bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational design and engineering of self-assembling multivalent microproteins with therapeutic potential against SARS-CoV-2
Authors: Qin Qin , Jiang Xinyi , Huo Liyun , Qian Jiaqiang , Yu Hongyuan , Zhu Haixia , Du Wenhao , Cao Yuhui , Zhang Xing , Huang Qiang 
Published: February 2024

AbstractMultivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the “3-RBD-up” conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses.
Graphical Abstract
An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review
Authors: Brulport Axelle , Bourdon Mathilde , Vaiman Daniel , Drouet Christian , Pocate-Cheriet Khaled , Bouzid Kheira , Marcellin Louis , Santulli Pietro , Abo Carole , Jeljeli Maxime , Chouzenoux Sandrine , Chapron Charles , Batteux Frédéric , Berthelot Camille , Doridot Ludivine 
Published: February 2024

AbstractBiomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease.
Graphical Abstract
COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome
Authors: Wang Fangzhou , Zhang Zhenpeng , Mao Mingsong , Yang Yudai , Xu Ping , Lu Shichun 
Published: February 2024

Abstract
Background
Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality.

Method
In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides.

Result
The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens.

Conclusion
Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.
Killing capacity analysis of tumor-infiltrating cytotoxic lymphocytes and impact on lymph node metastasis in differentiated papillary carcinoma of thyroid with the BRAF V600E mutation
Authors: Liu Xiaogang , Liu Honggang , Wang Lu , Han Yubing , Kong Linghong , Zhang Xinpeng 
Published: February 2024

Abstract
Background
Cytotoxic lymphocytes (CLs) express potent toxins, including perforin (P) and granzyme-B (G), which brings about target cell death. The purpose of this study was to evaluate the killing capacity of tumor-infiltrating CLs by means of P and G analysis, and explore the association with lymph node metastasis in papillary carcinoma of thyroid (PTC) without Hashimoto’s thyroiditis (HT).

Methods
Infiltration of lymphocytes in PTC was observed in frozen sections. Both fresh tumor tissues and paracancerous tissues with lymphocyte infiltration were collected and prepared into a single cell suspension. Flow cytometry was used to detect the percentages of CD3+P+, CD3+G+, CD8+P+, and CD8+G+ T lymphocytes (TLs) and CD16-CD56+P+ and CD16-CD56+G+ natural killer (NK) cells. Finally, we investigated differential expression of P and G in NK cells and cytotoxic T lymphocytes (CTLs) in paired tumor tissues (group T, n = 44) and paracancerous tissues (group N, n = 44) from patients with PTC with the BRAF V600E mutation. Furthermore, patients were divided into two groups according to whether cervical central lymph node metastasis (CCLNM) existed: group A (with lymph node metastases, n = 27) and group B (with nonlymph node metastases, n = 17). Patients were also divided into three groups according to the total number of positive CCLNM: group B, group C (with low-level lymph node metastases, less than 5, n = 17) and group D (with high-level lymph node metastases, no less than 5, n = 10).

Results
The percentage of CD3+P+ CTLs was significantly higher in group N than in group T (P < 0.05). The percentage of CD8+G+ CTLs was significantly higher in group T than in group N (P < 0.05). The percentages of CD3+G+, CD16-CD56+P+and CD16-CD56+G+ NK cells showed no significant difference in either group T or group N (P > 0.05). The percentages of CD3+P+ CTLs in group A and group C were significantly higher in the paracancerous tissue than in the tumor tissue (P < 0.05). The percentages of CD8+G+ CTLs in group A and group C were significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05). The percentage of CD16-CD56+G+ NK cells in group D was significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05).

Conclusions
The killing capacity of infiltrating CLs in PTC differed between tumor tissues and paracancerous tissues. In cases with CCLNM, higher expression of CD16-CD56+G+ NK cells in tumor tissues may be associated with a high risk of lymph node metastasis.
A roadmap for sustainable implementation of vocational rehabilitation for people with mental disorders and its outcomes: a qualitative evaluation
Authors: Noteboom Yvonne , van Nassau Femke , Bosma Astrid R. , van der Hijden Eric J. E. , Huysmans Maaike A. , Anema Johannes R. 
Published: February 2024

Abstract
Background
People suffering from mental health disorders have lower work participation compared to people without mental challenges. To increase work participation within this group vocational rehabilitation interventions are often offered. Collaboration between the mental health care and social security sectors is needed to enable professionals to perform optimally when carrying out these interventions. Yet, regulatory and financial barriers often hinder sustainable implementation. To overcome these barriers an experimental roadmap for sustainable funding based on a shared savings strategy was piloted in four regions. The aim of the present qualitative study was to gain understanding of the uses of this roadmap and the factors that were important in the experiment’s process.

Method
The roadmap consisted of five steps based upon insights from shared savings strategies and implementation science knowledge, and was initiated by a national steering board. The roadmap aimed to make sustainable funding agreements (based on shared savings) for the implementation of a vocational rehabilitation intervention. In four regions, stakeholders from the mental health care and social security services sector followed the roadmap. We conducted interviews (n = 16) with involved participants and project leaders of the experiment and collected 54 sets of field notes and documents to evaluate the roadmap process. A thematic analysis was used to analyse the data.

Results
Regions perceived improved stakeholder collaboration around vocational rehabilitation after they were guided by the roadmap. Three regions made, or intended to make, agreements on collaboration and funding, yet not based on shared savings. Moreover, going through the roadmap took more time than anticipated. Stakeholder collaboration depended on factors like personal and organizational interests and collaboration conditions and values. Financial legislation and politics were regarded as barriers and personal motives were mentioned as a facilitator in this process.

Conclusions
Our study showed that the roadmap supported stakeholders to establish a more sustainable collaboration, even though no sustainable financial agreements were made yet. Although participants acknowledged the function of financial insights and the need for financial resources, the driver for collaboration was found to be more on improving clients’ perspectives than on solving unfair financial distribution issues. This suggests modifying the focus of the roadmap from financial benefits to improving clients’ perspectives.
A low-input high resolution sequential chromatin immunoprecipitation method captures genome-wide dynamics of bivalent chromatin
Authors: Seneviratne Janith A. , Ho William W. H. , Glancy Eleanor , Eckersley-Maslin Melanie A. 
Published: February 2024

Abstract
Background
Bivalent chromatin is an exemplar of epigenetic plasticity. This co-occurrence of active-associated H3K4me3 and inactive-associated H3K27me3 histone modifications on opposite tails of the same nucleosome occurs predominantly at promoters that are poised for future transcriptional upregulation or terminal silencing. We know little of the dynamics, resolution, and regulation of this chromatin state outside of embryonic stem cells where it was first described. This is partly due to the technical challenges distinguishing bone-fide bivalent chromatin, where both marks are on the same nucleosome, from allelic or sample heterogeneity where there is a mix of H3K4me3-only and H3K27me3-only mononucleosomes.

Results
Here, we present a robust and sensitive method to accurately map bivalent chromatin genome-wide, along with controls, from as little as 2 million cells. We optimized and refined the sequential ChIP protocol which uses two sequential overnight immunoprecipitation reactions to robustly purify nucleosomes that are truly bivalent and contain both H3K4me3 and H3K27me3 modifications. Our method generates high quality genome-wide maps with strong peak enrichment and low background, which can be analyzed using standard bioinformatic packages. Using this method, we detect 8,789 bivalent regions in mouse embryonic stem cells corresponding to 3,918 predominantly CpG rich and developmentally regulated gene promoters. Furthermore, profiling Dppa2/4 knockout mouse embryonic stem cells, which lose both H3K4me3 and H3K27me3 at approximately 10% of bivalent promoters, demonstrated the ability of our method to capture bivalent chromatin dynamics.

Conclusions
Our optimized sequential reChIP method enables high-resolution genome-wide assessment of bivalent chromatin together with all required controls in as little as 2 million cells. We share a detailed protocol and guidelines that will enable bivalent chromatin landscapes to be generated in a range of cellular contexts, greatly enhancing our understanding of bivalent chromatin and epigenetic plasticity beyond embryonic stem cells.
Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis
Authors: Kim Daeun , Song Jaeseung , Mancuso Nicholas , Mangul Serghei , Jung Junghyun , Jang Wonhee 
Published: February 2024

Abstract
Background
Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear.

Methods
To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk.

Results
We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks.

Conclusion
Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.
Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial
Authors: Aashish Mondal , Arindam Naskar , Siddiqi Sheelu Shafiq , Bhosle Deepak , Mallikarjuna V. J. , Amol Dange , Sanket Sorate , Omkar Gavali , Parth Patel , Dhruvi Hasnani , Durga Prasad , Pradeep Dalwadi , Suresh Kumar , Vaishali Pathak , Mayura Chaudhari , Indraneel Basu , Jayashri Shembalkar , Arif Fariooqui , Raghavendra S. K. , Deepak Varade , Ravindra Thakkar , Shaishav Bhanushali , Vijay Gaikwad , Khan Kamran , Mahajani V. V. , Sharma A. D. , Mayabhate Mayur , Pawar R. R. , Aiwale A. S. , Vinayaka Shahavi 
Published: February 2024

Abstract
Background
Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM).

Methods
In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0–11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability.

Results
Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (− 1.64) vs. MS (− 1.32); between groups was [− 0.32% (95% CI, − 0.59, − 0.05)], P = 0.0208. Similar reductions were found in FPG [− 13.2 mg/dL (95% CI, − 22.86, − 3.71)], P = 0.0068, and PPG [− 20.83 mg/dL (95% CI, − 34.11, − 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug.

Conclusion
The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM.

Trial registration
Clinical Trials Registry of India, CTRI/2021/10/037461.
Microstructure of the silk fibroin-based hydrogel scaffolds derived from the orb-web spider Trichonephila clavata
Authors: Sun Yan , Ku Bon-Jin , Moon Myung-Jin 
Published: February 2024

AbstractDue to the unique properties of the silk fibroin (SF) made from silkworm, SF-based hydrogels have recently received significant attention for various biomedical applications. However, research on the SF-based hydrogels isolated from spider silks has been rtricted due to the limited collection and preparation of naïve silk materials. Therefore, this study focused on the microstructural characteristics of hydrogel scaffolds derived from two types of woven silk glands: the major ampullate gland (MAG) and the tubuliform gland (TG), in the orb-web spider Trichonephila clavate. We compared these spider glands with those of the silk fibroin (SF) hydrogel scaffold extracted from the cocoon of the insect silkworm Bombyx mori. Our FESEM analysis revealed that the SF hydrogel has high porosity, translucency, and a loose upper structure, with attached SF fibers providing stability. The MAG hydrogel displayed even higher porosity, as well as elongated fibrous structures, and improved mechanical properties: while the TG hydrogel showed increased porosity, ridge-like or wall-like structures, and stable biocapacity formed by physical crosslinking. Due to their powerful and versatile microstructural characteristics, the MAG and TG hydrogels can become tailored substrates, very effective for tissue engineering and regenerative medicine applications.
Induced seismicity data prep: Automate data processing and data set production in Texas and New Mexico using Python and ArcGIS Pro tools
Authors: Breton Caroline , Shensky Michael , Savvaidis Alexandros 
Published: February 2024

Causal factors of induced seismicity in the Permian Basin are investigated by collecting and processing data on reported earthquakes, hydraulic fracture operations, and salt water disposal (SWD). Data are collected from five online sources: (1) the TexNet Earthquake Catalog, which provides earthquake data for Texas; (2) the TexNet Injection Volume Reporting Tool, which provides daily SWD data for select Texas wells; (3) the FracFocus Chemical Disclosure Registry, which provides hydraulic fracture data to the public; and (4) B3 Insight and (5) IHS Enerdeq Browser, which are proprietary database services that provide current and historical well data through paid subscriptions. TexNet makes their data available to the public at dynamic map websites. We automate data processing and data management using Python and ArcGIS Pro tools. The workflow produces quick, reliable, consistent, and reproducible output. We developed a Python script for each collected data table to filter, select fields, and write a new table. We created ArcGIS Pro Model Builder models for each new table to control format properties at import to the geodatabase. Further models contain customized ArcToolbox tools arranged to run geospatial, quality assurance, and quality control processing steps. In addition to discussing the source data and general workflow, we also review the results of the automated data processing. To illustrate our method, we create areas of investigation around the 5.4 magnitude Coalson earthquake to collect and process available data to create maps, charts, and data products for use in subsequent analysis. We make our Python scripts available on GitHub.