bluuebunny/crossref_metadata_2025_split huggingface dataset:
MapTurns: mapping the structure, H-bonding, and contexts of beta turns in proteins
Authors: Newell Nicholas E 
Published: December 2024

Abstract

Motivation
Beta turns are the most common type of secondary structure in proteins after alpha helices and beta sheets and play many key structural and functional roles. Turn backbone (BB) geometry has been classified at multiple levels of precision, but the current picture of side chain (SC) structure and interaction in turns is incomplete, because the distribution of SC conformations associated with each sequence motif has commonly been represented only by a static image of a single, typical structure for each turn BB geometry, and only motifs which specify a single amino acid (e.g. aspartic acid at turn position 1) have been systematically investigated. Furthermore, no general evaluation has been made of the SC interactions between turns and their BB neighborhoods. Finally, the visualization and comparison of the wide range of turn conformations has been hampered by the almost exclusive characterization of turn structure in BB dihedral-angle (Ramachandran) space.

Results
This work introduces MapTurns, a web server for motif maps, which employ a turn-local Euclidean-space coordinate system and a global turn alignment to comprehensively map the distributions of BB and SC structure and H-bonding associated with sequence motifs in beta turns and their local BB contexts. Maps characterize many new SC motifs, provide detailed rationalizations of sequence preferences, and support mutational analysis and the general study of SC interactions, and they should prove useful in applications such as protein design.

Availability and implementation
MapTurns is available at www.betaturn.com. Sample code is available at: https://github.com/nenewell/MapTurns/tree/main.
End-to-end simulation of nanopore sequencing signals with feed-forward transformers
Authors: Beslic Denis , Kucklick Martin , Engelmann Susanne , Fuchs Stephan , Renard Bernhard Y , Körber Nils 
Published: December 2024

Abstract

Motivation
Nanopore sequencing represents a significant advancement in genomics, enabling direct long-read DNA sequencing at the single-molecule level. Accurate simulation of nanopore sequencing signals from nucleotide sequences is crucial for method development and for complementing experimental data. Most existing approaches rely on predefined statistical models, which may not adequately capture the properties of experimental signal data. Furthermore, these simulators were developed for earlier versions of nanopore chemistry, which limits their applicability and adaptability to the latest flow cell data.

Results
To enhance the quality of artificial signals, we introduce seq2squiggle, a novel transformer-based, non-autoregressive model designed to generate nanopore sequencing signals from nucleotide sequences. Unlike existing simulators that rely on static k-mer models, our approach learns sequential contextual information from segmented signal data. We benchmark seq2squiggle against state-of-the-art simulators on real experimental R9.4.1 and R10.4.1 data, evaluating signal similarity, basecalling accuracy, and variant detection rates. Seq2squiggle consistently outperforms existing tools across multiple datasets, demonstrating superior similarity to real data and offering a robust solution for simulating nanopore sequencing signals with the latest flow cell generation.

Availability and implementation
seq2squiggle is freely available on GitHub at: github.com/ZKI-PH-ImageAnalysis/seq2squiggle.
Unlocking the power of multi-institutional data: Integrating and harmonizing genomic data across institutions
Authors: Chen Yuan , Shen Ronglai , Feng Xiwen , Panageas Katherine 
Published: December 2024

ABSTRACT
Cancer is a complex disease driven by genomic alterations, and tumor sequencing is becoming a mainstay of clinical care for cancer patients. The emergence of multi-institution sequencing data presents a powerful resource for learning real-world evidence to enhance precision oncology. GENIE BPC, led by American Association for Cancer Research, establishes a unique database linking genomic data with clinical information for patients treated at multiple cancer centers. However, leveraging sequencing data from multiple institutions presents significant challenges. Variability in gene panels can lead to loss of information when analyses focus on genes common across panels. Additionally, differences in sequencing techniques and patient heterogeneity across institutions add complexity. High data dimensionality, sparse gene mutation patterns, and weak signals at the individual gene level further complicate matters. Motivated by these real-world challenges, we introduce the Bridge model. It uses a quantile-matched latent variable approach to derive integrated features to preserve information beyond common genes and maximize the utilization of all available data, while leveraging information sharing to enhance both learning efficiency and the model’s capacity to generalize. By extracting harmonized and noise-reduced lower-dimensional latent variables, the true mutation pattern unique to each individual is captured. We assess model’s performance and parameter estimation through extensive simulation studies. The extracted latent features from the Bridge model consistently excel in predicting patient survival across six cancer types in GENIE BPC data.
Debiased high-dimensional regression calibration for errors-in-variables log-contrast models
Authors: Zhao Huali , Wang Tianying 
Published: December 2024

ABSTRACT
Motivated by the challenges in analyzing gut microbiome and metagenomic data, this work aims to tackle the issue of measurement errors in high-dimensional regression models that involve compositional covariates. This paper marks a pioneering effort in conducting statistical inference on high-dimensional compositional data affected by mismeasured or contaminated data. We introduce a calibration approach tailored for the linear log-contrast model. Under relatively lenient conditions regarding the sparsity level of the parameter, we have established the asymptotic normality of the estimator for inference. Numerical experiments and an application in microbiome study have demonstrated the efficacy of our high-dimensional calibration strategy in minimizing bias and achieving the expected coverage rates for confidence intervals. Moreover, the potential application of our proposed methodology extends well beyond compositional data, suggesting its adaptability for a wide range of research contexts.
Epidermal stem cell-derived exosomes improve wound healing by promoting the proliferation and migration of human skin fibroblasts
Authors: Kang Deni , Wang Xiaoxiang , Chen Wentao , Mao Lujia , Zhang Weiqiang , Shi Yan , Xie Julin , Yang Ronghua 
Published: December 2024

Abstract

Background
Epidermal stem cells (ESCs) are primarily located in the basal layer of the epidermis and play a crucial role in wound healing. ESCs-derived exosomes (ESCs-Exo) are emerging as promising candidates for skin regeneration and wound healing. However, the underlying mechanisms remain unclear. This study aims to investigate the role and mechanisms of ESCs-Exo in promoting the proliferation, migration, and collagen synthesis of human skin fibroblasts (HSFBs).

Methods
This study generated, isolated, and characterized ESC-Exos. The effects of ESCs-Exo on the proliferation of human skin fibroblasts (HSFBs) were detected via Cell Counting Kit-8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU), and Proliferating Cell Nuclear Antigen (PCNA) and Marker of Proliferation Ki-67 (MKI67) gene expression methods. The effect of ESCs-Exo on the migration of HSFBs was detected via a transwell assay and a scratch test. The concentrations of collagen secreted by the HSFBs and the mRNAs of the two kinds of collagen expressed by the HSFBs were analyzed. We also analyzed the phosphorylation of Protein Kinase N1 (PKN1) and the expression of cyclins via western blotting. Finally, the effect of ESCs-Exo on wound healing was verified by animal experiments, and the key genes and signaling pathways of ESCs-Exo were excavated by transcriptomic analysis.

Results
Western blotting revealed that the exosomes of ESCs highly expressed established markers such as Alix, CD63, and CD9. ESC-Exos significantly promoted HSFB proliferation and migration in a dose-dependent manner, as well as HSFB collagen synthesis, and effectively increased the ratio of collagen III/I. In addition, bioinformatics analysis showed that the expression of key gene C-X-C motif chemokine ligand 9 was lower in the ESCs-Exo group, which may promote wound healing by regulating PKN1-cyclin and tumor necrosis factor signaling pathways. Animal experiments demonstrated that ESCs-Exo could reduce inflammation and accelerate wound healing.

Conclusions
In this study, we found that ESCs-Exo may improve wound healing by promoting the proliferation and migration of HSFBs.
Effect of bromodomain and extraterminal inhibitors with different bromodomain selectivity on mesenchymal stem cells
Authors: Tanimoto Riho , Wong Yung-Sing , Ebara Mitsuhiro , Uto Koichiro 
Published: December 2024

Abstract
This study examines the influence of bromodomain and extraterminal inhibitors with different selectivity for bromodomains on human mesenchymal stem cells. Our findings demonstrate that bromodomain and extraterminal inhibitors with higher selectivity for the second bromodomain exhibit lower cytotoxicity in human mesenchymal stem cells, suggesting that the inhibition of osteogenic differentiation in human mesenchymal stem cells is primarily due to the inhibition of the first bromodomain of bromodomain-containing protein 4, rather than the inhibition of its second bromodomain.
Identification of ZNF850 as a novel CTG repeat expansion-related gene in myotonic dystrophy type 1 patient-derived iPSCs
Authors: Kamon Masayoshi , Wakatsuki Shuji , Nakamori Masayuki , Takahashi Masanori P , Mori-Yoshimura Madoka , Komaki Hirofumi , Araki Toshiyuki 
Published: December 2024

Abstract
Myotonic dystrophy type 1 (DM1) is a dominantly inherited multi-system disease caused by expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Similar to other repeat disorders, the expanded trinucleotide repeat is unstable and demonstrates a tendency to increase repeat size with age in affected tissues. DNA mismatch repair system is implicated in somatic instability. It has been demonstrated that DM1 patient-derived induced pluripotent stem cells (DM1-iPSCs) show repeat instability, in which involvement of mismatch repair proteins has been suggested. Here we identified ZNF850 as a novel CTG repeat expansion-related molecule in DM1-iPSCs. ZNF850 was downregulated in a DM1-iPSC clone whose CTG repeat is exceptionally stable. We found that RNAi-mediated ZNF850 downregulation in DM1-iPSCs significantly reduced the repeat expansion and resulting instability. In adult skeletal muscle tissue of DM1 patients, ZNF850 expression levels were positively correlated with the repeat size. Furthermore, we found that ZNF850 protein can bind to the expanded CTG repeat sequence, and is located in proximity to MutSβ components. These results suggest that ZNF850 might play a role in repeat instability in DM1 by recruiting MutSβ to the repeat sequence.
Horizontal acquisitions of growth potential
Authors: Xia Fan , Walker Gordon 
Published: December 2024

Abstract
We analyze the operating performance of horizontal acquisitions between firms that differ in their growth potential: (I) low-potential firms that buy targets with high potential; and (II) high-potential firms that buy low-potential targets. These two types of acquisition have been the topic of research at three levels of analysis: the industry, the firm, and the transaction. At the industry level, incumbents in the core and innovative startups in the periphery are presumed to have complementary assets managed more effectively through co-ownership. In this vein, studies have focused chiefly on incumbents buying startups. We redress this imbalance. At the firm level, research on real options for growth has examined how multi-business firms exploit their relatedness in entry and exit decisions. Here, we study growth potential in terms of real options in horizontal deals and analyze their effect on post-acquisition performance. At the transaction level, a number of studies have focused on post-acquisition organizational structure and the transfer of knowledge between incumbents and startups. We expand this research by estimating the presumed flow of growth potential capabilities in both High–Low and Low–High deals. Our method uses a difference-in-differences fixed effect model design with Coarsened Exact Matching and Kernel-weighted Propensity Score Matching among comparable firm pairs to measure synergy and to control for endogeneity and portfolio effects using data on U.S. firms over 30 years. We also use a novel accounting adjustment formula to calculate comparable post-M&A operating performance.
Skewed X chromosome inactivation as a response to sexually antagonistic selection
Authors: Greenberg Naomi L , Patten Manus M 
Published: December 2024

Abstract
In eutherians, one of the X chromosomes in each cell of the early female embryo is rendered transcriptionally silent through X chromosome inactivation. The choice of which X chromosome to inactivate takes place independently in each cell and is stably inherited through development, leading to a roughly 50:50 ratio of cells in the adult body expressing one or the other X chromosome. However, X chromosome inactivation can be skewed, with certain X chromosomes showing a heritable tendency to avoid inactivation. Using population-genetic models, we test whether genetic variation for this trait can be maintained by linked sexually antagonistic selection. In favour of this hypothesis, we find that a neutral modifier that affects the chances of its chromosome’s inactivation—e.g., a variant of the X controlling element (Xce)—can spread when linked to a sexually antagonistic gene. We explore the logic of this modifier’s spread, which we find to be similar in many respects to that of a modifier of dominance. We also test for the presence of a “drift barrier”—i.e., a population size below which the indirect selective force favouring the modifier becomes too weak to overcome drift. On balance, we find that sexual antagonism may encourage the spread of skewed X chromosome inactivation, but only under favourable conditions.
Moving beyond population variable importance: concept, theory and applications of individual variable importance
Authors: Dai Guorong , Shao Lingxuan , Chen Jinbo 
Published: December 2024

Abstract
In a non-parametric regression setting, we introduce a novel concept of ‘individual variable importance’, which assesses the relevance of certain covariates to an outcome variable among individuals with specific characteristics. This concept holds practical importance for both risk assessment and association identification. For example, it can represent (i) the usefulness of expensive biomarkers in risk prediction for individuals at a specified baseline risk, or (ii) age-specific associations between physiological indicators. We quantify individual variable importance using a ratio parameter between two conditional mean squared errors. To estimate and infer this parameter, we develop fully non-parametric estimators and establish their asymptotic properties. Our method performs well in simulation studies. Applying our approach to analyse a real dataset reveals a scientifically interesting result: the association between body shape and systolic blood pressure diminishes with increasing age. Our finding aligns with the medical literature based on standard parametric regression techniques, but our approach is more reliable due to its robustness to model misspecification. More importantly, the fully non-parametric nature of our method allows it to be applied in settings with complex relationships between variables, which cannot be correctly characterized by traditional parametric interaction analyses.
ZNF143 binds DNA and stimulates transcription initiation to activate and repress direct target genes
Authors: Dong Jinhong , Sathyan Kizhakke Mattada , Scott Thomas G , Mukherjee Rudradeep , Guertin Michael J 
Published: December 2024

Abstract
Transcription factors bind to sequence motifs and act as activators or repressors. Transcription factors interface with a constellation of accessory cofactors to regulate distinct mechanistic steps to regulate transcription. We rapidly degraded the essential and pervasively expressed transcription factor ZNF143 to determine its function in the transcription cycle. ZNF143 facilitates RNA polymerase initiation and activates gene expression. ZNF143 binds the promoter of nearly all its activated target genes. ZNF143 also binds near the site of genic transcription initiation to directly repress a subset of genes. Although ZNF143 stimulates initiation at ZNF143-repressed genes (i.e. those that increase transcription upon ZNF143 depletion), the molecular context of binding leads to cis repression. ZNF143 competes with other more efficient activators for promoter access, physically occludes transcription initiation sites and promoter-proximal sequence elements, and acts as a molecular roadblock to RNA polymerases during early elongation. The term context specific is often invoked to describe transcription factors that have both activation and repression functions. We define the context and molecular mechanisms of ZNF143-mediated cis activation and repression.
Conformational switching of Arp5 subunit regulates INO80 chromatin remodeling
Authors: Shukla Shagun , Paul Somnath , Garcia Jeison , Zhong Yuan , Juste Sara Sanz , Beauchemin Karissa , Bartholomew Blaine 
Published: December 2024

Abstract
The INO80 chromatin remodeler is a versatile enzyme capable of several functions, including spacing nucleosomes equal distances apart, precise positioning of nucleosomes based on DNA shape/sequence and exchanging histone dimers. Within INO80, the Arp5 subunit plays a central role in INO80 remodeling, evidenced by its interactions with the histone octamer, nucleosomal and extranucleosomal DNA, and its necessity in linking INO80’s ATPase activity to nucleosome movement. We find two distinct regions of Arp5 binding near the acidic pocket of nucleosomes. One region has an arginine anchor that binds nucleosomes and is vital for INO80 mobilizing nucleosomes. The other region has a hydrophobic/acid patch of Leu and Asp that binds free histone H2A–H2B dimers. These two regions have different roles in remodeling nucleosomes as seen both in vitro and in vivo and the hydrophobic/acidic patch of Arp5 is likely needed for displacing DNA from the H2A–H2B surface and dimer exchange by INO80.
DNA target binding-induced pre-crRNA processing in type II and V CRISPR-Cas systems
Authors: Chen Jiyun , Lin Xiaofeng , Xiang Wenwen , Chen Ying , Zhao Yueming , Huang Linglong , Liu Liang 
Published: December 2024

Abstract
Precursor (pre)-CRISPR RNA (crRNA) processing can occur in both the repeat and spacer regions, leading to the removal of specific segments from the repeat and spacer sequences, thereby facilitating crRNA maturation. The processing of pre-crRNA repeat by Cas effector and ribonuclease has been observed in CRISPR-Cas9 and CRISPR-Cas12a systems. However, no evidence of pre-crRNA spacer cleavage by any enzyme has been reported in these systems. In this study, we demonstrate that DNA target binding triggers efficient cleavage of pre-crRNA spacers by type II and V Cas effectors such as Cas12a, Cas12b, Cas12i, Cas12j and Cas9. We show that the pre-crRNA spacer cleavage catalyzed by Cas12a and Cas9 has distinct characteristics. Activation of the cleavage activity in Cas12a is induced by both single-stranded DNA (ssDNA) and double-stranded DNA target binding, whereas only ssDNA target binding triggers cleavage in Cas9 toward the pre-crRNA spacer. We present a series of structures elucidating the underlying mechanisms governing conformational activation in both Cas12a and Cas9. Furthermore, leveraging the trans-cutting activity of the pre-crRNA spacer, we develop a one-step DNA detection method characterized by its simplicity, high sensitivity, and excellent specificity.
Multi-center real-world data-driven web calculator for predicting outcomes in IDH-mutant gliomas: Integrating molecular subtypes and treatment modalities
Authors: Xu Houshi , Liu Beining , Wang Yue , Zhu Ruize , Jiang Shan , Soliman Lina Akmal Fouad Abdelhamid , Chai Huihui , Sun Maoyuan , Chen Jiawen , Li Kay Ka-Wai , Ng Ho-Keung , Zhang Zhenyu , Wei Junji , Shi Zhifeng , Mao Ying 
Published: December 2024

Abstract

Background
Isocitrate dehydrogenase (IDH)-mutant gliomas generally have a better prognosis than IDH-wild-type glioblastomas, and the extent of resection significantly impacts prognosis. However, there is a lack of integrated tools for predicting outcomes based on molecular subtypes and treatment modalities. This study aimed to identify factors influencing gross total resection (GTR) rates and to develop a clinical prognostic tool for IDH-mutant gliomas.

Methods
We analyzed 650 patients with IDH-mutant gliomas from 3 Chinese medical centers (Shanghai, Hong Kong, and Zhengzhou). Data included age, sex, extent of resection, radiotherapy status, tumor grade, histology, and molecular markers (1p19q, TERT promoter, BRAF, EGFR, 10q). Patients were categorized based on GTR status, and a nomogram predicting 3-, 5-, and 10-year overall survival (OS) was developed using Cox proportional hazards regression and validated with time-dependent ROC and calibration plot analyses.

Results
Non-GTR was associated with diffuse astrocytoma (73.0% vs. 53.5%), 1p19q non-codeletion (67.9% vs. 48.7%), and wildtype TERT promoter (63.6% vs. 52.4%). The nomogram, incorporating age, TERT promoter status, extent of resection, grade, and radiotherapy status, demonstrated strong discriminatory ability (AUC &gt; 0.75) and good calibration. Decision curve analysis indicated that it outperformed WHO grade-based classification in identifying high-risk patients. An online calculator was developed for clinical use (http://www.szflab.site/nomogram/).

Conclusion
We developed and validated a nomogram and online tool that integrates molecular and clinical factors for predicting outcomes in IDH-mutant gliomas, enhancing clinical decision-making.