it targets the cAMP-PKA pathway. Notably, the MeJA-resistant mutant
FgGPA1
R178H
enhanced fungal growth, DON production, and cAMP levels in the presence of MeJA. Exogenous cAMP alleviated MeJA’s inhibitory effects on DON production, further supporting this pathway’s involvement. Interestingly, MeJA had no effect on all three MAP kinase pathways (Mgv1, Gpmk1, and FgHog1). Truncated and phospho-mimicking mutations in Mrt1 or FgSnt1 conferred MeJA resistance, suggesting they may act downstream of the cAMP-PKA pathway. In conclusion, MeJA presents a promising approach to control
F. graminearum
growth and DON production.

IMPORTANCE

Deoxynivalenol (DON) poses significant risks to both human and animal health and severely disrupts the global grain trade due to its prevalence as a common contaminant in wheat grains. With rising public concern over food safety, finding effective and sustainable methods to reduce DON contamination becomes increasingly urgent. In our study, we found that methyl jasmonate (MeJA), a natural plant hormone, can effectively inhibit the vegetative growth of
F. graminearum
and significantly reduce its DON toxin production. To explore the underlying molecular mechanism, we identified the mutations in MeJA-tolerant mutants and revealed that MeJA effectively exerts its antifungal activities by inhibiting the cAMP-PKA signaling pathway in
F. graminearum
. Our work provides a promising natural solution to reduce DON toxin contamination in cereal grains, enhancing food safety while decreasing the reliance on chemical fungicides and their associated environmental impact.
Industrialization drives the gut microbiome and resistome of the Chinese populations
Authors: Tian Chen , Zhang Tongzuo , Zhuang Daohua , Luo Yu , Li Teng , Zhao Fangfang , Sang Jianan , Tang Zecheng , Jiang Peicheng , Zhang Tao , Liu Pengfei , Zhu Lei , Zhang Zhigang 
Published: February 2025

ABSTRACT

Industrialization has driven lifestyle changes in eastern and western Chinese populations, yet we have a poor understanding of the dynamic changes in their gut microbiome and resistome under industrialization, which is essential for the scientific management of public health. Here, this study employed metagenomics to analyze the gut microbiota of 1,382 healthy individuals from China, including 415 individuals from the eastern region of advanced industrialization and 967 individuals from the western region of developing industrialization. Compared with western populations, eastern populations show a significant increase in interindividual dissimilarity of microbial species composition and metabolic pathways but a significant decrease in intraindividual species and functional diversity. Furthermore, our results found significantly less abundance and richness of antibiotic resistance genes (ARGs) in the gut microbiota of eastern populations, alongside a lower prevalence of unique core ARG subtypes. For the 12 core ARG types shared between eastern and western populations, the mean relative abundance of two types was notably higher in the eastern populations, while eight core ARG types had significantly higher mean relative abundance in the western populations. Based on the reconstruction of metagenomic assembled genomes, we found that
Escherichia coli
genomes from western populations carried more virulence factor genes (VFGs) and mobile genetic elements (MGEs) compared to those from eastern populations. This large-scale study for the first time revealed industrialization potentially led to unexpected alterations of the gut microbiome and resistome between eastern and western populations that provide a vital implication for Chinese public health and may aid in the development of region-specific strategies for managing pathogenic infections.

IMPORTANCE
As China experiences rapid but uneven industrialization, understanding its effect on people’s gut bacteria is critical for public health. This study reveals how industrialization may reshape the health risks related to gut bacteria and antibiotic resistance. This work provides crucial information to help create customized public health policies for different regions.
Resilience of human gut microbiomes in autism spectrum disorder: measured using stiffness network analysis
Authors: Chen Hongju (Daisy) , Yi Bin , Ma Zhanshan (Sam) 
Published: February 2025

ABSTRACT

Autism spectrum disorder (ASD) affects an estimated 1%–2% of children worldwide, but its specific etiology remains unclear. In recent years, the gut microbiome’s role in ASD pathogenesis has garnered increasing attention. However, the exact relationship between microbiota and ASD—such as which microbial species significantly impact disease onset and progression—remains unresolved, and effective methods to measure microbial interactions are still lacking. In this study, we introduce an innovative stiffness network analysis (SNA) method to quantify changes in microbial network structure and identify disease-specific microbial bacteria theoretically. The SNA method was applied to reanalyze eight ASD gut microbiome data sets, encompassing 898 ASD samples and 467 healthy control (HC) samples from 16S-rRNA sequencing data. Key findings include the following: (i) an “allies” biomarker subgroup consisting of
Bacteroides plebeius
,
Sutterella
,
Lachnospira
, and
Prevotella copri
was identified; (ii) a profile monitoring score of 0.72 for the biomarker subgroup, indicating significant relationship changes between HC and ASD states, and (iii) a P/N ratio of biomarker subgroup in ASD-associated gut bacteria that was three times higher than that of HC microbiomes. Additionally, we discuss the non-monotonic relationship alterations within microbial sub-communities in the ASD gut microbiome.

IMPORTANCE
It is crucial to assess alterations in network structure in different biological states in order to promote health. The stiffness network allows for the exploration of species interactions and the measurement of resilience in complex microbial networks. The objective of this study was to develop a stiffness network analysis (SNA) method for evaluating the contribution of microbial bacteria in differentiating disease samples from healthy control samples by examining changes in network stiffness parameters. Furthermore, the SNA method was employed on both simulated and real autism spectrum disorder gut microbiome data sets to identify potential microbial biomarker subgroups, with a particular focus on the relationship alterations within microbial networks.
Soil microbial communities in dry and moist tropical forests exhibit distinct shifts in community composition but not diversity with succession
Authors: Saltonstall Kristin , van Breugel Michiel , Navia Wayra , Castillo Hilda , Hall Jefferson S. 
Published: February 2025

ABSTRACT

Soil microbial communities are integral to ecosystem function but our understanding of how they respond to secondary succession in fragmented landscapes is limited, particularly in tropical dry forests. We used DNA metabarcoding to evaluate successional changes in soil bacteria and fungi, comparing land managed for cattle, young, and older secondary forests at moist and dry sites in the Republic of Panama. We highlight key functional groups of microbes that interact with plants, including arbuscular mycorrhizal fungi (AMF), nitrogen-fixing bacteria, and plant pathogenic fungi. Plant diversity was higher at the moist site and increased with succession as the plant communities changed at both sites. By contrast, bacterial diversity was similar across sites and successional stages, and while overall fungal diversity was higher at the moist site, it also showed no changes with succession at either site. However, microbial community composition did change, with pastures and older forests having distinct bacterial and fungal communities and young secondary forests often displaying transitional ones. Functional groups of microbes showed contrasting patterns between sites, with the dry forest having a higher diversity of Nitrogen-fixing bacteria despite lower densities of legumes, higher diversity and different communities of AMF, and a much lower incidence of putative fungal plant pathogens than the moist site. Our findings highlight the importance of looking at aboveground and belowground effects together and demonstrate that predictions generated for soil microbes in moist tropical forests may not apply to dry forests. These results may also inform the restoration of climate-resilient forests.

IMPORTANCE
Secondary forests are important components of neotropical landscapes and soil microbes help to shape these forests and the ecosystem services that they provide. This study demonstrates that soil microbial communities in moist and dry tropical forests can recover and reassemble after only 20 years of natural succession following the removal of cattle. However, successional patterns that are seen in the plant community are not always seen belowground. These patterns were more predictable at the moist than the dry site where the patchiness of the landscape likely restricts dispersal of both plants and soil microbes. We highlight the importance of preserving remaining tropical dry forests as they host unique microbial biodiversity that may help forests respond to drought conditions. As community shifts in soil microbes influence plant establishment, forest productivity, and other aspects of ecosystem functioning during the succession of tropical forest communities, our results can inform the restoration of climate-resilient forests.
Discordance in genotypic and phenotypic drug susceptibility results: time to reconsider critical concentration of rifampicin
Authors: Shrivas Arti , Singh Sarman , Singh Jitendra , Shankar Prem , Soni Payal , Rufai Syed Beenish , Maurya Anand , Purwar Shashank 
Published: February 2025

ABSTRACT

The objective of this study is to correlate
rpoB
mutations found on the new-generation sequencing (NGS) in
Mycobacterium tuberculosis
(MTB) isolates with minimum inhibitory concentrations (MICs) to the rifampicin (RIF). We assessed the minimum inhibitory concentrations for 151 archived clinical MTB isolates that were determined phenotypically susceptible to RIF (101; 66.89%), and the remaining 50 (50; 33.11%) were resistant to RIF by BACTEC MGIT SIRE DST. MIC values were determined using the colorimetric redox indicator (Resazurin/REMA) method, and results were correlated with
rpoB
gene mutations associated with rifampicin resistance found. Comparing the MIC and critical concentration, we found that 15 of these 101 (14.85%) isolates were misclassified by MGIT-960 as sensitive at standard critical concentration (1.0 µg/mL) though these were found to have low-level RIF resistance by CRI assay (MIC 0.50 to 1.0µg/mL) and NGS. We found that all 15 isolates contained non-synonymous mutations, the commonest being the
Ile572Phe
(7, 46.66%), followed by
Leu533Pro
(3, 20.0%),
His526Leu
(2, 13.33%),
His526Asn+Ile572
Phe (1),
Asp516Tyr
(1), and
Leu533Pro+Pro564
Arg (1). These mutations are reported to confer low-level RIF resistance. But we did not find any mutation at MIC ≤0.25 µg/mL. We found that a significant number of MTB isolates have phenotypic and genotypic discordance. Taking 1.0 µg/mL of rifampicin as a critical concentration, isolates from approximately 15% of patients are misidentified as susceptible to rifampicin, even when these strains carry low-level drug resistance-conferring mutations and have the potential to develop clinical multidrug-resistant tuberculosis.

IMPORTANCE
Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide, killing millions every year. The emergence of multidrug-resistant and extensively drug-resistant TB forms poses a challenge to the TB control programs. In the past few decades, several molecular tests for rapid detection and drug resistance determination have been developed. But these can miss the genetic mutations that confer low-level resistance to rifampicin (RIF), a critical constituent for treating drug-susceptible TB. On the other hand, for the phenotypic methods, a cutoff value is fixed, known as critical concentration (CC). The current WHO-endorsed CC for rifampicin is 1.0 μg/mL in liquid culture for confirmation of drug resistance; because of that in this system too, low-level RIF resistance may not be correctly identified. Therefore, it is important that either the CC for phenotypic methods is lowered or the specific mutations are included in the molecular tests. This study provides important insights in that direction.
Independent introductions and nosocomial transmission of
Candida auris
in Saudi Arabia ─ a genomic epidemiological study of an outbreak from a hospital in Riyadh
Authors: Guan Qingtian , Alasmari Faisal , Li Chang , Mfarrej Sara , Mukahal Mahmoud , Arold Stefan T. , AlMutairi Talal S. , Pain Arnab 
Published: February 2025

ABSTRACT

Candida auris
, a pathogenic yeast responsible for global healthcare-associated outbreaks, was involved in a significant outbreak at King Fahad Medical City (KFMC) in Riyadh, affecting 20 patients from August 2018 to May 2019. Our study analyzed 23
C
.
auris
isolates from these patients, utilizing whole genome sequencing, single-nucleotide polymorphism (SNP) analysis, phylogenetic analysis, and transmission network construction. We identified four phylogeographic clades in Saudi Arabia, with two present among the KFMC isolates. The transmission network predominantly displayed two star-like patterns, indicative of super-spreader events. Resistance to various azoles was common, and one isolate was resistant to 5-flucytosine, linked to specific mutations in the ERG11 and CIT1 genes. High genetic similarity of the isolates suggested a nosocomial origin of the KFMC outbreak. The distribution of phylogeographic clades suggests at least four separate introductions into Saudi Arabia from 2017 to 2019 and two into KFMC, underscoring both direct and nosocomial transmission pathways within the hospital.

IMPORTANCE

Candida auris
is an emerging multidrug-resistant yeast that poses a significant threat in healthcare settings worldwide. This study is one of the largest genomic investigations of a
Candida auris
outbreak in the Middle East, focusing on a hospital in Riyadh, Saudi Arabia. By analyzing the genomes of isolates from 20 patients, we uncovered multiple independent introductions of
C. auris
into the region, as well as its subsequent spread within a hospital. The findings highlight the complex transmission dynamics and the challenges in controlling this pathogenic yeast in healthcare environments. This research underscores the critical need for robust genomic surveillance and accurate identification methods to prevent and manage
C. auris
outbreaks, which are increasingly linked to high mortality rates and limited treatment options. The insights gained from this study contribute to our understanding of
C. auris
transmission and resistance, offering valuable guidance for public health strategies.
Divergence of sexual size dimorphism between wild and hatchery chum salmon under intensive Japanese hatchery programs
Authors: Morita Kentaro , Sato Shunpei 
Published: February 2025

Artificial propagation weakens sexual selection by reducing male–male competition and female choice, which favor larger males in natural reproduction. If homing ability and sexual selection were strong, wild-origin salmon would exhibit more pronounced male-biased sexual size dimorphism (SSD) than their hatchery-origin counterparts. We conducted field sampling of chum salmon ( Oncorhynchus keta) in two Japanese rivers, where hatchery fish were marked using otolith thermal marking. The length at maturity of hatchery salmon differed by only 1–2 cm between males and females, whereas the length at maturity of wild-dominated salmon was 5–6 cm larger in males than in females. The mean age at maturity of wild-dominated fish was 0.2–0.3 years higher than that of hatchery fish, but no significant sex differences were observed in either origin. Additionally, macro-level comparisons of SSD, calculated as log10(male length/female length), among 21 populations showed that wild-dominated populations had significantly higher SSD than hatchery-dominated populations. Overall, hatchery salmon exhibited weaker SSD, consistent with reduced sexual selection in the hatchery.