bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local adaptation, plasticity, and evolved resistance to hypoxic cold stress in high-altitude deer mice
Authors: Bautista Naim M. , Herrera Nathanael D. , Shadowitz Ellen , Wearing Oliver H. , Cheviron Zachary A. , Scott Graham R. , Storz Jay F. 
Published: June 2024

ABSTRACTA fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice (Peromyscus maniculatus) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6000 m. The final elevation of 6000 m far exceeds the highest attainable elevations within the species’ range, and therefore tests the animals’ ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species’ broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to a combination of genetically based local adaptation and plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives.SIGNIFICANCE STATEMENTIn species that are distributed across steep environmental gradients, the ability to inhabit a broad range of conditions may be attributable to local adaptation and/or a generalized acclimatization capacity (phenotypic plasticity). By experimentally acclimating highland and lowland deer mice (Peromyscus maniculatus) to progressively increasing levels of hypoxia during a simulated ascent to 6000 m, we assessed the relative roles of evolved and plastic changes in thermogenic capacity. At especially severe levels of hypoxia, the superior thermogenic performance of highland natives relative to lowland conspecifics suggests that the broad fundamental niche of deer mice is largely attributable to local adaptation to different elevational zones, including evolved plasticity in gene expression and respiratory traits.
Preliminary pharmacokinetics andin vivostudies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator
Authors: Costa Blaise M. , Hines De’Yana , Phillip Nakia , Boehringer Seth C. , Anandakrishnan Ramu , Council-Troche McAlister , Davis Jennifer L. 
Published: June 2024

AbstractNMDAR channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated thein vivoeffects of CNS4, a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours post-intraperitoneal injection, with brain concentrations reach values up to 8.4% of those in plasma (64.9 vs. 5.47 µg/ml). Preliminary results showed that CNS4, a non-opioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared to saline. In a fear conditioning (FC) experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs. 1; females, 19 vs. 3). CNS4 also improved hyperarousal behavior (25 vs. 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after FC training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects like those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel non-opioid analgesic, warranting further investigation.SignificanceNMDA-subtype glutamate receptors are an attractive target for chronic pain and PTSD treatments as they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, CNS4.Visual Abstract
Evaluating approaches of training a generative large language model for multi-label classification of unstructured electronic health records
Authors: Vithanage Dinithi , Deng Chao , Wang Lei , Yin Mengyang , Alkhalaf Mohammad , Zhang Zhenyu , Zhu Yunshu , Soewargo Alan Christy , Yu Ping 
Published: June 2024

AbstractMulti-label classification of unstructured electronic health records (EHR) is challenging due to the semantic complexity of textual data. Identifying the most effective machine learning method for EHR classification is useful in real-world clinical settings. Advances in natural language processing (NLP) using large language models (LLMs) offer promising solutions. Therefore, this experimental research aims to test the effects of zero-shot and few-shot learning prompting, with and without parameter-efficient fine-tuning (PEFT) and retrieval-augmented generation (RAG) of LLMs, on the multi-label classification of unstructured EHR data from residential aged care facilities (RACFs) in Australia. The four clinical tasks examined are agitation in dementia, depression in dementia, frailty index, and malnutrition risk factors, using the Llama 3.1-8B. Performance evaluation includes accuracy, macro-averaged precision, recall, and F1 score, supported by non-parametric statistical analyses. Results indicate that both zero-shot and few-shot learning, regardless of the use of PEFT and RAG, demonstrate equivalent performance across the clinical tasks when using the same prompting template. Few-shot learning consistently outperforms zero-shot learning when neither PEFT nor RAG is applied. Notably, PEFT significantly enhances model performance in both zero-shot and few-shot learning; however, RAG improves performance only in few-shot learning. After PEFT, the performance of zero-shot learning is equal to that of few-shot learning across clinical tasks. Additionally, few-shot learning with RAG surpasses zero-shot learning with RAG, while no significant difference exists between few-shot learning with RAG and zero-shot learning with PEFT. These findings offer crucial insights into LLMs for researchers, practitioners, and stakeholders utilizing LLMs in clinical document analysis.
A Multitrait Genome-Wide Association Study Reveals a Requirement for the Strigolactone Receptor MtDWARF14 in Optimal GOLVEN Signaling
Authors: Roy Sonali , Kang Yun , Zhang Shulan , Torres-Jerez Ivone , Jain Divya , Sanchez Bailey , Burghardt Liana , Cheng Xiaofei , Wen Jiangqi , Murray Jeremy D. , Scheible Wolf-Rüdiger , Udvardi Michael 
Published: June 2024

ABSTRACTGOLVEN/ROOT MERISTEM GROWTH FACTOR family of signaling peptides have been shown to control root lateral organ number, density and positioning in plants, although the signaling pathways involved remain obscure. A diverse set of 171Medicago truncatulaHapMap accessions with variation in responses to the GOLVEN 10 peptide, GLV10, were used to identify 74 significant loci controlling seven traits related to nodule formation and root architecture. Importantly, a single nucleotide polymorphism (SNP) in the upstream region of the MtGLV10 peptide-inducible strigolactone receptor gene,MtDWARF14was significantly associated with insensitivity of nodule density to GLV10, suggesting a link between strigolactone signaling and GLV10 responsiveness. Three independentd14mutants of the DWARF14gene were found to hypernodulate, while overexpression of the gene led to reduction in nodule number, phenocopying GLV10. A null mutant,mtd14-1, remained sensitive to GLV10’s effect on nodule density. However, at the transcriptional level, the mutant failed to effectively induce the expression of the GOLVEN marker genes,MtPLETHORA3andMtPINLIKES2. Our study uncovers a hitherto unknown link between the strigolactone and GLV peptide signaling pathways using genotype x environment analysis of Medicago HapMap lines and provides a putative molecular mechanism for recovery from frost damage to fine roots.
Translational activity of 80S monosomes varies dramatically across different tissues
Authors: Blandy Albert , Hopes Tayah , Vasconcelos Elton J. R. , Turner Amy , Fatkhullin Bulat , Agapiou Michaela , Fontana Juan , Aspden Julie L. 
Published: June 2024

SummaryTranslational regulation at the stage of initiation can impact the number of ribosomes translating each mRNA molecule. However, the translational activity of single 80S ribosomes (monosomes) on mRNA is less well understood, even though these 80S monosomes represent the dominant ribosomal complexes in vivo. Here, we used cryo-EM to determine the translational activity of 80S monosomes across different tissues inDrosophila melanogaster. We discovered that while head and embryo 80S monosomes are highly translationally active, testis and ovary 80S monosomes are translationally inactive. RNA-Seq analysis of head monosome- and polysome-translated mRNAs, revealed that head 80S monosomes preferentially translate mRNAs with TOP motifs, short 5’-UTRs, short ORFs and are enriched for uORFs. Overall, these findings highlight that regulation of translation initiation, and that protein synthesis is mostly performed by monosomes in head and embryo, whilst polysomes are the main source of protein production in testis and ovary.Graphical AbstractHighlightsD. melanogaster80S monosomes and polysomes purified from different tissues exhibit different translational activitiesHead and 0-2 hr embryo 80S monosomes are highly translationally activeTestis and ovary 80S monosomes are translationally inactiveHead 80S monosomes preferentially translate mRNAs with TOP motifs, short 5’-UTRs, short ORFs and are enriched for uORFsHead polysomes preferentially translate mRNAs with neuronal functions
CUT&Tag and DiBioCUT&Tag enable investigation of the AT-rich and dynamic epigenome ofPlasmodium falciparumfrom low input samples
Authors: Gockel Jonas , Ramón-Zamorano Gala , Spielmann Tobias , Bártfai Richárd 
Published: June 2024

ABSTRACTPhenotypic variation between malaria parasites is one of the major contributors to the pathogens success and is regulated by differences in heterochromatin-mediated gene silencing. Currently, the heterochromatin landscape is mostly profiled utilising chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq). However this technique has drawbacks regarding AT-content-related artifacts and requires substantial material and time investment, severely limiting profiling of scarce sample types (e.g. field isolates). In order to facilitate assessments of epigenetic states in low-input samples, we adopted the epigenetic profiling technique Cleavage Under Targets and Tagmentation (CUT&Tag) toPlasmodium falciparumparasites. Performing the reaction with 100,000 or even only 10,000 nuclei yielded reproducible results coherent with bulk-ChIP-seq data while using significantly less material. We also optimised sample preparation, permitting the use of crude saponin lysates, which decreases sample loss due to inefficient nuclei isolation and increases versatility of the protocol. Finally, we developed DiBioCUT&Tag, a novel way of utilising dimerisation-induced recruitment of biotin ligases for signal amplification prior to anti-biotin CUT&Tag, which we successfully deployed to profile both heterochromatin occupancy and a dynamically chromatin-associated protein (BDP5). Methods described here hence provide substantially improved means for epigenetic profiling of (transiently) chromatin-associated proteins from low-input samples in the malaria parasite and beyond.
Natural volatiles causing inhibition of mosquito biting behaviors: development of a virtual screening platform predicting antagonists of ORco function for accelerated discovery
Authors: Kythreoti Georgia , Thireou Trias , Karoussiotis Christos , Georgoussi Zafiroula , Liggri Panagiota GV , Papachristos Dimitrios P , Michaelakis Antonios , Karras Vasileios , Zographos Spyros E , Schulz Stefan , Iatrou Kostas 
Published: June 2024

ABSTRACTInsect olfactory receptors are heteromeric ligand-gated cation channels composed of an obligatory receptor subunit, ORco, and one of many variable subunits, ORx, in as yet undefined molar ratios. When expressed aloneex vivo, ORco forms homotetrameric channels gated by ORco-specific ligands acting as channel agonists. Using an insect cell-based system as a functional platform for expressing mosquito odorant receptorsex vivo,we identified small molecules of natural origin acting as specific ORco channel antagonists, orthosteric or allosteric relative to a postulated ORco agonist binding site, and causing severe inhibition of olfactory function in mosquitoes. In the present communication, we are reporting on the compilation of common structural features of such orthosteric antagonists and development of a ligand-based pharmacophore whose properties are deemed necessary for binding to the agonist binding site and inhibition of ORco’s biological function.In silicoscreening of an available collection of natural volatile compounds with this pharmacophore resulted in identification of several ORco antagonist hits. Cell-based functional screening of the same compound collection resulted in the identification of several compounds acting as orthosteric and allosteric antagonists of ORco channel functionex vivoand inducing anosmic behaviors toAedes albopictusmosquitoesin vivo.Comparison of thein silicoscreening results with those of the functional assays revealed that the pharmacophore predicted correctly 7 out of the 8 confirmed orthosteric antagonists and none of the allosteric ones. Because the pharmacophore screen also produced additional hits that did not cause inhibition of the ORco channel function, we generated a Support Vector Machine (SVM) model based on two descriptors of all pharmacophore hits. Training of the SVM on theex vivovalidated compound collection resulted in the selection of the confirmed orthosteric antagonists with a very low cross-validation out-of-sample misclassification rate. Employment of the combined pharmacophore-SVM platform forin silicoscreening of a larger collection of olfaction-relevant volatiles produced several new hits. Functional validation of randomly selected hits and rejected compounds from this screen confirmed the power of this virtual screening platform as convenient tool for identifying novel vector control agents. To the best of our knowledge, this study is the first one that combines a pharmacophore with a SVM model for identification of AgamORco antagonists and specifically orthosteric ones.
Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas
Authors: Monje Michelle , Mahdi Jasia , Majzner Robbie , Yeom Kristen , Schultz Liora M. , Richards Rebecca M. , Barsan Valentin , Song Kun-Wei , Kamens Jen , Baggott Christina , Kunicki Michael , Lim Alexandria Sung , Reschke Agnes , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Patel Shabnum , Chinnasamy Harshini , Erickson Courtney , Jacobs Ashley , Duh Allison K. , Rietberg Skyler P. , Tunuguntla Ramya , Klysz Dorota Danuta , Fowler Carley , Green Sean , Beebe Barbara , Carr Casey , Fujimoto Michelle , Brown Annie Kathleen , Petersen Ann-Louise G. , McIntyre Catherine , Siddiqui Aman , Lepori-Bui Nadia , Villar Katlin , Pham Kymhuynh , Bove Rachel , Musa Eric , Reynolds Warren , Kuo Adam , Prabhu Snehit , Rasmussen Lindsey , Cornell Timothy T. , Partap Sonia , Fisher Paul G. , Campen Cynthia J. , Grant Gerald , Prolo Laura , Ye Xiaobu , Sahaf Bita , Davis Kara L. , Feldman Steven A. , Ramakrishna Sneha , Mackall Crystal 
Published: June 2024

AbstractH3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trialNCT04196413administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.
THE ECONOMIC BURDEN OF INVASIVE FORMS OF MENINGOCOCCAL INFECTION
Authors: Sergienko E.N. , Kozhanova I.N. , Romanova O.N. , Solodov A.D. , Scutova P.A. 
Published: June 2024

AbstractRelevanceInvasive meningococcal infection (IMI) is a significant clinical problem and is associated with a high probability of severe complications and death. Vaccination programs against meningococcus can achieve significant clinical effectiveness and require significant financial costs. This makes it relevant to study the economic burden of meningococcal infection in the conditions of modern healthcare in order to obtain basic data for subsequent research in the field of evaluation of medical technologies.AimsTo assess the economic burden of IMI in children in the conditions of healthcare in the Republic of Belarus.Material and methodsa retrospective study using the “cost of illness” method was conducted for 22 children hospitalized in the city children’s infectious clinical diseases hospital in 2018-2019. All values are presented in belarusian rubles. The average ± standard deviation, minimum – maximum values, median [Q1, Q3], cost shares (%) are calculated for the cost values. The minimum– maximum values and median [Q1, Q3] were calculated for the age of the patients.Resultstaking into account the costs of treatment in healthcare organizations of all patients studied, the share of direct costs of hospitalization was 29.0%, the share of direct costs of diagnosis - 7.2%, the share of direct costs of pharmacotherapy - 8.3%. A significant part of the costs accounted for observations after discharge and amounted to 55.4%.Conclusiona retrospective study of the economic burden of MI in the Republic of Belarus using the “cost of illness” method in patients hospitalized in a public health organization demonstrates a significant economic burden of this disease, which in the long term is primarily due to the presence of complications in the patient, as well as the impact of the patient’s death on the value of total costs.
Neuronal DNA repair reveals strategies to influence CRISPR editing outcomes
Authors: Ramadoss Gokul N , Namaganda Samali J , Hamilton Jennifer R , Sharma Rohit , Chow Karena G , Macklin Bria L , Sun Mengyuan , Liu Jia-Cheng , Fellmann Christof , Watry Hannah L , Jin Julianne , Perez Barbara S , Sandoval Espinoza Cindy R , Matia Madeline P , Lu Serena H , Judge Luke M , Nussenzweig Andre , Adamson Britt , Murthy Niren , Doudna Jennifer A , Kampmann Martin , Conklin Bruce R 
Published: June 2024

ABSTRACTGenome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control of DNA repair outcomes hinders its therapeutic potential. DNA repair is especially understudied in nondividing cells like neurons, which must withstand decades of DNA damage without replicating. This lack of knowledge limits the efficiency and precision of genome editing in clinically relevant cells. To address this, we used induced pluripotent stem cells (iPSCs) and iPSC-derived neurons to examine how postmitotic human neurons repair Cas9-induced DNA damage. We discovered that neurons can take weeks to fully resolve this damage, compared to just days in isogenic iPSCs. Furthermore, Cas9-treated neurons upregulated unexpected DNA repair genes, including factors canonically associated with replication. Manipulating this response with chemical or genetic perturbations allowed us to direct neuronal repair toward desired editing outcomes. By studying DNA repair in postmitotic human cells, we uncovered unforeseen challenges and opportunities for precise therapeutic editing.
Antibiotic Resistance pattern in Bile from Cholecystectomised Patients by Multiplex PCR
Authors: Farhana Nasreen , Uddin Khan Mohammad Ashraf , Shamsuzzaman SM 
Published: June 2024

SummaryBackgroundBile in the biliary tract is normally sterile. Presence of gallstones, ascending infection from duodenum or bacterial translocation from portal vein leads to microfloral colonization in biliary system.AimThis study was aimed to evaluate the microbiological profile of bile from gall bladder for determination of the appropriate antibiotics in cholecystectomised patients.MethodsThis cross sectional study included patients who underwent laparoscopic or open cholecystectomy in Dhaka Medical College Hospital, Dhaka, from July, 2013 to December, 2014. Total 246 intraoperative bile were cultured aerobically in Blood agar and MacConkey’s agar media. The identified isolates were tested for their sensitivity pattern according to CLSI guidelines and multiplex PCR was used to detect virulence genes ofSalmonellaTyphi and anaerobic bacteria along with drug resistance genes.FindingsOut of 246 bile samples, organisms were identified in 171 (69.51%) cases; 119 (48.37%) were aerobic bacteria identified by culture and PCR and 52 (21.14%) were anaerobic bacteria identified by multiplex PCR.Escherichia coli(26.61%) were found predominantly followed byStaphylococcus aureus(19.35%),Clostridium perfringens(13.82%).Salmonella entericaserovar Typhi was detected by culture and PCR in 3 (1.22%) and 8 (3.45%) samples respectively. Prevalence of ESBLs, Carbapenemase producers and MRSA were detected phenotypically in 10.96%, 16.44% and 8.33% samples respectively and the resistance genes blaCTX-M-15 (50.0%), blaOXA-1-group (25.0%), blaNDM-1 (62.50%), OXA-181/OXA-84 (12.5%) and mecA (8.33%) were detected.ConclusionSignificant proportion of aerobic and anaerobic bacterial infection associated with biliary tract obstruction may warrants serious health risk to cholecystectomised patients in this region.