bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study on the biological applications of indole alkaloids derived from Nagaland biodiversity
Authors: Ovung Aben , Mavani A. , Roymahapatra Gourisankar , Bhattacharyya Jhimli 
Published: January 2025

AbstractThe north-eastern Indian state, Nagaland with its rich biodiversity, is well known for traditional, natural medicines. However, the scientific basis of the working principle(s) of such drugs are yet to be explored. Plant alkaloids, the nitrogen-containing organic molecules, are traditionally been used for various medicinal purposes from ages. There is a need for drug discovery from natural sources to create a broader drug portfolio for human use. And, Nagaland medicinal plant based bioactive molecules have huge potential for the same. As a pilot study, this work aims to study thein silicoabsorption, distribution, metabolism and excretion (ADME) properties, toxicity prediction and structural properties of the indole alkaloid molecules, Ajmalicine (AJM) and Serpentine (SER) and its docking interaction pattern with various forms of DNA. ADME analysis confirms that the alkaloids meet the criteria of a standard drug. The ProTox II prediction showed the probability of the toxicity profile of the input compounds. Density functional theory (DFT) revealed the HOMO-LUMO energy gap of the drug molecules along with the quantum chemical parameters from the optimized geometry of the ligands. Molecular docking (MD) analysis showed successful binding of the molecules into the groove region of the various forms of DNA structure for both the cases. The results of this theoretical pilot study provides information that will be helpful in the development of effective and modified drugs for medicinal and pharmaceutical purposes as well as in the planning of practical laboratory experiments.
Elucidating Protein Dynamics through the Optimal Annealing of Variational Autoencoders
Authors: Adhikari Subinoy , Mondal Jagannath 
Published: January 2025

AbstractProteins traverse intricate conformational landscapes, with transitions and long-lived states that hold the key to their biological function. Yet, unraveling these dynamics remains a formidable challenge. An emerging approach has been to train the conformational ensemble via deep Variational autoencoders (VAEs) in a bid to machine learn the underlying reduced dimensional representation. However, training VAEs typically involves a fixedβvalue of 1, whereβacts as the crucial weighing factor between the reconstruction and regularization terms. This static setup can often lead to poste-rior collapse, which significantly hinders the model’s ability to capture complex protein dynamics accurately. To mitigate this issue, annealing theβparameter offers a potential alternative. However, this approach frequently falls short in fully addressing the problem, majorly due to arbitrary choice of upper bound ofβand annealing schedule. In this work, we introduce an innovative approach for selecting theβparameter by utilizing the Fraction of Variance Explained (FVE) score to identify its optimal value. We demonstrate that training annealed VAEs at their optimumβin a single cycle consistently outperformed their non-annealed counterparts, as evident from their higher Variational Approach for Markov Processes-2 and Generalized Matrix Rayleigh Quotient scores and distinct free energy surface minima on both folded and intrinsically disordered proteins. The improved latent space representations significantly improve state space discretization, thereby refining Markov State Models and providing more accurate insights into conformational landscapes as reflected in distinct contact maps. These findings not only underscore the potential of annealed VAEs in resolving complex conformational spaces but also highlight the critical interplay between annealing schedules and latent space structures.
Threat reduction must be coupled with targeted recovery programmes to conserve global bird diversity
Authors: Stewart Kerry , Venditti Chris , Carmona Carlos P. , Baker Joanna , Clements Chris , Tobias Joseph A. , González-Suárez Manuela 
Published: January 2025

AbstractBiodiversity is undergoing severe declines while threats to natural populations continue to escalate worldwide. Ambitious international commitments have been made to preserve biodiversity, with the goal of preventing extinctions and maintaining ecosystem resilience, yet the efficacy of large-scale protection remains unclear. Here we use a trait-based approach to show that global actions – such as the immediate abatement of all threats across at least half of species ranges for ∼10,000 bird species - will only prevent half of projected species extinctions and functional diversity loss attributable to current and future threats in the next 100 years. Nonetheless, targeted recovery programmes prioritizing protection of the 100 most functionally unique threatened birds could avoid 68% of projected functional diversity loss. Actions targeting ‘habitat loss and degradation’ will prevent the greatest number of species extinctions and proportion of functional diversity loss relative to other drivers of extinction, whereas control of ‘hunting and collection’ and ‘disturbance and accidental mortality’ would save fewer species but disproportionately boost functional richness. These findings show that conservation of avian diversity requires action partitioned across all drivers of decline, and highlights the importance of understanding and mitigating the ecological impacts of species extinctions predicted to occur even under optimistic levels of conservation action.
LncRNA-BERT: An RNA Language Model for Classifying Coding and Long Non-Coding RNA
Authors: Romeijn Luuk , Cats Davy , Wolstencroft Katherine , Mei Hailiang 
Published: January 2025

AbstractUnderstanding (novel) RNA transcripts generated in next generation sequencing experiments requires accurate classification, given the increasing evidence that long non-coding RNAs (lncRNAs) play crucial regulatory roles. Recent developments in Large Language Models present opportunities for classifying RNA coding potential with sequence-based algorithms that can overcome the limitations of classical approaches that assess coding potential based on a set of predefined features. We present lncRNA-BERT, an RNA language model pre-trained and fine-tuned on human RNAs collected from the GENCODE, RefSeq, and NONCODE databases to classify lncRNAs. LncRNA-BERT matches and outperforms state-of-the-art classifiers on three test datasets, including the cross-species RNAChallenge benchmark. The pre-trained lncRNA-BERT model distinguishes coding from long non-coding RNA without supervised learning which confirms that coding potential is a sequenceintrinsic characteristic. LncRNA-BERT has been shown to benefit from pre-training on human data from GENCODE, RefSeq, and NONCODE, improving upon configurations pre-trained on the commonly used RNAcentral dataset. In addition, we propose a novel Convolutional Sequence Encoding method that is shown to be more effective and efficient than K-mer Tokenization and Byte Pair Encoding for training with long RNA sequences that are otherwise above the common context window size. lncRNA-BERT is available athttps://github.com/luukromeijn/lncRNA-Py.
C-reactive protein and the menstrual cycle in females with sickle cell disease
Authors: Wu Jessica , Bochenek Veronica , Gollomp Kandace , Roe Andrea H. 
Published: January 2025

ABSTRACTThere are notable sex disparities in the frequency and severity of vaso-occlusive pain episodes (VOEs) in sickle cell disease (SCD), with females experiencing more frequent and severe episodes during the reproductive years. Many individuals report a temporal link between VOEs and the menstrual cycle, suggesting that sex hormones may play a role in modulating inflammation and pain. This study explores the relationship between inflammatory markers and the menstrual cycle in females with SCD. Plasma samples from 13 female and 18 male individuals with confirmed SCD were analyzed for C-reactive protein (CRP) and other inflammatory biomarkers. In female patients, sex hormones were measured to determine the menstrual cycle phase. While no overall difference in CRP levels was observed between males and females, CRP levels fluctuated significantly across the menstrual cycle in females, with higher levels in the follicular phase compared to the luteal phase. Additionally, platelet counts were significantly elevated in females during the follicular phase compared to males. These findings suggest that cyclic inflammation may contribute to the increased frequency and severity of VOEs in females, particularly during the perimenstrual period. Further research is needed to explore whether hormonal interventions can reduce perimenstrual VOEs in SCD.
Regulation of protein abundance in normal human tissues
Authors: Fang Huaying , Jiang Lihua , da Veiga Leprevost Felipe , Jian Ruiqi , Chan Joanne , Glinos Dafni , Lappalainen Tuuli , Nesvizhskii Alexey I. , Reiner Alexander P. , Consortium GTEx , Snyder Michael P. , Tang Hua 
Published: January 2025

AbstractWe report a systematic quantification of 10,841 unique proteins from over 700 GTEx samples, representing five human tissues. Sex, age and genetic factors are associated with variation in protein abundance. In total, 1981 cis-protein quantitative trait loci (cis-pQTL) are identified, of which a majority of protein targets have not been assayed in the recent plasma-based proteogenomic studies. Integrating transcriptomic information from matching tissues delineates concordant as well as discordant expression patterns at RNA and protein levels. Juxtaposition of data from different tissues indicates both shared and tissue-specific genetic architecture that underlie protein abundance. Complementing genomic annotation, RNA-based eQTL studies, as well as the recent establishment of plasma-based proteogenomic characterization, tissue-pQTLs shed light on biology underlying genotype-phenotype association of complex traits and diseases.
12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice
Authors: Kaylan Kerim B. , Nargis Titli , Figatner Kayla , Wang Jiayi E. , Pratuangtham Sarida , Chakraborty Advaita , Casimiro Isabel , Nadler Jerry L. , Boxer Matthew B. , Maloney David J. , Anderson Ryan M. , Mirmira Raghavendra G. , Tersey Sarah A. 
Published: January 2025

ABSTRACTObesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the humanALOX12gene. As a model of obesity and dysglycemia, we administered these mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in whichAlox15was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.
Inhibitory effect of Dolosigranulum pigrum and Corynebacterium pseudodiphtheriticum on pneumococcal in vitro growth
Authors: Cisneros M , Blanco-Fuertes M , Lluansí A , Brotons P , Henares D , Pérez-Argüello A , González-Comino G , Ciruela P , Mira A , Muñoz-Almagro C 
Published: January 2025

ABSTRACTBackgroundStreptococcus pneumoniaeis a nasopharynx coloniser that can invade sterile tissues, causing Invasive Pneumococcal Disease (IPD).Dolosigranulum pigrumandCorynebacterium pseudodiphtheriticumare commensal bacteria commonly isolated from the nasopharynx of healthy children, potentially playing a protective role. This study aims to analyse the effects ofD. pigrumandC. pseudodiphtheriticumonS. pneumoniaein vitro growth.MethodsPneumococcal strains were collected from IPD patients and healthy carriers in Catalonia (2016-2023).D. pigrumandC. pseudodiphtheriticumstrains were isolated from a healthy child’s nasopharynx.S. pneumoniaewas co-cultured with each commensal bacterium in triplicate experiments. Pneumococcal growth was quantified using a real-time PCR assay targeting thelytAgene. The effect of commensal bacteria on pneumococcal growth was evaluated using a linear mixed-effect regression model.ResultsTwenty-eight pneumococcal strains expressing 24 different serotypes and 26 clonal types were analysed (18 isolated in blood and 10 in nasopharyngeal aspirate). Pneumococcal growth was decreased byD. pigrum(β = −0.763, 95% CI: −0.94 to −0.59, p < 0.0001) andC. pseudodiphtheriticum(β = −0.583, 95% CI: −0.76 to −0.41, p < 0.0001). The combined presence of both had a stronger inhibitory effect (β = −0.971, 95% CI: −1.15 to −0.79, p < 0.0001). No association was found between isolation site or serotype with pneumococcal growth.ConclusionD. pigrumandC. pseudodiphtheriticumsignificantly reduced pneumococcal growth, with a synergic effect when combined. This antagonistic effect supports the potential protective factor of healthy nasopharyngeal microbiota against IPD and the development of these microorganisms as probiotics.
Medicare Payment for Calcium Modification Technologies Among Patients Undergoing Percutaneous Coronary Intervention, 2021-2022
Authors: Schlacter Jamie , Yu Huihui , Tsuruo Sarah , Herrin Jeph , Ross Joseph S. , Horwitz Leora I. , Dhruva Sanket S. 
Published: January 2025

ABSTRACTBackgroundThe Centers for Medicare and Medicaid Services (CMS) New Technology Add-on Payment (NTAP) program supports adoption of new, costly medical technologies demonstrating substantial clinical improvement. In 2021, CMS waived the “substantial clinical improvement” criterion for devices designated under the FDA Breakthrough Devices Program (BDP). This study characterized risk-standardized payments associated with hospitalizations in which Medicare beneficiaries received calcium modification during PCI for acute myocardial infarction (AMI) following the adoption of the Shockwave C2Coronary Intravascular Lithotripsy (IVL) Catheter (Shockwave Medical) with BDP designation.MethodsWe analyzed Medicare beneficiaries hospitalized for AMI who underwent PCI between January 2021 and December 2022, stratifying them into four groups: no calcium modification, rotational atherectomy (RA), orbital atherectomy (OA), and coronary IVL. Risk-standardized Medicare payments at 30 days, including index facility, physician, and post-acute care costs, were assessed using non-parametric median and chi-square tests.ResultsAmong 87,238 patients, 76,462 (87.6%) received no calcium modification, 8,316 (9.5%) underwent RA, 793 (0.9%) underwent OA, and 1,668 (1.9%) underwent IVL. IVL use increased from 1.6% in October 2021 to 4.4% in December 2022. Median total risk-standardized Medicare payments were significantly higher for patients receiving calcium modification technologies ($27,579 for IVL, $27,353 for OA, $23,240 for RA) compared to those without ($19,115; p<0.001). Payment differences were largest for index facility payments.ConclusionCoronary IVL during PCI for Medicare patients hospitalized for AMI was associated with significantly increased Medicare payments. Further studies must determine whether IVL, and calcium modification technologies in general, improve outcomes for patients hospitalized for AMI undergoing PCI and thus warrant higher payments via NTAP.
Genetic mapping in Collaborative Cross mouse strains identifies loci that affect initial sensitivity to cocaine
Authors: Schoenrock SA , Gaines CH , Kumar P , Khan S , Farrington J , Ferris MT , Pardo-Manuel de Villena F , Valdar W , Bubier JA , Tarantino LM 
Published: January 2025

ABSTRACTWe identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response and self-administration of cocaine. In the current study, we crossed each of these strains to C57BL/6NJ (B6N) mice to produce two F2 populations and identify genetic loci that influence locomotor response to cocaine. We identified three significant loci on chromosomes 7, 11 and 14 in the CC041 F2 mapping cross that collectively explain 14% of the phenotypic variance for locomotor response to cocaine. We used a bioinformatic approach to identify high quality candidate genes that are genetically plausible, have functional relevance and are suitable for further exploration. Our study is the first to use CC strains to perform QTL mapping for addiction-related phenotypes and proposes several candidate genes for follow-up analyses.
Deep Tissue Second-Harmonics of Collagen Fibers in a Transparent Rat Heart from a Myocardial Infarction Model
Authors: Matsuyama Makoto 
Published: January 2025

AbstractThe combination of tissue-clearing techniques with light-sheet microscopy has enabled detailed visualization of histological changes from the micrometer to millimeter scale, deepening understanding of various disease processes. However, these protocols are not fully optimized for animal species beyond mice or for organs outside the brain. Additionally, the lack of suitable fluorescent probes for target molecules limits their broader application.In this study, we present a protocol for whole-organ clearing of rat hearts in a myocardial infarction model, achieving complete transparency and enabling label-free imaging of collagen fibers in the myocardial wall up to a depth of ∼5 mm using Second Harmonic Generation (SHG) microscopy. For the first time, we successfully compared collagen fiber orientations between infarcted and healthy myocardial regions. Our approach facilitates high-resolution tissue remodeling analysis in cardiovascular research without the need for antibody staining, demonstrating that tissue-clearing techniques are feasible even in animal species with limited available antibodies.Summary statementWe present a novel method for visualizing collagen fibers deep within the heart using a combination of tissue clearing and advanced microscopy, providing valuable data for cardiac research.
Catalytic degradation of circulating targets with FcRn-mediated cycling LYTACs
Authors: Kougentakis Christos , Shurtleff Matthew J. , Lieser Rachel M. , Chen Tao , Collins Christina L. , Johnson Isabel E. , Gu Siyi , Akama Keith T. , Doran Kyle H. , Fung Cyra K. , Hildebrandt Darin J. , Khaleghi Rozhan , Li Diana , Rank Steve , Tran Thomas-Toan , Yau Richard , Holly Ryan W. , Langsdorf Christopher , Lindhout Darrin A. , McWhirter Sarah M. , Iwig Jeffrey S. , Lewis Jason G. , Staben Steven T. , Turtle Eric D. , Lind Nicholas A. 
Published: January 2025

AbstractCirculating proteins are common targets for the discovery of occupancy-based inhibitors including monoclonal antibodies. Effective inhibition of target pathogenicity with blocking approaches, however, is often challenged by target parameters that lead to insufficient occupancy and/or incomplete pharmacology limited by only single site binding. Extracellular targeted protein degradation approaches, such as lysosomal targeting chimeras (LYTACs), offer an opportunity to minimize these challenges by an event-driven mechanism that selectively, thoroughly and irreversibly eliminates drivers of disease. First generation LYTACs, designed to traffic to the lysosome, show limited durability since the therapeutic is degraded along with the target protein of interest. Here we describe cataLYTACs, which overcome this limitation by combining stabilized asialoglycoprotein (ASGPR) ligands, pH-sensitive target binding and recycling via the neonatal Fc receptor (FcRn). These cataLYTACs degraded superstoichiometric levels of a target protein, IgE, in vitro and demonstrated deep and sustained clearance of human IgE in mouse models. In non-human primates, cataLYTACs resulted in >98% clearance of circulating endogenous IgE for 2 weeks and outperformed the standard of care blocking antibody, omalizumab (Xolair®), in both free IgE elimination and duration of action. CataLYTACs represent a new therapeutic modality for a wide range of disease states driven by circulating factors, with the potential for superior efficacy and duration of action compared to traditional inhibitors.
Peptidic tryptophan halogenation by a promiscuous flavin-dependent enzyme
Authors: Rice Andrew J. , Gadgil Mayuresh G. , Mitchell Douglas A. 
Published: January 2025

ABSTRACTAmino acids undergo numerous enzymatic modifications, including free amino acids and those incorporated into polypeptides. The extensive structural modifications observed in ribosomally synthesized and post-translationally modified peptides (RiPPs) provide compelling examples of natural modifications to amino acids. However, the broad applicability of amino acid-modifying enzymes for synthetic purposes is limited by narrow substrate scope and often unknown regulatory or accessory factor requirements. Here, we characterize ChlH, a flavin-dependent halogenase (FDH) from the chlorolassin biosynthetic gene cluster. Reconstitution of ChlH and the associated flavin reductase ChlRin vitrounexpectedly showed that ChlH acts on the linear precursor peptide ChlA rather than the threaded lasso peptide product. Unlike characterized peptide-modifying FDHs, which are limited to either heavily altered peptidic scaffolds or the terminus of a linear peptide, ChlH halogenates internal Trp residues of linear peptides, as well as N- and C-terminal Trp. Ala and Trp scanning mutagenesis of ChlA revealed a broad substrate tolerance and the capacity to modify Trp at nearly every position of the core region. Halogenation of disparate RiPP precursor peptides, pharmacologically relevant peptides, and an internal Trp of a protein was achieved using wild-type ChlH. A rapid cell-free biosynthetic assay was also used to assess a mutagenic panel of ChlA, which provided insight into ChlH’s preferences. In contrast to characterized FDHs, ChlH halogenates diverse peptide sequences, and we predict this promiscuity may find utility in the modification of additional peptide and protein substrates of biotechnological value.