bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial peptides (AMPs) of lizards: a first comprehensive characterization of beta-defensins, ovo-defensins and cathelicidins from the Balearic lizardPodarcis lilfordiand closely related Lacertidae species
Authors: Otalora Katherin , Gomez-Garrido Jessica , Baldo Laura 
Published: February 2025

AbstractReptiles are remarkably resistant to infections, providing a critical system to understand diversity and evolution of the innate immune defense and its major players, the antimicrobial peptides (AMPs). Here we present the first comprehensive characterization of AMPs in the family Lacertidae with the objective of understanding their diversity and patterns of evolution.By means of extensive genome mining, we first obtained a nearly complete catalogue of antimicrobial proteins from the Balearic lizardPodarcis lilfordi: 65 beta-defensins (BDs), eight ovo-defensins (OVODs), encompassing three proline-rich proteins (OVOD-PrAMPs), and four cathelicidins (CATHs). Using this fine-scale annotation we retrieved corresponding orthologues and closed paralogues from published Lacertidae species,P. muralis, P. raffoneiandZootoca vivipara(58 total AMPs). Comparative sequence analysis indicated that all AMPs consistently locate in chromosome 3 (BDs and OVODs) and chromosome 12 (CATHs), supporting a monophyletic origin of the reptilian antimicrobial defense. InP. lilfordi, the AMPs are arranged in clusters of mostly contiguous peptides, flanked by highly conserved marker proteins. All Lacertidae AMPs present a multiple exon structure (two to four) and a characteristic cysteine motif (six-cysteines in BDs, eight in OVODs and four in CATHs), consistently with previous findings in vertebrates. Comparative analyses support an ongoing process of gene expansion via duplication in tandem of both BDs and OVODs, whereas OVOD-PrAMPs and CATHs mostly present a one-to-one ortholog in all species. Despite this remarkable intra-genomic diversity, we also found multiple examples of distant species sharing identical or nearly identical peptides, providing clear evidence of convergent evolution.Overall, these findings substantially increased our understanding of AMP diversity and evolution in reptiles and set the basis to explore adaptive polymorphism maintenance and mechanisms of antimicrobial defense.
AstraPTM: Context-Aware PTM Prediction Model for Large-Scale Proteins
Authors: Goteti Aniruddh , Bozkurt Çağlar 
Published: February 2025

AbstractPost-translational modifications (PTMs) are critical molecular events that pro-foundly influence protein stability, localization, and function. While numerous computational tools exist for PTM site prediction, most struggle with handling large proteins and rely on separate models for each modification. To address these challenges, we introduceAstraPTM, a transformer-based framework that predicts 25 PTMs in a single pass. By leveraging advanced protein embeddings (ESM2) and training on a high-coverage dbPTM dataset, AstraPTM captures both short-range sequence motifs and long-range interactions across proteins without a sequence length limitation.AstraPTM combines a binary classification module—indicating whether a residue is modified—with a multi-label module that pinpoints specific PTM types. This dual approach achieves high accuracy on well-represented PTMs (e.g., phospho-rylation, glycosylation) while maintaining sensitivity for rarer modifications. In benchmarks against existing methods such as MusiteDeep and MIND-S, AstraPTM demonstrates competitive or superior performance, demonstrating AUC-ROC above 99% for well-represented modifications, underscoring its versatility for proteome-wide annotation. Beyond prediction, the model’s capacity to handle full-length proteins offers a powerful resource for researchers investigating PTM crosstalk and disease pathways, ultimately bridging the gap between large-scale omics data and targeted biomedical applications.
Inhibition of NLRP1 Inflammasome Activation by Tyrosine Kinase Inhibitors Restores Erythropoiesis in Diamond-Blackfan Anemia Syndrome
Authors: Lozano Gil Juan M. , Rodríguez-Ruiz Lola , Palacios Manuel , Peral Jorge , Navarro Susana , Fuster José L. , Beléndez Cristina , Jérez Andrés , Murillo-Sanjuán Laura , Díaz-de-Heredia Cristina , López-de-Hontanar Guzmán , Zubicaray Josune , Sevilla Julián , Ferrer-Marín Francisca , Sepulcre María P. , Cayuela María L. , García-Moreno Diana , Martínez-López Alicia , Tyrkalska Sylwia D. , Mulero Victoriano 
Published: February 2025

AbstractDiamond-Blackfan Anemia Syndrome (DBAS) is characterized by impaired erythropoiesis due to dysfunctional ribosome biogenesis and aberrant cellular signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome modulates erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis in Diamond-Blackfan anemia syndrome (DBAS) by inhibiting NLRP1 inflammasome activation. Specifically, nilotinib enhances erythroid differentiation in K562 cells through suppression of the ZAKα/P38/NLRP1/CASP1 axis, leading to increased GATA1 protein levels and upregulation of key erythroid genes involved in iron acquisition, hemoglobin synthesis, and erythrocyte structure. These effects were validated in human CD34+hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, along with other TKIs (imatinib, dasatinib, and bosutinib), promoted erythropoiesis at the expense of myelopoiesis and reduced caspase-1 activity. Importantly, in RPS19-deficient zebrafish and human models and HSPCs from patients with DBAS, nilotinib, imatinib and dasatinib rescued defective erythroid differentiation and restored hemoglobin levels. These findings highlight the potential of TKIs to address the erythroid defects observed in ribosomopathies like DBAS. Given the limited treatment options available for DBAS and other congenital anemias, our study provides compelling evidence for repurposing TKIs as a novel therapeutic strategy to alleviate pathological NLRP1 activation and improve erythropoiesis. This work opens new avenues for managing ribosome-related disorders and advancing personalized medicine approaches for hematopoietic diseases.
Genomic diversity in felids correlates with range and density, not census size
Authors: Meeus Michaël P. , Lescroart Jonas , Svardal Hannes 
Published: February 2025

AbstractAs the world is hit by the sixth mass extinction, it becomes increasingly important to understand the factors relevant to the conservation of species, so that we may protect biodiversity to the best of our abilities. Although genetic diversity is known to reflect population demography and contribute to genetic health and adaptability, it is not explicitly used as a criterion in assessments by the International Union for the Conservation of Nature (IUCN). Additionally, studies comparing diversity estimates between species often rely on summarizing results across studies, which use different methodologies and may not be suited for direct comparison. Here we performed a family-wide assessment of genomic diversity in Felidae, covering most extant species. We tested for correlations between autosomal heterozygosity and ecological traits across (sub)species, and whether a subspecies’ genetic diversity was associated with its IUCN threat category. We found evidence for genetic diversity to be strongly positively correlated with both geographic range size and population density, but not with census size. Furthermore, although genetic diversity was not significantly correlated with IUCN status overall, threatened cat species had significantly lower levels of genetic diversity than non-threatened species. Our results confirm the association of population parameters and assessment of extinction risk with genetic diversity in one of the most iconic and threatened families of land carnivores. While mechanisms and causality behind these associations will need to be the subject of further investigation, our study adds further credence to the importance of incorporating genomic information in risk assessment and conservation efforts.
SmART-TBI: A fully remote protocol for a randomized placebo-controlled double-blinded clinical trial for a dietary supplement to improve sleep in Veterans
Authors: Elliott Jonathan E. , Sicard Savanah J. , Olivo Cosette , Cunningham Hannah A. , Ekis Arlynn E. , Powers Katherine L. , Brewer Jessica S. , D’Silva Jennifer , Happ Sarah , Hildebrand Andrea , Cohen Akiva , Lim Miranda M. 
Published: February 2025

AbstractTraumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment, with limited effective therapeutic strategies. Our previous work showed dietary supplementation with branched chain amino acids (BCAAs; isoleucine, leucine, valine), the primary substrate forde novoglutamate/GABA synthesis in the CNS, restored normal sleep-wake patterns and improved cognitive function in rodents. Our recent pilot work in humans showed preliminary feasibility/acceptability and limited efficacy for BCAAs to improve sleep in Veterans with TBI. However, these pilot data were limited in sample size, treatment dosages/duration, and therefore unable to establish efficacy or provide insight into dosing/duration parameters. The present study, SmART-TBI (supplementation with amino acid rehabilitative therapy in TBI:NCT04603443), represents a fully powered, placebo-controlled, double-masked randomized clinical trial (target n=120). Covariate adaptive randomization controlling for age, sex, TBI recency, pain, depression, and PTSD, allocated participants 1:1:1:1 to four groups comprising 3 BCAA doses (‘high’ 30g b.i.d.; ‘medium’ 20g b.i.d.; and ‘low’ 10g b.i.d.) and one placebo-control (rice protein, 10g b.i.d.). Outcome measures were assessed following a 2-week baseline period; after 4 weeks, 8 weeks, and 12 weeks of intervention; and after 4 weeks and 12 weeks post-intervention. Primary outcomes were feasibility and acceptability of the protocol. Exploratory outcomes included preliminary efficacy in improving sleep, assessed via a combination of actigraphy, mattress-sensors, sleep diaries (all analyzed daily), as well as pre– and post-BCAA overnight polysomnography for sleep staging, cognition, and quality of life measures. Results indicated high feasibility and acceptability of this fully remote protocol among Veterans with TBI.
Pan T cells, Helper T cells, and Regulatory T cells are Associated with Negative Symptoms in Persons with Anti-Gliadin Antibody Positive Schizophrenia and Related Disorders
Authors: Salem Deepak , Clark Sarah M. , Roche Daniel J.O. , Singh Nevil J. , Talor Monica V. , Buchanan Robert W. , Harrington Valerie , Ye Zhenyao , Chen Shuo , Kelly Deanna L. 
Published: February 2025

AbstractBackgroundAbout one in three persons with a schizophrenia related disorder (SRD) have elevated anti-gliadin IgG antibodies (AGA). This AGA positive (AGA+) subgroup of SRD clinically has a higher burden of negative symptoms and are symptoms associated with high functional impairments with a lack of effective therapeutics. Alterations in T cells have been demonstrated in SRD, and we have previously shown regulatory T cells (Tregs) are increased and correlate with fewer negative symptoms in persons with SRD compared with healthy controls.MethodsTo further elucidate the role of the immune system in AGA+ SRD pathology, we investigated the relationship of T cells and negative symptoms in 26 medicated and clinically stable persons with SRD. Participants had blood drawn; AGA-IgG measured by ELISA (AGA positive defined as ≥20 U); had flow cytometry performed to quantify proportions of pan T cells (CD3+), helper T cells (CD3+CD4+), Tregs (CD3+CD4+CD25+Foxp3+), and activated Tregs (aTregs) (CD3+CD4+CD25+Foxp3+RA-); had serum cytokines measured; and completed the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms.Results46% of persons with SRD in this study were AGA+ and, in this group specifically, pan-T cells were correlated with worse SANS total, anhedonia, alogia, and avolition (p<0.05), while helper T cells and Tregs were correlated with less negative symptoms (respectively, SANS total and alogia; SANS total, anhedonia, alogia; P<0.05). AGA+ persons with SRD also had several elevated serum cytokines, corresponding with a broadly pro-inflammatory phenotype.ConclusionsThese hypothesis-generating findings highlight T cell dysfunction in AGA+ positive SRD, suggesting Tregs protecting against negative symptom severity but also an unidentified other T cell population to possibly be driving negative symptom severity.
Localization of KANK2 to Focal or Fibrillar Adhesions Influences Migration in Melanoma Cell Lines
Authors: Stojanović Nikolina , Rac-Justament Anja , Lončarić Marija , Tadijan Ana , Paradžik Mladen , Acman Marta , Humphries Jonathan D. , Humphries Martin J. , Ambriović-Ristov Andreja 
Published: February 2025

ABSTRACTIntegrins form focal adhesions (FAs) at the cell edge and fibrillar adhesions (FBs) located centrally, with both serving as a link to the actin cytoskeleton. Talins 1 and 2, key mechanosensitive proteins, are not functionally redundant. Talin1 is essential to FAs, while talin2 is found in large FAs and FBs. KANK (kidney ankyrin repeat-containing) family proteins regulate adhesion dynamics, with KANK2 binding both talins in FAs and localizing to FBs where only talin2 is present. Previously, we showed in melanoma cell line MDA-MB-435S that talin2 within integrin αVβ5 FAs interacts with KANK2 to regulate actin-microtubule (MT) dynamics, and knocking down either protein reduces cell migration. Here, we demonstrate that RPMI-7951 melanoma cells also use integrin αVβ5 FAs for adhesion but additionally form integrin α5β1 FBs, and that KANK2 and talin2 are present in both structures. KANK2 functionally interacts with talin1 to maintain FAs, and with talin2 to regulate their dynamics. KANK2 within FBs regulates cell migration. This was demonstrated upon KANK2 knockdown that mirrors integrin α5 knockdown, increasing migrationviaMTs. Overall, our study highlights the distinct roles of KANK2 and talin2 in different adhesion structures, influencing melanoma cell migration.
Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation
Authors: Castranio Emilie L. , Varghese Merina , Argyrousi Elentina K. , Tripathi Kuldeep , Söderberg Linda , Bresnahan Erin , Lerner David , Garretti Francesca , Zhang Hong , van de Loo Jonathan , Stimpson Cheryl D. , Talty Ronan , Glabe Charles , Levy Efrat , Wang Minghui , Ilkov Marjan , Zhang Bin , Lannfelt Lars , Guérin Brigitte , Lubell William D. , Rahimipour Shai , Dickstein Dara L. , Gandy Sam , Arancio Ottavio , Ehrlich Michelle E. 
Published: February 2025

AbstractAPPE693Qtransgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of Aβ (NFA-Aβ) and APP α-carboxy terminal fragments. TheAPPE693Qmutation disrupts amyloid fibril formation, and no plaques develop in these mice. In the current study, the aging-related accumulation of NFA-Aβ inAPPE693Qmice was revealed by A11 immunohistochemistry and NFA-Ab-detecting cyclic D,L-α-peptide-FITC microscopy. The presynaptic termini ofAPPE693Qmice developed aging-related physiological abnormalities in post-tetanic potentiation, synaptic fatigue, and synaptic vesicle replenishment. Single-cell RNA sequencing showed that excitatory neurons exhibited the most altered transcriptomic profile, especially involving “protein translation” and “oxidative phosphorylation”. Direct measurements of electron transport chain catalysis revealed reduction in mitochondrial complex I activity in Dutch mice. Microglial transcript analysis revealed no evidence of inflammation. The incomplete clinical response to fibrillar Aβ immunodepletion in human patients may be attributable to residual NFA-Aβ that are undetectable by currently available biofluid or neuroimaging biomarkers. The depletion or neutralization of both fibrillar and NFA-Aβ may be needed for complete elimination of Aβ toxicity.TeaserAPPE693Q“NFA-Aβ only” mice reveal clinically relevant mechanisms despite the absence of detectable inflammation
Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development
Authors: Kota Savithri Balasubramanian , Kota Satya K. 
Published: February 2025

AbstractHistone methyltransferases and demethylases play crucial roles in gene regulation and are vital for proper functioning of multiple tissues. Lysine-specific histone demethylase 1A (Kdm1a), is responsible for the demethylation of specific lysines, namely K4 and K9, on histone H3. In this study, we investigated the functions of Kdm1a during mouse kidney development upon targeted deletion in renal progenitor cells. Loss ofKdm1a in Six2-positive nephron progenitors resulted in significant reduction in renal mass, tissue structural changes and impaired function. To further understand the molecular function of Kdm1a during kidney development, we conducted multi-omics analyses that included transcriptome profiling, Chromatin immunoprecipitation (ChIP) sequencing, and methylome assessments. These omic analyses identified Kdm1a as a critical gene regulator required for sustained expression of several nephron segment marker genes, as well as vast number of solute carrier (Slc) genes and a few imprinted genes. Absence of Kdm1a in kidneys led to an increase in global H3K9 methylation peaks, which correlated with the transcriptional downregulation of numerous genes. Among these were markers of nephron progenitors and presumptive tubular precursors. We also observed that specific gene bodies exhibited altered DNA methylation patterns at intragenic differentially methylated regions (DMRs) upon Kdm1a deletion, while the overall global levels of DNA methylation remained unchanged. Our data point to a key regulatory role for Kdm1a in the renal progenitor epigenome, influencing kidney specific gene expression in the developing nephrons. Together the study highlights an indispensable role for Kdm1a for proper development of mouse kidneys, and its absence leading to significant developmental and functional impairment.
Targeting anterior cingulate cortex with tDCS: an overview and analysis of electric field magnitude
Authors: Konstantinović U. , Stanković M. 
Published: February 2025

AbstractThe anterior cingulate cortex (ACC) is a brain region with a key role in various cognitive, emotional, and sensory processes. Given its extensive functional repertoire, modulating ACC activity to enhance cognitive functioning and alleviate symptoms of certain clinical conditions holds great potential. Over the past decades, transcranial direct current stimulation (tDCS) has gained popularity due to its ability to non-invasively affect the cortical excitability. Nevertheless, using tDCS to target regions located beneath superficial cortical areas, such as the ACC, could pose a challenge due to the unpredictable distribution of the electric field (E-field). To systematize the current state of evidence regarding the use of tDCS to modulate ACC activity, we conducted a systematic review focusing on analyzing the E-field distribution across the brain and its magnitude within the ACC as the region of interest. Our goal was to review the stimulation parameters used thus far and examine whether the E-field characteristics are linked to the observed effects. After the literature search and study selection, 14 studies were included in the review. Most of the studies were sham-controlled single-session experiments aiming to modulate specific cognitive processes in healthy adults. The most prominent process of interest was cognitive control, and most of the included studies observed behavioural effects. Our results show that cathodal stimulation led to significant results more frequently, regardless of E-field magnitude in ACC or specificity of E-field distribution throughout the brain. When it comes to anodal tDCS, more focal stimulation of the ACC was associated with a higher frequency of significant effects. We discuss these findings considering diverse methodological designs, the (un)specificity of ACC targeting, and other factors that could contribute to the variability of tDCS effects across studies.
Membrane-permeable 5-fluorodeoxyuridine triphosphate derivatives inhibit the proliferation ofPlasmodium falciparum
Authors: Nikolova Vella , Linnemannstöns Karen , Bendel Marie-Elise , Machado Marta , Ganter Benedikt , Budimir Patricia , Vogts Michelle , Ganter Markus , Meier Chris , Dobbelstein Matthias 
Published: February 2025

ABSTRACTMalaria tropica remains one of the most impactful infectious diseases worldwide, necessitating the development of novel therapies targetingPlasmodium falciparum(P. falciparum), its causative agent. Nucleoside analogues are widely used to treat viral infections and cancer due to their ability to interfere with nucleotide biosynthesis, or to integrate into nascent nucleic acids, after cellular uptake and phosphorylation. However, the absence of nucleoside kinases inP. falciparumseverely limits the therapeutic potential of modified nucleosides. Conversely, phosphorylated nucleoside drug candidates mostly lack cell permeability, diminishing their efficacy. To overcome this challenge, we evaluated cell-permeable derivatives of 5-fluorodeoxyuridine triphosphate (FdUTP) for their ability to inhibit the proliferation ofP. falciparumin cultured human red blood cells (RBCs). Remarkably, cell-permeable FdUTP (cpFdUTP) demonstrated rapid and potent anti-parasitic effects, permanently arresting parasite development predominantly at the trophozoite-to-schizont stage transition. Treatment of aP. falciparumnuclear cycle sensor line showed that the presence of cpFdUTP led to stalled DNA replication. While cpFdUTP also inhibited human cell proliferation, the addition of thymidine or cell-permeable deoxythymidine triphosphate (cpdTTP) fully rescued human cells from growth inhibition by cpFdUTP, without restoringP. falciparumproliferation. This establishes a therapeutic window and highlights the potential application of cpFdUTP in combination with thymidine as a novel approach to treat malaria.Graphical abstract
Untangling dopamine and glutamate in the ventral tegmental area
Authors: Prévost Emily D. , Ward Lucy A. , Alas Daniel , Aimale Giulia , Ikenberry Sara , Fox Katie , Pelletier Julianne , Ly Annie , Ball Jayson , Kilpatrick Zachary P. , Price Kailyn , Polter Abigail M. , Root David H. 
Published: February 2025

ABSTRACTVentral tegmental area (VTA) dopamine neurons are of great interest for their central roles in motivation, learning, and psychiatric disorders. While hypotheses of VTA dopamine neuron function posit a homogenous role in behavior (e.g., prediction error), they do not account for molecular heterogeneity. We find that glutamate-dopamine, nonglutamate-dopamine, and glutamate-only neurons are dissociable in their signaling of reward and aversion-related stimuli, prediction error, and electrical properties. In addition, glutamate-dopamine and nonglutamate-dopamine neurons differ in dopamine release dynamics. Aversion-related recordings of all dopamine neurons (not considering glutamate co-transmission) showed a mixed response that obscured dopamine subpopulation function. Within glutamate-dopamine neurons, glutamate and dopamine release had dissociable contributions toward reward and aversion-based learning and performance. Based on our results, we propose a new hypothesis on VTA dopamine neuron function: that dopamine neuron signaling patterns and their roles in motivated behavior depend on whether or not they co-transmit dopamine with glutamate.