bluuebunny/crossref_metadata_2025 huggingface dataset:
Generative modeling for RNA splicing predictions and design
Authors: Wu Di , Maus Natalie , Jha Anupama , Yang Kevin , Wales-McGrath Benjamin D. , Jewell San , Tangiyan Anna , Choi Peter , Gardner Jacob R. , Barash Yoseph
Published: January 2025

Alternative splicing (AS) of pre-mRNA plays a crucial role in tissue-specific gene regulation, with disease implications due to splicing defects. Predicting and manipulating AS can therefore uncover new regulatory mechanisms and aid in therapeutics design. We introduce TrASPr+BOS, a generative AI model with Bayesian Optimization for predicting and designing RNA for tissue-specific splicing outcomes. TrASPr is a multi-transformer model that can handle different types of AS events and generalize to unseen cellular conditions. It then serves as an oracle, generating labeled data to train a Bayesian Optimization for Splicing (BOS) algorithm to design RNA for condition-specific splicing outcomes. We show TrASPr+BOS outperforms existing methods, enhancing tissue-specific AUPRC by up to 2.4 fold and capturing tissue-specific regulatory elements. We validate hundreds of predicted novel tissue-specific splicing variations and confirm new regulatory elements using dCas13. We envision TrASPr+BOS as a light yet accurate method researchers can probe or adopt for specific tasks.
The impact of SGLT-2 Inhibitors on the Risk of Atrial Fibrillation in Heart Failure
Authors: Fretz Thomas , Ilonze Onyedika J , Tanawuttiwat Tanyanan , Das Mithilesh
Published: January 2025

Background Heart failure (HF) and atrial fibrillation (AF) are closely linked, each exacerbating the other. While sodium-glucose cotransporter-2 inhibitors (SGLT2i) are known to provide substantial benefits in HF management, their effect on AF incidence in this population is not well-defined. Objective This study aims to assess the effect of SGLT2i therapy on the development of new-onset AF in patients with HF. Methods This retrospective analysis included all patients hospitalized with a primary diagnosis of HF and no prior diagnosis of AF over a 3-year period. The primary outcome was the occurrence of new-onset AF within 12 months following HF hospitalization. Results Of 3,953 patients 720 (18.2%) developed AF within one year. SGLT2i use was associated with significantly lower risk of AF (HR 0.69, 95% CI:0.55-0.87; p=0.002) across all HF types- reduced, mid-range, and preserved ejection fraction. Kaplan-Meier survival analysis revealed significantly reduced AF-free survival in patients not on SGLT2i therapy, compared to patients on SGLT2i therapy, across subgroups categorized by diabetes, hypertension, coronary artery disease, age >65 years, and BMI >30Kg/m2 (p <0.05 for all). Among those who developed AF, SGLT2i use had significantly lower incidence of AF during follow-up as compared to when not used (12.1% vs. 19.5%, p<0.001). SGLT2 use also delayed onset of AF compared to those not treated with an SGLT2i (339 + 80 days vs. 317 + 106 days; p<0.001). Conclusions The use of SGLT2i therapy is associated with a significantly lower risk of the developing AF following hospitalization for HF.
Pre- and post-capillary exercise contributions to pulmonary hypertension in older adults
Authors: Karvasarski Elizabeth , Park Joy , Savaris Simone , Beale Anna , Wright Stephen P. , Bentley Robert F. , Granton John T. , Mak Susanna
Published: January 2025

Background

Diagnosing pulmonary arterial hypertension (PAH) versus pulmonary hypertension associated with left hear disease (PH-LHD) can be challenging in patients with risk factors for both conditions. When resting pulmonary artery wedge pressure (PAWP) is proximate to a threshold of 15mmHg, exercise has been recommended to differentiate pre- versus post-capillary contributions to PH. To improve our understanding of this practice recommendation, we studied relationships between resting PAWP and the balance of pre- and post-capillary contributions to exercise PH.

Methods

Patients suspected of PAH (n=29, 72±2y, 52% F) with risk factors for LHD were prospectively recruited to undergo cycle ergometry at time of diagnostic right-heart catheterization. Hemodynamic data, including pressure-flow slopes and contributions of transpulmonary gradient (TPG) and PAWP to mPAP, were analyzed to evaluate pre- and post-capillary contributions, respectively, at rest and during exercise.

Results

PAWP ranged from 0 to 20 mmHg. Exercise pressure-flow slopes demonstrated 62% with post-capillary PH, and 31% with pre-capillary PH only. The relationship between resting PAWP and the pre- versus post-capillary contributions to exercise PH was not straightforward. Of patients with PAWP<12mmHg, 67% had post-capillary contributions to exercise PH. Conversely, 50% of patients with PAWP>15mmHg had pre-capillary contributions to exercise PH. Exercise-associated increases in pulmonary artery pressures were more strongly associated with pre-capillary contributions regardless of post-capillary contributions or the value of resting PAWP.

Conclusion

In this population, post-capillary contributions to exercise PH were commonly disclosed over a range of resting PAWP, including <12mmHg. The severity of exercise PH was determined by the pre-capillary contributions.
A single-chain antibody-based AID2 system for conditional degradation of GFP-tagged and untagged proteins
Authors: Islam Moutushi , Negishi Takefumi , Kitamoto Naomi , Hatoyama Yuki , Gamo Kanae , Hayashi Ken-ichiro , Kanemaki Masato T.
Published: January 2025

Protein knockdown using an improved auxin-inducible degron (AID2) technology has proven to be a powerful tool for studying protein function. The current approach requires the fusion of target proteins with a degron tag, a process typically achieved through CRISPR knock-in. However, knock-in remains challenging in non-model organisms and humans, limiting the broader applicability of AID2. To overcome this limitation, we developed a single-chain antibody AID2 (scAb-AID2) system. This approach employs an adaptor composed of a single-chain antibody fused with a degron, which recognises a target protein and induces rapid degradation in the presence of the inducer 5-Ph-IAA. We demonstrated that scAb-AID2, in combination with an anti-GFP nanobody, degraded GFP-fused proteins in human cells andC. elegans. Furthermore, we showed that endogenous p53 and H/K-RAS were conditionally degraded in cells expressing an adaptor encoding an anti-p53 nanobody and -RAS monobody, respectively, and led to aphidicolin sensitivity in cell culture and growth inhibition in mouse xenografts. This study paves the way for broader application of AID2-based target depletion in model and non-model organisms and for advancing therapeutic strategies.
An Evolutionary Conserved Multi-Stress Sensory Histidine Kinase NblS Associates With Photosystem II Proteins And Responds To Its Redox Status In The CyanobacteriumSynechococcus elongatusPCC 7942
Authors: Tsurumaki Tatsuhiro , Tanaka Kan
Published: January 2025

Responding to stress caused by various environmental changes is essential for living organisms. In cyanobacteria that perform oxygenic photosynthesis, the highly conserved histidine kinase Hik33/NblS homologs respond to diverse stressors such as high light, low temperature, high salts, high osmolarity, and reactive oxygen species. However, how this unique protein kinase responds to such divergent stresses remains unknown. This study has focused on the underlying stress sensing mechanism of NblS inSynechococcus elongatusPCC 7942. First, the sensory response by NblS was analyzedin vivoby monitoring the NblS-regulatedhliAtranscript accumulation with treatment of various benzoquinone reagents known as photosystem II (PSII) electron acceptors. It was found that molecular responses induced by various stresses were diminished in the presence of 2,6-dichloro-1,4-benzoquinone, which accepts electrons specifically from the PSII-bound plastoquinone QB. Cell fractionation analysis indicated that NblS was localized in the thylakoid membrane, which was consistent with its predicted membrane-spanning structure. In the thylakoid membrane, NblS was found in approximately 400 kDa and 800 kDa unknown complexes in clear native PAGE (CN-PAGE). Immunoprecipitation analysis of the cross-linked thylakoid membrane revealed that NblS is associated with D2 and CP47 proteins but not with CP43 protein, and thus it was suggested that dimeric NblS is associated with RC47-like complex, an assembly intermediate complex of PSII, as [RC47like-NblS2] (370 kDa) or [RC47like-NblS2]2(740 kDa). We propose that the redox status of an RC47-bound plastoquinone molecule is a cue for the NblS response.
A Domain-Specific Language Model Approach for Identifying Immunogenic Epitopes from Publicly Available Data: EpitopeMiner
Authors: Tan Wei Kit , Tang Wei Lin , Chadha Agamjyot Singh , Niedu Roopa , Lee Wendy , Lim Jing Quan , Rajapakse Menaka Priyadharsani , Wilson Solomon , Duan Kaibo , Chong Raymond Wei Liang , Ong Choon Kiat , Lee Bernett , Rotzschke Olaf , Lau Mai Chan
Published: January 2025

Personalized cancer vaccines represent a transformative approach in immunotherapy, leveraging tumor-specific antigens, such as neoantigens, to stimulate durable and targeted immune responses. However, identifying immunogenic neoantigen epitopes through conventional approaches - relying on in silico predictions followed by experimental validation - remains a significant challenge due to limitations of computational tools and scattering of experiment data. To address these challenges, we introduce EpitopeMiner, a domain-specific large language model (LLM) enhanced with a Retrieval-Augmented Generation (RAG) framework, specifically designed to identify immunogenic epitopes predicted by existing computational tools. EpitopeMiner utilizes a custom database of MHC-I-associated epitope-related literature to provide domain-specific knowledge, enhancing the precision and relevance of LLM-generated responses. EpitopeMiner offers three key features: First, the ability to identify epitopes with similar sequences and potentially similar immunogenic effects, which is especially valuable for neoantigens that are patient-specific and rarely found in public datasets. Second, it supports multiple epitope searches with structured outputs, enhancing scalability. Third, it provides original text chunks and paper identifiers, significantly simplifying validation and further exploration of the retrieved knowledge. Applying EpitopeMiner to well-characterized MHC class I epitopes demonstrates its ability to consistently retrieve relevant papers, efficiently providing targeted insights on T-cell response and immunogenicity, outperforming a commercial AI-powered literature tool. Notably, when applied to lymphoma patient-derived neoantigens, EpitopeMiner successfully retrieves immune response information for a few similar epitopes, despite operating with a relatively smaller database compared to the benchmark tool. All in all, EpitopeMiner bridges the gap between computational prediction and experimental validation, providing a scalable solution for extracting knowledge from public data, fostering cross-study synergies, and accelerating the development of personalized cancer vaccines.
ERGA-BGE genome ofAndrosace saussureiDentant, Lavergne, F. C. Boucher & S. Ibanez, a recently described plant from the rooftops of Europe
Authors: Lavergne Sébastien , Rosa Alexy , Peng Chuan , Monteiro Rita , Böhne Astrid , Marcussen Thomas , Struck Torsten , Oomen Rebekah A. ,   Genoscope Sequencing Team, Moussy Alice , Cruaud Corinne , Labadie Karine , Téodori Emilie , Demirdjian Lola , Wincker Patrick , Oliveira Pedro H. , Aury Jean-Marc , Brown Tom
Published: January 2025

The reference genome ofAndrosace saussurei(Ericales: Primulaceae: Primuloideae) provides a valuable resource for understanding the mechanisms of plant adaptations to the most extreme environments where flowering plants can thrive and the speciation mechanisms of plants dwelling on high alpine sky islands. The entirety of the genome sequence was assembled into 20 contiguous chromosomal pseudomolecules. This chromosome-level assembly encompasses 413 Mb, composed of 253 contigs and 101 scaffolds, with contig and scaffold N50 values of 4.95 Mb and 21.2 Mb, respectively.
Does repeated administration of baclofen in free feeding rats reduce body weight by stimulating brown fat metabolism through activation of the sympathetic nervous system?
Authors: Ebenezer Ivor S
Published: January 2025

The results of previous research have suggested that chronic administration of the GABABreceptor agonist baclofen can lead to weight loss in rodents by potentially activating brown adipose tissue (BAT) to increase metabolism rate. Studies in anaesthetised rats have shown that baclofen injected directly into the ventromedial nucleus of the hypothalamus (VMH) stimulates BAT to increase thermogenesis. This effect was attenuated by pretreatment with the beta-adrenoceptor antagonist propranolol, suggesting that baclofen microinjected into the VMH stimulate the sympathetic outflow to BAT, consequently increasing metabolic rate. The present study was designed to test this hypothesis by investigating whether pretreatment with propranolol would attenuate the weight loss induced by repeated daily administration of baclofen in free feeding rats. In the first experiment, male Wistar rats were injected intraperitoneal (ip) once daily for 24 days with either saline followed by saline, saline followed by baclofen (4 mg / kg), propranolol (10 or 20 mg / kg) followed by saline, or propranolol (10 mg / kg) followed by baclofen (4 mg / kg), with 5 minutes separating each injection. Body weight was measured each day 24 h after drug administration. Baclofen treatment resulted in significant reductions in daily body weight compared to the saline group. Propranolol alone had no significant effect on body weight. Importantly, pretreatment with propranolol did not attenuate the weight loss induced by baclofen. A similar experimental protocol as described above was used in a second experiment except that the rats were pretreated with a 20 mg / kg dose of propranolol and body weight was measured for 6 days. The high dose of propranolol significantly decreased body weight compared with control data and potentiated the baclofen-induced reduction in body weight. These results suggest that the effects of baclofen of body weight in free feeding rats may not be dependant on the the activation of BAT through stimulation of the sympathetic nervous system (SNS). Further research is therefore necessary to understand how baclofen influences metabolism and weight loss.
Lipogenic Mothers Alter Offspring Gut Microbiome Development via Breastmilk-Mediated Microbial Transfer
Authors: Cao Jianhong , Umar Abdulrahim , Yu Zheng
Published: January 2025

Mammals provide breastmilk as the primary source of nutrition for their offspring, which plays a crucial role in the development of gut microbiota (GM) and the establishment of immunity. Therefore, maternal dietary conditions during lactation significantly influence GM development. This study investigates the impact of a maternal high-fat diet on GM development in their offspring. Tissue and fecal samples were collected from both pups and their mothers (dams) that were fed a high-fat and a controlled diet. Their amplicon sequencing variants were used to perform comprehensive bioinformatic analysis.

Our findings revealed breastmilk’s protective effect, inhibiting the proliferation of pathogenic bacteria, and regulating gut homeostasis during lactation. However, lipogenic dams induce microbial dysbiosis in their pups leading to an increased relative abundance of gut pathogenic bacteria leading to a heightened risk of chronic diseases. In contrast, pups from dams on a controlled diet exhibited an improved relative abundance of beneficial bacteria, includingMuribaculaceae,Faecalibaculum, andBifidobacterium. However, GM transferred from lipogenic dams adversely affected pups’ GM development and stability, leading to several physical consequences.

This research revealed valuable insights into the relationship between breastmilk and gut microbiota, as specific genera were highly expressed at the beginning of lactation. This highlights the importance of timely interventions for the development of offspring gut microbiota to enhance overall gut health.
Revisiting the cancer microbiome using PRISM
Authors: Ghaddar Bassel C. , Blaser Martin J. , De Subhajyoti
Published: January 2025

Recent controversy around the cancer microbiome highlights the need for improved microbial analysis methods for human genomics data. We developed PRISM, a computational approach for precise microorganism identification and decontamination from low-biomass sequencing data. PRISM removes spurious signals and achieves excellent performance when benchmarked on a curated dataset of 62,006 known true- and false-positive taxa. We then use PRISM to detect microbes in 8 cancer types from the CPTAC and TCGA datasets. We identify rich microbiomes in gastrointestinal tract tumors in CPTAC and identify bacteria in a subset of pancreatic tumors that are associated with altered glycoproteomes, more extensive smoking histories, and higher tumor recurrence risk. We find relatively sparse microbes in other cancer types and in TCGA, which we demonstrate may reflect differing sequencing parameters. Overall, PRISM does not replace gold-standard controls, but it enables higher-confidence analyses and reveals tumor-associated microorganisms with potential molecular and clinical significance.
Condensin II mediates efficient chromatid resolution and resistance to genotoxic stress in Arabidopsis
Authors: Vladejić Jovanka , Prochazkova Klara , Tomaštíková Eva Dvořák , de Cock Zynke , Zwyrtková Jana , Kaduchová Kateřina , Pavlíková Markéta , Pecinka Ales
Published: January 2025

Genome functions are regulated by the means of chromatin and 3D chromosome organization. Dynamic condensation and relaxation of chromosomes during cell cycle is largely controlled by the Condensin complexes. We mapped mutants in Condensin II subunitsSMC2A,CAP-D3andCAP-H2as hypersensitive to DNA-protein crosslink (DPC) inducer zebularine. This suggested that Condensin II complex is required for resistance to genotoxic stress in Arabidopsis and prompted us to explore the underlying phenotypes. We show that the Condensin II role in resistance to zebularine is independent of the DNA damage response signaling by SOG1 and the homology-directed repair pathway. Furthermore, we found that Arabidopsis Condensin II mutants have incompletely condensed mitotic chromosomes and show abnormal chromatin connections during anaphase. Based on the structural and temporal analyses, we propose that the connections represent catenated chromatids. The chromosome connections were more frequent when the Condensin II mutants were treated by zebularine or TOP2 crosslinker and inhibitor ICRF-187. Altogether, we demonstrate that the proper large-scale chromatin organization by Condensin II is important for resistance to DNA damage response-inducing agents in Arabidopsis.
Assessing the impact of yield plasticity on hybrid performance in maize
Authors: Davis Jensina M. , Coffey Lisa M. , Turkus Jonathan , López-Corona Lina , Linders Kyle , Ullagaddi Chidanand , Santra Dipak K. , Schnable Patrick S. , Schnable James C.
Published: January 2025

Improving crop resilience in the face of increasingly extreme and unpredictable weather and reduced access to agricultural inputs such as nitrogen fertilizer and water will require an improved understanding of phenotypic plasticity in crops. To understand the roles of different component traits in determining overall plasticity for grain yield, we generated data from a panel of 122 maize (Zea mays) hybrids grown in replicated field trials in 34 environments spanning 700 miles (1126 km) of the U.S. Corn Belt. We observed that the levels of genetic versus environmental control and the relationships between mean parent release year, overall performance, and linear plasticity were trait-dependent across the 18 agronomic and yield components studied. Importantly and unexpectedly, we observed no clear tradeoff between linear plasticity and mean performance and found only rare examples where genotype-by-environment interactions would alter selection decisions based on the environments tested in our dataset. Furthermore, we showed that overall plasticity was repeatable and appears to be under considerable genetic control but that plasticity in response to nitrogen fertilization was not, which may help explain the limited success in breeding for nitrogen use efficiency. Together, these findings improve our understanding of phenotypic plasticity, with implications for maize breeding.
Impact of infusion conditions and anesthesia on CSF tracer dynamics in mouse brain
Authors: Zhu Yuran , Zhu Junqing , Ni Chenxin , Chen Anbang , Li Longshun , Gao Yue , Shoffstall Andrew J. , Yu Xin
Published: January 2025

Tracer imaging has been instrumental in mapping the brain’s solute transport pathways facilitated by cerebrospinal fluid (CSF) flow. However, the impact of tracer infusion parameters on CSF flow remains incompletely understood. This study evaluated the influence of infusion location, rate, and anesthetic regimens on tracer transport using dynamic contrast-enhanced MRI with Gd-DTPA as a CSF tracer. Infusion rate effects were assessed by administering Gd-DTPA into the cisterna magna (ICM) at two rates under isoflurane anesthesia. Anesthetic effects were evaluated by comparing transport patterns between isoflurane and ketamine/xylazine (K/X) anesthesia at the slower rate. Gd-DTPA transport was also examined after lateral ventricle (ICV) infusion, the primary site of CSF production. The results demonstrate that, besides anesthesia, both the location and rate of infusion substantially affected solute transport within the brain. ICV infusion led to rapid, extensive transport into deep brain regions, while slower ICM infusion resulted in more pronounced transport to dorsal brain regions. Cross-correlation and hierarchical clustering analyses of region-specific Gd-DTPA signal time courses revealed that ICM infusion facilitated transport along periarterial spaces, while ICV infusion favored transport across the ventricular-parenchymal interface. These findings underscore the importance of experimental conditions in influencing tracer kinetics and spatial distribution in the brain.
Genomic connectivity and adaptation signals of the freshwater spongeEphydatia muelleriacross its distribution
Authors: Cassidy Robert , de la Cruz Laura , Mitsi Konstantina , Galià-Camps Carles , Benítez-López Ana , Gracia-Sancha Carlota , Lorente-Sorolla Jose , Álvarez Almudena , Mozo Rocío , Kolomyjec Stephen , Nichols Scott , Manconi Renata , Pereira Raquel , Evans Karen , Itskovitch Valeria , Horton April L. , Leys Sally P. , Taboada Sergio , Riesgo Ana
Published: January 2025

1.

Freshwater sponges fulfill critical ecological functions, including maintaining water quality, regulating nutrient dynamics, offering habitats for diverse taxa, and serving as a vital food source for various species. However, their patterns of dispersal and genetic connectivity remain inadequately understood, posing significant challenges to effective conservation assessments. We examined genetic connectivity and genetic adaptation to local environmental conditions inEphydatia muelleriacross its geographic range using ddRADseq-derived SNPs from 106 individuals collected from 11 localities spanning North America, Europe, and Asia. Analysis of 3,182 neutral SNPs revealed low connectivity and strong genetic structure among regions within two main genetic clusters of North America and Eurasia, while 115 SNPs identified to be under selection showed considerable evidence for differentiated, polygenic adaptation to light and temperature conditions across sampled locations, as well as selection on gene regulatory processes. These findings align with the “monopolization hypothesis”, suggesting that historical climatic and geological conditions of the Last Glacial Maximum, including habitat expansion, contraction, and natural barriers, have contributed more to the current genetic structure ofE. muelleripopulations than contemporary gene flow, which is restricted by monopolistic habitat colonization by this species. Our results provide novel support for ecological theory on dispersal in aquatic invertebrates, as well as insights into the plasticity ofE. muelleriin the face of varying environmental conditions that are fundamentally important for freshwater ecosystem conservation.
High-frequencyWus2-integrated transformation toolkit enhancesCas9editing efficiency and expands capability withSpRYin sorghum
Authors: Shen Jianqiang , Aregawi Kiflom , Anwar Sultana , Miller Tamara , Lemaux Peggy G.
Published: January 2025

Sorghum bicolorL. (Moench) ranks as the fifth most important crop globally, serving diverse purposes such as forage, food, feed, and fuel. Its natural tolerance to various environmental stresses makes it a valuable resource for addressing climate resilience. Harnessing such genetic resources for crop improvement requires highly efficient genetic transformation and genome editing tools. However, sorghum has historically been recalcitrant to genetic transformation, and publicly available engineering tools remain limited. In this study, we report a high-efficiency engineering toolkit, including shuttle and binary vectors, optimized for genome editing viaAgrobacterium-mediated transformation. Using this toolkit, we successfully introduced CRISPR/Cas9-based editing machinery to target thephytoene desaturase(PDS) gene, achieving editing efficiencies up to 95.7% with monocistronic gRNA expression cassettes. To further expand the genome editing repertoire, we employed a protospacer adjacent motif (PAM)-flexibleCas9variant,SpRY(ZmSpRYi), and achieved comparable editing efficiencies. Using our toolkit increases the potential for advanced editing tools to be used in engineering genetic variation of agronomically important quantitative traits. It also paves the way for deploying advanced genome editors, such as prime editors and base editors, to manipulate genetic and genomic resources. These advances provide a robust approach for advancing research in sorghum and other cereals, offering new opportunities for sustainable crop improvement.
The paradoxical impact of drought on West Nile virus risk: insights from long-term ecological data
Authors: Sambado Samantha , Sipin Terrell J , Rennie Zoe , Larsen Ashley , Cunningham James , Quandt Amy , Sousa Dan , MacDonald Andrew J
Published: January 2025

Mosquito-borne diseases are deeply embedded within ecological communities, with environmental changes – particularly climate change – shaping their dynamics. Increasingly intesense droughts across the globe have profound implications for the transmission of these diseases, as drought conditions can alter mosquito breeding habitats, host-seeking behaviors, and mosquito-host contact rates. To quantify the effect of drought on disease transmission, we use West Nile virus (WNV) as a model system and leverage a robust mosquito and virus dataset consisting of over 500,000 trap nights collected from 2010-2023, spanning a historic drought period followed by atmospheric rivers. We pair this surveillance dataset with a novel modeling approach that incorporates monthly changes in bird host community competence, along with drought conditions, to estimate the effect of drought severity on WNV risk using panel regression models. Our results show that while drought decreases mosquito abundances, it paradoxically increases WNV infection rates. This counterintuitive pattern likely stems from reduced water availability, which concentrates mosquitos and pathogen-amplifying bird hosts around limited water sources, thereby increasing disease transmission risk. However, the magnitude of the effect depends critically on mosquito species, suggesting species-specific behavioral traits are key to understanding the effect of drought on mosquito-borne disease risk across real landscapes.
Transcriptome responses of twoHalophila stipulaceaseagrass populations from pristine and impacted habitats, to single and combined thermal and excess nutrient stressors, reveal local adaptive features and core stress-response genes
Authors: Nguyen Hung Manh , Yaakov Beery , Beca-Carretero Pedro , Procaccini Gabriele , Wang Guannan , Dassanayake Maheshi , Winters Gidon , Barak Simon
Published: January 2025

In their natural habitats, seagrasses face multiple abiotic stressors, which can often occur simultaneously. However, most studies investigating the effects of environmental stressors on seagrasses have focused on growth and physiological responses to single stressors. Here, we examined the transcriptome responses of the tropical seagrassHalophila stipulaceacollected from a northern Gulf of Aqaba pristine site (South Beach - SB) and an anthropogenically-impacted site (Tur Yam - TY), grown in a mesocosm, and exposed to ecologically-relevant, single and combined, thermal and excess nutrient stressors. The combined thermal and nutrient stressor elicited greater transcriptome reprogramming than the single stressors in both populations and induced the expression of a combination-specific set of genes involved in abiotic and biotic stress responses. Furthermore, thermal stress exerted a more dominant influence than excess nutrient stress upon the transcriptome response to the combined stress. Transcriptomes of plants from the impacted TY site displayed reduced plasticity, the presence of genes exhibiting a “stress-ready” mode of expression under all stresses, and increased resilience (recovery to control transcriptomes). We also identified core stress-response genes that could be leveraged as early indicators of stress in the field. Overall, our data suggest that environmental conditions in seagrass habitats can drive local molecular adaptation, and that the response of seagrasses to combined stressors associated with climate change and coastal anthropogenic stressors cannot be predicted from the response to single stressors.
Mathematical Characterization of Drug-Induced Persistence in Cancer
Authors: Park Ji Tae , Levine Herbert
Published: January 2025

We introduce a general phenomenological framework for understanding how phenotypic plasticity gives rise to drug persisters. These persisters, often quiescent but sometimes which again return to cycling, survive in the presence of treatment and eventually can lead to mutants with true resistance. Our framework builds on recent experimental observations regarding variations between and among single-cell clones and the possible role of the drug itself in enhancing the survival strategy. Predictions of our approach include the existence of an optimum drug concentration as well as an optimum drug holiday schedule to minimize the persistence-based threat.
Exploring genetic diversity in the species-rich genusLiolaemus: The interplay among isolation by distance, body size, and environmental variability
Authors: Ruiz-Monachesi M. R. , Cruz F. B. , Martínez J. J.
Published: January 2025

Intraspecific genetic variation enhances the specieś capacity to endure diverse environments. Such variation may drive genetic divergence among populations, often manifesting as isolation by distance (IBD). Here, we investigated how ecological, environmental, life-history, morphological, and phylogenetic factors, shape IBD and genetic diversity (π) inLiolaemuslizards. Further we explored differences related to reproductive modes and taxonomic groups. Using data from GenBank, we examined two mitochondrial genes: Cytb (86 species) and 12S rRNA (37 species). We integrated geographic information for each species to evaluate genetic differentiation concerning spatial distribution. We calculated the IBD slope (βIBD), Manteĺsr, and π for each gene, then tested for an association between βIBDand π. Phylogenetic multiple linear regression revealed that IBD, in the case of Cytb, was present in 56.16% of species and was negatively associated with snout-vent length (SVL). At the same time βIBD-Cytbwas positively linked to geographic range size. Additionally, π of Cytb gene declined with increasing temperature range variability and body size. In contrast, for 12S rRNA, IBD was present in 42.42% of species but showed no relation with SVL; instead, phylogenetic history played a more substantial role in determining π-12S rRNA. Remarkably, only Cytb showed a positive association between β and π. These results underscore different evolutionary patterns across the two genes and suggest that both, isolation by distance, alongside thermal heterogeneity, shape genetic diversity within particular reproductive modes and phylogenetic contexts inLiolaemus.
Cis-regulatory Mutations Drive Tissue-specific Subfunctionalization of sRNA loci Regulating Soybean Seed Color During Domestication
Authors: Vodkin Lila O. , Jones Sarah I. , Cho Young B.
Published: January 2025

Gene duplication and structural rearrangements have played a pivotal role in plant genome evolution, enabling functional divergence and the development of novel traits. In soybeans (Glycine max), theIlocus, which regulates seed color through tissue-specific subfunctionalization of sRNA loci, offers an example of these mechanisms. Using long-read sequencing, we investigated structural variations underlying four major alleles (I, ii, ik,andi) at theIlocus. Our study revealed that large-scale rearrangements, including duplications, inversions, and deletions, within a 180-kb CHS repeat-rich region drive allele-specific RNA silencing through small interfering RNAs (siRNAs). The dominantIallele contains a cis-regulatory region of DnaJ upstream of CHS genes, while theiiandikalleles feature subtilisin- and P450-driven siRNA loci, respectively. The recessiveiallele lacks siRNA production due to deletions or inversions disrupting CHS gene clusters. Phenotypic analyses and RNA-seq confirmed allele-specific, tissue-dependent expression of siRNAs correlating with seed coat pigmentation patterns. This study highlights the evolutionary role of repeat-rich regions in generating regulatory innovations and phenotypic diversity. Our findings underscore the importance of structural rearrangements in domestication traits and demonstrate the power of long-read sequencing for resolving complex genomic regions, advancing both evolutionary biology and crop improvement.

SIGNIFICANCE

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Naturally occurring mutations in the soybean seed coat have revealed the evolution of sRNA genes and their subfunctionalization, resulting in tissue-specific gene expression.

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Non-homologous recombination of repetitive sequences drives cis-regulatory region rearrangements, leading to the subfunctionalization of sRNA loci that regulates one of domestication traits.
Robustness of a Bistable Biomolecular Positive Feedback Circuit to Global Parametric Perturbations
Authors: Chorasiya G. , Prakash R. , Sen S.
Published: January 2025

Achieving robustness to global perturbations where all parameters can change at the same time is challenging because the controller would also face the same disturbance as the plant. For nonlinear positive feedback, an important mechanism for cell fate determination in biomolecular contexts, quantitative aspects of robustness to such perturbations are generally unclear. Here we used mathematical methods of control and dynamical systems, interval analysis, and a benchmark model of a bistable biomolecular positive feedback circuit to address this. We confirmed that such perturbations can change the qualitative behaviour of the system extinguishing bistability. We obtained a quantitative relation between the relative variation in the stable steady state and the unstable steady state in terms of the relative changes in the parameters. We showed how the deviation in the trajectories near the unstable steady state due to global perturbations could diverge almost exponentially, after an initial transient, which could have a significant impact on the bistable switching dynamics. We found that the size of the eigenvalue for the unstable steady state was greater than that for the stable steady state, and proved this for certain parameters using a rigorous numerical construction. We noted a tradeoff between enhancing the parameter space of bistability and the increased sensitivity in the bistable dynamics due to parametric perturbations. We obtained rigorous bounds on the entire transient response for global parametric perturbations. These results provide a quantitative insight into the robustness of a bistable biomolecular positive feedback circuit to global parametric perturbations.
De novoAutogenic Engineered Living Functional Materials
Authors: Hammad Hoda M. , Swarnadeep Seth , Crater Erin R. , Moore Robert B. , Deshmukh Sanket , Manjula-Basavanna Avinash , Duraj-Thatte Anna M.
Published: January 2025

Autogenic engineered living materials (ELMs) involvein situproduction and engineering of native extracellular matrix (ECM). However, the existing autogenic ELMs have limited scope and functionalities. Herein, we report a platform forde novoautogenic functional ELMs. By protein mining, we have discovered CsgA-like 33,564 homologs that can find potential utility asde novoECM of protein nanofibers. By employing AlphaFold2 and molecular dynamics simulations, we shed insights into the CsgA-like β-solenoid protein structures and stability. By hackingEscherichia colicurli machinery, we demonstrate the production ofde novoautogenic ELMs from CsgA-like proteins (≤9-times the molecular weight and β-sheet repeat units) of extremophilic non-model bacteria. Additionally, we biomanufacture macroscopic materials with tunable mechanical properties (enhancing storage modulus by 3-times) and programmable functionalities (3D printability, binding to nanoparticles/antibodies). This work showcases a versatile platform to discover, rationally design, and harness the sophisticated functionalities of natural systems for futuristic autogenic ELMs.
Patient Experiences of Treatment Deferral for Evaluation and Monitoring after a Trace Xpert Ultra Result
Authors: Visek Caitlin , Mukiibi James , Nantale Mariam , Nalutaaya Annet , Biché Patrick , Sung Joowhan , Kayondo Francis , Akampurira Joab , Mukiibi Michael , Kiyonga Rogers , Katamba Achilles , Kendall Emily A.
Published: January 2025

Background

A “trace” result from the Xpert Ultra molecular TB test indicatesMycobacterium tuberculosisDNA detection but may not always signify TB disease. Little is known about the experiences of individuals with trace results who are not immediately treated.

Methods

We enrolled Ugandan adults and adolescents with trace Xpert Ultra sputum results, plus positive and negative controls, from community-screening and clinic settings. After a comprehensive TB evaluation, participants not recommended to start treatment immediately were closely monitored with interval reassessments. Surveys captured participants’ perceptions and preferences related to their uncertain TB status at baseline and during follow-up.

Results

A total of 321 people with trace sputum (PWTS), 236 positive controls, and 279 negative controls were enrolled. A minority of PWTS thought they were highly likely to have or develop TB, and most reported low associated anxiety initially (258/321, 80%) and during follow-up. While about half (172/321, 54%) would have favored treatment at baseline if not in the study, those who remained untreated were less inclined toward treatment at six months. Participants generally preferred sensitive diagnostic tests, even with frequent false positives.

Conclusions

Deferring treatment for PWTS, with sufficient testing and monitoring, is acceptable to most patients.
Derived Intoxicating Cannabis Vape Product Attributes and Marketing in an Online Retail Environment
Authors: Chen-Sankey Julia , LoParco Cassidy R. , La Capria Kathryn , Meng Siyan , Mazzeo Rosanna , Vijayakumar Neha , Kong Amanda Y. , Tillett Kayla K. , Berg Carla , Rossheim Matthew E.
Published: January 2025

Introduction

The 2018 Farm Bill unintentionally allowed the proliferation of derived intoxicating cannabis vape products (DICVPs), raising concerns about associated health risks. To inform public health prevention efforts, this study analyzed the product attributes and marketing features of DICVPs in an online retail environment.

Methods

In 2023, we extracted information on product attributes and descriptions of 490 DICVPs from two online retail websites with high web traffic. In 2024, two trained coders thematically coded product descriptions for their product characteristics and marketing features.

Results

Overall, 95 unique brands and 26 unique intoxicating cannabinoids were identified. The most frequent marketing features were overall vape product design and use (99.0%), including vaping satisfaction, discreetness, convenience, and use instructions. Regulation and compliance messages (91.6%) were also prevalent, including lab testing for additives and/or chemicals, health warnings, hemp-derived labels, references to the 2018 Farm Bill, and FDA approval statements. Other prominent themes included: flavor and sensation claims (79.6%, i.e., flavor variety, fruit flavors); psychoactive effect claims (43.3%, e.g., potency or expected user experience); product quality claims (38.4%, e.g., “quality,” “natural,” “purity”); and other positive effect claims (33.9%, e.g., mood enhancement, relaxation).

Discussion

The DICVP online marketplace is highly fragmented with a variety of brands and intoxicating compounds. Common marketing strategies promoting appealing flavors and positive vaping experiences may increase product use interest among young people. Features related to product legality and quality may reduce perceived barriers and risks of using products. Continuous monitoring of the DICVP marketplace is needed to inform policymaking.
The Red Thread: Stakeholder Perspectives on Menstrual Health and Hygiene in Ghana
Authors: Gbogbo Sitsofe , Wuresah Israel , Klutse Priscilla , Mantey Sarah Odi , Boateng Ishmael , Nelson Paramount Eli , Charles-Unadike Veronica , El Reda Darline K , Currier Constance
Published: January 2025

Background: Menstrual hygiene management is a challenge for girls and women in Ghana due to a lack of access to affordable menstrual products, water, sanitation, and hygiene (WASH) facilities, inadequate menstrual health education; and social stigma surrounding menstruation. This study aimed to explore the experiences and perspectives of various stakeholders and identify strategies for improving menstrual health and hygiene (MHH) among adolescent girls. Methods: We recruited stakeholders for focus group discussions (FGDs) from basic schools (primary and junior high, grades 1-9) in Hohoe, Volta Region, Ghana. We conducted FGDs with adolescent boys (n=60), parents (n=48), and gatekeepers (n=19). Semi-structured guides were developed and used during FGDs, recorded and supplemented by field notes. Transcripts were thematically analyzed using MAXQDA 2024 software (1). Results: The themes identified were menstrual health management, perceptions and understanding of menstruation, social and cultural practices, and education and awareness. The following strategies were identified: 1) the need for adequate wash facilities, 2) the need to address stigma associated with MHH, 3) the need to reduce the cost of sanitary materials, and 4) the need for improved menstrual health education. Conclusion: These results confirm that cultural stigmas, inadequate facilities, and financial constraints still exist. These act as key barriers to MHH for schoolgirls in Hohoe, Ghana. To support girls' health, dignity, and education, recommendations include inclusive education programs, improved WASH facilities, and affordable and/or sustainable menstrual products.
Brain injury biomarkers in major and simple neurocognitive psychosis: association with tryptophan catabolites
Authors: Al-Hakeim Hussein Kadhem , Al-Issa Ameer Abdul Razzaq , Niu Mengqi , Zhang Yingqian , Maes Michael
Published: January 2025

Background

Schizophrenia is categorized into qualitatively distinct classes, i.e. major (MNP) and simple (SNP) neurocognitive psychosis. MNP is accompanied by more severe neurocognitive deficits and symptomatology, activated immune-inflammatory and oxidative stress pathways, and induction of the tryptophan catabolite (TRYCAT) pathway with increased quinolinic acid (QA) and lowered kynurenic acid (KA) levels.

Aims

To examine whether MNP and increased QA levels are associated with increased brain injury markers, including S100 calcium-binding protein B (S100B), neuroepithelial stem cell protein (Nestin), neuron-specific enolase (NSE), phosphorylated tau217 (pTau217), and glial fibrillary acidic protein (GFAP).

Methods

This case-control study included 52 MNP subjects, 68 SNP subjects, and 60 healthy controls and assessed the above brain injury biomarkers and TRYCATs.

Results

NSE and GFAP were significantly higher in MNP than in SNP, and in both MNP or SNP than in controls. Serum S100B levels were substantially higher in MNP than in controls and SNP. The results indicate injuries to neurofilaments in MNP and SBP, and that MNP is additionally characterized by damage to cell bodies, axons, glial cell projections, reduced neurogenesis and synaptic plasticity as compared with SNP. Increased QA levels and lowered KA predict increased pTau217, NSE and GFAP. The QA/KA ratio is the best predictor of these three brain injury markers

Conclusions

These findings validate the differentiation between the two distinct subclasses with MNP being characterized by more profound injuries to brain cells and structures as compared with SNP. Increases in peripheral QA levels may contribute to these brain injuries in MNP.
A Cysteine-Less and Ultra-Fast Split Intein Rationally Engineered from Being Aggregation-Prone to Highly Efficient in Protein trans-Splicing
Authors: Humberg Christoph , Yilmaz Zahide , Fitzian Katharina , Dörner Wolfgang , Kümmel Daniel , Mootz Henning D.
Published: January 2025

Split inteins ligate their fused extein protein sequences while undergoing self-removal. This unique proteintrans-splicing reaction has been harnessed for numerous applications in protein modification. However, several purified split intein precursors splice only partially or are entirely inactive for unknown reasons. We have studied the split Aes123 PolB1 intein, which splices only to about 30%. As a rare representative of cysteine-less split inteins, the Aes intein is attractive due to its resistance to oxidative conditions and orthogonality to thiol chemistries. We revealed that the reduced splicing efficiency is caused by the formation of soluble, β-sheet dominated aggregates of the N-terminal precursor. We computationally, biochemically and biophysically characterized the fully active monomeric fraction to identify sequence regions important for aggregation. Guided by a crystal structure we designed stably monomeric mutants with virtually complete splicing activity. The triple mutant CLm intein (Cysteine-Less and monomeric) retained the ultra-fast rate discovered for the wildtype and exhibits superior utility as a thiol-independent protein modification tool. Characterization of two other benchmark split inteins suggests that the discovered aggregation propensity reflects an inherent challenge to keep the split intein precursor in the partially disordered form required to fold with its complementary partner into the active complex.