bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thiamin priming to control early blight in potato: investigation of its effectiveness and molecular mechanisms
Authors: Berrian Trenton W. , Fabian Matthew L. , Rogan Conner J. , Anderson Jeffrey C. , Clarke Christopher R. , Goyer Aymeric J. 
Published: September 2024

AbstractBackgroundPrevious reports in several plant species have shown that thiamin applied on foliage primes plant immunity and is effective in controlling fungal, bacterial, and viral diseases. However, the effectiveness of thiamin against potato (Solanum tuberosum) pathogens has seldom been investigated. Additionally, the transcriptomics and metabolomics of immune priming by thiamin have not previously been investigated. Here, we tested the effect of thiamin application againstAlternaria solani,a necrotrophic fungus that causes early blight disease on potato foliage, and identified associated changes in gene expression and metabolite content.ResultsFoliar applications of thiamin reduced lesion size by approximately 33% when applied at an optimal concentration of 10 mM. However, the effect of thiamin on preventing lesion growth was temporally limited, as we observed a reduction of lesion size when leaves were inoculated 4 h, but not 24 h, following thiamin treatment. Additionally, we found that the effect of thiamin on lesion size was restricted to the site of application and was not systemic. Gene expression analysis via RNA-seq showed that thiamin induced the expression of genes involved in the synthesis of salicylic acid (SA) and phenylpropanoids to higher levels than the pathogen alone, as well as fatty acid metabolism genes that may be related to jasmonic acid biosynthesis. Thiamin also delayed the downregulation of photosynthesis-associated genes in plants inoculated withA. solani, which is a typical plant response to pathogens, but could also induce a similar repression of primary metabolic pathways in non-infected leaves. Metabolite analyses revealed that thiamin treatment in the absence of pathogen decreased the amounts of several organic compounds involved in the citric acid cycle as well as sugars, sugar alcohols, and amino acids.ConclusionsOur study indicates that thiamin priming of plant defenses may occur through perturbation of primary metabolic pathways and a re-allocation of energy resources towards defense activities.
Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes inDrosophila
Authors: Mosley Olivia L. , Villa Joel A. , Kamalakkannan Advaitha , James Eliyashaib , Hoffman Jessica M. , Lyu Yang 
Published: September 2024

AbstractDietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols inDrosophilaand to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.
Assessing the Impact of Haulage drivers in Uganda’s COVID-19 Delta Wave
Authors: Muwonge Adrian , Bessell Paul R , Bronsvoort Mark Barend de Clare , Mugerwa Ibrahim , Mwaka Erisa , Ssebaggala Emmanuel , Wee Bryan Aidan , Kiayias Aggelos , Mpyangu Christine Mbabazi , Joloba Moses Lutakome 
Published: September 2024

AbstractBackgroundHaulage truck drivers can quickly connect distant communities, with risks of potential disease introduction. However, interventions to limit such risk must balance public health protection, economic continuity, and individual rights. Here distinguishing between their role in disease introduction and its onward spread is crucial for achieving this balance.MethodsTo investigate the role of haulage during the Delta wave of COVID-19 in Uganda. We fit a susceptible-infectious-recovered (SIR) model to the 625,422 records in the national surveillance dataset to assess the notion of a “core-risk group” by examining the incidence and impact of haulage-targeted interventions in border districts associated with heavy haulage traffic compared to the districts in the central region of Uganda.ResultsAlthough haulage drivers accounted for only 0.036% of the cases, the border districts associated with them registered 12.02% more cases than inland districts, suggesting a role in disease introduction. This risk was particularly higher in Tororo, compared to Amuru and Kyotera, which border Kenya, South Sudan, and Tanzania, respectively. Some interventions even increased the risk in Tororo by as much as 6%. However, in general, the haulage targeted interventions reduced the case load in border districts but registered limited impact on inland districts. This suggests a limited role in secondary within country spread. We note that combining such interventions with vaccination achieved greater reduction in case load.ConclusionsOur findings suggest that truck drivers were a core risk group, though this risk was transient and in some cases exacerbated by some interventions. Pandemic preparedness strategies should characterize risks posed by core groups to ensure interventions balance public safety with individual rights in key sectors like supply chains.
Left ventricular concentric remodeling is highly common among veterans previously deployed to Southwest Asia Theater of Military Operations and associated with impaired exercise performance
Authors: Cassady Steven J. , Abitante Thomas J. , Pappas Gregory G. , Alexander Thomas , Falvo Michael J. ,   Post-Deployment Cardiopulmonary Evaluation Network
Published: September 2024

AbstractBackgroundEnvironmental factors, such as exposure to airborne hazards, contribute to cardiac remodeling through a variety of mechanisms including direct cardiotoxicity. Left ventricular concentric remodeling (LVCR) is a pathological process of adaptive myocardial change that may represent a precursor state for systolic and diastolic dysfunction and left ventricular hypertrophy. Given that potentially cardiotoxic airborne hazards, such as those produced by open burn pits, have been found to occur in excess in active military combat zones, deployed veterans may be at increased risk for adverse cardiac remodeling, but this has not been thoroughly investigated.Methods139 veterans of Southwest Asia Theater of Military Operations underwent transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and health questionnaires. Two-dimensional echocardiography was used to quantify relative wall thickness (RWT) to classify left ventricular (LV) geometry as normal, concentric/eccentric hypertrophy, or LVCR. Observed rates of LVCR were compared to those reported in the Framingham Heart Study, and CPET results were compared between those with and without LVCR. We examined the association between RWT and select CPET outcomes via an adjusted multivariate regression model.ResultsThe prevalence of LVCR in the veteran sample (30.2%) was elevated compared to the Framingham Heart Study cohort (6–16%). Demographics and risk factors were similar between veterans with LVCR and normal geometry; however, veterans with LVCR had reduced exercise capacity (V̇O2,23.7 vs 26.2 ml/kg/min, p<0.05), more inefficient exercise ventilation (VE/V̇CO2nadir: 26.8 vs 25.2, p<0.05), and increased heart rate (HR) reserve (24.7 vs 17.4, p<0.05). RWT was independently associated only with peak HR attained and HR reserve.ConclusionsIn our sample of deployed veterans without significant risk factors, the observed rates of LVCR are 2- to 5-fold greater than those reported in a historical civilian cohort. Further, veterans with LVCR also had impaired exercise performance relative to those with normal LV geometry despite otherwise appearing similar. These findings underscore the importance of cardiovascular assessments as part of a dyspnea evaluation for deployed veterans with airborne hazards exposure and raise concerns about their long-term cardiovascular health.
Integrating multi-tissue expression and splicing data to prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes with therapeutic potential
Authors: Hazelwood Emma , Canson Daffodil M. , Wang Xuemin , Kho Pik Fang , Legge Danny , Constantinescu Andrei-Emil , Lee Matthew A. , Bishop D. Timothy , Chan Andrew T. , Gruber Stephen B. , Hampe Jochen , Marchand Loic Le , Woods Michael O. , Pai Rish K. , Schmit Stephanie L. , Figueiredo Jane C , Zheng Wei , Huyghe Jeroen R. , Murphy Neil , Gunter Marc J. , Richardson Tom G. , Whitehall Vicki L. J. , Vincent Emma E. , Glubb Dylan M. , O’Mara Tracy A. 
Published: September 2024

AbstractNumerous potential susceptibility genes have been identified for colorectal cancer (CRC). However, it remains unclear which genes have a causal role in CRC risk, whether these genes are associated with specific types of CRC, and if they have potential for therapeutic targeting. We performed a multi-tissue transcriptome-wide association study (TWAS) across six relevant normal tissues (n=187-670) and applied a causal framework (involving Mendelian randomisation and genetic colocalisation) to prioritise causal associations between gene expression or splicing events and CRC risk (52,775 cases; 45,940 controls), incorporating sex- and anatomical subsite-specific analyses. We identified 35 genes with robust evidence for a potential causal role in CRC, including ten genes not previously identified by TWAS. Among these genes,SEMA4Demerged as a significant discovery; it is not located at any established CRC genome-wide association study (GWAS) risk locus and its encoded protein is targeted by an antibody currently being clinically studied for CRC treatment. Several genes showed increased expression associated with CRC risk and evidence of CRC cell dependency in CRISPR screen analyses, highlighting their potential as targets for therapeutic inhibition. A female-specific association with CRC risk was observed forCCM2expression, which is involved in progesterone signalling pathways. Subsite-specific associations were also found, including a link between rectal cancer risk and expression ofLAMC1, which encodes a target for a clinically approved drug. Additionally, we performed a focused analysis of established drug targets to further identify potential therapies for CRC, revealingPDCD1, the product of which (PD-1) is targeted by a clinically approved CRC immunotherapy. In summary, our comprehensive analysis provides valuable insights into the molecular underpinnings of CRC and supports promising avenues for therapeutic intervention.
Enhancing Dietary Supplement Question Answer via Retrieval-Augmented Generation (RAG) with LLM
Authors: Hou Yu , Zhang Rui 
Published: September 2024

AbstractObjectiveTo enhance the accuracy and reliability of dietary supplement (DS) question answering by integrating a novel Retrieval-Augmented Generation (RAG) LLM system with an updated and integrated DS knowledge base and providing a user-friendly interface. With.Materials and MethodsWe developed iDISK2.0 by integrating updated data from multiple trusted sources, including NMCD, MSKCC, DSLD, and NHPD, and applied advanced integration strategies to reduce noise. We then applied the iDISK2.0 with a RAG system, leveraging the strengths of large language models (LLMs) and a biomedical knowledge graph (BKG) to address the hallucination issues inherent in standalone LLMs. The system enhances answer generation by using LLMs (GPT-4.0) to retrieve contextually relevant subgraphs from the BKG based on identified entities in the query. A user-friendly interface was built to facilitate easy access to DS knowledge through conversational text inputs.ResultsThe iDISK2.0 encompasses 174,317 entities across seven types, six types of relationships, and 471,063 attributes. The iDISK2.0-RAG system significantly improved the accuracy of DS-related information retrieval. Our evaluations showed that the system achieved over 95% accuracy in answering True/False and multiple-choice questions, outperforming standalone LLMs. Additionally, the user-friendly interface enabled efficient interaction, allowing users to input free-form text queries and receive accurate, contextually relevant responses. The integration process minimized data noise and ensured the most up-to-date and comprehensive DS information was available to users.ConclusionThe integration of iDISK2.0 with an RAG system effectively addresses the limitations of LLMs, providing a robust solution for accurate DS information retrieval. This study underscores the importance of combining structured knowledge graphs with advanced language models to enhance the precision and reliability of information retrieval systems, ultimately supporting better-informed decisions in DS-related research and healthcare.
Single-stranded HDR templates with truncated Cas12a binding sequences improve knock-in efficiencies in primary human T cells
Authors: Nitulescu Ana-Maria , Du Weijie , Glaser Viktor , Kath Jonas , Greensmith Robert , Mikkelsen Nanna Steengaard , Stein Maik , Bak Rasmus O. , Kaminski Michael , Wagner Dimitrios L. 
Published: September 2024

AbstractNon-viral gene editing via CRISPR-Cas12a offers an alternative to Cas9-based methods, providing better targeting of AT-rich regions, simplified guide RNA manufacturing, and high specificity. However, the efficacy of editing outcomes is subject to various factors, with template format playing a crucial role. Currently, the predominant non-viral template format for inducing homology-directed repair (HDR) after nuclease-induced DNA breaks is double-stranded DNA (dsDNA), which is toxic when transfected at high doses. Previous studies have demonstrated that using single-stranded DNA (ssDNA) with flanking double-stranded Cas-target-sequences (CTS) as a repair template for Cas9-mediated gene editing can mitigate this toxicity and increase knock-in efficiency. Here, we investigate CTS design for AsCas12a Ultra by exploring PAM orientation and binding requirements of the Cas12a-crRNA complex. Additionally, we rule outin vitrossDNase activity of AsCas12a Ultra under cell-physiological Mg2+conditions. Finally, we showcase the advantage of using ssDNA with double-stranded CTS end modifications (ssCTS) at high doses for delivering clinically relevant transgenes of varying sizes into three T-cell receptor-CD3 complex genes (TRAC,CD3ζ, CD3ε), achieving up to 90% knock-in rates for a 0.8kb insert at theCD3ε locus. Overall, AsCas12a Ultra and ssCTS donors represent a platform for highly efficient knock-in in primary human T cells with minimal toxicity.
Differential interference with actin-binding protein function by acute Cytochalasin B
Authors: Lambert Christopher , Karger Marius , Steffen Anika , Tang Yubo , Döring Hermann , Stradal Theresia E. B. , Lappalainen Pekka , Faix Jan , Bieling Peter , Rottner Klemens 
Published: September 2024

SummaryDynamic actin filament remodeling is crucial for a plethora of fundamental cell biological processes, ranging from cell division and migration to cell communication, intracellular trafficking or tissue development. Cytochalasin B and -D are fungal secondary metabolites frequently used for interference with such processes. Although generally assumed to block actin filament polymerization at their rapidly growing barbed ends and compete with regulators at these sites, our molecular understanding of their precise effects in dynamic actin structures is scarce. Here we combine live cell imaging and analysis of fluorescent actin-binding protein dynamics with acute treatment of lamellipodia in migrating cells with cytochalasin B. Our results show that in spite of an abrupt halt of lamellipodium protrusion, cytochalasin B affects various actin filament barbed end-binding proteins in a differential fashion. Cytochalasin B enhances instead of diminishes the accumulation of prominent barbed end-binding factors such as Ena/VASP family proteins and heterodimeric capping protein (CP) in the lamellipodium. Similar results were obtained with cytochalasin D. All these effects are highly specific, as cytochalasin-induced VASP accumulation requires the presence of CP, but notvice versa, and coincides with abrogation of both actin and VASP turnover. Cytochalasin B can also increase apparent barbed end interactions with the actin-binding β-tentacle of CP and partially mimic its Arp2/3 complex-promoting activity in the lamellipodium. In conclusion, our results reveal a new spectrum of cytochalasin activities on barbed end-binding factors, with important implications for the interpretation of their effects on dynamic actin structures.
SusC/D-like proteins inGammaproteobacteriathat utilize fructans
Authors: Zühlke Marie-Katherin , Bahr Alexandra , Bartosik Daniel , Solanki Vipul , Teune Michelle , Unfried Frank , Barbeyron Tristan , Ficko-Blean Elizabeth , Cladière Lionel , Jeudy Alexandra , Susemihl Anne , Hartmann Fabian , Jouanneau Diane , Jam Murielle , Höhne Matthias , Delcea Mihaela , Bornscheuer Uwe T. , Becher Dörte , Hehemann Jan-Hendrik , Czjzek Mirjam , Schweder Thomas 
Published: September 2024

AbstractSusC/D-like proteins are essential components of glycan utilization machineries inBacteroidota, but remain unknown in other bacterial phyla. The glycan-binding SusD-like protein forms a ‘lid’ on top of the SusC-like TonB-dependent transporter (TBDT) and both are structurally designed to function as a complex in sugar uptake. In comparison,Gammaproteobacteriaimport glycans using ‘classical’ TBDTs without an accessory SusD-like protein. We have now identified a SusD-like protein and a SusC-like TBDT in a fructan polysaccharide utilization locus (PUL) of the marine gammaproteobacteriumPseudoalteromonas distincta, which are tandemly organized as inBacteroidota. Proteome analysis revealed an increased production of PUL-encoded proteins during growth on inulin- and levan-type fructans. However,P. distinctapreferred inulin over plant-derived levan and hardly grew on bacterial levan. Further analysis showed that the SusD-like protein has a weak affinity (Ka43 M-1) for oligosaccharides from inulin. The PUL-encoded glycoside hydrolase from family 32 (GH32) hydrolyzes inulin and plant-derived levan, but also has a low activity on bacterial levan, which confirms the growth experiments. Comparative genomics identified further SusC/D-like proteins inGammaproteobacteriagenomes, most of which (83%) were encoded in fructan PULs.Significance statementIt is a mystery why the Gram-negativeBacteroidotaandGammaproteobacteriause different transport systems for glycan utilization. In contrast to this observation, we found that the gammaproteobacteriumPseudoalteromonas distinctauses aBacteroidota-like transport complex in fructan uptake, composed of a glycan-binding SusD-like protein and a SusC-like TonB-dependent transporter. Proteome analysis revealed that the SusC/D-like proteins and a fructan-degrading enzyme are produced at high levels in fructan-grown cells. Weak affinity of the SusD-like protein to inulin oligosaccharides and enzyme activity on fructans confirmed their fructan specificity. Further SusC/D-like pairs were detected in otherGammaproteobacteria, mostly associated with fructan-related gene clusters. This study thus describes marine fructan use byGammaproteobacteriaand indicates an exchange of protein functions between phyla.
Complete mitochondrial genomes of riverineLamprologus(Actinopterygii, Cichlidae) with an emphasis on the blind cichlidL. lethops
Authors: Jimenez Sebastian M. , Kurata Naoko P. , Stiassny Melanie L. J. , Alter S. Elizabeth , Chakrabarty Prosanta , Alda Fernando 
Published: September 2024

ABSTRACTLamprologine cichlids are a diverse group of fishes distributed in Lake Tanganyika and the Congo River. Nine species ofLamprologusoccur in the Congo River basin including the only blind cichlidLamprologus lethops, but little is known about the natural history and evolution of this enigmatic species. To alleviate this knowledge gap, we characterized the complete mitochondrial genomes ofL. lethopsand its riverine congeners and provided a phylogenetic hypothesis based on these data. We recovered complete mitochondrial genomes from eleven specimens of eight species ofLamprologus. Mitogenomes were identical in the number and order of genes and similar in size (16,579-16,587 bp). In contrast to previous phylogenomic studies, riverineLamprologuswere recovered in two non-sister mitochondrial lineages that were more closely related to other genera of Lake Tanganyika lamprologines than to each other. In the first lineage, most relationships were not highly supported. In the second lineage,L. lethopswas recovered as the sister species ofL. markerti, L. mocquardiandL. tigripictilis. Interestingly, sequences fromL. mocquardiwere found in the two mitochondrial lineages. Our results hint at multiple events of past introgression and highlight the importance of increasing taxonomic and genomic sampling to study complex evolutionary histories.