bluuebunny/crossref_metadata_2025 huggingface dataset:
Desire for Body Contouring Surgery after Bariatric Surgery: A Nationwide Cross-sectional Study in Saudi Arabia
Authors: Rabah Sari M. , Albrahim Razan A. , Almajed Ebtesam H. , AlZabin Alya K. , Aldawish Reema A. , Alyahiwi Lara S. , Alshabnan Rand A.
Published: December 2023

Background:

The obesity pandemic in Saudi Arabia has led to a high demand for bariatric surgery (BS). Post-BS patients experience rapid and massive weight loss, with most patients experiencing redundant skin, leading to a desire for body contouring surgery (BCS).

Methods:

A cross-sectional study was conducted from September 2022 to May 2023 among patients who underwent BS in Saudi Arabia, using an online self-administered questionnaire. The questionnaire comprised sociodemographic data, weight, and BS-related questions, and the post-BS appearance questionnaire assessed the desire for BCS, excess skin satisfaction, and overall appearance.

Results:

A total of 410 of the patients electively enrolled. The mean perceived satisfaction of post-BS patients with the body’s excess skin was rated as 4.28 ± 1.69 out of 7 points. The overall desire for BCS among the post-BS population was equal to a collective mean desire of 2.10 ± 0.92 out of 4 points. The desired body sites for BCS were focused on the abdomen/waist, followed by the lower back, then upper arms, buttocks, and thighs. Only 25.1% of the patients fulfilled their desires and recently underwent BCS.

Conclusions:

The study highlights the importance of incorporating plastic and reconstructive surgery as an integral part of the multidisciplinary approach to morbidly obese patients after BS and the need for national guidelines on the referral pathway for post-BS BCS.
Radioactive iodine therapy for follicular thyroid cancer: a 15 years follow-up study of Chinese patients
Authors: Shi He , Yang Bo , Feng Jian-Iin , Li Jian-hua , Cheng Xu , Li Yong-jun , Fu Yu , Xu Xin-dan , Qian Lei-hang , Tang Li-jun , Liu Wei
Published: December 2023

Purpose

To identify long-term predictors of distant metastases (DM) and the overall survival (OS) of follicular thyroid cancer (FTC) patients who underwent radioactive iodine (RAI) therapy. And to expand the knowledge about the clinical course and experience of RAI treatment for FTC.

Materials

A total of 117 FTC patients who underwent RAI therapy at our institution from 2005 to 2020 were retrospectively studied. Patient characteristics, serum stimulating thyroglobulin (sTg) and thyroglobulin antibody levels, treatment process and follow-up data were collected until 26 April 2022.

Results

A total of 16 patients (13.7%) were lost to follow-up. A total of 23 (19.7%) patients with DM died and all FTC without DM were still alive. DM was seen in 58.4% (59/101) of patients. The most common location for metastatic lesions was the lung. Then was bone. The mean survival time of FTC with RAI was 156 months [95% confidence interval (CI): 142–171]. Five-year and 10-year cumulative survival rates of them were 88.8% and 67.4%, respectively. As for patients with DM were 80.4% and 41.3%, respectively. Age at diagnosis [odds ratio (OR) = 1.080, P = 0.009], RAI therapy sessions (OR = 2.959, P = 0.001) and sTg level (OR = 1.006, P = 0.002) were predictive of DM occurrence in FTC with RAI. In the group of FTC with DM, survival analysis showed that males were more likely to have a lower OS than females (P = 0.039).

Conclusion

Age, number of RAI therapy sessions, and sTg level were predictive of the occurrence of DM in FTC patients with RAI. Sex would influence the OS of FTC patients with DM.
From tutor to future educator: Investigating the role of peer-peer tutoring in shaping careers in medical education
Authors: Stokes Lauren , Singh Harinder
Published: December 2023

In the effort to promote academic excellence and provide authentic teaching experiences and training for medical students, the University of California, Irvine, School of Medicine (UCISOM) built a novel peer tutoring program, Collaborative Learning Communities with Medical Students as Teachers (CLC-MSAT). While the role of peer-assisted learning in student success on academic courses is well established, we wanted to assess the impact of our peer-assisted learning program on tutor’s career interest in medical education. Through a mixed-methods analysis of our peer tutors’ experiences, we found >80% were overall satisfied with their positions; >85% learned new skills; >88% felt they were strong teachers; >88% felt they now had a stronger grasp of the medical curriculum. Our findings suggest that the CLC-MSAT program has a positive impact in exposing medical students to teaching experience and training, which may help prepare the next generation of academic clinicians.
Synthetic Health Data Can Augment Community Research Efforts to Better Inform the Public During Emerging Pandemics
Authors: Prasanna Anish , Jing Bocheng , Plopper George , Miller Kristina Krasnov , Sanjak Jaleal , Feng Alice , Prezek Sarah , Vidyaprakash Eshaw , Thovarai Vishal , Maier Ezekiel J. , Bhattacharya Avik , Naaman Lama , Stephens Holly , Watford Sean , John Boscardin W. , Johanson Elaine , Lienau Amanda
Published: December 2023

The COVID-19 pandemic had disproportionate effects on the Veteran population due to the increased prevalence of medical and environmental risk factors. Synthetic electronic health record (EHR) data can help meet the acute need for Veteran population-specific predictive modeling efforts by avoiding the strict barriers to access, currently present within Veteran Health Administration (VHA) datasets. The U.S. Food and Drug Administration (FDA) and the VHA launched the precisionFDA COVID-19 Risk Factor Modeling Challenge to develop COVID-19 diagnostic and prognostic models; identify Veteran population-specific risk factors; and test the usefulness of synthetic data as a substitute for real data. The use of synthetic data boosted challenge participation by providing a dataset that was accessible to all competitors. Models trained on synthetic data showed similar but systematically inflated model performance metrics to those trained on real data. The important risk factors identified in the synthetic data largely overlapped with those identified from the real data, and both sets of risk factors were validated in the literature. Tradeoffs exist between synthetic data generation approaches based on whether a real EHR dataset is required as input. Synthetic data generated directly from real EHR input will more closely align with the characteristics of the relevant cohort. This work shows that synthetic EHR data will have practical value to the Veterans’ health research community for the foreseeable future.
ChatGPT for automating lung cancer staging: feasibility study on open radiology report dataset
Authors: Nakamura Yuta , Kikuchi Tomohiro , Yamagishi Yosuke , Hanaoka Shouhei , Nakao Takahiro , Miki Soichiro , Yoshikawa Takeharu , Abe Osamu
Published: December 2023

Objectives

CT imaging is essential in the initial staging of lung cancer. However, free-text radiology reports do not always directly mention clinical TNM stages. We explored the capability of OpenAI’s ChatGPT to automate lung cancer staging from CT radiology reports.

Methods

We used MedTxt-RR-JA, a public de-identified dataset of 135 CT radiology reports for lung cancer. Two board-certified radiologists assigned clinical TNM stage for each radiology report by consensus. We used a part of the dataset to empirically determine the optimal prompt to guide ChatGPT. Using the remaining part of the dataset, we (i) compared the performance of two ChatGPT models (GPT-3.5 Turbo and GPT-4), (ii) compared the performance when the TNM classification rule was or was not presented in the prompt, and (iii) performed subgroup analysis regarding the T category.

Results

The best accuracy scores were achieved by GPT-4 when it was presented with the TNM classification rule (52.2%, 78.9%, and 86.7% for the T, N, and M categories). Most ChatGPT’s errors stemmed from challenges with numerical reasoning and insufficiency in anatomical or lexical knowledge.

Conclusions

ChatGPT has the potential to become a valuable tool for automating lung cancer staging. It can be a good practice to use GPT-4 and incorporate the TNM classification rule into the prompt. Future improvement of ChatGPT would involve supporting numerical reasoning and complementing knowledge.

Clinical relevance statement

ChatGPT’s performance for automating cancer staging still has room for enhancement, but further improvement would be helpful for individual patient care and secondary information usage for research purposes.

Key points

ChatGPT, especially GPT-4, has the potential to automatically assign clinical TNM stage of lung cancer based on CT radiology reports.

It was beneficial to present the TNM classification rule to ChatGPT to improve the performance.

ChatGPT would further benefit from supporting numerical reasoning or providing anatomical knowledge.

Graphical abstract
STAT4 Phosphorylation of T-helper Cells predicts surgical outcomes in Refractory Chronic Rhinosinusitis
Authors: Abidin Michael R. , Alpan Oral , Plassmeyer Matthew , Kozhaya Lina , Loizou Denise , Dogan Mikail , Upchurch Zachary , Manes Nathan P , Nita-Lazar Aleksandra , Unutmaz Derya , Sønder Søren Ulrik
Published: December 2023

Objective: Chronic rhinosinusitis (CRS) impacts an estimated 5% to 15% of people worldwide, incurring significant economic healthcare burden. There is a urgent need for the discovery of predictive biomarkers to improve treatment strategies and outcomes for CRS patients.

Study design: Cohort study of CRS patients and healthy controls using blood samples. Setting: Out-patient clinics.

Methods: Whole blood samples were collected for flow cytometric analysis. Mechanistic studies involved the transfection of human primary T cells and Jurkat cells.

Results: Our analysis began with a 63-69 year-old female patient diagnosed with refractory CRS,. Despite undergoing multiple surgeries, she continually faced sinus infections. Whole exome sequencing pinpointed a heterozygous IL-12Rb1 mutation situated in the linker region adjacent to the cytokine binding domain. When subjected to IL-12 stimulation, the patient’s CD4 T-cells exhibited diminished STAT4 phosphorylation. However, computer modeling or T-cell lines harboring the same IL-12 receptor mutation did not corroborate the hypothesis that IL-12Rb could be responsible for the reduced phosphorylation of STAT4 by IL-12 stimulation.

Upon expanding our investigation to a broader CRS patient group using the pSTAT4 assay, we discerned a subset of refractory CRS patients with abnormally low STAT4 phosphorylation.

The deficiency showed improvement both in-vitro and in-vivo after exposure toLatilactobacillus sakei(akaLactobacillus sakei), an effect at least partially dependent on IL-12.

Conclusion: In refractory CRS patients, an identified STAT4 defect correlates with poor clinical outcomes after sinus surgery, which can be therapeutically targeted byLatilactobacillus sakeitreatment. Prospective double-blind placebo-controlled trials are needed to validate our findings.
Literature Review Interventions to Anticipate Catheter-Related Urinary Tract Contaminations in Seriously Care Units: Philosophy of Nursing
Authors: Rusmini Sri , Pandin Moses Glorino Rumambo
Published: December 2023

Background

Urinary tract infections are among the adverse outcomes of urinary catheter placement. After the installation of a catheter, urinary tract infections happen more often than twice a day. Examining prevention strategies for UTIs in critical care units is the aim of this writing audit.

Method

Use ProQuest, Scopus, and ScienceDirect to look up review literature. Urinary tract infections, prevention and management, and intensive care unit were the search terms used to find publications. Search parameters for full-text, open-access, English-language papers published between 2019 and 2023.

Results

The study’s findings indicate that adherence to patient information recording, installation and maintenance procedures, guidelines for the detection and prevention of CAUTI, staff education and good nursing practices, and the application of CAUTI prevention can all help lower the incidence of urinary tract infections.

Conclusion

Healthcare facilities need to have a program in place to avoid urinary tract infections brought on by catheter installation, as well as the best care possible for patients who use them. In order to solve the problem, all interdisciplinary teams must collaborate and analyze the issue using the PDSA methodology.
Leveraging neuroscience education to address stigma related to opioid use disorder (OUD) in the community: A pilot study
Authors: Kyzar Evan J. , Arbuckle Melissa , Abba-Aji Adam , Balachandra Krishna , Cooper Joseph , Dela Cruz Adriane , Edens Ellen , Heward Brady , Jibson Michael , Jordan Ayana , Moreno-De-Luca Daniel , Pazderka Hannah , Singh Mohit , Weleff Jeremy , Yau Bernice , Young Justin , Ross David A.
Published: December 2023

Opioid use disorder (OUD) and overdose deaths are a public health crisis. One contributing factor is stigma towards people who use opioids. We developed and conducted a public-facing, half-day educational event designed to challenge misperceptions about OUD from a contemporary neuroscience perspective. Participants engaged with three different resources on the neurobiology of addiction; at the end of the event, they rated its effectiveness. We also collected and compared pre- and post-event composite OUD stigma scales. Participants rated our approach and the overall event as highly effective. Additionally, OUD stigma scores were lower immediately following the event, and this decrease was primarily driven by decreased internalized stigma. Here, we demonstrate an effective proof-of-concept that an accessible, public-facing, neuroscience education event may reduce OUD stigma in the community.
Bifurcation Coronary Intervention is Associated with Higher Mortality and Complications
Authors: Nathan Allistair , Hashemzadeh Mehrtash , Movahed Mohammad Reza
Published: December 2023

Background

Percutaneous coronary intervention (PCI) in patients with bifurcation lesions is associated with higher complexity and adverse outcomes. The goal of this study was to evaluate the inpatient outcomes of patients with PCI of bifurcation lesions.

Methods

The National Inpatient Sample (NIS) database, years 2016-2020, was studied using ICD 10 codes. Patients with bifurcation lesion PCI were compared to other PCIs excluding chronic total occlusions (CTO). We evaluated post-procedural inpatient mortality and complications.

Results

PCI in patients with a bifurcation lesion was associated with higher mortality and post-procedural complications. A weighted total of 9,795,154 patients underwent PCI, with 43,480 having a bifurcation lesion. The bifurcation group had a 3.79% mortality rate vs 2.56%. (OR, 1.50; CI:1.34–1.68; p<0.001). After adjusting for age, sex, race, diabetes mellitus, and chronic kidney disease, bifurcation lesion PCI remained significantly associated with higher mortality (OR, 1.68; 95% CI, 1.49– 1.88; p<0.001). Furthermore, bifurcation PCI was associated with higher rates of myocardial infarction (OR, 2.26; 95% CI, 1.68 – 3.06; p<0.001), coronary perforation (OR, 7.97; 95% CI, 6.25-10.17; p<0.001), tamponade (OR, 3.46; 95% CI, 2.49-4.82, p<0.001), and procedural bleeding (OR, 5.71; 95% CI, 4.85-6.71, p<0.001). All post-procedural complications were more than 4 times more likely in patients with bifurcation than in those without (OR, 4.33; 95% CI, 3.83-4.88; p<0.001).

Conclusion

Using a large national inpatient database, PCI performed in patients with a Non-CTO bifurcation lesions were associated with significantly higher mortality and post-procedural complications.
EEG-Based Frequency Domain Separation of Upward and Downward Movements of the Upper Limb
Authors: Ahangama T.V. , Gurunayake G.M.K.G.G.B. , Yalpathwala I.A. , Wijayakulasooriya J.V. , Dassanayake T.L. , Harischandra N. , Kim Kwangtaek , Ranaweera R.D.B.
Published: December 2023

One of the fundamental challenges encountered when implementing the Motor Imagery based Brain-Computer Interfacing (BCI) paradigm is accurately classifying the Electroencephalography (EEG) signals that originate due to the same joint movements. This emanates from the limited spatial proximity in the corresponding brain regions. Here, we explore the feasibility of distinguishing arm-reaching movements specific to the right hand using multiple frequency bands in EEG signals despite the limited spatial differentiation of induced potentials. To address this challenge, a channel averaging method was used combining six electrodes positioned in close proximity to the motor cortex, intending to isolate and enhance electromagnetic activity in the brain associated with arm movements. This study was further refined by focusing on two distinct frequency bands: mu (8-12Hz) and beta (12-30Hz), each associated with different cognitive and motor functions. The results of our study revealed promising outcomes across two classification methods. Utilizing the Support Vector Machine (SVM) classification method, our proposed approach achieved an average accuracy of 59.3% while the K-Nearest Neighbors (KNN) classification approach yielded an average accuracy of 61.63% in distinguishing between upward and downward movements of the right arm.
Implementation of Agile in health care: Methodology for a multi-site home hospital accelerator
Authors: Desai Meghna , Tardif-Douglin Miriam , Miller Indigo R. D. , Blitzer Stephanie C. , Gardner David L. , Thompson Teresa M. , Edmondson LaPonda , Levine David M.
Published: December 2023

Background

The diffusion of innovation in health care is sluggish. Evidence-based care models and interventions take years to reach patients. We believe the health care community could deliver innovation to the bedside faster if it followed other sectors by employing an organizational framework for efficiently accomplishing work. Home hospital is an example of sluggish diffusion. This model provides hospital-level care in a patient’s home instead of in a traditional hospital with equal or better outcomes. Home hospital uptake has steadily grown during the COVID-19 pandemic, yet barriers to launch remain for health care organizations, including access to expertise and implementation tools. The Home Hospital Early Adopters Accelerator was created to bring together a network of health care organizations to develop tools necessary for program implementation.

Methods

The Accelerator used the Agile framework known as Scrum to rapidly coordinate work across many different specialized skill sets and blend individuals who had no experience with one another into efficient teams. Its goal was to take 40 weeks to develop 20 “knowledge products,” or tools critical to the development of a home hospital program such as workflows, inclusion criteria, and protocols. We conducted a mixed methods evaluation of the Accelerator’s implementation, measuring teams’ productivity and experience.

Results

Eighteen health care organizations participated in the Accelerator to produce the expected 20 knowledge products in only 32 working weeks, a 20% reduction in time. Nearly all (97.4%) participants agreed or strongly agreed the Scrum teams worked well together, and 96.8% felt the teams produced a high-quality product. Participants consistently remarked that the Scrum team developed products much faster than their respective organizational teams. The Accelerator was not a panacea: it was challenging for some participants to become familiar with the Scrum framework and some participants struggled with balancing participation in the Accelerator with their job duties.

Conclusions

Implementation of an agile-based accelerator that joined disparate health care organizations into teams equipped to create knowledge products for home hospital proved both efficient and effective. We demonstrate that implementing an organizational framework to accomplish work is a valuable approach that may be transformative for the sector.
A yeast modular cloning (MoClo) toolkit expansion for optimization of heterologous protein secretion and surface display inSaccharomyces cerevisiae
Authors: O’Riordan Nicola M. , Jurić Vanja , O’Neill Sarah K. , Roche Aoife P. , Young Paul W.
Published: December 2023

Saccharomyces cerevisiaeis an attractive host for expression of secreted proteins in a biotechnology context. Unfortunately, many heterologous proteins fail to enter, or efficiently progress through, the secretory pathway, resulting in poor yields. Similarly, yeast surface display has become a widely used technique in protein engineering but achieving sufficient levels of surface expression of recombinant proteins is often challenging. Signal peptides (SPs) and translational fusion partners (TFPs) can be used to direct heterologous proteins through the yeast secretory pathway, however, selection of the optimal secretion promoting sequence is largely a process of trial and error. The yeast modular cloning (MoClo) toolkit utilises Type IIS restriction enzymes to facilitate efficient assembly of expression vectors from standardized parts. We have expanded this toolkit to enable the efficient incorporation of a panel of sixteen well-characterized SPs and TFPs and five surface display anchor proteins intoS. cerevisiaeexpression cassettes. The secretion promoting signals were validated using five different proteins of interest. Comparison of intracellular and secreted protein levels revealed the optimal secretion promoting sequence for each individual protein. Large, protein of interest-specific variations in secretion efficiency were observed. SP sequences were also used with the five surface display anchors and the combination of SP and anchor protein proved critical for efficient surface display. These observations highlight the value of the described panel of MoClo compatible parts to allow facile screening of SPs, TFPs and anchor proteins for optimal secretion and/or surface display of a given protein of interest inS. cerevisiae.

GRAPHICAL ABSTRACT
Rapid High-Throughput Method for Investigating Physiological Regulation of Neutrophil Extracellular Trap Formation
Authors: Zukas Kieran , Cayford Justin , Serneo Finley , Atteberry Brandi , Retter Andrew , Eccleston Mark , Kelly Theresa K
Published: December 2023

Neutrophils, the most abundant white blood cells in humans, play pivotal roles in innate immunity, rapidly migrating to sites of infection and inflammation to phagocytose, neutralize, and eliminate invading pathogens. Neutrophil Extracellular Trap (NET) formation in response to pathogens is increasingly recognized as an essential rapid innate immune response, but when dysregulated contributes to pathogenesis of sepsis and immunothrombotic disease. Current models of NETosis are limited, routinely employing non-physiological triggers that can bypass natural NET regulatory pathways. Models utilizing isolated neutrophils and immortalized cell lines, do not reflect the complex biology underlying neutrophil activation and NETosis, that occurs in whole-blood. Here we describe a novel, high-throughputex-vivowhole blood induced NETosis model using combinatorial pooling of native NETosis inducing factors in a more biologically relevant Synthetic-Sepsis™ model. We found different combinations of factors evoked distinct neutrophil responses in the rate of NET generation and/or magnitude of NETosis. Despite inter-donor variability, similar sets of pro-inflammatory molecules induced consistent responses across donors. We found at least three biological triggers were necessary to induce NETosis in our system including either TNF-α or LT-α. To our knowledge, we report the first humanex-vivomodel utilizing naturally occurring molecules to induce NETosis in whole blood. This approach could be used for drug screening and, importantly, inadvertent activators of NETosis. These findings emphasize the importance of investigating neutrophil physiology in a biologically relevant context to enable a better understanding of disease pathology, risk factors, and therapeutic targets, potentially, providing novel strategies for disease intervention and treatment.

Essentials

NETosis is a vital immune response, but dysregulation leads to disastrous health outcomes.

Current NETosis models don’t reflect the complex endogenous signaling that occurs in whole blood

Netosis induction stimuli differs between isolated neutrophils and whole blood.

A minimum of three physiological factors are required to induce NETosis in whole blood.
Clustered Regularly Interspaced Short Palindromic Repeats-Cas system regulatesSalmonellavirulence
Authors: Sharma Nandita , Das Ankita , Nair Abhilash Vijay , Sethi Palash , Negi Vidya Devi , Chakravortty Dipshikha , Marathe Sandhya Amol
Published: December 2023

Objectives

Investigating the type 1-E CRISPR-Cas-mediated regulation ofSalmonellapathogenesis.

Methods

We assessed the pathogenicity of the wild-type and CRISPR-Cas knockout strains using infection models. The mechanisms were elucidated using antimicrobial assays and expression analysis.

Results

CRISPR-Cas knockout strains were defective in invasion and proliferation in intestinal epithelial cells and macrophages. However, proliferation defects were not observed in the Gp91phox-/-macrophages, suggesting the system’s role in antioxidant defence. The knockout strains show hampered colonization inin-vivoinfection models, possibly due to increased sensitivity against innate immune barriers like antimicrobial peptides, complement proteins and oxidative stress. The expression studies of various virulence regulators:pmrgenes, anti-oxidant genes, SPI-1 and SPI-2 encoded master regulators, and effectors showed repressed expression in the knockout strains. Some of these genes could be directly regulated by the CRISPR-spacers owing to partial complementarity between the sequences.

Conclusion

Overall, our study shows that the CRISPR-Cas system positively regulatesSalmonellapathogenesis by regulating the expression of different virulence factors.
Inhibition of hERG K channels by verapamil at physiological temperature: Implications for the CiPA Initiative
Authors: Johnson Ashley A. , Trudeau Matthew C.
Published: December 2023

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative reassesses using the inhibition of hERG channels by drugs as the major determinant for assessment of a drug’s potential to cause ‘Torsades de Pointes’ (TdP) cardiac arrhythmias. Here we report on one phase of CiPA: independent determination of hERG inhibitory properties in order to test the reproducibility of data gathered in different labs and the practicality of using the CiPA-defined recording conditions. We measured inhibition of hERG1a potassium channels stably expressed in HEK293 cells using manual whole-cell patch-clamp electrophysiology recordings at the physiological temperature of 37°C by verapamil, a known hERG inhibitor. We report that the IC50 for inhibition (180.4nM) and the Hill coefficient (1.4) for verapamil measured in an academic lab were similar to the IC50 (204nM) and Hill coefficient (0.9) measured at the Food and Drug Administration labs, indicating low variability in measurements between labs. We report that the CiPA step voltage protocol, a series of voltage steps characterized by 10 second duration depolarizing pulses at 37°C, resulted in a very low (5%) experimental success rate per cell in our hands. To circumvent the low success rate, we shortened the duration of the depolarizing pulse to 3 seconds (from 10 seconds) and shortened the duration of interpulse intervals, which is more consistent with the duration of voltage pulses used in biophysical studies of hERG, such that the entire revised protocol was shortened from over 30 minutes to approximately 10 minutes in duration. Using the revised protocol, we found an IC50 of inhibition by verapamil of 210.5 nM and Hill coefficient of 1.2. These values were similar to those generated using the original, longer CiPA step protocol. Furthermore, our success rate using the shortened protocol rose to 25%, an increase of 5-fold over the initial protocol. In summary, we captured key pharmacological data for subsequent analysis in CiPA using a revised, shorter protocol with an enhanced success rate and an overall enhanced feasibility. We propose the shorter protocol is more pragmatic for generation of hERG channel drug inhibition data for CiPA and other regulatory sciences.
Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma
Authors: Flesken-Nikitin Andrea , Ralston Coulter Q. , Fu Dah-Jiun , De Micheli Andrea J. , Phuong Daryl J. , Harlan Blaine A. , Armstrong Amanda P. , McKellar David , Ghuwalewala Sangeeta , Schimenti John C. , Cosgrove Benjamin D. , Nikitin Alexander Yu.
Published: December 2023

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell markerSlc1a3can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation ofTrp53andRb1, whose pathways are commonly altered in HGSC, leads to elimination of targetedSlc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+,Prom1+,Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a previously unrecognized cancer-prone cell state and point to pre-ciliation mechanisms as novel diagnostic and therapeutic targets.
Sex differences in responses to aggressive encounters among California mice
Authors: Kuske Jace X. , Godoy Alexandra Serna , Ramirez Alison V. , Trainor Brian C.
Published: December 2023

Despite how widespread female aggression is across the animal kingdom, there remains much unknown about its neuroendocrine mechanisms, especially in females that engage in aggression outside the peripartum period. Although the impact of experience in aggressive encounters on steroid hormone responses have been described, little is known about the impact of these experiences on female behavior or their neuropeptide responses. In this study, we compared behavioral responses in both male and female adult California mice based on if they had 0, 1, or 3 aggressive encounters using a modified resident intruder paradigm. We measured how arginine vasopressin and oxytocin cells in the paraventricular nucleus responded to aggression using c-fos immunohistochemistry. We saw that both sexes disengaged with intruders with repeated aggressive encounters, but that on the final day of testing females were most likely to freeze when they encountered intruders compared to no aggression controls – which was not significant in males. Finally, we saw that percent of arginine vasopressin and c-fos co-localizations in the posterior region of the paraventricular nucleus increased in males who fought compared to no aggression controls. No difference was observed in females. Overall, there is evidence that engaging in aggression induces stress responses in both sexes, and that females may be more sensitive to the effects of fighting.
Variant Graph Craft (VGC): A Comprehensive Tool for Analyzing Genetic Variation and Identifying Disease-Causing Variants
Authors: Li Jennifer , Yang Andy , Carneiro Benedito A , Uzun Ece Gamsiz , Massingham Lauren , Uzun Alper
Published: December 2023

The Variant Call Format (VCF) file is providing a structured and comprehensive text file that contains essential information about variant positions in the genome, as well as other critical details, such as alleles, genotype calls, and quality scores. Due to its rich data and format, the VCF file has become an increasingly popular resource for researchers and clinicians alike, enabling them to interpret and understand genomic variation data. However, analyzing and visualizing these files poses significant challenges, demanding access to diverse resources and a robust set of features for in-depth exploration. We introduce Variant Graph Craft (VGC), a VCF file visualization and analysis tool offering a wide range of features for exploring genetic variations, including extraction of variant data, intuitive visualization of variants, and the provision of a graphical representation of samples, complete with genotype information. Furthermore, VGC seamlessly integrates with external resources to offer valuable insights into gene function and variant frequencies in sample data. VGC offers gene function and pathway information from Molecular Signatures Database (MSigDB) for GO terms, as well as KEGG, Biocarta, Pathway Interaction Database, and Reactome. Additionally, the tool also provides a dynamic link to gnomAD for variant information, and includes ClinVar data for pathogenic variant information. VGC operates locally, assuring users of data security and privacy by eliminating the need for cloud-based VCF uploads. It supports the Human Genome Assembly Hg37, ensuring compatibility with a wide range of data sets. With its versatility, VGC accommodates various approaches exploring genetic variation data, and can be tailored to the specific needs of the user by using optional phenotype input data. In conclusion, VGC is a useful resource for exploring genetic variation in a secure and user-friendly environment. With its user-tailored set of features, this tool enables researchers and clinicians to easily explore and understand genomic variation data in a comprehensive and accessible manner. From identifying specific genetic mutations to analyzing patterns of variation across the genome, the VCF file visualization and analysis tool is an essential tool for those working in the field of genomics. VGC is freely available athttps://sites.brown.edu/gmilab/variantgraphcraft/
Angiotensin II type 1 receptor activation facilitates pain hypersensitivity via dorsal horn pericyte mediated vasoconstriction
Authors: Hardowar Lydia D. , Sheavyn Matt , McTernan Philip G. , Bates Dave O. , Hulse Richard P.
Published: December 2023

Vascular disturbance is a key factor in the development of neurological disease, with reduced integrity of the capillary network in the dorsal horn implicated in activation of nociceptive neural circuits and induction of pain hypersensitivity. Pericytes regulate capillary health and tone, with pericyte dysfunction in cerebral tissue associated with neurodegenerative disorders. Our work demonstrates that nociceptive processing is influenced by angiotensin II type 1 (AT1) receptor mediated pericyte contractility in the dorsal horn. Intravital imaging of the mouse spinal cord demonstrated angiotensin II induced cessation of spinal cord capillary perfusion. Intrathecal administration of angiotensin II induced pericyte contractility and narrowing of capillary diameter, which was accompanied by mechanical allodynia and heat hyperalgesia. Angiotensin II mediated pericyte activation and reduction of spinal cord blood flow, was prevented by inhibition of AT1 receptor via losartan treatment. In addition, losartan either systemically or intrathecally administered, prevented angiotensin II induced pain in male and female adult mice. This was associated with protection of the dorsal horn capillary endothelium, with intrathecal co-treatment with losartan preventing loss of CD31 immunoreactivity in the dorsal horn following administration of angiotensin II. This investigation demonstrates that AT1 mediated pericyte regulation of the dorsal horn capillary network, is fundamental in modulating nociceptive processing and perception of pain. Here we identify a novel cellular and mechanistic target for the development of new analgesic.
Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change
Authors: Dehkordi Siavash Raeisi , Wong Ivy Tsz-Lo , Ni Jing , Luebeck Jens , Zhu Kaiyuan , Prasad Gino , Krockenberger Lena , Xu Guanghui , Chowdhury Biswanath , Rajkumar Utkrisht , Caplin Ann , Muliaditan Daniel , Coruh Ceyda , Jin Qiushi , Turner Kristen , Teo Shu Xian , Pang Andy Wing Chun , Alexandrov Ludmil B. , Chua Christelle En Lin , Furnari Frank B. , Paulson Thomas G. , Law Julie A. , Chang Howard Y. , Yue Feng , DasGupta Ramanuj , Zhao Jean , Mischel Paul S. , Bafna Vineet
Published: December 2023

Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.
Tandem MutSβ binding to long extruded DNA trinucleotide repeats underpins pathogenic expansions
Authors: Li Jun , Wang Huaibin , Yang Wei
Published: December 2023

Expansion of trinucleotide repeats causes Huntington’s disease, Fragile X syndrome and over twenty other monogenic disorders1. How mismatch repair protein MutSβ and large repeats of CNG (N=A, T, C or G) cooperate to drive the expansion is poorly understood. Contrary to expectations, we find that MutSβ prefers to bind the stem of an extruded (CNG) hairpin rather than the hairpin end or hairpin-duplex junction. Structural analyses reveal that in the presence of MutSβ, CNG repeats with N:N mismatches adopt a B form-like pseudo-duplex, with one or two CNG repeats slipped out forming uneven bubbles that partly mimic insertion-deletion loops of mismatched DNA2. When the extruded hairpin exceeds 40-45 repeats, it can be bound by three or more MutSβ molecules, which are resistant to ATP-dependent dissociation. We envision that such MutSβ-CNG complexes recruit MutLγ endonuclease to nick DNA and initiate the repeat expansion process3,4. To develop drugs against the expansion diseases, we have identified lead compounds that prevent MutSβ binding to CNG repeats but not to mismatched DNA.
MBD2 couples DNA methylation to Transposable Elements silencing during male gametogenesis
Authors: Wang Shuya , Wang Ming , Ichino Lucia , Boone Brandon A. , Zhong Zhenhui , Papareddy Ranjith K. , Lin Evan K. , Yun Jaewon , Feng Suhua , Jacobsen Steven E.
Published: December 2023

DNA methylation is an essential component of transposable element (TE) silencing, yet the mechanism by which methylation causes transcriptional repression remains poorly understood1–5. Here we study theArabidopsis thalianaMethyl-CpG Binding Domain (MBD) proteins MBD1, MBD2, and MBD4, and show that MBD2 acts as a transposable element (TE) repressor during male gametogenesis. MBD2 bound chromatin regions containing high levels of CG methylation, and MBD2 was capable of silencing theFWAgene when tethered to its promoter. MBD2 loss caused TE activation in the vegetative cell (VC) of mature pollen without affecting DNA methylation levels, demonstrating that MBD2-mediated silencing acts strictly downstream of DNA methylation. Loss of silencing inmbd2became more significant in thembd5 mbd6oradcp1mutant backgrounds, as well as in plants with chemically induced genome-wide DNA demethylation, suggesting that MBD2 acts redundantly with other silencing pathways to safeguard TEs from activation. Overall, our study identifies MBD2 as a novel methyl reader that acts downstream of DNA methylation to silence TEs during male gametogenesis.
Characterization of carotenoid-producingMuricaudasp. strains isolated from the reef-building coralGalaxea fascicularisand subtropical seawater
Authors: Endo Funa , Motone Keisuke , Kai Kenji , Kitakaze Tomoya , Nishikawa Yumi , Nishimura Yuna , Kitamura Ruriko , Takagi Toshiyuki , Ito Michihiro , Miura Natsuko , Kataoka Michihiko
Published: December 2023

Bacterial symbionts in corals and coral-associated zooxanthellae are attracting increasing attention as potential probiotics. Some members of the family Flavobacteriaceae are zooxanthellae-associated bacteria, which are known to protect zooxanthellae from stresses such as heat and light by producing carotenoids that reduce reactive oxygen species production. This study characterized two Flavobacteriaceae bacteria,Muricaudasp. strains ORYM1 (NBRC115792) and ORYM2 (NBRC115793), isolated from the reef-building coralGalaxea fascicularisand its surrounding seawater in Okinawa, Japan, respectively. TheMuricaudasp. strain ORYM2 was isolated from subtropical seawater, and carotenoid production was assessed using ORYM2 as well as ORYM1, which was previously isolated fromG. fascicularis. De novogenome sequencing revealed that both strains contain complete sets of zeaxanthin biosynthesis genes, similar to those found in otherMuricaudaspp. Thin-layer chromatography and high-performance liquid chromatography analyses demonstrated that ORYM1 and ORYM2 produce several carotenoids. The bacterial strains and carotenoids identified in this study provide insights into the biological roles of zooxanthellae-associated bacteria in protecting zooxanthellae and reef-building corals from environmental stresses.

Statements and declarations

Competing interests: The authors declare no competing interests.
The Role of Anthropogenic Roosting Ecology in Shaping Viral Outcomes in Bats
Authors: Betke Briana A , Gottdenker Nicole , Meyers Lauren Ancel , Becker Daniel J
Published: December 2023

The ability of some wildlife to live in anthropogenic structures in response to rapid land-use change is widely observed across mammals. However, the influence of this adaptation in shaping viral hosting ability and diversity are not well understood, especially for the order Chiroptera. Anthropogenic roosting may have important consequences for predicting virus spillover and spillback risk, particularly as the propensity of bats to roost in anthropogenic structures (e.g., buildings, bridges, homes, and tunnels, etc.) directly relates to human exposure. Here, we integrate novel roosting ecology data with a machine learning approach to assess the importance of anthropogenic roosting in predicting viral outcomes and evaluate if this novel trait improves prediction of undetected but likely host species. Our results show that the importance of anthropogenic roosting varies moderately across viral outcomes. Anthropogenic roosting is most important for predicting virus hosting ability across bats, followed by zoonotic hosting ability, viral richness, and the proportion of viruses that are zoonotic. Anthropogenic roosting status is less important than human population density but more important than most family, diet, and foraging traits of bat species, and models with anthropogenic roosting predict a narrowed list of undetected virus hosts compared to models excluding this trait. We identified 35 bat species likely to host a virus, 18 of which roost in anthropogenic structures. Additionally, we identified 51 undetected zoonotic host species, 30 of which are anthropogenic roosting. Maps of predicted virus host distributions show distinct spatial patterns between anthropogenic and exclusively natural-roosting bats. These findings suggest that anthropogenic roosting has a non-trivial role in shaping viral outcomes in bats, specifically virus hosting ability.
Does novelty influence foraging decision of a scavenger?
Authors: Bhattacharjee Debottam , Sau Shubhra , Das Jayjit , Bhadra Anindita
Published: December 2023

Acquiring knowledge about the environment is crucial for survival. Animals, often driven by their explorative tendencies, gather valuable information regarding food resources, shelter, mating partners, etc. While neophilia, or the preference for novel environmental stimuli or objects, can promote exploratory behaviour, neophobia, or avoidance of novel environmental stimuli, can constrain such behaviour. Neophobia can reduce predation risk, yet decreased exploratory behaviour resulting from it may limit the ability to discover potentially highly rewarding resources. Dogs (Canis familiaris) living in semi-urban and urban environments as free-ranging populations are, although subject to various selection forces, typically have negligible predation pressure. These dogs are scavengers in human-dominated environments; thus, selection against object-neophobia can provide benefits when searching for novel food resources. Although pet and captive pack-living dogs are known to exhibit neophilia when provided with novel objects, little is known about free-ranging dogs’ behavioural responses to novel objects, particularly in foraging contexts. Using an object choice experiment, we tested 274 free-ranging dogs from two age classes, adult and juvenile, to investigate their object-neophobia in a scavenging context. We employed a betweensubject study design, providing dogs with a familiar and a potentially novel object, both baited with equal but (partially)hidden food rewards. Adult and juvenile dogs significantly inspected the novel object first compared to the familiar one, even when we reduced the visual obscurity of the familiar object, i.e., when the hidden food reward was partially visible. Furthermore, novel objects with varying strengths of olfactory cues (baited vs. false-baited) were inspected comparably by adults and juveniles. No significant differences were found in the latencies to inspect the objects. These results indicate that free-ranging dogs, evidently from an early ontogenic phase, do not show object-neophobia, as demonstrated by their preference for novel over familiar food sources. We conclude that little to no constraint of neophobia on exploratory behaviour, yet selection for object-neophilia in semi-urban and urban-dwelling animals can guide foraging decision-making processes, providing adaptive benefits.