bluuebunny/crossref_metadata_2025 huggingface dataset:
Buffer specificity of ionizable lipid nanoparticle transfection efficiency and bulk phase transition
Authors: Carucci Cristina , Philipp Julian , Müller Judith A. , Sudarsan Akhil , Kostyurina Ekaterina , Blanchet Clement E. , Schwierz Nadine , Parsons Drew F. , Salis Andrea , Rädler Joachim O.
Published: January 2025

Lipid nanoparticles (LNPs) are efficient and safe carriers for mRNA vaccines based on advanced ionizable lipids. It is understood that the pH dependent structural transition of the mesoscopic LNP core phase plays a key role in mRNA transfer. However, buffer specific variations in transfection efficiency remain obscure. Here we analyze the effect of buffer type on the structure and transfection efficiency of LNPs. We find that LNPs formulated with the cationic ionizable lipid DLin-MC3-DMA (MC3) in citrate compared to phosphate and acetate buffers exhibit earlier onset and stronger mRNA-GFP expression in-vitro. Using synchrotron small angle X-ray scattering (SAXS) we determine the pH dependent mesophases of ionizable lipid MC3/cholesterol/water dialyzed against the various buffers. The results show that the phase transition with decreasing pH from inverse micellar cubic to inverse hexagonal (Fd3m-HII) is shifted by one unit to a lower transition pH for acetate and phosphate compared to citrate buffer. Based on continuum theory and ion specific adsorption obtained from all-atom MD simulations, we propose a mechanism for buffer specificity. Citrate stabilizes the inverse hexagonal phase thus shifting the formation of HIIto a higher pH. By contrast, phosphate and acetate stabilize LII. We propose that the Fd3m-to-HIItransition, which is facilitated in citrate buffer, is responsible for a sensitized pH-response of the LNP core phase. This, in turn, enhances endosomal release efficiency and accounts for the earlier onset of gene expression observed in LNPs prepared with citrate buffer.
Genome Sequencing, Molecular Marker Development and Genetic Diversity Assessment of Economically Important Vulnerable Tree SpeciesSaraca asoca (Roxb.) W.J de Wilde
Authors: Mahalakshmi P , Hegde Santhosh N , Gowda Malali , Kareem Abdul , Anbarashan M , Noorunnisa Begum S , Kukkupuni Subrahmanya Kumar , Narendran Pavithra
Published: January 2025

Saraca asoca, is an understory tree along streams in evergreen to semi-evergreen forests up to 600 m. It is an important tree in cultural tradition and medicinally significant. It is native to India and Sri Lanka. Globally the species is found to occur in India, Sri Lanka, Myanmar, Bangladesh. It was introduced in Malaysia. Within India, it’s found in Western Ghat and Eastern Ghat. It is occasionally planted in gardens.Saraca asocais known for its extensive pharmacological properties, particularly its bark is used in treating menorrhagia, dysfunctional uterine bleeding, hemorrhagic dysentery, and other gynecological issues, it holds a prominent place in Ayurvedic medicine. This study was undertaken to sequence the whole genome ofSaraca asocausing the Illumina HiSeq2500 platform, and evaluating the genetic diversity among samples from Kolluru and other locations in southern India through Genotyping by Sequencing (GBS). Analysis of 49 samples established genetic diversity relationships using a distance matrix. Sequencing yielded 1.6 Gb, covering 76% of the estimated genome size. The genome includes 764 million bases of repetitive DNA elements. A survey of Simple Sequence Repeats (SSRs) identified 584,615 SSRs, with 236,123 sequences containing SSRs. Utilizing the KEGG database, biosynthesis pathways for catechin and epicatechin within the flavonoid synthesis pathway were identified. This comprehensive genomic analysis ofSaraca asoca(Sita Ashoka) provides critical insights for conservation efforts aimed at preserving this vulnerable species,Saraca asoca(Roxb.) Willd.
Genome wide analyses reveal the role of mutator phenotypes in the emergence of drug resistance inMycobacterium tuberculosis
Authors: Zein-Eddine R. , Le Meur A. , Skouloubris S. , Jelsbak L. , Refrégier G. , Myllykallio H.
Published: January 2025

Antimicrobial combination therapy is widely used to combatMycobacterium tuberculosis(Mtb), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, are a known source of resistance in other bacterial infections, but their global role inMtbremains unclear. Here, we provide a comprehensive overview of the contribution of single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3R) genes to resistance inMtb. Through large-scale bioinformatics analysis of 53,589 whole-genomes, we identified 18 novel SNPs linked to genotypic drug resistance in 3R genes, covering 12.5% of clinical isolates/strains with available genome sequences. Notably, a number of the detected SNPs were positively selected duringMtbevolution. Experimental mutation frequency tests further indicated functional defects of these sequence variants in key DNA repair pathways. Our findings indicate that the role of mutability in 3R genes plays a significant role inMtbresistance at the global level.
Evolution of circadian clock and light-input pathway genes in Hemiptera
Authors: Smykal Vlastimil , Tobita Hisashi , Dolezel David
Published: January 2025

Circadian clocks are timekeeping mechanisms that help organisms anticipate periodic alterations of day and night. These clocks are widespread, and in the case of animals, they rely on genetically related components. At the molecular level, the animal circadian clock consists of several interconnected transcription-translation feedback loops. Although the clock setup is generally conserved, some important differences exist even among various insect groups. Therefore, we decided to identifyin silicoall major clock components and closely related genes in Hemiptera. Our analyses indicate several lineage-specific alterations of the clock setup in Hemiptera, derived from gene losses observed in the complete gene set identified in the outgroup, Thysanoptera, which thus presents the insect lineage with a complete clock setup.Nilaparvataand Fulgoroidea, in general, lost the (6-4) photolyase, while all Hemiptera lost FBXL3, and several lineage-specific losses of dCRY and jetlag were identified. Importantly, we identified non-canonical splicing variants ofperiodandm-crygenes, which might provide another regulatory mechanism for clock functioning. Lastly, we performed a detailed reconstruction of Hemiptera’s light input pathway genetic repertoire and explored the horizontal gene transfer of cryptochrome-DASH from plant toBemisia. Altogether, this inventory reveals important trends in clock gene evolution and provides a reference for clock research in Hemiptera, including several lineages of important pest species.

Bullet points (highlights)

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Evolution of clock genes (including light input pathway) was reconstructed in Hemiptera

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Newm-cryandpersplicing variants were identified in certain species

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A unique horizontal gene transfer of plant/fungal CRY-DASH was found inBemisia

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Clock setup was identified for pests:Nilaparvata,Bemisia,Halyomorpha, and aphids

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Future clock research directions in Hemiptera are proposed
Independent and repeated acquisition of endosymbiotic bacteria across the diversification of feather lice
Authors: Soto-Patiño Juliana , Walden Kimberly K. O. , Doña Jorge , Alessio Lorenzo D’ , Bush Sarah E. , Clayton Dale H. , Dale Colin , Johnson Kevin P.
Published: January 2025

Many parasitic insects, including lice, form close relationships with endosymbiotic bacteria that are crucial for their survival. In this study, we used genomic sequencing to investigate the distribution and evolutionary history of the bacterial genusSodalisacross a broad range of feather louse species spanning 156 genera. Phylogenomic analysis revealed significant diversity amongSodalislineages in feather lice, and robust evidence for their independent and repeated acquisition by different louse clades throughout their radiation. Among the 1,020 louse genomes analyzed, at least 22% containedSodalis, distributed across 57 louse genera. Cophylogenetic analyses between theSodalisand feather louse phylogenies indicated considerable mismatch. This phylogenetic incongruence between lice andSodalis, along with the presence of distantly relatedSodalislineages in otherwise closely related louse species, strongly indicates repeated independent acquisition of this endosymbiont. Additionally, evidence of cospeciation among a few closely related louse species, coupled with frequent acquisition of these endosymbionts from free-living bacteria, further highlights the diverse evolutionary processes shapingSodalisendosymbiosis in feather lice.
Urbanisation and Habitat Shape Resource-Driven Dietary Shifts in Wild Birds
Authors: Chatelain Marion , Rennstam Rubbmark Oskar , Rüdisser Johannes , Traugott Michael
Published: January 2025

Urbanisation affects bird ecology and evolution, with changes in nutritional intake considered a key driver. However, most studies provide only snapshots of urban bird feeding ecology due to methodological limitations in analysing diets across space and time. Here, we address this gap by examining the diets of two common species with differing feeding ecologies: the great tit (Parus major) and blue tit (Cyanistes caeruleus). Diet samples from 370 birds, captured over a year at 147 locations across an urbanised landscape in Innsbruck, Austria, were molecularly analysed. Results revealed species-and season-specific diet patterns influenced by urbanisation: urban great tits exhibited higher diet diversity but reduced arthropod consumption during the breeding season, while urban blue tits compensated for lower moth intake by increasing their consumption of crab spiders and aphids. Prey consumption mirrored prey availability, highlighting resource-driven dietary shifts. Habitat type also played a significant role, with urban green spaces enhancing plant-based food diversity and residential areas increasing anthropogenic food consumption. These findings support the hypothesis that diet drives fitness and phenotypic differences between urban and rural bird populations. They highlight the need to consider both urbanisation levels and habitat characteristics to fully understand its ecological and evolutionary impacts.
Prenatal maternal infection promotes maternal microchimeric cells to alter infection risk in male offspring
Authors: Jimena Brittany , Kazimierczyk Daniel , Kazimierczyk Simon , Moya Haley , Shin Eva , Li Li , Korgaonkar Parimal , Porter Caryn , Seed Brian , Cherayil Bobby J. , Jain Nitya
Published: January 2025

Vertically transferred maternal cells or maternal microchimeric cells (MMCs) engraft the fetus and persist in offspring for long periods of time. How altered maternal immune states arising from infection affect MMCs and their function in offspring is poorly understood. Here, we show that pregnancy-associated transient maternal infection alters MMCs to differentially regulate immunity in offspring. In male offspring of dams previously infected withYersinia pseudotuberculosis, MMCs confer a pro-inflammatory type 17 T effector phenotype that leads to enhanced protective immunity to an unrelatedSalmonellainfection. Thus, acquired maternal cells imprinted by microbial exposure during pregnancy exert an antigen agnostic and sex-differential effect on offspring immunity, and may potentially be targeted to deliver immune benefits to infants in the vulnerable early life period.
Alginate-εPLL core-shell hydrogel beads as a tool for an effective, stable and scalable microbial encapsulation
Authors: Amaro-Cruz Alba , García-Román Miguel , Moya-Ramírez Ignacio
Published: January 2025

Synthetic microbial consortia offer significant potential for biotechnological applications. However, achieving stable and reproducible co-cultures is challenging due to competitive dynamics and unbalanced growth rates among species. Here, we present an effective method for microbial encapsulation based on alginate-based core-shell hydrogel beads coated with ε-poly-L-lysine (εPLL-HB). This method ensures complete microbial containment while allowing for consistent growth inside the beads of several microbial species with a wide variability in their features. Compared to chitosan and α-poly-L-lysine, two of the most used coating agents for this kind of encapsulation, εPLL demonstrated superior performance in avoiding cellular escape across diverse culture conditions and for all the microbial strains tested, while allowing their proliferation inside the capsule. εPLL-HB enabled the construction of spatially organized co-cultures, effectively balancing populations between microorganisms with different growth rates. Furthermore, εPLL-HB provided protection against toxic compounds in lignocellulosic-derived media and maintained their encapsulation efficacy and viability after long-term storage at -80°C. The superior microbial containment, structural integrity and chemical resistance of εPLL-HB, combined with their low price and ease of preparation, makes them a versatile tool for engineering synthetic microbial consortia, with broad applicability in biotechnological processes.
Pervasive and programmed nucleosome distortion patterns on single mammalian chromatin fibers
Authors: Yang Marty G , Richter Hannah J , Wang Simai , McNally Colin P , Harris Nicole , Dhillon Simaron , Maresca Michela , de Wit Elzo , Willenbring Holger , Maher Jacquelyn , Goodarzi Hani , Ramani Vijay
Published: January 2025

We present a genome-scale method to map the single-molecule co-occupancy of structurally distinct nucleosomes, subnucleosomes, and other protein-DNA interactions via long-read high-resolution adenine methyltransferase footprinting.IterativelyDefinedLengths of Inaccessibility (IDLI) classifies nucleosomes on the basis of shared patterns of intranucleosomal accessibility, into: i.) minimally-accessible chromatosomes; ii.) octasomes with stereotyped DNA accessibility from superhelical locations (SHLs) ±1 through ±7; iii.) highly-accessible unwrapped nucleosomes; and iv.) subnucleosomal species, such as hexasomes, tetrasomes, and other short DNA protections. Applying IDLI to mouse embryonic stem cell (mESC) chromatin, we discover widespread nucleosomal distortion on individual mammalian chromatin fibers, with >85% of nucleosomes surveyed displaying degrees of intranucleosomally accessible DNA. We observe epigenomic-domain-specific patterns of distorted nucleosome co-occupancy and positioning, including at enhancers, promoters, and mouse satellite repeat sequences. Nucleosome distortion is programmed by the presence of bound transcription factors (TFs) at cognate motifs; occupied TF binding sites are differentially decorated by distorted nucleosomes compared to unbound sites, and degradation experiments establish direct roles for TFs in structuring binding-site proximal nucleosomes. Finally, we apply IDLI in the context of primary mouse hepatocytes, observing evidence for pervasive nucleosomal distortionin vivo.Further genetic experiments reveal a role for the hepatocyte master regulator FOXA2 in directly impacting nucleosome distortion at hepatocyte-specific regulatory elementsin vivo. Our work suggests extreme—but regulated—plasticity in nucleosomal DNA accessibility at the single-molecule level. Further, our study offers an essential new framework to model transcription factor binding, nucleosome remodeling, and cell-type specific gene regulation across biological contexts.
Breaking the Phalanx: Overcoming Bacterial Drug Resistance with Quorum Sensing Inhibitors that Enhance Therapeutic Activity of Antibiotics
Authors: Beasley Jon-Michael , Dorjsuren Dorjbal , Jain Sankalp , Rath Marielle , Tieghi Ricardo Scheufen , Tropsha Alexander , Simeonov Anton , Zakharov Alexey V. , Muratov Eugene
Published: January 2025

Antibiotic-resistant bacterial infections loom over humanity as an increasing deadly threat. There exists a dire need for new treatments, especially those that synergize with our existing arsenal of antibiotic drugs to help overcome the gap in antibiotic efficacy and attenuate the development of new antibiotic-resistance in the most dangerous pathogens. Quorum sensing systems in bacteria drive the formation of biofilms, increase surface motility, and enhance other virulence factors, making these systems attractive targets for the discovery of novel antibacterials. Quorum sensing inhibitors (QSIs) are hypothesized to synergize with existing antibiotics, making bacteria more sensitive to the effects of these drugs. In this study, we aimed to find the synergistic combinations between the QSIs and known antibiotics to combat the two deadliest hospital infections -Pseudomonas aeruginosaandAcinetobacter baumannii.We mined biochemical activity databases and literature to identify known, high efficacy QSIs against these bacteria. We used these data to develop and validate a Quantitative Structure-Activity Relationship (QSAR) model for predicting QSI activity and then employed this model to identify new potential QSIs from the Inxight database of approved and investigational drugs. We then tested binary mixtures of the identified QSIs with 11 existing antibiotics using a combinatorial matrix screening approach with ten (five of each) clinical isolates ofP. aeruginosaandA. baumannii. Amongst explored drug combinations, 31 exhibited a synergistic effect, including mixtures involving naldemedine and telotristat, two drugs predicted by our model with previously undescribed QSI activity. Although no mixture inhibiting all the strains was found, piperacillin combined with curcumin, ketoprofen, indomethacin, and piroxicam demonstrated the broadest antimicrobial action. We anticipate that further preclinical investigation of these combinations of novel repurposed QSIs with a known antibiotic may lead to novel clinical candidates.

Table of Content Graphic
Coupling between membrane undulations and lipid curvature leads to transient local enrichment of cardiolipin in mitochondrial membranes
Authors: Lee Christopher T , Venkatraman Kailash , Budin Itay , Rangamani Padmini
Published: January 2025

Organelles such as mitochondria have characteristic shapes that are critical to their function. Recent efforts have revealed that the curvature contributions of individual lipid species can be a factor in the generation of membrane shape in these organelles. Inspired by lipidomics data from yeast mitochondrial membranes, we used Martini coarse-grained molecular dynamics simulations to investigate how lipid composition facilitates membrane shaping. We found that increasing lipid saturation increases bending rigidity while reducing the monolayer spontaneous curvature. We also found that systems containing cardiolipin exhibited decreased bending rigidity and increased spontaneous curvature when compared to bilayers containing its precursor phosphatidylglycerol. This finding contradicts some prior experimental results that suggest that bilayers containing tetraoleoyl cardiolipin have greater rigidity than dioleoyl phosphatidylcholine bilayers. To investigate this discrepancy, we analyzed our simulations for correlations between lipid localization and local curvature. We found that there are transient correlations between curved lipids such as cardiolipin (CDL) and phosphatidylethanolamine (PE) and curvature; these interactions enrich specific bilayer undulatory modes and cause bilayer softening. Furthermore, we show that curvature-localization some lipids such as cardiolipin can influence lipids in the opposing leaflet. These observations add to the emerging evidence that lipid geometric features give rise to local interactions, which can cause membrane compositional heterogeneities. The cross-talk between composition-driven tuning of membrane properties and membrane shape has implications for membrane organization and its related functions.
Ketone body b-Hydroxybutyrate does not extend lifespan, but upregulates fecundity in food-limitedDaphnia, with a transgenerational effect
Authors: Pearson A. C. , Bhadra S. , Yampolsky L. Y.
Published: January 2025

Ketone bodies accumulate on ketogenic diets and are known to have numerous beneficial health and longevity effects. Here we investigate the effects of exposure to environmental b-hydroxybutyrate (BHB), a ketone body, on longevity and fecundity of a model organismDaphnia magna,a plankton crustacean, maintained at limited food availability. We report that exposure to continuous or intermittent lifetime exposure to 2.5 – 10 mM of BHB reducesDaphnialifespan, while intermittent exposure administered for 20-day periods has little effect on post-exposure survival, regardless of the age at exposure onset. On the other hand, various BHB exposure regimes significantly increased fecundity, including fecundity up to 100 days past a 20-day exposure. We further demonstrate that even relatively brief early life maternal exposure to BHB can increase daughters’ fecundity, although this transgenerational effect is genotype-specific. We argue that this effect must have a signaling nature rather than simply manifestation of additional source of energy provided by BHB and discuss potential significance of genetic variation in transmission of such signals.
Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma
Authors: Li Keva , Tolman Nicholas , Segrè Ayellet V. , Stuart Kelsey V. , Zeleznik Oana A. , Vallabh Neeru A. , Hu Kuang , Zebardast Nazlee , Hanyuda Akiko , Raita Yoshihiko , Montgomery Christa , Zhang Chi , Hysi Pirro G. , Do Ron , Khawaja Anthony P. , Wiggs Janey L. , Kang Jae H. , John Simon WM , Pasquale Louis R. ,   UK Biobank Eye and Vision Consortium
Published: January 2025

Glaucoma polygenic risk scores (PRS) effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study in the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve=0.579), they offered modest prediction improvement in PRS-only-based models (P=0.004). We identified a metabolomic signature associated with resilience in the top PRS decile, with elevated glycolysis-related metabolites—lactate (P=8.8E-12), pyruvate (P=1.9E-10), and citrate (P=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction=0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval [CI]=0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (P=0.002) and optic nerve damage (P<0.0003) inLmx1bV265Dmice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.
Fluid and White Matter Suppression Contrasts MRI Improves Deep Learning Detection of Multiple Sclerosis Cortical Lesions
Authors: Gordaliza Pedro M. , Müller Jannis , Cagol Alessandro , Molchanova Nataliia , La Rosa Francesco , Tsagkas Charidimos , Granziera Cristina , Bach Cuadra Meritxell
Published: January 2025

Purpose

To investigate, for the first time, the efficacy of Fluid and White Matter Suppression (FLAWS) MRI sequence in improving Deep Learning (DL)-based detection and segmentation of cortical lesions in Multiple Sclerosis (MS) patients even, with applicability to clinical settings where only standard T1-weighted images are available.

Materials and Methods

In this retrospective multi-site study, we analyzed 204 MS patients using DL models developed with FLAWS and Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequences. Reference standard annotations were established through two approaches: (1) consensus of three expert raters across all contrasts, and (2) single-rater annotations for individual modalities. Models were validated on both internal and external datasets, with performance assessed usingF1-score for detection and DSC for segmentation accuracy.

Results

Models involving FLAWS demonstrated superior performance over MP2RAGE-only models. The combined MP2RAGE+FLAWS model achieved CL detection with medianF1-score of 0.667[0.339−0.840] compared to multirater consensus. Models trained on comprehensive consensus annotations outperformed those trained on single-modality annotations. Notably, a model exclusively based on MP2RAGE images and trained with FLAWS-derived annotations showed, showed strong generalization to external Magnetization Prepared Rapid Gradient-Echo (MPRAGE) clinical datasets (medianF1-score: 0.55[0.211−0.998]).

Conclusion

Integration of FLAWS-derived contrasts and annotations significantly improves DL-based CL detection and segmentation. The models demonstrate capability in identifying lesions missed by individual raters and maintain robust performance even without FLAWS sequences in standard clinical settings. This advancement facilitates clinical translation, supported by publicly available inference models on DockerHub.

Graphical Abstract

Highlights

MP2RAGE+FLAWS MRI sequences achieves superior cortical lesion detection performance

Quantitative validation shows medianF1of 0.667[0.339−0.840] with combined sequences

FLAWS-trained model generalizes well to standard MPRAGE images (F1: 0.55[0.211−0.998)

Model demonstrates immediate clinical applicability on standard MPRAGE without FLAWS input

Implementation publicly accessible via DockerHub for widespread clinical adoption
Effect of Hyperbaric Oxygen After Moderate-Intensity Exercise on Fatigue: A Single-blind Crossover Randomized Trial
Authors: Yagishita Kazuyoshi , Aizawa Junya , Ohji Shunske , Hoshino Takashi , Oyaizu Takuya
Published: January 2025

Objectives

Although insufficient delivery of oxygen might be a factor in physical and perceived fatigue, the relationship between exposure to hyperbaric oxygen (HBO) and recovery from perceived fatigue remains unexplained. The purpose of this study was to investigate the effects of exposure to HBO after long-duration, medium-intensity training on recovery from perceived fatigue in a single-blind study.

Methods

Fatigue was induced in nine male university students (mean age: 21.3 years) using an ergometer exercise bike at a moderate intensity of 75% of their maximum heart rate for 60 min. Post-workout, subjects randomly received an intervention comprising exposure to HBO or an air placebo in a single-blind experimental trial. Blood tests were conducted, and perceived fatigue was evaluated by using visual analog scales (VAS) at five time points. One week later, a crossover trial was conducted.

Results

For the HBO group, pre- to post-intervention mean VAS scores for whole-body fatigue significantly improved from 48.4 to 28.7 (p<0.001). However, in the placebo group, the improvement was not statistically significant. Hematological evaluations, including C-reactive protein level, white blood cell count, creatine kinase level, lactic acid level, T-cell count, CD4/CD8 ratio, and natural killer cell count, did not show any significant between-group differences except only BUN and free fatty acids levels 1.5 h after intervention and Mg levels immediately after intervention. There were also no significant differences in the results of other hematological assessments.

Conclusions

The results of this study showed that perceived fatigue evaluated by VAS scores significantly improved in the HBO group in a blinded trial. However, this was not objectively supported by blood test results. HBO may have effects on recovery from perceived fatigue following long-duration, moderate-intensity exercise. However, the results of this study could not determine the efficacy of HBO on exercise-induced fatigue.
Unbiased co-occurring mutational landscapes in tumorigenesis
Authors: Li Yizhou , Xiong Yangfang , Wei Wensheng
Published: January 2025

Mutations with a synergistic effect on tumorigenesis were positively selected during tumor evolution, showing a tendency to co-occur in cancer genomes. To systematically gain insight of tumorigenic crosstalk at the mutation level, we utilized the FP-Growth algorithm in frequent pattern mining to create an unbiased map of co-occurring mutations from clinical genome sequencing data. We identified 100,933 frequent co-occurring mutation pairs across 22 cancer types. The co-mutation pairs involving cancer driver genes highlighted potential mechanisms for collaborative tumor formation, suggesting promising targets to disrupt tumorigenesis. Additionally, the large number of intra-gene co-mutations with strong dependencies indicated possible combinational effects on the oncogenic properties of specific proteins, which might be overlooked when individual mutations are not hotspots. Furthermore, our whole-genome mining strategy revealed a significant number of co-mutations in non-coding regions, with an enrichment of regulatory elements suggesting their potential role in modulating the co-expression of related genes. Finally, we demonstrated that our pipeline could systematically identify high-order co-mutations. In summary, our study provides the most extensive co-occurring mutations in tumor development, offering valuable insights into mechanisms and potential therapeutic targets.
Detailed mapping of mesothelioma cases in Denmark to identify areas with elevated risk: a nationwide population-based study
Authors: Christensen Heidi Søgaard , Jensen Rikke Hedegaard , Nielsen Lars Hernández , Bertelsen Lise Dueholm , Teglgaard Christian , Bønløkke Jakob , Severinsen Marianne Tang , Bøgsted Martin
Published: January 2025

Objectives

Previous studies mapping pleural mesothelioma in Denmark have found that the risk varies between Danish regions. However, evaluating disease risk for such relatively large geographical units ignores any heterogeneity within the unit and can thus diminish more local spikes in risk, missing smaller areas of excess risk. In this study, we examined the distribution of pleural mesothelioma in Denmark on an unprecedented detailed scale, mapping cases to each of the Danish parishes.

Methods

We identified individuals diagnosed with pleural mesothelioma between 1990 and 2021 in the Danish Cancer Registry. Considering age- and sex-standardised incidence rate ratios, we used a conditional autoregressive random effects model to smooth incidence rate ratios across parishes. Parishes with a smoothed parish-to-national incidence rate ratio higher than 1.25 or 2.0 with a posterior probability of more than 95% were flagged as parishes with an excess risk of pleural mesothelioma.

Results

We identified 3105 incident cases of pleural mesothelioma in the study period. A total of 73 and 14 parishes were flagged with incidence rate ratios significantly above 1.25 and 2.0, respectively. The flagged parishes had smoothed incidence rate ratios ranging from 1.80 to 4.65.

Conclusions

We provided a detailed mapping of pleural mesothelioma cases in Denmark and found five distinct areas, each covering several parishes, with a significantly elevated risk. All these areas were in the proximity of previous asbestos-using industries.
Explanatory factors for the occurrence of the cholera epidemic in the Kadutu health zone, city of Bukavu in the Democratic Republic of Congo
Authors: Kachelewa Bonhomme Kalimira , Ngondo Denise , Mata Henry , Kokolomami Jack , Bobanga Thiery Lengu , Kyloka Jean Nyandwe
Published: January 2025

Background

The Kadutu Health Zone (HZK) in Bukavu, located in the east of the Democratic Republic of Congo, is one of the areas most affected by cholera. This study aims to identify the factors explaining the occurrence of cholera epidemics in this region.

Methods

A case-control study was conducted between January and June 2024, with a sample drawn from cholera cases of the 2023 outbreak. A questionnaire was administered to 112 cases and 224 controls. Data were analyzed using SPSS v 25 software.

Results

The results revealed nine factors significantly associated with the onset of the epidemic: low monthly income (OR = 2.49; p = 0.010), non-washing of hands before eating (OR = 25.85; p < 0.001) and before breastfeeding (OR = 3.06; p = 0.006), lack of hygiene of soiled hands (OR = 19.37; p < 0.001), defecation outside the toilet (OR = 4.54; p < 0.001), recourse to traditional practitioners (OR = 3.28; p = 0.033), lack of toilets (OR = 2.07; p = 0.017), and lack of knowledge of the modes of transmission (OR = 2.94; p = 0.032) and prevention (OR = 1.75; p = 0.037).

Conclusion

Cholera prevention in the HZK requires a multisectoral approach, taking into account sociodemographic, economic, environmental, cultural and health factors.
A pragmatic randomized controlled trial of artificial intelligence (AI)-based predictive analytics monitoring for early detection of clinical deterioration
Authors: Keim-Malpass Jessica , Ratcliffe Sarah J , Clark Matthew T , Krahn Katy N , Monfredi Oliver J , Hamil Susan , Yousevfand Gholamreza , Jones Marieke K , Nelson Ashley , Moorman Liza P , Moorman J. Randall , Bourque Jamieson M
Published: January 2025

Background

This pragmatic randomized controlled trial aimed to assess the effect of a passive display of artificial intelligence (AI)-based predictive analytics on hours free of clinical deterioration events among medical and surgical patients in an acute care cardiology medical-surgical ward.

Methods

10,422 inpatient visits were randomly assigned by cluster to the intervention group of a display of risk trajectories or to a control group of usual medical care. The trial was undertaken on an 85-bed inpatient cardiology and cardiac surgery ward of an academic hospital with a substantial implementation and education plan. This was a passive display with no specific response mandated. The primary analysis compared events of clinical deterioration (death, emergent ICU transfer, emergent endotracheal intubation, cardiac arrest, or emergent surgery) and compared mortality 21 days after admission.

Results

Patients with a large spike in risk score had, on average, twice the length of hospital stay (6.8 compared to 3.4 days). There was no change in the primary outcome between groups. Among those who had a clinical event, there were more event-free hours in the intervention/display-on group compared to the standard-of-care/display-off, but this did not approach statistical significance. 11% of patients were transferred into or out of display beds, a censoring event removing them from the analysis, thereby undermining aspects of the randomized nature of the study.

Conclusion

Predictive analytics monitoring incorporating continuous cardiorespiratory monitoring and displays of risk trajectories coupled with an education plan did not improve patient outcomes or reduce deaths. While necessary to conduct the study, the pragmatic design allowed for significant movement towards intervention/displayed beds for sicker patients. Design considerations in the future must focus on understanding clinicians’ interpretation, care processes, and communication practices.

Trial registration

NCT04359641
Sparks fade with distance: The effect of electric field distribution on global motion perception using different tES techniques
Authors: Pavan Andrea , Ghin Filippo , Contillo Adriano , Akyuz Sibel , Campana Gianluca
Published: January 2025

Previous evidence has shown that high frequency transcranial random noise stimulation (hf-tRNS) decreases motion coherence thresholds when a cephalic montage (i.e., return over Cz) is used. Extracephalic montages have also been employed to modulate behavioral performance, eliminating stimulation of regions under the return electrode. In this study, we examined the effects of different transcranial electrical stimulation (tES) protocols on visual motion discrimination, placing the return electrode on the ipsilateral arm. We assessed the impact of electrode localization using hf-tRNS, anodal, cathodal transcranial direct current stimulation (tDCS), and Sham stimulation over hMT+, a brain region involved in global motion perception. Motion direction discrimination was measured using random dot kinematograms (RDKs). Due to the increased distance between the stimulation and return electrodes in this montage, we expected a smaller reduction in motion discrimination thresholds compared to our previous study. The results suggest that increased interelectrode distance mitigates the efficacy of hf-tRNS. Additionally, no significant effects were observed with the other tES protocols tested. Our findings imply that the positioning of the two electrodes affects current flow characteristics, leading to reduced neuromodulation. These results underscore the importance of stimulation configuration, particularly the effect of interelectrode distance on performance. Given the widespread application of brain stimulation techniques in clinical and cognitive research, our results can guide future studies in carefully considering this further aspect of stimulation montage configurations.
Delayed copulation and mating in the malaria vectorAnopheles funestuscompared toAnopheles arabiensis
Authors: Hape Emmanuel Elirehema , Ngonyani Alex Thadei , Mabula Daniel Mathias , Nkya Joel Daniel , Thomas Claus Augustino , Omari Mohamed Jumanne , Siria Doreen Josen , Ngowo Halfan Said , Koekemoer Lizette Leonie , Okumu Fredros Oketch
Published: January 2025

Mating is a vital behavior for mosquito reproduction, yet it remains poorly understood under captive conditions. We examined the copulation dynamics of two key malaria vectors,Anopheles funestus, andAnopheles arabiensis, in controlled laboratory settings in Tanzania. We observed how variations in mosquito age and artificial lighting influence mating success for these two mosquito species within cages under controlled conditions. We conducted observations in 24-hour cycles, monitoring copulation events and insemination in females. We used generalized linear mixed models (GLMMs) for statistical analyses to assess how environmental conditions influence mating behavior. We found thatAnopheles arabiensisexhibited rapid copulation, with 32.4% of individuals mating by Day 3 post-emergence, whileAn. funestusshowed delayed activity, reaching a similar mating rate by Day 8. The introduction of artificial red light significantly accelerated copulation inAn. funestusbut did not affectAn. arabiensis. Dissection confirmed successful sperm transfer and mating plug delivery in over 92% of copulating pairs for both species. Mating occurred primarily at night, with distinct peaks at 22:00 forAn. arabiensisand 23:00 forAn. funestus. In conclusion, our findings reveal species-specific differences in reproductive behavior, which could improve the colonization ofAn. funestus, a species historically challenging to rear in captivity. These insights may also inform the development of new vector control technologies, such as sterile insect techniques and genetic-based approaches, that exploit mosquito mating behaviors.
Variation in genome architecture and epigenetic modification across the microsporidia phylogeny
Authors: Angst Pascal , Ebert Dieter , Fields Peter D.
Published: January 2025

Microsporidia are a model clade for studying intracellular parasitism, being well-known for their streamlined genomes and their extreme life history. Although microsporidia are highly diverse and ecologically important to a broad range of hosts, previous research on genome architecture has focused primarily on the mammal-infecting genusEncephalitozoon. Here, we expand that work, testing the universality of the patterns observed inEncephalitozoonby investigating and comparing variation in genetic and epigenetic architectures in the high-quality genome assemblies of several major microsporidia clades. Our comparison of nine genomes, including the first genome assemblies ofBinucleata daphniae,Gurleya vavrai, andConglomerata obtusa, and revised, improved assemblies ofGlugoides intestinalisandOrdospora colligata, found limited conservation of genetic and epigenetic architecture across all microsporidia, although many genomic characteristics, such as nucleotide composition and repeat content, were shared between genomes of the same or related clades. For example, rRNA genes were hypermethylated in all species, but their position close to chromosome ends was only found in theEncephalitozoonand its sister clade. GC- content varied widely, linked to genome size, phylogenetic position and activity of repeat elements. These findings enhance our insight into genome evolution and, consistent with findings from other systems, suggest epigenetic modification as a regulatory mechanism of gene expression and repeat element activity in microsporidia. Our comparative genome analysis reveals higher variation among microsporidia than previously supposed.
Valosin-containing Protein is Cargo in Amyloid Precursor Protein Extracellular Vesicles
Authors: Lu Yue , Abdullah Mohammad , Healy Liam R. , Tambini Marc D.
Published: January 2025

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer’s disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-inAppmutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App. The presence of Vcp suggests a role for App-EVs in the clearance of protein aggregates.
Contribution of the Tobamovirus resistance gene Tm-1 to control of ToBRFV resistance in tomato
Authors: Zinger Avner , Doron-Faigenboim Adi , Gelbart Dana , Levin Ilan , Lapidot Moshe
Published: January 2025

Tomato brown rugose fruit virus (ToBRFV) is a rapidly spreading pathogen that poses a significant threat to tomato production worldwide. We previously identified a locus on tomato chromosome 11 controlling tolerance to the virus. We further established that combining this locus with one that maps to the Tm-1 region on chromosome 2 confers resistance to the virus. Here we sought to determine whether, and how, the Tm-1 gene itself is involved in ToBRFV resistance. Overexpression of Tm-1 in a tolerant genotype significantly reduced viral accumulation, conferring resistance to ToBRFV. On the other hand, overexpression of Tm-1 in a susceptible genotype only delayed symptom appearance. Moreover, effective RNAi-silencing of Tm-1 in the resistant genotype yielded susceptible plants. These findings show that the Tm-1 gene interacts genetically with the locus controlling tolerance on chromosome 11 and that this interaction is critical for achieving effective resistance to ToBRFV. In addition, the symptomatic plants obtained following silencing of Tm-1 in the resistant genotype indicate that tolerance is also dependent on normal expression levels of the recessive tm-1 allele
Phosphoinositide- and Collybistin-Dependent Synaptic Clustering of Gephyrin
Authors: Burdina Nele , Liebsch Filip , Macha Arthur , Ortuño Gil Joaquín Lucas , Frommelt Pia , Rais Irina , Basler Fabian , Pöpsel Simon , Schwarz Guenter
Published: January 2025

Gephyrin is the main scaffolding protein at inhibitory synapses clustering glycine and GABA type A receptors. At specific GABAergic synapses, the nucleotide exchange factor collybistin recruits gephyrin to the postsynaptic membrane via interaction with phosphoinositides. However, the molecular mechanisms underlying the formation, maintenance and regulation of collybistin-dependent gephyrin clusters remain poorly understood.

This study sheds light on the molecular mechanism of gephyrin cluster formation based on gephyrin self-oligomerization induced by collybistin, leading to the formation of a high-molecular weight (>5 MDa) gephyrin-collybistin complex, which is regulated in two ways: First, plasma-membrane phosphoinositides promote complex formation demonstrating their critical role in membrane targeting and stabilization of gephyrin-collybistin clusters at postsynaptic sites. Second, gephyrin phosphorylation at Ser325 abolishes complex formation with collybistin thus impairing collybistin-dependent gephyrin clustering at GABAergic synapses. Collectively, our data demonstrates a molecular mechanism for synaptic clustering of gephyrin which involves collybistin- and phosphoinositide-dependent formation of high-molecular gephyrin oligomers.
Identifying mood instability and circadian rest-activity patterns using digital remote monitoring and actigraphy in participants at risk for bipolar disorder
Authors: Panchal Priyanka , Nelissen Natalie , McGowan Niall M. , Atkinson Lauren Z. , Saunders Kate E. A. , Harrison Paul J. , Rushworth Matthew , Draschkow Dejan , Geddes John , Nobre Anna C. , Harmer Catherine J.
Published: January 2025

Mood instability and circadian rhythm disruptions are both of increasing interest with regard to a number of psychiatric disorders, notably bipolar disorder (BD), but understanding of their nature and their interrelationship are incomplete. By definition, both have an integral temporal component and, as such, measuring them longitudinally and remotely is desirable.

We conducted the Cognition and Mood Evolution across Time (COMET) study to assess the feasibility and value of digital devices to capture mood, its instability, and daily rest-activity patterns, over a 10-week period, in two groups of participants. The first group (n=37) were selected as scoring>7 on the Mood Disorder Questionnaire (MDQ) (‘high MDQ’), thereby having a history of mood elevation and being at risk for BD. They were compared with a group (n=37) scoring<5 on the MDQ (‘low MDQ’). Over a 10-week period, using a tablet, mood was rated daily, clinical ratings of depression, mania, and anxiety were captured weekly via the True Colours app, and a GENEactiv actigraph was worn to capture rest-activity pattern data.

The main findings are that (1) MDQ score predicts mood instability; (2) high MDQ score is associated with more negative affect and mood symptoms than people with low MDQ, and with a different circadian activity profile; and (3) mood instability and circadian indices appear uncorrelated.

The implications are that (1) remote monitoring of these domains is feasible and valuable; (2) selection of participants based on MDQ score is useful for studying mood (in)stability; and (3) the approach has potential for studies of clinical populations and for experimental medicine studies assessing interventions to reduce mood instability.