bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)
Authors: Blankenship Kaley , Chang Ti-Cheng , Fan Yiping , Gordon Brittney , Wright William C. , Kieffer Matthew , Karlstrom Asa , Jeon Jongrye , Patel Anand G. , Dapper Jason , Caufield William V. , Freeman Burgess B. , Federico Sara , Clay Michael R. , Wu Gang , Zhou Xin , Hoffmann Lauren , Geeleher Paul , Dyer Michael A. , McEvoy Justina , Stewart Elizabeth 
Published: July 2024

AbstractPediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.Translational RelevanceThis study demonstrates the value of utilizing fully characterized preclinical models of pediatric solid tumors to evaluate the response to precision medicine approaches. Our results demonstrate the importance of performing comprehensive preclinical testing using multiple orthotopic patient derived xenografts to validate and prioritize vulnerabilities identified through genomic or integrated analyses which can be translated into clinical trials. Importantly, this study identified combinations using nano-liposomal irinotecan in a precision drug delivery approach that may benefit pediatric solid tumor patients. In addition, all models and their associated data are made freely available to the scientific community through the Childhood Solid Tumor Network.
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth ofMycobacterium tuberculosis
Authors: Simwela Nelson V. , Jaecklein Eleni , Sassetti Christopher M. , Russell David G. 
Published: July 2024

AbstractMycobacterium tuberculosis(Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellularMtbutilize host derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellularMtb. Our analyzes demonstrate that macrophages which cannot either import, store or catabolize fatty acids restrictMtbgrowth by both common and divergent anti-microbial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive toMtbreplication, but increased induction of the same fails to rescueMtbgrowth. Our work expands our understanding of how host fatty acid homeostasis impactsMtbgrowth in the macrophage.
Cleavage region organizes the structural architecture of the B2 SINE ribozyme
Authors: Singhal Ankush , Mrozowich Tyler , Chaudhury Susmit Narayan , Rivera Carlos , Badmalia Maulik , Lee Jeannie T. , Patel Trushar R. , Sanbonmatsu Karissa Y. 
Published: July 2024

AbstractThe SINE-encoded B2 retrotransposon is an RNA Polymerase III transcript that gets upregulated during various cellular stress responses. The B2 noncoding RNA can directly inhibit RNA Polymerase II, leading to a significant downregulation of transcripts during stress. Our recent findings have shown that B2 is a self-cleaving epigenetic ribozyme and that cleavage can be induced by interactions with epigenetic factors, co-regulating its function across distinct chromatin-binding target loci. Here, by integrating RNA chemical probing, small angle X-ray scattering, and 3D motif modeling, we determine structural ensemble-to-function relations for the B2 SINE ribozyme RNA. Perturbations of the RNA suggest that the B2 SINE ribozyme has a well-defined secondary structure and dynamic tertiary structure that both critically depend on the presence of the active site of cleavage. In an RNA engineering approach, we examine the effect of point mutations, deletions of the main cleavage site and deletions of the cleavage domain on the structural ensemble of the RNA. By combining this with functional data, we obtain relations of structural ensembles to various functional states. This perturbative approach serves as a template to unravel the relation of structural ensembles to functional states for other ncRNA and mRNA systems.
Red harvester ants (Pogonomyrmex barbatus) do not distinguish between sorghum head mold symptomatic and asymptomatic seeds
Authors: Elliott-Vidaurri Lilly V. , Penn Hannah J. , Choudhury Robin A. 
Published: July 2024

ABSTRACTRed harvester ants,Pogonomyrmex barbatus(Smith) (Hymenoptera: Formicidae), common in the Lower Rio Grande Valley of Texas, are known to gather seeds from areas around their nests and store the seeds inside their nests for later consumption. As these ants often nest in and near agricultural fields, some of these seeds may be from crops and may also be infected with fungal plant pathogens. These pathogens can degrade seed coats and may cause the seeds to rot within the ant nests, decreasing storage time and potentially spreading the pathogen to other stored seeds. We studied how head mold, a common sorghum disease, changed ant preferences for sorghum seeds. Using seed depots, we evaluated foraging preferences for sorghum seeds with and without head mold and then monitored how many seeds of each type were collected by the colonies after 1, 2, 4, and 24 hours. We found that red harvester ants did not have any significant preference for infected or uninfected seeds, taking both equally over time. Given this non-preference, ants were assumed to be storing infected seeds next to uninfected seeds within their colonies. However, the risk that stored pathogen-infected seeds poses as a source of future seed infection to seeds within the nest and plants in the surrounding field needs to be further examined.
Cryptosporidiumoocysts andGiardiacysts at two South African wastewater treatment plants
Authors: Gonose Thandubuhle , Du Preez Hein , Venter Stephanus N , Grundlingh Monique 
Published: July 2024

ABSTRACTCryptosporidiumandGiardiaare one of the most prominent parasitic protozoans found in wastewater treated by wastewater treatment plants (WWTPs). They cause Cryptosporidiosis and Giardiasis respectively, which can be fatal in immuno-compromised individuals. Thus, their removal by WWTPs is essential. This study aimed at investigating the prevalence ofCrytposporiumandGiardiathrough treatment processes at two South African wastewater treatment plants and assessing the efficiency of the WWTPs in removing them. A total of 162 samples (54 raw influents, 36 primary treated effluents, 36 secondary treated effluents and 36 final treated effluents) were collected from two South African WWTPs over a period of one year. Results obtained from the study show thatCryptosporidiumwas detected in 98% (159/162) of the samples collected, whilst Giardia was detected in 99% (160/162) of the samples collected from both wastewater treatment plants. BothCrytposporiumandGiardiawere detected in 100% (n=54) of raw influent samples. The same result was obtained in primary treated effluent, where bothCryptosporidiumandGiardiawas detected in 100% (n=36) of the samples collected. In secondary treated effluent, 36 samples were collected andCryptosporidiumwas detected in 94% of the samples, whereasGiardiawas detected in 100% of the samples. In the final treated effluent samples, bothCryptosporidiumandGiardiawhere detected 97% (n=36) of the samples collected. Detection ofCryptosporidiumandGiardiain most of the wastewater treatment stages indicated these parasites are prevalent in the two WWTPs. Although the two WWTPs showed high removal of the two parasites in wastewater, their presence in the final treated effluent indicated the inefficiency of treatment processes in their removal. This highlights the potential of these WWTPs in contaminating receiving water sources.IMPORTANCE OF THE STUDYThis study will specifically evaluate the removal of Cryptosporidium oocysts and Giardia cysts by two South African WWTPs and will estimate their ability of removing them. The study will also attempt to give insight into the potential and extend of treated effluent in polluting surface water resources with respect to Cryptosporidium and Giardia. Identification of the potential sources of the pollution is one of the significant parts in resolving this problem. Hence the finding of the study are very important in an endeavour to eliminate pollution of water source.
ASO-mediated knockdown of GPNMB in mutant-GRNandGrn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses
Authors: Wallings Rebecca L. , Gillett Drew A. , Staley Hannah A. , Mahn Savanna , Mark Julian , Neighbarger Noelle , Kordasiewicz Holly , Hirst Warren D. , Tansey Malú Gámez 
Published: July 2024

AbstractBackgroundIncreases in GPNMB are detectable in FTD-GRNcerebrospinal fluid (CSF) and post-mortem brain, and brains of agedGrn-deficient mice. Although no upregulation of GPNMB is observed in the brains of youngGrn-deficient mice, peripheral immune cells of these mice do exhibit this increase in GPNMB. Importantly, the functional significance of GPNMB upregulation in progranulin-deficient states is currently unknown. Given that GPNMB has been discussed as a potential therapeutic target inGRN-mediated neurodegeneration, it is vital for the field to determine what the normal function of GPNMB is in the immune system, and whether targeting GPNMB will elicit beneficial or deleterious effects.MethodsThe effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRNpatients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn-/-) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription.ResultsWe demonstrate here that ASO-mediated knockdown of GPNMB increases lysosomal burden and cytokine secretion in FTD-GRN carrier and neurologically healthy controls (NHCs) monocytes. ASO-mediated knockdown of GPNMB inGrn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation. In addition, ASO-mediated knockdown of GPNMB increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages fromGrn-deficient females. Finally, ASO-mediated knockdown of GPNMB dysregulated IFNγ-stimulated cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the GPNMB extracellular fragment (ECF).ConclusionsOur data herein reveals that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells via secretion of its ECF. Therefore, in progranulin-deficient states, the drastic upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion in FTD-GRNwould not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions.
Murine aortic valve cell heterogeneity at birth
Authors: Bluemn Theresa , Kessler Julie R. , Kim Andrew J , Drnevich Jenny , Lincoln Joy 
Published: July 2024

ABSTRACTHeart valve function requires a highly organized extracellular matrix (ECM) network that provides the necessary biomechanical properties needed to withstand pressure changes during each cardiac cycle. Lay down of the valve ECM begins during embryogenesis and continues throughout postnatal stages when it is remodeled into stratified layers and arranged according to blood flow. Alterations in this process can lead to dysfunction and if left untreated, heart failure. Despite this, the mechanisms that establish structure-function relationships of the valve, particularly during postnatal maturation, are poorly understood. To address this, single cell transcriptomics was performed on murine aortic valve structures at postnatal day one (PND1). Overall, 18 clusters of 7 diverse cell populations were identified, including a novel VEC subpopulation unique to PND1, and three previously unappreciated VIC subpopulations defined as “primitive”, “remodeling” and “bioactive”. Additional lineage tracing of the “primitive” VIC subpopulation in mice uncovered a temporal and spatial trajectory throughout postnatal maturation. In summary, this work highlights the heterogeneity of cell types within the aortic valve structure at birth that contribute to establishing and maintaining structure and function throughout life.
Effectiveness of Pasteurization for the Inactivation of H5N1 Influenza Virus in Raw Whole Milk
Authors: Alkie Tamiru , Nasheri Neda , Romero-Barrios Pablo , Catford Angela , Krishnan Jay , Pama Lemarie , Hooper-McGrevy Kathleen , Nfon Charles , Cutts Todd , Berhane Yohannes 
Published: July 2024

AbstractHighly pathogenic avian influenza (HPAI) clade 2.3.4.4b H5Nx viruses continue to cause episodic incursions and have been detected in more than 12 taxonomic orders encompassing more than 80 avian species, land and marine mammals, including recent detections in dairy cattle. The HPAI H5N1 spillover to these important livestock species creates a new interface for human exposure and raises food safety concerns. Presence of H5N1 genetic material in one out of five retail pasteurized milk samples in the USA has prompted the evaluation of pasteurization processes for the inactivation of influenza viruses. Our study examined whether pasteurization could effectively inactivate HPAI H5N1 inoculated raw whole milk samples. We heated 1 mL of non-homogenized cow’s milk samples to attain an internal temperature of 63°C or 72°C and spiked with 6.3 log EID50of clade 2.3.4.4b H5N1 virus. Complete inactivation was achieved after incubation of the H5N1 spiked raw milk at 63°C for 30 minutes. In addition, complete viral inactivation was observed in seven out of eight replicates of raw milk samples treated at 72°C for 15 seconds. In one replicate, a 4.56 log reduction was achieved, which is about 1 log higher than the average viral quantities detected in bulk tanks in affected areas. Therefore, we conclude that pasteurization of milk is an effective strategy for mitigation of risk of human exposure to milk contaminated with H5N1 virus.
Staphylococcal superantigens promote bacterial persistence following postoperative surgical site infection
Authors: Dufresne Karine , Tuffs Stephen W. , Walton Nicholas R. , Kasper Katherine J. , Mohorovic Ivor , Hasan Farah , Bentall Tracey , Heinrichs David E. , Delport Johan , Mele Tina S. , McCormick John K. 
Published: July 2024

AbstractStaphylococcus aureusis a predominant cause of postoperative surgical site infections and persistent bacteremia. Here we describe a patient that following a total knee arthroplasty subsequently experienced three episodes ofS. aureusbacteremia over a period of 4 months. The initial blood stream isolate (SAB-0429) was a clonal complex (CC) 5 and methicillin resistantS. aureus(MRSA), whereas two subsequent blood stream isolates (SAB-0485 and SAB-0495) were CC5 isolates but methicillin sensitiveS. aureus(MSSA). The two latter isolates harbored a plasmid encoding three superantigen genes not present in the primary MRSA isolate. SAB-0485 and SAB-0495 expressed the plasmid encoded staphylococcal enterotoxin R (SER) exotoxin and demonstrated increased superantigen activity compared with SAB-0429. Compared to SAB-0429, the latter isolates also demonstrated an increased bacterial burden in a mouse bacteremia model that was dependent on increased IFNγ production. Curing of the plasmid from SAB-0485 reduced this virulence phenotype. These findings suggest that the superantigen exotoxins may provide a selective advantage in chronic postsurgical infections.
Unhealthful plant-based diet associates with frailty risk predominantly in men with low income from the UK Biobank cohort
Authors: Schorr Kerstin , Rodriguez-Girondo Mar , van den Berg Niels , de Groot Lisette CPMG , Slagboom P. Eline , Beekman Marian 
Published: July 2024

AbstractObjectivePlant-based diets (PBD) are generally promoted as beneficial for health. However, whether this is also the case at older ages, when energy deficits, muscle loss and frailty affect health, is unclear. Research has shown that among older adults, particularly in men, a healthful PBD is associated with a lower frailty risk. This relation was however, not studied in the context of socio-economic status (SES), a major factor influencing the risk of frailty. Therefore, we aim to assess whether plant-based diets associate with frailty risk at older ages and whether this association is moderated by sex and income in a large population-based dataset.Methodswe investigated data from the UK Biobank (UKB) (n=73 180, mean age=55.48±7.87). We applied a plant-based diet index [range 17-85], differentiating between a healthful (hPDI) and unhealthful plant-based diet (uPDI). Frailty was assessed by the Fried frailty phenotype and categorized into 0-4 symptoms of frailty. Average household income was divided into three categories: low (<18.000 £), medium (18.000-52.000 £) and high (>52.000 £). We applied an ordinal logistic regression model with frailty as the categorical outcome and PDI as continuous predictor while adjusting for age, sex, ethnicity, education, BMI and UKB assessment center. Secondly, we included an interaction term (PDI*sex*income). To identify subgroups driving any interactions, we stratified by sex and subsequently by income group to determine the effect of PDI in subgroups while additionally adjusting for lifestyle factors.Resultsa 10-unit increase in hPDI, was associated with 3.4% lower odds for frailty (OR=0.966, 95%CI [0.946, 0.987]), whereas a 10-unit increase in uPDI was associated with 7.7% greater odds for frailty (OR=1.077, 95%CI [1.054, 1.101]). The association between uPDI and frailty was moderated by income and sex (uPDI*income*sex, p=0.002), whereas no such moderation was found for hPDI (p=0.602). Subsequent stratification reveals a significant effect of uPDI on frailty particularly among men with low income (OR=1.177, 95% CI [1.069, 1.298]), but not for women. This association in men largely persisted after adjustment for additional lifestyle factors (OR=1.119, 95%CI [0.995, 1.258]).Conclusionwe observed that adherence to an unhealthful plant-based diet was associated with a higher risk for frailty. This relation was especially observed for men with lower incomes and not explained by other lifestyle factors. Therefore, this group may profit from refraining from an unhealthful plant-based diet.HighlightsHealthful plant-based diet associated with lower frailty riskAssociation of unhealthful plant-based diet and higher frailty risk is moderated by income and sexUnhealthful plant-based diet is associated with frailty particularly in men with low income
Five-year changes in 24-hour sleep-wake activity and dementia risk in oldest old women
Authors: Milton Sasha , Cavaillès Clémence , Ancoli-Israel Sonia , Stone Katie L , Yaffe Kristine , Leng Yue 
Published: July 2024

ABSTRACTINTRODUCTIONSleep disruptions are associated with cognitive aging in older adults. However, it is unclear whether longitudinal changes in 24-hour multidimensional sleep-wake activity are linked to cognitive impairment in the oldest old.METHODSWe studied 733 cognitively unimpaired women (mean age=82.5±2.9 years) who completed two actigraphy assessments over five years. We performed hierarchical clustering on principal components in nine sleep, napping, and circadian rest-activity rhythm parameters to identify multidimensional sleep-wake change profiles and multinomial logistic regression to evaluate the associations between sleep-wake changes and risk of cognitive impairment at follow-up.RESULTSWe identified three sleep-wake change profiles: Stable Sleep (43.8%), Declining Nighttime Sleep (34.9%), and Increasing Sleepiness (21.3%). After adjustment for demographics and comorbidities, women with Increasing Sleepiness had approximately doubled (odds ratio=2.21, p=0.018) risk of dementia compared to those with Stable Sleep.DISCUSSIONIncreasing sleepiness may be an independent marker or risk factor for dementia in oldest old women.
Strength and durability of indirect protection against SARS-CoV-2 infection through vaccine and infection-acquired immunity
Authors: Tan Sophia T. , Rodríguez-Barraquer Isabel , Kwan Ada T. , Blumberg Seth , Park Hailey J. , Hutchinson Justine , Leidner David , Lewnard Joseph A. , Sears David , Lo Nathan C. 
Published: July 2024

AbstractEarly investigation revealed that COVID-19 vaccines confer indirect protection to fully susceptible and unvaccinated persons, defined as a reduced risk of SARS-CoV-2 infection among social contacts of vaccinated individuals. However, indirect protection from infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both infection-acquired and vaccine-derived immunity independently yield indirect protection to close social contacts with key differences in their strength and waning. Analyzing anonymized data from a system-wide SARS-CoV-2 surveillance program of 177,319 residents across 35 California state prisons from December 2021 to December 2022 in a case-control design, we find that vaccine-derived indirect protection against Omicron SARS-CoV-2 infection is strongest within three months post-vaccination [30% (95% confidence interval: 20-38%)] with subsequent modest protection, whereas infection-acquired immunity provides 38% (24-50%) indirect protection to roommates for 6 months after SARS-CoV-2 infection, with moderate indirect protection persisting for over one year. Variant-targeted vaccines (bivalent formulation including Omicron subvariants BA.4/BA.5) confer strong indirect protection for at least three months [40% (3-63%)]. These results have important implications for understanding the long-term transmission dynamics of SARS-CoV-2 and can guide vaccine policy and public health measures, especially in high-risk environments such as prisons.