bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of DNA sequences on thermodynamic and structural stability of ZTA transcription factor - DNA complex: An all-atom molecular dynamics study
Authors: Duraisamy Boobalan , Pramanik Debabrata 
Published: November 2024

AbstractThe Epstein-Barr virus (EBV) is one of the cancer-causing gamma type viruses. Although more than 99% people are infected by this virus at some point, it remains in the body in a latent state, typically causing only minor symptoms. Our current understanding is that a known transcription factor (TF), the ZTA protein, binds with dsDNA (double stranded deoxyribonucleic acid) and plays crucial role in mediating the viral latent-to-lytic cycle through binding of specific ZTA responsive elements (ZREs). However, there is no clear understanding of the effect of DNA sequences on the structural stability and quantitative estimation of the binding affinity between the ZTA TF and DNA, along with their mechanistic details. In this study, we employ integrated classical all-atom molecular dynamics (MD) and enhanced sampling simulations to study the ZTA-dsDNA structural properties, thermodynamics, and mechanistic details for the ZTA protein and for two different dsDNA systems: core motif and core motif with flanking end sequences. For each system, we studied three different ZTA responsive elements (ZREs) sequences: ZRE 1, ZRE 2 and ZRE 3. We performed structural analyses, including RMSD and RMSF calculations, to assess conformational stability, along with detailed interaction profiles and hydrogen bond analysis. We conducted residue-level and nucleic acid-level analyses to assess the important protein residues and DNA bases forming interactions between the ZTA and dsDNA systems. We also explored the effect of adding flanking end sequences to the core motif on DNA groove lengths and interstrand hydrogen bonds. Our results indicate that the flanking sequences surrounding the core motif significantly influence the structural stability and binding affinity of the ZTA-dsDNA complex. Among ZRE 1, ZRE 2, and ZRE 3, particularly when paired with their naturally occurring flanking ends, ZRE 3 exhibits higher stability and binding affinity. These findings provide insights into the molecular mechanisms underlying EBV pathogenesis and may indicate potential targets for therapeutic intervention. A detailed of the binding mechanisms will allow for the design of better-targeted therapies against EBV-associated cancers. This study will serve as a holistic benchmark for future studies on these viral protein interactions.
A non-specialist worker delivered digital assessment of cognitive development (DEEP) in young children: a longitudinal validation study in rural India
Authors: Bhavnani Supriya , Ranjan Alok , Mukherjee Debarati , Divan Gauri , Prakash Amit , Yadav Astha , Lal Chaman , Gajria Diksha , Irfan Hiba , Sharma Kamal Kant , Todkar Smita Dattatraya , Patel Vikram , McCray Gareth 
Published: November 2024

AbstractBackgroundCognitive development in early childhood is critical for life-long well-being. Existing cognitive development surveillance tools require lengthy parental interviews and observations of children. Developmental Assessment on an E-Platform (DEEP) is a digital tool designed to address this gap by providing a gamified, direct assessment of cognition in young children which can be delivered by front-line providers in community settings.MethodsThis longitudinal study recruited children from the SPRING trial in rural Haryana, India. DEEP was administered at 39 (SD 1; N=1359), 60 (SD 5; N=1234) and 95 (SD 4; N=600) months and scores were derived using item response theory. Criterion validity was examined by correlating DEEP-score with age, Bayley’s Scales of Infant Development (BSID-III) cognitive domain score at age 3 and Raven’s Coloured Progressive Matrices (CPM) at age 8; predictive validity was examined by correlating DEEP-scores at preschool-age with academic performance at age 8 and convergent validity through correlations with height-for-age z-scores (HAZ) and early life adversities.FindingsDEEP-score correlated strongly with age (r=0.83, 95% CI 0.82-0.84) and moderately with BSID-III (r=0.50, 0.39-0.60) and CPM (r=0.37; 0.30 – 0.44). DEEP-score at preschool-age predicted academic outcomes at school-age (0.32; 0.25 – 0.41) and correlated positively with HAZ and negatively with early life adversities.InterpretationDEEP provides a valid, scalable method for cognitive assessment. It’s integration into developmental surveillance programs could aid in monitoring and early detection of cognitive delays, enabling timely interventions.FundingSPRING, REACH and COINCIDE were funded through Wellcome Trust, Madura Microfinance Ltd and Wellcome Trust/DBT India Alliance respectively.
TomoPicker: Annotation-Efficient Particle Picking in cryo-electron Tomograms
Authors: Uddin Mostofa Rafid , Ahmed Ajmain Yasar , Tahmid Md Toki , Ul Alam Md Zarif , Freyberg Zachary , Xu Min 
Published: November 2024

AbstractParticle picking in cryo-electron tomograms (cryo-ET) is crucial for in situ structure detection of macro-molecules and protein complexes. The traditional template-matching-based approaches for particle picking suffer from template-specific biases and have low throughput. Given these problems, learning-based solutions are necessary for particle picking. However, the paucity of annotated data for training poses substantial challenges for such learning-based approaches. Moreover, preparing extensively annotated cryo-ET tomograms for particle picking is extremely time-consuming and burdensome. Addressing these challenges, we present TomoPicker, an annotation-efficient particle-picking approach that can effectively pick particles when only a minuscule portion (∼ 0.3 − 0.5%) of the total particles in a cellular cryo-ET dataset is provided for training. TomoPicker regards particle picking as a voxel classification problem and solves it with two different positive-unlabeled learning approaches. We evaluated our method on a benchmark cryo-ET dataset of eukaryotic cells, where we observed about 30% improvement by TomoPicker against the most recent state-of-the-art annotation efficient learning-based picking approaches.
SingleFrag: A deep learning tool for MS/MS fragment and spectral prediction and metabolite annotation
Authors: Pérez-Ribera Maribel , Khan Muhammad Faizan , Giné Roger , Badia Josep M. , Junza Sandra , Yanes Oscar , Sales-Pardo Marta , Guimerà Roger 
Published: November 2024

ABSTRACTMetabolite and small molecule identification via MS/MS involves matching experimental spectra with prerecorded spectra of known compounds. This process is hindered by the current lack of comprehensive reference spectral libraries. To address this gap, we need accuratein silicofragmentation tools for predicting MS/MS spectra of compounds for which empirical spectra do not exist. Here, we present SingleFrag, a novel deep learning tool that predicts individual fragments separately, rather than attempting to predict the entire fragmentation spectrum at once. Our results demonstrate that SingleFrag surpasses state-of-the-artin silicofragmentation tools, providing a powerful method for annotating unknown MS/MS spectra of known compounds. As a proof of concept, we successfully annotate three previously unidentified compounds frequently found in human samples.
Chlorpyrifos induces lung metastases and modulation of cancer stem cell markers in triple negative breast cancer model
Authors: Lasagna Marianela , Mardirosian Mariana , Zappia Daniel , Enriquez Lucia , Miret Noelia , Dahir Lara , Zotta Elsa , Randi Andrea , Núñez Mariel , Cocca Claudia 
Published: November 2024

AbstractBreast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in anin vivotriple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and BCSC markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in anin vivomodel induced in mice.
Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells
Authors: Chen Yu-Chia , Takada Mamoru , Nagornyuk Aerica , Muhan Wu , Yamada Hideyuki , Nagashima Takeshi , Ohtsuka Masayuki , DeLuca Jennifer G. , Markus Steven , Takaku Motoki , Suzuki Aussie 
Published: November 2024

AbstractMicrotubule-targeting agents (MTAs) have been successfully translated from basic research into clinical therapies and have been widely used as first- and second-line chemotherapy drugs for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. In this study, we demonstrate that inhibition of the p38-MK2 (MAP kinase-activated protein kinase 2) pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus-end, leading to the inhibition of tumor growth and cancer cell invasion in bothin vitroandin vivomodels. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed RPE1 cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of sub-clinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.
Disconnect betweenin vitroandin vivoefficacy of the MPS1 inhibitor NTRC 0066-0 against glioblastoma
Authors: de Gooijer Mark C. , Zhang Ping , Buil Levi C.M. , Çitirikkaya Ceren H. , Çolakoğlu Hilal , Maia Ana Rita R. , Bočkaj Irena , Espitia-Ballestas Margarita , Kuil Laura E. , Beijnen Jos H. , van Tellingen Olaf 
Published: November 2024

ABSTRACTPurposeGlioblastoma (GBM) is the most common adult primary brain tumor for which new therapeutic strategies are desperately needed. Monopolar spindle 1 (MPS1) is a mitotic kinase that plays a pivotal role in the spindle assembly checkpoint (SAC). GBM appears to be dependent on SAC fidelity, as MPS1 is overexpressed in many GBM patients. Thus, inhibiting MPS1 seems a viable therapeutic strategy to enhance mitotic cell death by attenuating SAC fidelity. NTRC 0066-0 is an MPS1 inhibitor that combines low nanomolar potency with a relatively long on-target residence time.MethodsWe here investigate the potential of NTRC 0066-0 as monotherapy and in combination with chemo-radiation for treatment of GBM using variousin vitroand orthotopicin vivomodels.ResultsWe show that NTRC 0066-0 efficiently induces GBM cell deathin vitro, following continuous exposure with IC50s in the low nanomolar range. In contrast to previous reports of studies with other MPS1 inhibitors, we did not observe synergyin vitrowith anti-microtubule drugs, such as docetaxel and vincristine. We demonstrate that NTRC 0066-0 has a high brain penetration, despite being a substrate of the efflux transporter P-glycoprotein. However, even when using recipientAbcb1a/b;Abcg2-/-mice with superior brain penetration and administering NTRC 0066-0 using a dose-dense regimen, we did not observe antitumor efficacy against an orthotopic GBM mouse model, neither as monotherapy nor in combination with standard-of-care temozolomide chemotherapy and radiotherapy.ConclusionThese data indicate that GBM is probably not a suitable indication for developing MPS1 inhibitors.
Amino acid properties, substitution rates, and the nearly neutral theory
Authors: James Jennifer E. , Lascoux Martin 
Published: November 2024

AbstractDo the properties of amino acids affect their rates of substitution? The nearly neutral theory predicts that greater selective constraint leads to slower rates of evolution; similarly, we expect amino acids that are more different from each other to have lower rates of exchange because such changes are most likely to affect protein structure and function. Here we test these predictions, using substitution rates estimated from empirical amino acid exchangeability matrices. To measure degree of amino acid difference, we focussed on two physicochemical properties, hydrophobicity and molecular weight, uncorrelated metrics that are known to have important implications for protein structure and function. We find that for both hydrophobicity and molecular weight, amino acid pairs with large differences had lower rates of substitution. We also found that amino acids that differed in both properties had the lowest rates of substitution, suggesting that both physicochemical properties are under selective constraint. Mutation properties, such as the number of mutations or the number of transitions as opposed to transversions separating amino acid pairs, were also important predictors of substitution rates. The relationship between amino acid substitution rates and differences in their physiochemical properties holds across several taxonomically restricted datasets. This finding suggests that purifying selection affects amino acid substitution rates in a similar manner across taxonomic groups with different effective population sizes.
Platelet-specific P2Y1receptor deficient mice have suppressed leukocyte recruitment in response to lipopolysaccharide
Authors: Pan Dingxin , Oralman Tolga , Evans Reah , Baker Oliver , Cocks Graham , Page Clive P. , Pitchford Simon C. 
Published: November 2024

AbstractA role for the P2Y1receptor in inflammation has been established using a pharmacological approach over an acute 4 hour time span. However, nucleotide-structure P2Y1receptor antagonists have limited experimental use due to inadequate pharmacokinetics, and inability to decipher global versus cell specific effectsin vivo. The creation of a conditional knock out (platelet) P2Y1transgenic mouse model was designed to overcome these restrictions.A homozygous P2Y1LoxPmouse colony was created using CRISPR/Cas9 technology, and crossed with a hemizygous P2Y1LoxPwith PF4-cre to provide offspring that are homozygous for P2Y1LoxPflanked allele, and hemizygous for the PF4cre (platelet P2Y1-/-) and offspring homozygous for P2Y1LoxPflanked allele, but non-carriers for PF4cre (control mice). Animals were intranasally administered LPS to induce pulmonary inflammation to assess the influence of phenotype on leukocyte recruitment.24 hours post intranasal LPS administration; pulmonary neutrophil and platelet recruitment were significantly suppressed, despite the fact that neutrophils retained the ability to migrate to fMLPex vivo. Circulating platelet and leukocyte numbers were not different between control and platelet P2Y1-/-animals. Tail bleeding times revealed the platelet P2Y1-/-mice had a severe bleeding phenotype.This is the first demonstration of a platelet specific P2Y1-/-mouse model to confirm the importance of platelet P2Y1receptors in the regulation of inflammatory responses with a 60-70% inhibition of leukocyte recruitment over an extended time period compared to previous pharmacological studies. platelet P2Y1-/-mice will help further elucidate the mechanisms by which P2Y1receptors regulate platelet activation during inflammation.Key PointsMice selectively deficient in the platelet P2Y1have suppressed leukocyte and platelet recruitment during inflammation.We provide a methodology to determine mechanistic relevance that is otherwise limited by pharmacological approaches.
Septins regulate heart contractility through modulation of cardiomyocyte store-operated calcium entry
Authors: Tripoli Benjamin A. , Smyth Jeremy T. 
Published: November 2024

ABSTRACTHighly regulated cardiomyocyte Ca2+fluxes drive heart contractions. Recent findings from multiple organisms demonstrate that the specific Ca2+transport mechanism known as store-operated Ca2+entry (SOCE) is essential in cardiomyocytes for proper heart function, and SOCE dysregulation results in cardiomyopathy. Mechanisms that regulate SOCE in cardiomyocytes are poorly understood. Here we tested the role of cytoskeletal septin proteins in cardiomyocyte SOCE regulation. Septins are essential SOCE modulators in other cell types, but septin functions in cardiomyocytes are nearly completely unexplored. We show using targeted genetics and intravital imaging of heart contractility inDrosophilathat cardiomyocyte-specific depletion of septins 1, 2, and 4 results in heart dilation that phenocopies the effects of SOCE suppression. Heart dilation caused by septin 2 depletion was suppressed by SOCE upregulation, supporting the hypothesis that septin 2 is required in cardiomyocytes for sufficient SOCE function. A major function of SOCE is to support SERCA-dependent sarco/endoplasmic reticulum (S/ER) Ca2+stores, and augmenting S/ER store filling by SERCA overexpression also suppressed the septin 2 phenotype. We also ruled out several potential SOCE-independent septin functions, as septin 2 phenotypes were not due to septin function during development and septin 2 was not required for z-disk organization as defined by α-actinin labeling. These results demonstrate, for the first time, an essential role of septins in cardiomyocyte physiology and heart function that is due, at least in part, to septin regulation of SOCE function.
A common garden ofHalichondriasponges: taxonomic revision of Northeast Pacific Halichondriidae reveals many cryptic introduced species
Authors: Turner Thomas L. , Morrow Christine , Picton Bernard , Goodwin Claire , Thacker Robert W. 
Published: November 2024

AbstractSponges (phylum Porifera) possess biochemical, cellular, and physiological traits with valuable biotechnical applications. However, our ability to harness these natural innovations is limited by a classification system that does not fully reflect their evolutionary history. In this study, we uncover numerous cryptic species within the genusHalichondriathat are morphologically indistinguishable from the well-knownH. panicea. Many of these species have habitat preferences and geographic distributions that strongly suggest they have been dispersed by human activity. Most of these species are broadly sympatric with their closest relatives, and these overlapping distributions allow us to use patterns of DNA variation to infer reproductive isolation between clades in nature. With reproductively isolated species thus delineated, we can use DNA states as taxonomic characters to formally describe them. Though much remains to be learned about these newly discovered species, the natural “common gardens” of introduced sponges in California, New York, and other locations provide opportunities to test hypotheses about their diversification in future work.
Shapes of Plasma Membrane Vesicles and PC-Cholesterol Vesicles Reveal Their Effective Spontaneous Curvature
Authors: Kaur Harshmeet , Pandey Tanmay , Bhatia Tripta 
Published: November 2024

AbstractGiant membrane vesicles (GUVs) and giant plasma membrane vesicles (GPMVs) are useful models for studying cellular membrane properties. Our research analyzed the reduced volume of vesicles made from phospholipid and 10% cholesterol to investigate transbilayer sugar asymmetries. We found that GPMVs have an average reduced volume of (0.88±0.06) with buffer asymmetry of 323 mM, lower than the (0.92±0.08) observed for DOPC: cholesterol vesicles with sucrose/glucose asymmetry of 390 mM. GUVs with different sugars inside and outside were more deflated, demonstrating a greater volume reduction than those with the same sugar inside and out. We applied the area-difference elasticity (ADE) model to map GPMVs and used the spontaneous curvature (SC) model to analyze DOPC: cholesterol GUVs, extracting spontaneous curvature based on their reduced volume.TOC Graphic
Highly efficientXISTreactivation in female hPSC by transient dual inhibition of TP53 and DNA methylation during Cas9 mediated genome editing
Authors: Motosugi Nami , Hasegawa Keita , Kurosaki Natsumi , Kawaguchi Erika , Izumi Kenji , Iida Yumi , Higashiseto Misaki , Yokoyama Keiko , Sasaki Ayumi , Nakabayashi Kazuhiko , Fukuda Atsushi 
Published: November 2024

SummaryErosion of X-chromosome inactivation (XCI) complicates disease and developmental modeling in female human pluripotent stem cells (hPSCs). Previous studies demonstrated that Cas9-mediated editing of theXISTpromotervianon-homologous end joining (NHEJ) or homology-directed repair (HDR) with a selection cassette upstream ofXISTcan trigger DNA demethylation andXISTreactivation, restoring XCI. Here, we show that NHEJ-mediated XCI reacquisition is more stable during differentiation than HDR. We further developed a novel, efficientXISTreactivation method by combining TP53 inhibition with DNA methylation maintenance suppression during Cas9-mediated NHEJ, offering a robust approach to achieving stable XCI in female hPSCs for diverse applications.
Accurate Detection of Tandem Repeats from Error-Prone Sequences with EquiRep
Authors: Song Zhezheng , Zahin Tasfia , Li Xiang , Shao Mingfu 
Published: November 2024

AbstractA tandem repeat is a sequence of nucleotides that occurs as multiple contiguous and near-identical copies positioned next to each other. These repeats play critical roles in genetic diversity, gene regulation, and are strongly linked to various neurological and developmental disorders. While several methods exist for detecting tandem repeats, they often exhibit low accuracy when the repeat unit length increases or the number of copies is low. Furthermore, methods capable of handling highly mutated sequences remain scarce, highlighting a significant opportunity for improvement. We introduce EquiRep, a tool for accurate detection of tandem repeats from erroneous sequences. EquiRep estimates the likelihood of positions originating from the same position in the unit by self-alignment followed by a novel approach that refines the estimation. The built equivalent classes and the consecutive position information will be then used to build a weighted graph, and the cycle in this graph with maximum bottleneck weight while covering most nucleotide positions will be identified to reconstruct the repeat unit. We test EquiRep on simulated and real HOR and RCA datasets where it consistently outperforms or is comparable to state-of-the-art methods. EquiRep is robust to sequencing errors, and is able to make better predictions for long units and low frequencies which underscores its broad usability for studying tandem repeats.