bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Platelet-Rich Plasma in the Management of Alopecia Areata
Authors: Cook Madison K. , De Souza Brianna R. , Gosch Marianne E. , Yu Dongfang , Pichardo Rita O.
Published: September 2023

Introduction

Classic treatment options for patients with alopecia areata (AA) include intralesional and topical steroids as well as oral immunotherapy. Although these options can be effective for some patients, topical therapies are often inconvenient, and there can be many side effects with oral medications. Platelet-rich plasma (PRP) is an autologous preparation of concentrated platelets that is an emerging therapy for various conditions such as chronic nonhealing wounds, muscle injuries, and, more recently, hair loss.

Case Presentation

A 71-year-old woman with diffuse hair loss diagnosed previously as AA presented to our clinic after nonresponse to topical steroids and adverse events with topical minoxidil use. At our clinic, the patient underwent three treatments with PRP injections. Total hair regrowth without relapse was noted 6 months after treatment cessation.

Discussion/Conclusion

Our case illustrates a situation in which PRP served as an effective, rapid, and safe treatment option in a patient with AA who was unresponsive to previous standard therapies and feared side effects of oral medications.
Hats Off for Full-term Healthy Newborns
Authors: Lazzeri Jessica , Giordano Nicholas A. , Christ Lori , Polomano Rosemary C. , Stringer Marilyn
Published: September 2023

Background:

Hyperthermia is a known risk for sudden unexpected infant death. The practice of hat placement at birth to prevent transient hypothermia may not be necessary and sets an early standard for clothing infants that may lead to hyperthermia postnatally.

Objective:

To examine the elimination of hats on thermoregulation (eg, hypothermia, <97.6°F) in full-term newborns with no abnormalities within 24 hours of birth.

Methods:

In 2018, an institution guideline discontinued the use of hats at birth. Subsequently, newborn body temperatures were respectively extracted from electronic health records and data were compared from 482 infants (>38 weeks' gestation and newborn birth weight >2500 g) prior to (n = 257) and following (n = 225) the practice change. Body temperatures prior to and after the practice change to eliminate hats use were compared.

Results:

No statistically significant difference was observed: (1) in the proportion of infants experiencing hypothermia with or without hat use, respectively, 23.7% compared with 31.1% (P = .09) and (2) in the odds of an infant experiencing hypothermia when adjusting for relevant covariates (odds ratio = 1.44; 95% confidence interval 0.89-2.32); P = .14).

Conclusions:

Our findings demonstrate that the use of hats on infants at birth had no measurable impact on newborn thermoregulation.
The PBL teaching method in neurology education in the traditional Chinese medicine undergraduate students: An observational study
Authors: Kim Yun Jin
Published: September 2023

The objective of this study was to investigate the impact of the problem-based learning (PBL) method on Neurology education for Traditional Chinese Medicine (TCM) undergraduate students. This observational study was conducted during the 2020/02 and 2020/04 intakes of the third year TCM undergraduate students at School of Traditional Chinese Medicine, Xiamen University Malaysia. A total of 86 students were enrolled in the study and randomly assigned to either conventional learning groups or PBL groups. Students who missed more than 1 session of the course or did not complete the questionnaires during the evaluation periods were excluded from the study (n = 0). An independent sample t test was used to compare the results between the 2 groups, with a significance level set as P < .05. The PBL group demonstrated significantly higher scores in theoretical and clinical practical examinations, satisfaction with the teaching level, students perspectives, and self-learning skills. Additionally, the PBL group had significantly higher scores on the dundee ready educational environment measure compared to students in the conventional group (P < .05). The implementation of the PBL teaching method in Neurology education for TCM undergraduate students proved to be an engaging and effective learning approach. It significantly improved students learning performance and their ability to analyze and solve problems related to neurology diseases and their management knowledge.
Global research hotspots and frontier trends of epigenetic modifications in autoimmune diseases: A bibliometric analysis from 2012 to 2022
Authors: Gao Xiang , Huang Xin , Wang Yehui , Sun Sheng , Chen Tao , Gao Yongxiang , Zhang Xiaodan
Published: September 2023

Background:

Recent studies have shown substantial progress in understanding the association between epigenetics and autoimmune diseases. However, there is a lack of comprehensive bibliometric analysis in this research area. This article aims to present the current status and hot topics of epigenetic research in autoimmune diseases (ADs) from a bibliometric perspective, as well as explore the frontier hotspots and trends in epigenetic studies related to ADs.

Methods:

This study collected 1870 epigenetic records related to autoimmune diseases from the web of science core collection database, spanning from 2012 to 2022. Analysis of regions, institutions, journals, authors, and keywords was conducted using CiteSpace, VOSviewer, and the R package “bibliometrix” to predict the latest trends in epigenetic research relevant to autoimmune diseases.

Results:

The number of epigenetic publications related to autoimmune diseases has been increasing annually. The United States has played a major role in this field, contributing over 45.9% of publications and leading in terms of publication volume and citation counts. Central South University emerged as the most active institution, contributing the highest number of publications. Frontiers in Immunology is the most popular journal in this field, publishing the most articles, while the Journal of Autoimmunity is the most co-cited journal. Lu QJ is the most prolific author, and Zhao M is the most frequently co-cited author. “Immunology” serves as a broad representative of epigenetic research in ADs. Hot topics in the field of epigenetic modifications associated with autoimmune diseases include “regulatory T cells (Treg),” “rheumatoid arthritis,” “epigenetic regulation,” “cAMPresponsive element modulator alpha,” “cell-specific enhancer,” “genetic susceptibility,” and “systemic lupus erythematosus.” Furthermore, the study discusses the frontiers and existing issues of epigenetic modifications in the development of autoimmune diseases.

Conclusions:

This study provides a comprehensive overview of the knowledge structure and developmental trends in epigenetic research related to autoimmune diseases over the past 11 years.
Associations between non-coding RNAs genetic polymorphisms with ovarian cancer risk: A systematic review and meta-analysis update with trial sequential analysis
Authors: Liu Huaying , Sun Lili , Liu Xiaoping , Wang Ruichai , Luo Qinqin
Published: September 2023

Background:

This systemic review and meta-analysis seeks to systematically analyze and summarize the association between non-coding RNA polymorphisms and ovarian cancer risk.

Methods:

We searched PubMed, Web of Science and CNKI for available articles on non-coding RNA polymorphisms in patients with ovarian cancer from inception to March 1, 2023. The quality of each study included in the meta-analysis was rated according to the Newcastle–Ottawa Scale.

Odds ratios (ORs) with their 95% confidence intervals (95% CI) were used to assess associations. Chi-square Q-test combined with inconsistency index (I2) was used to test for heterogeneity among studies. Lastly, trial sequential analysis (TSA) software was used to verify the reliability of meta-analysis results, and in-silico miRNA expression were also performed. The meta-analysis was registered with PROSPERO (No. CRD42023422091).

Results:

A total of 17 case-control studies with 18 SNPs were selected, including 2 studies with H19 rs2107425 and HOTAIR rs4759314, and 5 studies with miR-146a rs2910164 and miR-196a rs11614913. Significant associations were found between H19 rs2107425, miR-146a rs2910164, and miR-196a rs11614913 and ovarian cancer risk. Three genetic models of H19 rs2107425 (CT vs TT (heterozygote model): OR = 1.36, 95% CI = 1.22–1.52, P < .00001; CC + CT vs TT (dominant model): OR = 1.12, 95% CI = 1.02–1.24, P = .02; and CC vs CT + TT (recessive model): OR = 1.23, 95% CI = 1.16–1.31, P < .00001), 2 genetic models of miR-146a rs2910164 (allele model: OR = 1.75, 95% CI = 1.05–2.91, P = .03; and heterozygote model: OR = 0.33, 95% CI = 0.11–0.98, P = .05), 3 genetic models of miR-196a rs11614913 (allele model: OR = 0.70, 95% CI = 0.59–0.82, P < .0001; dominant model: OR = 1.62, 95% CI = 1.18–2.24, P = .0001; and recessive model: OR = 0.70, 95% CI = 0.57–0.87, P = .03) were statistically linked to ovarian cancer risk. Subgroup analysis for miR-146a rs2910164 was performed according to ethnicity. No association was found in any genetic model. The outcomes of TSA also validated the findings of this meta-analysis.

Conclusion:

This study summarizes that H19 rs2107425, miR-146a rs2910164, and miR-196a rs11614913 polymorphisms are significantly linked with the risk of ovarian cancer, and moreover, large-scale and well-designed studies are needed to validate our result.
Efficacy and safety of diacerein and celecoxib combination therapy for knee osteoarthritis: A double-blind, randomized, placebo-controlled prospective study
Authors: Youn Sangah , Choi Ji Hye , Kim Chulmin , Kim Seon-Mee , Choi Whan Seok
Published: September 2023

Background:

Osteoarthritis is a degenerative disease with a growing burden in South Korea. Corresponding drugs are commonly used for pain relief and joint function improvement. Specifically, symptomatic slow-acting drugs for osteoarthritis are frequently used, with diacerein being the most common symptomatic slow-acting drugs for osteoarthritis in South Korea. In this study, we evaluated the efficacy and safety of diacerein and celecoxib combination therapy in patients with osteoarthritis.

Methods:

A total of 71 subjects were randomly assigned to group 1 (diacerein and celecoxib), 2 (diacerein and placebo), or 3 (celecoxib and placebo). The primary outcome measure was the change in the visual analog scale (VAS) score 12 weeks after treatment.

Results:

The combination therapy group exhibited a significant decrease in the VAS score, alongside the other control monotherapy groups. Although there was no significant difference between the groups, the combination therapy group exhibited a greater decrease in the absolute value of the VAS score than the other groups. Four weeks after treatment, the combination therapy group showed significantly higher improvement in the stiffness and physical function categories of the Western Ontario and McMaster Universities Osteoarthritis Index than the other groups. Additionally, no serious adverse events occurred following combination therapy, with most adverse events being mild and resolving without specific treatment.

Conclusions:

Diacerein and celecoxib combination therapy is as safe and effective as corresponding monotherapies. A relatively early improvement in stiffness and physical function following treatment with this combination therapy indicates that physicians should consider this for the early-stage treatment of patients with symptomatic osteoarthritis.
The effects of exenatide and insulin glargine treatments on bone turnover markers and bone mineral density in postmenopausal patients with type 2 diabetes mellitus
Authors: Akyay Ozlem Zeynep , Canturk Zeynep , Selek Alev , Cetinarslan Berrin , Tarkun İlhan , Cakmak Yagmur , Baydemir Canan
Published: September 2023

Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway.
Meta-analysis of the efficacy of ω-3 polyunsaturated fatty acids when treating patients with polycystic ovary syndrome
Authors: Huang Yue , Zhang Xiang
Published: September 2023

Objective:

To systematically assess the efficacy of ω-3 polyunsaturated fatty acids (PUFAs) when treating polycystic ovary syndrome (PCOS).

Methods:

This meta-analysis follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. We searched PubMed, EMBASE, ScienceDirect, Cochrane Library, China journal full-text database, VIP full-text Database, Wanfang Database, and Chinese Biomedical Literature Data for clinical trials on ω-3 PUFAs’ efficacy in treating PCOS. Two independent reviewers examined and analyzed studies, resolving inconsistencies through discussion. RevMan5.3 software performed heterogeneity-based fixed and random-effects meta-analysis. We assessed bias using the Cochrane bias risk assessment tool.

Results:

Our meta-analysis included 7 clinical control studies comprising 574 samples to evaluate the impact of ω-3 PUFAs on various metabolic markers in PCOS patients. We observed a significant reduction in total cholesterol (TC) and triglyceride (TG) levels (P < .05), along with a decrease in insulin resistance as measured by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (P < .05). Testosterone (T) levels were also lowered in the study group post-treatment (P < .05). However, no notable effects were found on body mass index (BMI), fasting blood sugar (FBS), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and Ferriman-Gallwey (mFG) scores (P > .05). Publication bias was not detected, enhancing the robustness of our results. Our study suggests that ω-3 PUFAs could be beneficial in managing specific metabolic markers in PCOS, although the results showed marked heterogeneity.

Conclusion:

In PCOS patients, PUFAs can enhance reproductive endocrine, glucose, and lipid levels. However, additional research and extended follow-up are required to confirm this.
A Cross-Sectional Study of Pediatric Feeding Disorder in Children with Cystic Fibrosis
Authors: Bashir Anam , Antos Nicholas , Miller Tami , Challa Sai Alekha , Pan Amy Y. , Gosa Memorie , Silverman Alan , Goday Praveen S.
Published: September 2023

Background:

The exact prevalence of feeding problems in children with cystic fibrosis (CF) is unknown. Pediatric feeding disorder (PFD) encompasses poor oral intake with associated medical, nutrition, psychosocial, or feeding skill dysfunction. We hypothesized that PFD is common in CF and aimed to categorize feeding dysfunction across various domains in children with CF.

Methods:

An observational cross-sectional study was conducted in children with CF. Data collected included anthropometrics, nutrition data (including need for tube feeding/enteral nutrition [EN] or high-energy beverages, dietary diversity), feeding skills (Pediatric version of the Eating Assessment tool [pEAT]), and psychosocial function (About Your Child’s Eating questionnaire [AYCE] in children 2–17 years of age/Behavioral Pediatric Feeding Assessment Scale [BPFAS] in children 12–23 months of age). PFD was defined as poor oral intake with: (a) pEAT score > 5; and/or (b) AYCE or BPFAS score > 2 standard deviation of normative controls; and/or (c) nutrition dysfunction (body mass index/weight-for-length z score < −1 and/or preference of oral high energy beverages or dependence on EN and/or decreased dietary diversity).

Results:

Of 103 children in the study, 62 (60.1%) had PFD, 7 children (6.8%) were malnourished, 10 needed EN (9.7%), and 30 (29.1%) needed oral high-energy beverages. Dietary diversity was decreased in 42 children (41.5%), 1 child had feeding skill dysfunction, and 11 (10.8%) met criteria for psychosocial dysfunction.

Conclusion:

Almost 2/3rd of children with CF have PFD and many have poor dietary diversity. A significant percentage of children rely on EN and oral supplements, but psychosocial dysfunction is less prevalent.
Recent Advances in the Genetic Pathogenesis, Diagnosis, and Management of Esophageal Atresia and Tracheoesophageal Fistula: A Review
Authors: O’Shea Delia , Schmoke Nicholas , Porigow Chloe , Murray Laurie P. , Chung Wendy K. , Kattan Meyer , Jang Minyoung , Antosy Alexandra , Middlesworth William , Khlevner Julie
Published: September 2023

Infants born with esophageal atresia and tracheoesophageal fistula, a complex congenital malformation occurring in 1/2500–4000 live births, may suffer threats to their cardiac, respiratory, and digestive health in addition to anomalies that may exist in the genitourinary and musculoskeletal systems. Optimal care for these patients throughout their lives is best achieved through a coordinated, multidisciplinary approach that our health care system is not always well-equipped to provide. This review, though not exhaustive, highlights the components of care that pertain to initial surgical reconstruction and subsequent diagnosis and management of the complications that are most frequently encountered. Authors from among the many specialties involved in the care of these patients summarize the current best practice with attention to the most recent advances. Assessment and improvement of quality of life and transition to adult specialists as children grow to adulthood is also reviewed.
Facial Rejuvenation in a Patient With Granulomatosis With Polyangiitis—Treatment Protocol for Compromised Skin Flap
Authors: Salehi Parsa P. , Salehi Pauniz , Peng Grace Lee , Nassif Paul
Published: September 2023

Facial rejuvenation outcomes have not been well studied in patients with granulomatosis with polyangiitis (GP)—formerly Wegener granulomatosis. This report highlights a case of a 49-year-old female with a history of GP, presenting with facial aging and functional nasal concerns. The patient underwent facial rejuvenation and nasal reconstruction procedures, including primary open functional rhinoplasty, septal perforation repair with Alloderm, deep-plane rhytidectomy, platysmaplasty, nanofat grafting, and fractionated erbium laser to the face (sparing the nose and peri-incisional areas). Despite a routine operation, postoperative course was complicated by wound healing and vascular congestion issues related to her underlying autoimmune disease. This case highlights the risks associated with postsurgical healing in patients with GP undergoing esthetic surgery. To the best of our knowledge, this report is the first to discuss management considerations in a patient with GP undergoing facial rejuvenation surgery.
Unearthing New Learning Opportunities: Adapting and Innovating through the 'Antibiotics Under Our Feet' Citizen Science Project in Scotland during COVID-19
Authors: Cornwell Rebecca Mary , Ross Kirsty , Gibeily Caius , Guthrie Isobel , Li Pak Hei , Seeley Laurence Taylor , Kong Yaxuan , True Ava , Barnes Arun , Nimmo Emma , Len Gloriya , Oprea Ioana , Lin Boyang , Sasi Aswin , Chu Vicky , Davidson Chloe , Ulasavets Daniil , Renouf-Bilanski Grace , Dmitrieva Maria , Leung Yana , Ye Ziying , Brown Sasha , Vaidya Meghna , Hynes Jenna , Mullner Catherine , Agarwal Priyansha , Thorley Charlotte , Melo Czekster Clarissa
Published: September 2023

“Antibiotics under our feet” is a Scottish citizen science project that aimed to raise science capital in primary school learners and their teachers through measurement of microbial diversity in urban soil samples in the search for novel antimicrobial compounds. Resistance to antibiotics is rising, posing a global threat to human health. Furthermore, Science, Technology, Engineering and Maths (STEM) skills are in crisis, jeopardising our capacity to mobilise as a society to fight antimicrobial resistance (AMR). Originally conceived as a response to the AMR and STEM emergencies, our project was hit by the unprecedented challenge of engaging with schools during the COVID-19 pandemic. We describe how we adapted our project to enable remote participation from primary schools and youth groups, utilising COVID-19 response initiatives as opportunities for multi-level co-creation of resources with learners in primary, secondary, and higher education. We produced portable kit boxes for soil sample collection with learning activities and videos linked to the Scottish Curriculum for Excellence.We also addressed glaring project specific content gaps relating to microbiology on English and Simple English Wikipedia. Our hybrid model of working extended our geographical reach and broadened inclusion. We present here the inception, implementation, digital resource outputs, and evaluation of pedagogical aspects of “Antibiotics under our feet”. Our strategies and insights are applicable post-pandemic for educators to develop STEM skills using soil, microbes, and antibiotics as a theme.
Direct extrusion of multifascicle prevascularized human skeletal muscle for volumetric muscle loss surgery
Authors: Duong Van Thuy , Dang Thao Thi , Le Van Phu , Le Thi Huong , Nguyen Chanh Trung , Phan Huu Lam , Seo Jongmo , Back Sung Hoon , Koo Kyo-in
Published: September 2023

Volumetric skeletal muscle injuries are prevalent, highlighting the imperative need for scaffolds to facilitate the healing process of such wounds. Human skeletal muscle is composed of multiple fascicles, which are parallel bundles of muscle fibres surrounded by a layer of connective tissue that contains blood vessels and nerves. Replicating these structures presents a considerable challenge. Here, we developed a method to fabricate multifascicle human skeletal muscle scaffolds that mimic the natural structure of human skeletal muscle bundles using a seven-barrel nozzle. To form the core material to generate the fascicle structure, human skeletal myoblasts were encapsulated in Matrigel with calcium chloride. Meanwhile, to create the shell that plays a role as the connective tissue structure, human fibroblasts and human umbilical vein endothelial cells within a mixture of porcine muscle decellularized extracellular matrix and sodium alginate at a 95:5 ratio was used. We assessed four types of extruded scaffolds monolithic-monoculture (Mo-M), monolithic-coculture (Mo-C), multifascicle-monoculture (Mu-M), and multifascicle-coculture (Mu-C) to determine the structural effect of muscle mimicking scaffold. The Mu-C scaffold demonstrated cell proliferation, differentiation, vascularization, mechanical properties, and functionality that were superior to those of the other scaffolds. Furthermore, in anin vivomouse model of volumetric muscle loss, the Mu-C scaffold effectively regenerated the tibialis anterior muscle defect, demonstrating its potential for volumetric muscle transplantation. The multibarrel nozzle device was applied to create functional Mu-C muscle scaffolds that structurally mimicked human skeletal muscle. Our nozzle will be further used to produce other volumetric functional tissues, such as tendons and peripheral nerves.
IL-2–induced Stat3 Signaling is Critical for Effector Treg Cell Programming
Authors: Dean Emma C. , Ditoro Daniel F. , Pham Duy , Gao Min , Zindl Carlene L. , Frey Blake , Harbour Stacey N. , Figge David A. , Miller Aidan T. , Glassman Caleb R. , Garcia K. Christopher , Hatton Robin D. , Weaver Casey T.
Published: September 2023

Maintenance of immune homeostasis to the intestinal mictrobiota is dependent on a population of effector regulatory T (eTreg) cells that develop from microbiota-reactive induced (i)Treg cells. A cardinal feature of eTreg cells is their production of IL-10, which plays a non-redundant role in immune tolerance of commensal microbes. Here, we identify an unexpected role for IL-2-induced Stat3 signaling to program iTreg cells for eTreg cell differentiation andIl10transcriptional competency. IL-2 proved to be both necessary and sufficient for eTreg cell development – contingent on Stat3 output of the IL-2 receptor coordinate with IL-2 signaling during early Treg cell commitment. Induction of iTreg cell programming in absence of IL-2-induced Stat3 signaling resulted in impaired eTreg cell differentiation and a failure to produce IL-10. An IL-2 mutein with reduced affinity for the IL-2Rγ (γc) chain was found to have blunted IL-2R Stat3 output, resulting in a deficiency ofIl10transcriptional programming that could not be fully rescued by Stat3 signaling subsequent to an initial window of iTreg cell differentiation. These findings expose a heretofore unappreciated role of IL-2 signaling that acts early to program subsequent production of IL-10 by developing eTreg cells, with broad implications for IL-2–based therapeutic interventions in immune-mediated diseases.
Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer associated fibroblasts
Authors: Burt Richard J. , Dey Aditi , Akarca Ayse , Allen Hermione , Amerikanou Rodothea , Atkinson Samantha , Auty David , Chatzigerou Jenny , Cutler Emily , Guerra-Assuncao Jose Afonso , Kirschner Kristina , Kumari Ruchi , Manji Jiten , Marafiotti Teresa , Fielding Adele K.
Published: September 2023

Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, PDX and primary cells or their conditioned media can also trigger CAF formation, in an oncogene-dependent manner. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that degradation of dsRNA in ALL cell conditioned media by DMSO ablates the ability of the conditioned media to stimulate MSC to CAF transition. Since we find that only specific primary driver genetic subtypes of B-ALL possess the property to directly generate CAFs, we propose this phenomenon as the first mechanistic insight into the strong relationship between acute lymphoblastic leukaemia genetic subtype and survival outcomes.

Key points

X

Exposure of MSC to B-precursor ALL cell lines triggers cancer-associated fibroblast formation in an oncogene-dependent manner

The proximate trigger for CAF formation is ALL-derived mitochondrial double stranded RNA
Determining the effects of temperature on the evolution of bacterial tRNA pools
Authors: Jain Vatsal , Cope Alexander L.
Published: September 2023

The genetic code consists of 61 codon coding for 20 amino acids. These codons are recognized by transfer RNAs (tRNA) that bind to specific codons during protein synthesis. Most organisms utilize less than all 61 possible anticodons due to base pair wobble: the ability to have a mismatch with a codon at its third nucleotide. Previous studies observed a correlation between the tRNA pool of bacteria and the temperature of their respective environments. However, it is unclear if these patterns represent biological adaptations to maintain the efficiency and accuracy of protein synthesis in different environments. A mechanistic mathematical model of mRNA translation is used to quantify the expected elongation rates and error rate for each codon based on an organism’s tRNA pool. A comparative analysis across a range of bacteria that accounts for covariance due to shared ancestry is performed to quantify the impact of environmental temperature on the evolution of the tRNA pool. We find that thermophiles generally have more anticodons represented in their tRNA pool than mesophiles or psychrophiles. Based on our model, this increased diversity is expected to lead to increased missense errors. The implications of this for protein evolution in thermophiles are discussed.

Significance

Protein synthesis is a vital biological process; however, our understanding of the impact of environmental factors, such as temperature, on the evolution of the molecular mechanisms involved in protein synthesis is limited. In this study, we investigated the impact of environmental temperature on the evolution of the tRNA pool. Our analyses revealed that heat-loving bacteria (thermophiles) generally have more anticodons represented in their tRNA pool. Based on a simple model of ribosome elongation, this observed increase in tRNA diversity in thermophiles is expected to also increase the frequency of translation errors. We speculate that the increased diversity of the tRNA pool could be due to the decreased efficiency of wobble base pairing at higher temperatures, necessitating more tRNA with exact codon-anticodon pairings. Our findings provide key insights into the role of the environment in shaping the tRNA pool.
Molecular Dynamics Activation of γ-Secretase for Cleavage of Notch1 Substrate
Authors: Do Hung N. , Malvankar Shweta R. , Wolfe Michael S. , Miao Yinglong
Published: September 2023

γ-Secretase is an intramembrane aspartyl protease complex which cleaves the transmembrane domain of over 150 peptide substrates, including amyloid precursor protein (APP) and the Notch family of receptors, via two conserved aspartates D257 and D385 in the Presenilin-1 (PS1) catalytic subunit. However, while the activation of γ-secretase for cleavage of APP has been widely studied, the cleavage of Notch by γ-secretase remains poorly explored. Here, we combined Gaussian accelerated Molecular Dynamics (GaMD) simulations and mass spectrometry (MS) analysis of proteolytic products to present the first dynamic models for cleavage of Notch by γ-secretase. MS showed that γ-secretase cleaved the WT Notch at Notch residue G34, while cleavage of L36F mutant Notch occurred at Notch residue C33. Initially, we prepared our simulation systems starting from the cryoEM structure of Notch-bound γ-secretase (PDB: 6IDF) and failed to capture the proper cleavages of WT and L36F Notch by γ-secretase. We then discovered an incorrect registry of the Notch substrate in the PS1 active through alignment of the experimental structure of Notch-bound (PDB: 6IDF) and APP-bound γ-secretase (PDB: 6IYC). Every residue of APP substrate was systematically mutated to the corresponding Notch residue to prepare a resolved model of Notch-bound γ-secretase complexes. GaMD simulations of the resolved model successfully captured γ-secretase activation for proper cleavages of both WT and L36F mutant Notch. Our findings here provided mechanistic insights into the structural dynamics and enzyme-substrate interactions required for γ-secretase activation for cleavage of Notch and other substrates.
Multiepitope-based vaccine design against DiiA inStreptococcus pneumoniae, An immunoinformatics approach
Authors: Soliman Mariam M. , Sheikhani Dania , Nassar Jihan , Elsabbagh Sherif , Ibrahim Tamer M.
Published: September 2023

Streptococcus pneumoniae(SPN) infection has resulted in significant morbidity and mortality worldwide in children and adults. It is responsible for colonizing the human nasopharynx and can also cause diseases, including otitis media, pneumonia, bacteraemia, and meningitis. SPN is exhibiting resistance to multiple antibiotics and current vaccines have a number of limitations including poor immunogenicity and limited effectiveness against all pneumococcal serotypes. Here, we explain the design of a novel multi-epitope vaccine using Dimorphic invasion-involved protein A (DiiA) as a target protein. For designing the vaccine, the sequence of DiiA was obtained and various bioinformatics tools were employed to predict multiple CTL, HTL, B lymphocyte epitopes of DiiA. After evaluating antigenicity, allergenicity, toxicity, and immunogenicity, the most promising epitopes were chosen for constructing the vaccine, followed by an analysis of their physicochemical and immunological characteristics.The prediction, refinement, and validation of the 3D structure of the vaccine were carried out. Molecular docking, molecular dynamic simulation, and immune simulation were executed to examine the binding affinities and biological interactions at the atomic level between the vaccine and Toll-like receptor (TLR4). Vaccine translation, codon optimization were performed and expression efficiency was assessed through an in-silico cloning experiment performed to transfer into pET28a(+) plasmid vector.The obtained results proved that the vaccine maintained structural stability and possessed the capability to stimulate an efficient immune response againstS. pneumoniaeinfection. The constructed vaccine has the potential for subsequent wet lab experimentation, leading to the development of an innovative vaccine.
Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation
Authors: Mas-Ponte David , Supek Fran
Published: September 2023

Local mutation rates are highly heterogeneous across the human genome. This variability was better studied at the scale of megabase-sized chromosomal domains on the one extreme, and at the scale of oligonucleotides at the other extreme. The intermediate, kilobase-scale heterogeneity in mutation risk was less studied. Here, by analyzing thousands of somatic genomes, we considered the hypothesis there are mutation risk gradients along gene bodies, representing a genomic scale spanning roughly 1 kb – 10 kb, and that different mutational mechanisms are differently distributed across gene segments. The main intragenic heterogeneity concerns several kilobases at the transcription start site and further into 5’ ends of gene bodies, which are commonly hypomutated with respect to several mutational signatures, most prominently the ubiquitous mutational signature of C>T changes at CpG dinucleotides. Width and shape of this mutational coldspot at 5’ gene ends is variable across genes, and corresponds to variable interval of lowered DNA methylation across genes. These hypomutated genic intervals correspond to hypomethylation that can originate from various causes, including intragenic enhancers, Polycomb-marked regions, or chromatin loop anchor points. Tissue-specific DNA hypomethylation begets tissue-specific local hypomutation. However, direction of mutation rate effect is inverted for some mutational processes, where signatures of AID/APOBEC3 cytosine deaminase activity are actually increased in hypomethylated regions. Overall, local DNA methylation determines mutation rate heterogeneity at the sub-gene level, and can generate either mutational coldspots or hotspots, depending on the mutagen exposure history of a cell.
Evaluating goodness-of-fit of animal movement models using lineups
Authors: Fieberg John , Freeman Smith , Signer Johannes
Published: September 2023

Models of animal movement are frequently fit to animal location data to understand how animals respond to and interact with local environmental features. Several open-source software packages are available for analyzing animal movements and can facilitate parameter estimation, yet there are relatively few methods available for evaluating model goodness-of-fit. We describe how a simple graphical technique, thelineup protocol, can be used to evaluate goodness-of-fit of integrated step-selection analyses and hidden Markov models, but the method can be applied much more broadly. We leverage the ability to simulate data from fitted models, and demonstrate the approach using both methods applied to fisher (Pekania pennanti) data. A variety of responses and movement metrics can be used to evaluate models, and the lineup protocol can be tailored to focus on specific model assumptions or movement features that are of primary interest. Although it is possible to evaluate goodness-of-fit using a formal hypothesis test, the method can also be used in a more exploratory fashion (e.g., to visualize variability in model behavior across stochastic simulations or identify areas where the model could be improved). We provide coded examples and two vignettes to demonstrate the flexibility of the approach and encourage movement ecologists to consider how their models will be applied when choosing appropriate graphical responses for evaluating goodness-of-fit.
Lymphoma B cells remodel bone marrow stromal cell organization and function to induce a supportive cancer-associated fibroblast network
Authors: Dessauge Elise , Brauge Baptiste , Léonard Simon , Roulois David , Monvoisin Céline , Lejeune Thomas , Destin Jérôme , Jouan Florence , Llamas-Gutierrez Francisco , Mourcin Frédéric , Tarte Karin
Published: September 2023

Bone marrow (BM) involvement is a common feature of lymphomas deriving from germinal-center B cells and is associated with a bad prognosis. In particular, follicular lymphoma (FL) infiltrates the BM in 70% of cases, in association with a remodeling of surrounding tumor microenvironment. Analysis ofin vitro-expanded FL mesenchymal stromal cells (MSCs) revealed an extensive alteration of BM stromal cell phenotypic, transcriptomic, and functional profiles. However, the mechanisms supporting the direct interplay between lymphoma B cells and their permissive stromal nichein situhave not been yet identified. In the current work, we identified in the BM milieu of FL patients a deregulation of soluble and extracellular matrix (ECM) components reflecting inflammation and ectopic differentiation into lymphoid-like stromal cells. We reproduced the same alterations in a murine model of lymphoma B-cell xenograft where a scRNAseq approach identified LepRposMSCs as specifically and progressively reprogramed by tumor B-cell invasion. Analysis of FL BM collected before and after treatment confirmed that BM niche was partly dependent on the continuous contact with tumor B cells. Altogether, this work shed new lights on the kinetic and mechanisms of BM stromal niche reshaping in B-cell lymphoma.
Testing for a role of postzygotic incompatibilities in rapidly speciated Lake Victoria cichlids
Authors: Feller Anna F. , Peichel Catherine L. , Seehausen Ole
Published: September 2023

Intrinsic postzygotic hybrid incompatibilities are usually due to negative epistatic interactions between alleles from different parental genomes. While such incompatibilities are thought to be uncommon in speciation with gene flow, they may be important if such speciation results from a hybrid population. Here we aimed to test this idea in the endemic cichlid fishes of Lake Victoria. Hundreds of species have evolved within the lake in <15k years from a hybrid progenitor. While the importance of prezygotic barriers to gene flow is well established in this system, the possible relevance of postzygotic genetic incompatibilities is unknown. We inferred the presence of negative epistatic interactions from systematic patterns of genotype ratio distortions in experimental crosses and wild samples. We then compared the positions of putative incompatibility loci to regions of high genetic differentiation between sympatric sister species as well as between members of clades that may have arisen at the start of this radiation, and further determined if the loci showed fixed differences between the closest living relatives of the lineages ancestral to the hybrid progenitor. Overall, we find little evidence for a major role of intrinsic postzygotic incompatibilities in the Lake Victoria radiation. However, we find putative incompatibility loci significantly more often coinciding with islands of genetic differentiation between species that separated early in the radiation than between the youngest sister species, consistent with the hypothesis that such variants segregated in the hybrid swarm and were sorted between species in the early speciation events.
SASH1 interacts with TNKS2 and promotes human melanocyte stem cell maintenance
Authors: Lambert Karoline A. , Clements Christopher M. , Mukherjee Nabanita , Pacheco Theresa R. , Shellman Samantha X. , Henen Morkos A. , Vögeli Beat , Goldstein Nathaniel B. , Birlea Stanca , Hintzsche Jennifer , Tan Aik-Choon , Zhao Rui , Norris David A. , Robinson William A. , Wang Yizhou , VanTreeck Jillian G , Shellman Yiqun G.
Published: September 2023

Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1S519Nvariant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1S519Nwas defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1’s promotion of stem-like function. Further, the SASH1S519Nvariant is in abona fideTankyrase-binding motif, and SASH1S519Nalters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.
Pan tissue analysis of humanNUMBalternative splicing
Authors: Zhang Yangjing , McGlade C. Jane
Published: September 2023

Alternative splicing (AS) of pre-mRNA generates multiple protein isoforms from a single gene. It is developmentally regulated and mis-regulation is associated with many diseases. Previous studies that examined AS of the cell fate determinantNUMBdemonstrated that it undergoes a regulated switch in the inclusion of protein coding exons 3 and 9 during rodent development and the differentiation of human cell lines. Here we extend this work by comparing exon 9 and exon 3 inclusion levels of the humanNUMBgene across different normal human tissues by analysis of RNA sequencing data deposited in the Genotype-Tissue Expression (GTEx) and the Vertebrate Alternative Splicing and Transcription (VastDB) databases. Our results support earlier studies and reveal specific Numb isoform expression patterns in previously unexamined tissue and cell types, suggesting that Numb isoform expression is regulated in the normal development of a broad range of tissue types throughout the body.
Novel Epidermal Oxysterols Function as Alarm Substances in Zebrafish
Authors: Li Yaxi , Yan Zhi , Lin Ainuo , Yang Xiao , Li Xiaodong , Yin Xiuli , Li Weiming , Li Ke
Published: September 2023

Aquatic animals often use chemical cues to signal predation risk. When injured, shoaling fish skins release alarm substances that induce intense fear and a suite of anti-predator behaviors in other shoal members. However, the chemical nature of alarm substances remains largely unknown. Here we show that zebrafish alarm substance comprises 24-methyl-5α-cholestane-3α,7α,12α,24,28-pentahydroxy 28-sulfate, a novel oxysterol sulfate, and 5α-cyprinol sulfate. These compounds are present in zebrafish skin extract and, at concentrations of less than one nanomolar, each induces anti-predator behaviors and increases cortisol levels. Their mixture, at its natural ratio, replicates the skin extract in eliciting the full suite of anti-predator behavior patterns. Our findings reveal a molecular-level mechanism whereby fish signal predation danger.
Substrate promiscuity of xenobiotic-transforming hydrolases from stream biofilms impacted by treated wastewater
Authors: Yu Yaochun , Trottmann Niklas Ferenc , Schärer Milo R. , Fenner Kathrin , Robinson Serina L.
Published: September 2023

Organic contaminants enter aquatic ecosystems from various sources, including wastewater treatment plant effluent. Freshwater biofilms play a major role in the removal of organic contaminants from receiving water bodies, but knowledge of the molecular mechanisms driving contaminant biotransformations in complex stream biofilm (periphyton) communities remains limited. Previously, we demonstrated that biofilms in experimental flume systems grown at higher ratios of treated wastewater (WW) to stream water displayed an increased biotransformation potential for a number of organic contaminants. We identified a positive correlation between WW percentage and biofilm biotransformation rates for the widely-used insect repellent,N,N-diethyl-meta-toluamide (DEET). Here, we conducted deep shotgun sequencing of flume biofilms and identified a positive correlation between WW percentage and metagenomic read abundances of DEET hydrolase (DH) homologs. To test the causality of this association, we constructed a targeted metagenomic library of DH homologs from flume biofilms. We screened our complete metagenomic library for activity with four different substrates and a subset thereof with 183 WW-related organic compounds. The majority of active hydrolases in our library preferred aliphatic and aromatic ester substrates while, remarkably, only a single reference enzyme was capable of DEET hydrolysis. Of the 626 total enzyme-substrate combinations tested, approximately 5% were active enzyme-substrate pairs. Metagenomic DH family homologs revealed a broad substrate promiscuity spanning 22 different compounds when summed across all enzymes tested. We biochemically characterized the most promiscuous and active enzymes identified based on metagenomic analysis from uncultivatedRhodospirillaceaeandPlanctomycetaceae. In addition to characterizing new DH family enzymes, we exemplified a framework for linking metagenome-guided hypothesis generation with experimental validation. Overall, this study expands the scope of known enzymatic contaminant biotransformations for metagenomic hydrolases from WW-receiving stream biofilm communities.

Graphical abstract

Highlights

Metagenomic DEET hydrolase abundances higher in biofilms grown in treated wastewater.

Eleven out of 64 metagenomic hydrolases tested exhibited hydrolysis activity.

Related enzymes in a single family of DEET hydrolases biotransform 20+ contaminants.

Reference DEET hydrolase shows a substrate preference for benzamide moieties.

‘True’ DEET hydrolases are in low abundance even in biofilms that degrade DEET.
HybriSeq: Probe-based Device-free Single-cell RNA Profiling
Authors: Foyt Daniel , Brown David , Zhou Shuqin , Huang Bo
Published: September 2023

We have developed the HybriSeq method for single-cell RNA profiling, which utilizes in situ hybridization of multiple probes for targeted transcripts, followed by split-pool barcoding and sequencing analysis of the probes. We have shown that HybriSeq can achieve high sensitivity for RNA detection with multiple probes and profile differential splicing. The utility of HybriSeq is demonstrated in characterizing cell-to-cell heterogeneities of a panel of 95 cell-cycle-related genes and the detection of misannotated transcripts.