bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breaking Free: Development of Circular AAV Cargos for Targeted Seamless Integration in the Liver
Authors: Estes Brett J.G. , Gandhi Nisha , Von Stetina Jessica , Paudel Dev , Nan Angela X. , Amin Parth , Rose Joshua , Wu Shuai , Zheng Kangni , Zhang Yijun , Cochrane Jesse C. , Finn Jonathan D. , Xie Jenny 
Published: October 2024

SummaryRecent advancements in gene insertion have shifted from DNA repair-dependent mechanisms to more precise approaches, enhancing safety and predictability for editing outcomes. Integrase-mediated programmable genomic integration (I-PGI) utilizes a DNA cargo to insert transgenes in a targeted, unidirectional manner.In vivo, where nuclear delivery of DNA is challenging, adeno-associated virus (AAV) can act as the cargo vector. While I-PGI does not require DNA double-stranded breaks (DSBs) for activity, linear DNA cargo, like AAV, stimulates DNA end joining activity after integration. To mitigate potential risks from DSBs with linear viral cargo, we developed two circular genome types capable of seamless gene insertion in non-dividing cells. We first harnessed the orthogonal property of large serine integrases to produce circle-AAV (cAAV) from linear viral genomes in cells. cAAV demonstrated faithful seamless cargo integration in primary human hepatocytes (PHH) and robust DSB-free insertion structuresin vivo. We then investigated the delivery of packaged circular AAV cargo (AAV.AD), which eliminates the need for enzymatic manipulation in the cell. AAV.AD proved to be a viable cargo for I-PGI, exhibiting functional integration in PHH andin vivo, that resulted in seamless insertion structures. Together, these findings provide the first reported evidence of DSB-free programmable genomic integration using integrase and AAV cargo, addressing a previously unrecognized challenge in the field.
Harnessing Smartphone RGB Imagery and LiDAR Point Cloud for Enhanced Leaf Nitrogen and Shoot Biomass Assessment - Chinese Spinach as a Case Study
Authors: Harikumar Aravind , Shenhar Itamar , Pebes-Trujillo Miguel R. , Qin Lin , Moshelion Menachem , He Jie , Ng Kee Woei , Gavish Matan , Herrmann Ittai 
Published: October 2024

AbstractAccurate estimation of leaf nitrogen concentration and shoot dry-weight biomass in leafy vegetables is crucial for crop yield management, stress assessment, and nutrient optimization in precision agriculture. However, obtaining this information often requires access to reliable plant physiological and biophysical data, which typically involves sophisticated equipment, such as high-resolution in-situ sensors and cameras. In contrast, smartphone-based sensing provides a cost-effective, manual alternative for gathering accurate plant data.In this study, we propose an innovative approach for estimating leaf nitrogen concentration and shoot biomass by integrating smartphone RGB imagery with Light Detection and Ranging (LiDAR) data, usingAmaranthus dubius(Chinese spinach) as a case study. The influence of varying nitrogen dosages on individual spectral and structural features derived from smartphone RGB imagery and LiDAR data was modeled. Additionally, the spectral indices from RGB imagery and structural indices from LiDAR data were combined to model both leaf nitrogen concentration and shoot biomass.The performance of crop parameter modeling was evaluated using support vector regression, random forest regression, and lasso regression. Results demonstrate that the combined use of smartphone RGB imagery and LiDAR data can accurately estimate leaf total reduced nitrogen concentration, leaf nitrate concentration, and shoot dry-weight biomass, with average relative root mean square errors as low as 0.06, 0.16, and 0.05, respectively. Furthermore, the optimal nitrogen dosage for maximizing biomass yield in Chinese spinach was also estimated using the smartphone data. This study lays the groundwork for smartphone-based estimate leaf nitrogen concentration and shoot biomass, supporting accessible precision agriculture practices.
EGF and IgA in maternal milk, donor milk and milk fortifiers in the Neonatal Intensive Care Unit setting
Authors: Tamar Christian , Greenfield Kara , McDonald Katya , Levy Emily , Brumbaugh Jane , Knoop Kathryn 
Published: October 2024

AbstractHuman milk contains a variety of factors that positively contribute to neonatal health, including epidermal growth factor (EGF) and immunoglobulin A (IgA). When maternal milk cannot be the primary diet, maternal milk alternatives like donor human milk or formula can be provided. Donor human milk is increasingly provided to infants born preterm or low birth weight with the aim to supply immunological factors at similar concentrations to maternal milk. We sought to assess the concentrations of human EGF and IgA in the diet and stool of neonates between exclusive maternal milk, donor human milk, or formula-based diets. Using a prospective cohort study, we collected samples of diet and stool weekly from premature and low birth weight neonates starting at 10 days postnatal through five weeks of life while admitted to a neonatal intensive care unit (NICU). Compared to formula, there was significantly more EGF in both the milk and the stool of the infants fed human milk. Donor milk pooled from multiple donors contained similar concentrations of EGF and IgA to maternal milk, which was also significantly more compared to formula diets. Maternal milk fortified with fortifier derived from human milk contained significantly more EGF and IgA compared to unfortified maternal milk or maternal milk fortified with fortifier derived from bovine milk. Further analysis of human milk-derived fortifiers confirmed these fortifiers contained significant concentrations of EGF and IgA, contributing to an increased concentration of those factors when added to maternal milk compared to bovine milk-derived fortifiers. These findings illustrate how the choice of diet for a newborn, and even how that diet is modified through fortifiers or pasteurization before ingestion, impacts the beneficial biomolecules the infant receives from feeding.
Semi-supervised Contrastive Learning for Bioactivity Prediction using Cell Painting Image Data
Authors: Bushiri Pwesombo David , Beese Carsten , Schmied Christopher , Sun Han 
Published: October 2024

AbstractMorphological profiling has recently demonstrated remarkable potential for identifying the biological activities of small molecules. Alongside the fully supervised and self-supervised machine learning methods recently proposed for bioactivity prediction from Cell Painting image data, we introduce here a semi-supervised contrastive (SemiSupCon) learning approach. This approach combines the strengths of using biological annotations in supervised contrastive learning and leveraging large unannotated image datasets with self-supervised contrastive learning. SemiSupCon enhances downstream prediction performance of classifying MeSH pharmacological classifications from PubChem, as well as mode of action and biological target annotations from the Drug Repurposing Hub across two publicly available Cell Painting datasets. Notably, our approach has effectively predicted the biological activities of several unannotated compounds, and these findings were validated through literature searches. This demonstrates that our approach can potentially expedite the exploration of biological activity based on Cell Painting image data with minimal human intervention.
Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm
Authors: Vasileva Elena , Arata Claire , Luo Yongfeng , Burgos Ruben , Gage Crump J. , Amatruda James F. 
Published: October 2024

AbstractEwing sarcoma is a malignant small round blue cell tumor of bones and soft tissues caused by chromosomal translocations that generate aberrant fusion oncogenes, most frequently EWSR1::FLI1. The cell of origin and mechanisms of EWSR1::FLI1-driven transformation have remained unresolved, largely due to lack of a representative animal model. By developing a zebrafish Ewing sarcoma model, we provide evidence for a neural crest origin of this cancer. Neural crest-derived cells uniquely tolerate expression of EWSR1::FLI1 and targeted expression of EWSR1::FLI1 in these cells generates Ewing sarcomas. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins throughout the body. By profiling chromatin accessibility and genome-wide EWSR1::FLI1 binding, we find that the fusion oncogene hijacks developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation. These findings show how a single mutation profoundly alters embryonic cell fate decisions to initiate a devastating childhood cancer.
Tuning and validation of a virtual mechanical testing pipeline for condylar stress fracture risk assessment in Thoroughbred racehorses
Authors: Irandoust Soroush , Whitton R. Christopher , Henak Corinne R. , Muir Peter 
Published: October 2024

AbstractCondylar stress fracture of the third metacarpal/metatarsal bone (MC3/MT3) in Thoroughbred racehorses is a common catastrophic injury, putting racehorse and jockey safety at risk. Microdamage forms in the distal MC3 and may result in strain elevation and higher risk of stress fracture, directly and through focal osteolysis resulting from the associated process of repair by remodeling in the condylar parasagittal grooves (PSG). Standing computed tomography (sCT) is a practical screening tool for detection of fatigue-induced structural changes, but the clinical interpretation remains subjective. The goal of this study was to develop and validate a sCT-based subject-specific finite element analysis (FEA) pipeline for virtual mechanical testing of the distal MC3. Twelve (n=12) MC3 condyles with availableex vivostrain were selected. Half of the specimens were used for tuning of the Young’s modulus in fatigue sites, and the other half to examine validity of the pipeline for prediction of PSG strain. The tuned model improved prediction of strain and predicted higher strain in bones with PSG lysis over the untuned model, which is an essential feature for a diagnostic screening tool. The presented pipeline is expected to assist clinicians with interpretation of sCT-detectable structural changes and ultimately condylar fracture risk assessment.
Site-specific free energy surface parameters from single-molecule fluorescence measurements of exciton-coupled (iCy3)2dimer probes positioned at DNA replication fork junctions
Authors: Maurer Jack , Albrecht Claire S. , von Hippel Peter H. , Marcus Andrew H. 
Published: October 2024

AbstractSingle-stranded (ss) – double-stranded (ds) DNA replication forks and primer-template junctions are important recognition sites for the assembly and function of proteins involved in DNA replication, recombination and repair. DNA ‘breathing’ – i.e., thermally-induced local fluctuations of the sugar-phosphate backbones and bases – can populate metastable conformational macrostates at positions near such junctions and likely play key roles in the functional interactions of the regulatory proteins that bind at these sites. Recently, Maureret al. (1) performed polarization-sweep single-molecule fluorescence (PS-SMF) studies on exciton-coupled (iCy3)2dimer-labeled ss-dsDNA fork constructs, which revealed that the nucleobases and backbones immediately adjacent to the dimer probes undergo conformational fluctuations on time scales ranging from hundreds-of-microseconds to hundreds-of-milliseconds. The local conformations sensed by the dimer probes consist of four quasi-stable macrostates whose populations and dynamics depend on dimer probe position relative to these junctions. Here we present theoretical analyses of these PS-SMF data that quantify the relative stabilities and activation barriers of the free energy surfaces (FESs) of site-specific DNA ‘breathing’ events at key positions within these junctions. Our results suggest a detailed molecular picture for DNA ‘breathing’ at these positions, thus providing insights into understanding the molecular mechanisms of the proteins that operate at these sites.
Sirtuin2 blockade inhibits replication of Human Immunodeficiency Virus-1 andMycobacterium tuberculosisin macrophages and humanized mice
Authors: Singh Vipul. K. , Mishra Abhishek , Truong Khangy , Bohorquez Jose Alejandro , Sharma Suman , Khan Arshad , Bracher Franz , Zhang Kangling , Endsley Janice , Endsley Mark , Rice Andrew P. , Kimata Jason T. , Yi Guohua , Jagannath Chinnaswamy 
Published: October 2024

ABSTRACTCoinfections withMycobacterium tuberculosis(Mtb) and HIV-1 present a critical health challenge and require treatment for survival. We found that human M1 macrophages inhibit Mtb growth, while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, we found that HIV-1 augmented Sirt2 gene expression in MФs. Therefore, we explored the therapeutic potential of sirtuin-modulating drugs in MФs. Sirtinol, a Sirt2 inhibitor, significantly reduced HIV-1 growth in M0, M1, and M2-MФs by >1 log10 over 7 days. Conversely, individual doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with resveratrol was neither synergistic nor antagonistic. Sirtinol upregulatediNOSandATG5mRNA in HIV-1 infected MФs in a phenotype-dependent manner. In a humanized mouse model (Hu-NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, or in combination with combination antiretroviral therapy (cART), showed promising results; Sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel dual therapeutic strategy for treating HIV-1 and Mtb coinfections.
Identification of diagnostic KASP markers for selection of crown rust resistance in oats
Authors: Nguyen Duong T. , Lewis David , Henningsen Eva C. , Mago Rohit , Sperschneider Jana , Dodds Peter N. , Figueroa Melania 
Published: October 2024

AbstractOat crown rust, caused byPuccinia coronataf. sp.avenae, poses a significant threat to global oat production (Avena sativaL.). Molecular markers are essential to assist in the integration of multiple resistance genes into a single oat cultivar to achieve genetic resistance durability. Here, we validated previously reported markers for the race-specific resistance genesPc39,Pc45/PcKM,Pc54, andPc68, and developed new KASP markers closely linked to these loci. These markers were subsequently screened across a collection of 150 oat cultivars. Analysis of molecular marker data, pedigree information, and disease resistance profile indicated several oat cultivars likely carryingPc39andPc68. Newly identified carriers ofPc68include the cultivars Galileo and Graza80, while Warrego, Kowari, Possum, Forester, Drummond, Hokonui, Glider, and Culgoa were identified as potential carriers ofPc39. Discrepancies between the previous postulation ofPcgene carriers and our phenotyping and genotyping analysis were also found. For example, the oat line Glider was previously postulated to carryPc58orPc59,but it was positive for thePc39-associated marker and had a similar resistance profile toPc39carriers. These findings underscore the importance of the utilisation of molecular markers in tracking the resistance genes in breeding germplasm.Key messageThis study has developed and validated KASP molecular markers associated with crown rust resistance genesPc39,Pc45/PcKM,Pc54, andPc68that could be used for marker-assisted selection in oats.
The epidemiology of Brucellosis and Q fever in a cross-sectional serosurvey of occupationally exposed groups in peri-urban Lomé, Togo
Authors: Kerr Charlotte L. , Patassi Akouda , Pato Pidemnéwé S. , Guitian Javier , Diop Sylvie Audrey , Mangtani Punam , Nguipdop-Djomo Patrick 
Published: October 2024

AbstractBackgroundBrucellaspecies andCoxiella burnetiihave been detected in livestock populations in Togo. Populations exposed to livestock ruminants through occupation may be at increased risk of infection.Methods/Principal FindingsA cross-sectional serosurvey was conducted in 108 abattoir and 81 dairy farm workers (from 52 dairy farms) in peri-urban Lomé, Togo in 2019-2020. Sera were tested using the Rose Bengal plate agglutination test (RBT) and the indirect Brucella IgG Enzyme-Linked Immunosorbent Assay (ELISA) for Brucella, and the IgG ELISA forCoxiella burnetiiin Phase 1 and in Phase 2. Fresh bulk milk from farms were tested using an indirect milk ELISA for Brucella IgG.Eighteen workers (9.5%, 95% CI 5.5-16.0) were Brucella seropositive. Twenty-eight percent (95% CI 22.5-34.3) of workers were seropositive forC. burnetii. Twenty of fifty-one farms which gave milk samples tested positive for Brucella (39.2%, 95% CI 26.6 - 53.4%).Farmworkers had nearly twice the odds of being Brucella seropositive compared to abattoir workers (OR 1.93, 95% CI: 0.94-3.93, p=0.07). In farmworkers, working on farms with animal ill health, a positive milk test, participating in small animal husbandry and assisting with cattle abortion were all associated with increased odds of seropositivity. Workers who consumed unboiled milk at least every month were more likely to be seropositive (OR 3.79, 95% CI: 2.34-6.13, p<0.001) while participants who consumed fermented milk and cheese had greater odds of being seropositive forC.burnetii(OR 1.59, 95% CI: 1.26-2.00, p<0.001 and OR 1.70, 95% CI: 0.97-2.98, p=0.07 respectively).ConclusionsLivestock workers in peri-urban Lome have been exposed to bothBrucellaandCoxiella burnetiidbacteria. The widespread consumption of unboiled dairy products and lack of PPE use is of concern as both dairy consumption and participation in animal husbandry activities have been seen to increase odds of seropositivity for both pathogens.Author summaryHuman and animal health are inextricably linked, particularly for those who live and work closely with animals. Brucellosis and Q fever are two zoonotic diseases transmitted through animal contact and dairy product consumption, which cause non-specific fevers and for which diagnostic tests are lacking in many LMIC contexts. Previous studies have shown that both bacteria circulate in livestock in Togo. We undertook a survey in dairy farm and abattoir workers in peri-urban Lomé, Togo, and found that 9.5% and 28% of workers were seropositive forBrucellaandC.burnetiirespectively. We found that risk factors included animal husbandry practices and consumption of dairy products. Mitigating practices such as the use of PPE and boiling milk are simple ways that livestock workers could protect themselves from these and other zoonotic disease.
Untangling age and menopausal status reveals no effect of menopause on white matter hyperintensity volume
Authors: Wezel Denise , Parent Olivier , Costantino Manuela , Sifi Lina , Pigeau Grace , Gervais Nicole J. , McQuarrie Ann , Maranzano Josefina , Devenyi Gabriel Allan , Dadar Mahsa , Chakravarty M. Mallar 
Published: October 2024

AbstractBackground and objectivesWhite matter hyperintensities (WMHs) are radiological abnormalities indicative of cerebrovascular dysfunction associated with increased risk for cognitive decline and increase in prevalence in older age. However, there are known sex-differences as older females harbour higher WMH burden than males. Some have hypothesized that the increase in this dementia-related risk factor is related to the menopausal transition.MethodsTo untangle the effects of age and menopause, we leveraged a large sample from the UK Biobank (n = 10,519) to investigate differences in WMH volumes across the menopausal transition using a strict age-matching procedure.ResultsSurprisingly, we find increased WMH volumes in premenopausal women compared to postmenopausal women when simply correcting for age with linear models, but we find no effect in the age-matched sample. Menopause-related characteristics, such as age at menopause or hormone replacement therapy, did not replicate previous literature reporting an association with WMH volumes. Cardiovascular lifestyle variables, such as smoking and blood pressure, were significant predictors of WMH volume in the full sample without age-matching. These effects varied by menopausal status only for days of moderate activity.DiscussionIn sum, our findings in a well-powered study suggest that previous reports of menopause-related differences in WMH burden are potentially confounded by age. We further show that the effect of positive lifestyle factors on brain health, as indexed with WMH burden, generally does not change after menopause. Factors other than the menopausal transition are likely at play in explaining the difference in WMH burden between males and females in later life.
HORNET: Tools to find genes with causal evidence and their regulatory networks using eQTLs
Authors: Lorincz-Comi Noah , Yang Yihe , Ajayakumar Jayakrishnan , Mews Makaela , Bermudez Valentina , Bush William , Zhu Xiaofeng 
Published: October 2024

AbstractMotivationNearly two decades of genome-wide association studies (GWAS) have identify thousands of disease-associated genetic variants, but very few genes with evidence of causality. Recent methodological advances demonstrate that Mendelian Randomization (MR) using expression quantitative loci (eQTLs) as instrumental variables can detect potential causal genes. However, existing MR approaches are not well suited to handle the complexity of eQTL GWAS data structure and so they are subject to bias, inflation, and incorrect inference.ResultsWe present a whole-genome regulatory network analysis tool (HORNET), which is a comprehensive set of statistical and computational tools to perform genome-wide searches for causal genes using summary level GWAS data that is robust to biases from multiple sources. Applying HORNET to schizophrenia, we identified differential magnitudes of gene expression causality. Applying HORNET to schizophrenia, we identified differential magnitudes of gene expression causality across different brain tissues.Availability and ImplementationFreely available athttps://github.com/noahlorinczcomi/HORNETorMac, Windows, and Linux users.Contactnjl96@case.edu.
Reducing Information and Selection Bias in EHR-Linked Biobanks via Genetics-Informed Multiple Imputation and Sample Weighting
Authors: Salvatore Maxwell , Kundu Ritoban , Du Jiacong , Friese Christopher R , Mondul Alison M , Hanauer David , Lu Haidong , Pearce Celeste Leigh , Mukherjee Bhramar 
Published: October 2024

ABSTRACTElectronic health records (EHRs) are valuable for public health and clinical research but are prone to many sources of bias, including missing data and non-probability selection. Missing data in EHRs is complex due to potential non-recording, fragmentation, or clinically informative absences. This study explores whether polygenic risk score (PRS)-informed multiple imputation for missing traits, combined with sample weighting, can mitigate missing data and selection biases in estimating disease-exposure associations. Simulations were conducted for missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) conditions under different sampling mechanisms. PRS-informed multiple imputation showed generally lower bias, particularly when combined with sample weighting. For example, in biased samples of 10,000 with exposure and outcome MAR data, PRS-informed imputation had lower percent bias (3.8%) and better coverage rate (0.883) compared to PRS-uninformed (4.5%; 0.877) and complete case analyses (10.3%; 0.784) in covariate-adjusted, weighted, multiple imputation scenarios. In a case study using Michigan Genomics Initiative (n=50,026) data, PRS-informed imputation aligned more closely with a sample-weighted All of Us-derived benchmark than analyses ignoring missing data and selection bias. Researchers should consider leveraging genetic data and sample weighting to address biases from missing data and non-probability sampling in biobanks.