bluuebunny/crossref_metadata_2025 huggingface dataset:
Cre-Lox miRNA-delivery technology optimized for inducible microRNA and gene-silencing studies in zebrafish
Authors: Guo Fangfei , Tromp Alisha , Wang Haitao , Hall Thomas E , Giacomotto Jean
Published: January 2025

While many genetic tools exist for zebrafish, this animal model still lacks robust gene-silencing and microRNA-delivery technologies enabling spatio-temporal control and traceability. We have recently demonstrated that engineered pri-miR backbones can trigger stable gene knockdown and/or express microRNA(s) of choice in this organism. However, this miRNA-expressing technology presents important limitations. First, to trigger potent knockdown(s), multiple synthetic-miRNAs must be expressed simultaneously, compromising the co-expression of fluorescent marker(s) and knockdown traceability. Second, when gene(s) knockdown triggers significant phenotypes, like homozygous mutants with severe early phenotypes, it is difficult, if not impossible, to maintain transgenic carriers. To solve these problems and provide a mature RNAi and microRNA-delivery technology, we have generated new RNAi reagents and an inducible delivery system based on the Cre/Lox technology. This system allows the creation of asymptomatic/silent carriers, easing the production of embryos with potent knockdowns that can be traced and spatiotemporally controlled. We further demonstrated the utility of this approach by establishing novel inducible and tissue-specific models of spinal muscular atrophy, opening new avenues for studying smn1-gene function and pathogenicity. All in all, these materials and techniques will be invaluable in studying microRNA biology and in modelling or tackling conditions in which gene dosage is key.
Perceived Harm of Vaping Relative to Smoking and Associations With Subsequent Smoking and Vaping Behaviors Among Young Adults: Evidence From a UK Cohort Study
Authors: East Katherine , Taylor Eve , McNeill Ann , Bakolis Ioannis , Taylor Amy E , Maynard Olivia M , Munafò Marcus R , Khouja Jasmine
Published: January 2025

Introduction

There is a lack of evidence on whether vaping harm perceptions can predict vaping and smoking behaviors among young adults in the United Kingdom. We aimed to assess whether the perceived harm of vaping relative to smoking is associated with subsequent changes in vaping and smoking behaviors in this population.

Methods

Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective cohort study. Longitudinal associations were assessed between the perceived harm of vaping relative to smoking at baseline (approximately 24 years old; Nov’15–Aug’17) and the following smoking/vaping outcomes at follow-up (approximately 30 years old; May–Oct’22): (1) stopping smoking, (2) initiation of ever smoking and/or vaping, and (3) uptake of past 30-day smoking and/or vaping. Multinomial logistic regressions were used, adjusting for sociodemographic factors.

Results

Among young adults who smoked but did not vape at baseline (n = 687), the perception that vaping is less harmful than smoking (vs. equally/more harmful, or don’t know) was associated with stopping smoking and now vaping at follow-up (adjusted Relative Risk Ratio (aRRR)=1.69, 95%CI = 1.02 to 2.81, p = .04). Initiation of ever smoking/vaping, or uptake of past 30-day smoking/vaping, were not common during the study period and there was little evidence that these outcomes were associated with relative vaping harm perceptions at baseline.

Conclusions

Among young adults who smoke, perceiving vaping as less harmful than smoking was associated with switching from smoking to vaping six years later. Few young adults who did not smoke or vape initiated these behaviors during the study period.

Implications

This is the first study in England to find that young adults who smoked and who accurately perceived vaping as less harmful than smoking were more likely to switch to vaping 6 years later. This is consistent with prior studies among adults and highlights the need for interventions to improve the pervasive misperceptions about vaping that are currently observed among young adults who smoke.
A first-in-human study of JNJ-70218902, a bispecific T-cell-redirecting antibody against TMEFF2 in metastatic castration-resistant prostate cancer
Authors: Calvo Emiliano , Doger Bernard , Carles Joan , Peer Avivit , Sarid David , Eigl Bernhard J , Avadhani Anjali , Yao David , Lin Vincent , Wu Shujian , Jaiprasart Pharavee , Loffredo John , Tamegnon Monelle , Xu Weichun , Xie Hong , Hansen Aaron R
Published: January 2025

Background

Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis, necessitating the investigation of novel treatments and targets. This study evaluated JNJ-70218902 (JNJ-902), a T-cell redirector targeting transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains 2 (TMEFF2) and cluster of differentiation 3, in mCRPC.

Patients and methods

Patients who had measurable/evaluable mCRPC after at least one novel androgen receptor–targeted therapy or chemotherapy were eligible. Participants received subcutaneous JNJ-902 0.3, 1.0, 1.5, 3.0, or 6.0 mg once weekly (QW) or 2.0, 3.0, 4.0, or 6.0 mg biweekly (Q2W). Study objectives included assessment of safety, pharmacokinetics, immunogenicity, and preliminary efficacy.

Results

Eighty-two participants were enrolled to receive at least one dose of JNJ-902 (QW; n = 38; Q2W; n = 44). Median duration of treatment was 1.91 (0.0-19.4) months across dosing groups. All participants experienced at least one treatment-emergent adverse event (TEAE) and 76 (92.7%) experienced treatment-related TEAEs. Fourteen participants (17.1%) experienced a TEAE that led to study discontinuation, of which 3 (3.7%) were related to JNJ-902. Dose-limiting toxicities were observed in 2 participants (2.4%). Five participants (15.2%) with measurable disease had a confirmed partial response and 10 participants (12.2%) had ≥50% decrease from baseline prostate-specific antigen levels. Clinical activity was not dose related and no clear exposure-response relationship was observed.

Conclusions

In this study, dose escalation was limited by emerging dose-limiting toxicities. Although a recommended phase II dose was not determined, findings indicate TMEFF2 to be a potential target in mCRPC that warrants further investigation.
Steroid-refractory immune mediated hepatitis managed with budesonide in patients with metastatic melanoma: proof of concept and literature review
Authors: Kankaria Roma A , Johnson Douglas B
Published: January 2025

Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma. However, some patients develop ICI-associated toxicities like hepatitis (ie, immune-mediated hepatitis; IMH). Although these toxicities usually resolve with steroids, steroid-refractory events may occur, which may be a major source of morbidity and mortality without obviously defined treatment algorithms. Herein, we present 2 patients with metastatic melanoma who had IMH that was steroid-refractory and only partially mycophenolate-responsive, but fully resolved with budesonide. The case suggests that budesonide is a potential option to treat IMH that is refractory to standard treatments, but further investigation in a larger series is needed to identify the most optimal setting for budesonide use.
Exploring female genital self-image: a psychological and sociocultural perspective
Authors: Mohammed Ghada Farouk , Al-Dhubaibi Mohammed Saleh , AbdElneam Ahmed Ibrahim , Bahaj Saleh Salem , Al-Dhubaibi Ahmed Mohammed
Published: January 2025

Introduction

Female genital self-image (FGSI) refers to one’s perception of the external and internal appearance of female genitalia. FGSI is a multidisciplinary research area influenced by psychological, sociocultural, and clinical factors, influencing sexual satisfaction, desire, self-perception, and partner perception.

Objectives

The review aims to improve doctors’ understanding of genital self-image by incorporating psychological and sociocultural perspectives, thereby promoting a comprehensive and holistic approach.

Methods

A comprehensive search technique was used to obtain research papers from the following databases: PubMed (MEDLINE), Scopus, and Web of Science. Google Scholar was also manually searched. The search results were imported into Rayyan reference management and assessed using the established inclusion criteria. The quality of the articles was assessed using the appropriate JBI checklist (ie, according to the study design), and the JBI grades of recommendation were used to grade the evidence.

Results

Psychological theories like self-schema, body image, and female personal harm view offer insights into FGSI, but none provide a comprehensive explanation of subjective body image dissatisfaction.

Research indicates women often experience anxiety about discussing genitalia and accepting sexual attention, but limited literature on negative self-image causes. Interventions include sexological counseling, therapy, educational programs, and public statements. Understanding FGSI is crucial for effective pre-surgical counseling, incorporating online portrayals, attitudes, and reasons for cosmetic surgery, and addressing psychological and sociocultural factors.

This text delves into the intricate psychological and sociocultural factors that shape FGSI, presenting a model of intra- and interpersonal dynamics. The link between FGSI and negativism is unclear, but it is linked to women’s confidence and subjectivity, with positive self-perceptions predicting higher sexual satisfaction and mental health.

Conclusions

FGSI has an imperative role in healthy female sexual function. The study suggests an interdisciplinary approach to managing FGSI, integrating psychological and sociological approaches, to better understand women’s anatomy and address gendered distress.
Effects of milk replacer composition on growth and development of beef × dairy crossbred calves
Authors: Carter Rachel E , Emenheiser Joseph C , Zinn Steven A , Govoni Kristen E , Felix Tara L , Reed Sarah A
Published: January 2025

The production of crossbred beef × dairy (B × D) calves is increasing; however, evaluation of pre-weaning feeding strategies for B × D calves is limited. We hypothesized that both male and female B × D calves fed added fat and protein through milk replacer would have increased muscle growth, muscle fiber cross-sectional area, average daily gain, BW, and morphometric measurements. We also hypothesized that calves fed the additional fat and protein milk replacer would have upregulation of regulatory genes involved in muscle hypertrophy. SimAngus × Holstein calves (n = 42) were assigned to one of two milk replacers: 30.0% crude protein (CP), 32% crude fat (CF) milk replacer (HPHF, n = 11 males, 11 females), or 22% CP, 20% CF milk replacer (CON, n = 10 males, 10 females) from 0 to 8 wk of age. B × D calves were weighed at birth and weekly thereafter. At week 2 and 8, longissimus muscle biopsies were collected for muscle fiber cross-sectional area (CSA) or gene expression analysis. Ultrasounds were performed at 4 and 8 wk of age to quantify ribeye area (REA), and backfat and rump fat thickness. Morphometric measurements, BW, CSA, and ultrasound data were analyzed with PROC MIXED with animal as the subject and fixed effects of milk replacer, age, sex, and their interactions. Gene expression data were analyzed in R Studio. Calves that consumed the HPHF milk replacer were heavier than calves consuming the CON milk replacer (HPHF: 70.7 ± 0.39 kg; CON: 68.5 ± 0.41 kg; P < 0.01). At 8 wk of age, HPHF calves tended to have 14% larger muscle fiber CSA than CON calves (P = 0.06). No differences due to diet were observed for REA or fat thickness (P ≥ 0.38). Expression of MyoD tended to be 34% greater in CON females than HPHF females at 2 wk (P = 0.06), but at 8 wk, HPHF females tended to express 39% more MyoD than CON females (P = 0.09). Myogenin expression was 3% greater in CON calves than HPHF calves at 2 wk (P = 0.02), and CON females tended to express 52% more IGF-1 than HPHF females (P = 0.07). Feeding a milk replacer with a protein and fat content similar to beef cow milk improves B × D calf growth compared with a conventional milk replacer with less protein and fat. Improvements in early growth may improve B × D carcass quality and quantity, with the potential to increase return to the producer.
Genome Sequence Resource of Neopestalotiopsis cubana, a Pathogen to Guava
Authors: Xu Peidong , Huo Siyan , Qin Chunxiu , Justice Norvienyeku , Chen Di , Miao Weiguo , Liu Wenbo
Published: January 2025

The pestalotiopsis-like taxa, inclusive of Pseudopestalotiopsis, Pestalotiopsis, and Neopestalotiopsis, constitute a well-recognized fungal family. Recently, species within the Neopestalotiopsis genus have been identified as plant pathogens affecting crops and fruits. However, there is currently a paucity of reference genome data for Neopestalotiopsis cubana in germplasm resource evaluation research. In this study, we present a chromosome-level reference genome of N. cubana, constructed using DNBSEQ platform and PacBio RS II platform. The assembled genome spans a total length of 50,399,148 bp, with a GC content of 50.17%. Furthermore, the reference genome contains annotations for a total of 15,709 protein-coding genes and 657 non-coding RNAs (ncRNAs). The availability of this genome sequence data enhances our understanding of the lifestyle strategy and pathogenesis of Neopestalotiopsis species. Our study significantly contributes to the species richness of Neopestalotiopsis spp. and provides a foundation for future research.
Development and Validation of an RPA Assay for Detecting Xanthomonas citri subsp. citri A, A* and Aw and X. fuscans subsp. aurantifolii B and C
Authors: Hill Raquel S. , Pal Archana , Dewdney Megan , Cano Liliana , Harmon Carrie Lapaire
Published: January 2025

Citrus canker, caused by Xanthomonas citri subsp. citri (Xcc) and X. fuscans subsp. aurantifolii (Xfa), is a destructive disease of citrus. It is sparsely distributed in the Caribbean, and effective biosecurity measures, including accurate pathogen detection systems, are essential to prevent further spread. Current in-field screening methods rely on visual symptom identification and serological tools like Agdia’s X. axonopodis subsp. citri (Xac) ImmunoStrips®. However, they failed to detect the Aw and C pathotypes in this study. Nucleic acid amplification is the gold standard for confirming detection but is resource-intensive and less accessible in Caribbean plant diagnostic laboratories and regulatory services. To address this, a rapid recombinase polymerase amplification (RPA) assay was developed using a portable fluorometer and primers designed to detect all canker-causing pathotypes. The RPA assay accurately detected all five citrus canker pathotypes and was selective against Xanthomonas euvesicatoria pv. citrumelonis, the fastidious citrus greening bacteria Candidatus Liberibacter asiaticus, and the xylem-limited bacterial pathogen Xylella fastidiosa. However, X. perforans, X. citri pv. glycines, and X. citri pv. phaseoli, pathogens unrelated to citrus and unlikely to be present in citrus, were detected. Real-time detection was completed in 25 minutes with high sensitivity levels of 0.001 pg/µl (Xcc A), 0.1 pg/µl (Xfa B), and 1 pg/µl (Xfa C) of DNA. This RPA assay offers a robust, in-field detection method, combining molecular sensitivity and specificity with the field-friendly simplicity of crude extraction and single-tube reactions.
Differential transcriptomic profiling of lipid metabolism and collagen remodeling in fast‐ and slow‐twitch skeletal muscles in aging
Authors: Liu Yujia , Xia Guofang , Zhu Simeng , Shi Yifan , Huang Xueping , Wu Jin , Xu Congfeng , Du Ailian
Published: January 2025

Skeletal muscle function gradually declines with aging, presenting substantial health and societal challenges. Comparative analysis of how aging affects fast‐ and slow‐twitch muscles remains lacking. We utilized 20‐month‐old mice to reveal the aging effects on muscle structure and fiber composition, followed by bulk RNA sequencing for fast‐ and slow‐twitch muscles and integration with human single‐cell RNA sequencing dataset providing a comparative analysis across species. In mouse slow‐twitch muscles, aging induced a switch from fast to slow fibers and distinctively altered lipid metabolism in ceramide and triglyceride, with the upregulation of regulatory genes Gk and Ppargc1a also observed in human slow fibers. Additionally, both types of muscles exhibited common collagen deposition and fibrosis, possibly due to the imbalance between collagen synthesis and degradation. The extracellular matrix gene changes substantially overlapped between mice and humans in aging, yet also highlighted clear differences. This integrative analysis provides further understanding of aged fast‐ and slow‐twitch muscles and offers new insights into the molecular changes in aging.
Implementing Early Kangaroo Mother Care
Authors: Hull William L. , Gongora Priscilla
Published: January 2025

Background:

Kangaroo Mother Care (KMC) has numerous maternal and neonatal benefits. KMC is often overlooked as a vital neonatal stabilization tool. Factors that influence the initiation of KMC by bedside staff include a lack of specific education on KMC, low confidence, and hesitancy due to the infant’s clinical illness. Parents can pick up on the staff’s hesitancy and may not realize they can request to hold their baby.

Purpose:

The purpose of this quality improvement (QI) project was to decrease the time to the first opportunity for eligible neonates for KMC within the first 24 hours.

Method:

The location of the project was in a 35-bed NICU, private, and semi-private room mix. The project leads revised, updated, and received facility approval for a KMC policy. Parent education was provided via a bi-lingual pamphlet and video. KMC Champions were utilized to increase early KMC rates.

Results:

During the 12th week of the 3-month monitoring period, all eligible infant dyads were held within the first 24 hours, achieving the goal of 100%. Offering various educational opportunities led to enthusiastic staff participation. Additionally, reinforcement of importance and exposure to KMC led to an increase in staff buy-in.

Implications for Practice and Research:

Increasing staff knowledge on the importance of KMC may lead to increased confidence and competence, and a potential decrease in apprehension in offering and performing KMC. Further research needs to explore and define causes of staff hesitancy that lead to a decrease in KMC opportunities.
Effects of dynamic resistance training on postexercise hypotension and its mechanisms in hypertensive men
Authors: Fecchio Rafael Yokoyama , Sousa Julio C.S. de , Oliveira-Silva Laura , Silva Junior Natan D. da , Pio-Abreu Andrea , Silva Giovânio V. da , Drager Luciano F. , Low David A. , Forjaz Cláudia L.M.
Published: January 2025

Background

A possible chronic effect of exercise training is the attenuation of the acute decrease in blood pressure (BP) observed after the execution of a session of exercise [i.e. called postexercise hypotension (PEH)]. However, there are few empirical data regarding this issue, and the possible mechanisms involved in this blunted response have not been studied.

Aim

The study aimed to evaluate the effects of dynamic resistance training (DRT) on PEH and its systemic, vascular, and autonomic mechanisms.

Methods

Data from 16 middle-aged treated hypertensive men who underwent DRT (eight exercises, 50% of 1RM, three sets until moderate fatigue) three times/week for 10 weeks were analyzed. Before and after the training period, the participants underwent an experimental session in which BP (auscultation), systemic hemodynamics (CO2 rebreathing), vascular function (duplex ultrasound), and cardiovascular autonomic modulation (spectral analysis of heart rate and BP variabilities) were assessed before and after a session of DRT.

Results

DRT reduced preexercise systolic BP and mitigated the systolic PEH that occurred before but not after the training period (P = 0.017). DRT did not change the diastolic PEH that occurred with similar magnitude before and after the training period (P = 0.024). DRT did not change the PEH mechanisms, except for cardiac sympathovagal balance that increased significantly more after the session of DRT conducted in the posttraining evaluation (P = 0.017).

Conclusion

In medicated hypertensive men, 10 weeks of DRT decreased preexercise systolic BP, abolished systolic PEH, and induced a greater increase in postdynamic resistance exercise sympathovagal balance.
Validation of the Microlife BP3T01-1B blood pressure monitoring device in adults and adolescents according to the ISO 81060-2:2018 protocol
Authors: Botta Beate , Bramlage Carsten , Hachaturyan Violetta , Jost Lena , Bramlage Peter
Published: January 2025

Background

Accurate measurement of blood pressure (BP) is crucial for the diagnosis and ongoing management of hypertension. Only devices that have been validated using an established protocol should be used to measure BP. The aim of this study was to validate the Microlife BP3T01-1B, an automated upper-arm BP measuring device, according to the DIN EN ISO 81060-2:2018-11 (ANSI/AAMI/ISO 81060-2:2018) standard protocol.

Methods

BP measurements were performed in 85 adults and adolescents (age range: 13–86 years) using the same-arm sequential method of the DIN EN ISO 81060-2:2018-11 protocol, alternating between the test device and a reference mercury sphygmomanometer.

Results

A total of 255 valid comparisons were available for the analysis of criterion 1. The mean ± SD difference between the test device and the reference device values was −2.56 ± 7.53 mmHg for SBP and −3.10 ± 5.65 mmHg for DBP. The mean differences met the pass criterion of less than or equal to ±5 mmHg and the SD values met the pass criterion of ≤8 mmHg. All 85 participants were included in the analysis of criterion 2. The mean ± SD intraindividual difference between the test and reference devices was −2.56 ± 6.15 mmHg for SBP and −3.10 ± 4.85 mmHg for DBP. Both were within the required pass range of SD ≤6.43 mmHg for SBP and SD ≤6.20 mmHg for DBP.

Conclusion

The Microlife BP3T01-1B BP monitoring device fulfilled the criteria of the DIN EN ISO 81060-2:2018-11 (ANSI/AAMI/ISO 81060-2:2018) protocol in a general population and can be recommended for the measurement of BP in adults and adolescents.
The Goal Processing Scale: cognitive correlates of an ecologically valid measure of executive functioning in mild traumatic brain injury
Authors: Tessier Jillian M. , Kryza-Lacombe Maria , Santiago Rachel , Abrams Gary , Chen Anthony , Rome Scott , Novakovic-Agopian Tatjana
Published: January 2025

The objective of this study was to further validate the Goal Processing Scale (GPS), an ecologically valid functional assessment of executive functioning requiring planning and executing a complex goal. Veterans (N = 69, mean age = 44.5 years) with a history of chronic mild traumatic brain injury and self-reported cognitive difficulties completed the GPS and neuropsychological measures of working memory, sustained attention, mental flexibility, inhibition, and memory during participation in one of three studies. Associations between overall GPS performance and composite neuropsychological measures of attention/executive functioning and memory were significant and medium-to-large in magnitude. Associations of similar magnitude also emerged between subcomponents of the GPS (e.g. self-monitoring, attentional switching, attention maintenance) and neuropsychological subdomains (e.g. mental flexibility, inhibition, working memory). Results suggest that the GPS facilitates structured assessment of goal-directed performance requiring integration of multiple executive functioning subdomains. The GPS may be valuable in assessing and predicting real-world functional difficulties not captured by traditional neuropsychological assessment.
Preliminary validation of CCRacer serious game for assessing executive function after acquired brain injury
Authors: Vidacic Maja , Mlinaric Lesnik Vesna , Politakis Vida Ana , Podlesek Anja , Cizman Staba Ursa
Published: January 2025

Acquired brain injuries can profoundly impact executive functioning, yet traditional neuropsychological assessments often have limitations, such as being time-intensive, lacking ecological validity, or failing to engage patients effectively. To address these challenges, CCRacer, a serious game, was developed as a novel tool for assessing executive functions in clinical populations. This study evaluated the convergent and discriminant validity of CCRacer by applying it alongside established neuropsychological tests to a sample of 78 participants with acquired brain injury. Results revealed varying levels of convergent validity across tasks, with stronger correlations for measures of working memory (0.28–0.51) and planning (−0.46 to 0.34) and weaker correlations for inhibitory control (0.22). These findings suggest that CCRacer has the potential as a complementary tool in the neuropsychological assessment of an acquired brain injury, combining engaging and ecologically valid testing with the possibility of future use in cognitive training.
Test–retest reliability and responsiveness of an adapted version of the ABILHAND questionnaire to assess performance in bimanual daily life activities in stroke patients in sub-Saharan Africa
Authors: Sogbossi Emmanuel Segnon , Niama-Natta Didier , Dossa Eric , Bani Faouziath , Niyomwungere Ernest , Tiamiyou Rafiath , Alagnidé Etienne , Kpadonou Toussaint , Batcho Charles Sebiyo
Published: January 2025

The ABILHAND is a widely used questionnaire assessing bimanual daily life activities in adults with stroke. A recently modified version tailored for the sub-Saharan African population (ABILHAND-Stroke Benin) has been created. This study aimed to investigate its test–retest reliability and responsiveness. The study included 132 adults with stroke with a mean (SD) age = 54.6 (11.2) years and 40% women. The mean (SD) time since stroke was 15.2 (12) months for the subsample (n = 51) included in the reliability analysis and 1 (0.6) month for the subsample (n = 81) of the responsiveness analysis. Participants were assessed within a week interval with the ABILHAND-Stroke Benin questionnaire for the reliability analysis. As for the responsiveness analysis, they were additionally assessed with the ACTIVLIM-Stroke questionnaire, the Box and Block Test (BBT), and the Stroke Impairment Assessment Set, at baseline (T1), 2-month later (T2), and on average of 1.5 (0.5) years after stroke (T3). The ABILHAND-Stroke Benin questionnaire showed an excellent test–retest reliability (intraclass correlation coefficient = 0.98, P < 0.001, minimal detectable change = 10.3%). Regarding the responsiveness analysis, participants showed a larger improvement during the acute phase (T1–T2) compared with the chronic phase (T2–T3). Changes with the ABILHAND-Stroke Benin questionnaire were significantly correlated with changes with the other outcome measures (correlations ranged from 0.36 to 0.70, P < 0.05) except with the BBT less affected hand. The ABILHAND-Stroke Benin questionnaire demonstrates an excellent test–retest reliability and was responsive to changes in adults with stroke.
The future approach for the management of acute bacterial skin and skin structure infections
Authors: Tiseo Giusy , Falcone Marco
Published: January 2025

Purpose of review

To discuss the new available options for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and how to implement in the clinical practice innovative approaches for their management.

Recent findings

The availability of long-acting antibiotics, including dalbavancin and oritavancin, changed the approach to patients with ABSSSI. Direct discharge from the emergency department and early discharge from the hospital should be considered in patients with ABSSSI. Despite limited data about different bactericidal properties, the choice between dalbavancin and oritavacin is usually based on patients’ characteristics and comorbidities. Delafloxacin and omadacycline are other options and have the advantage to be available for both intravenous and oral formulations, allowing a sequential therapy and switch from intravenous to oral treatment in clinically stable patients. Further studies should elucidate the profile of patients who may beneficiate from these drugs.

Early discharge from the hospital should be considered in patients with ABSSSI at a high risk of methicillin-resistant Staphylococcus aureus and in vulnerable patients for which hospitalization may have detrimental consequences. In elderly individuals, patients with diabetes mellitus, oncological people who need for continuing their healthcare pathway, this approach may reduce complications and costs related to hospitalization.
Genome resource of chitin-degrading bacterium Brevibacillus formosus YSY-2.2
Authors: TRAN Dinh Minh , Huynh To Uyen , Nguyen Dinh Sy , Pentekhina Iuliia
Published: January 2025

This work announced the whole genome resource of Brevibacillus formosus YSY-2.2, a chitin-degrading bacterium possessing antifungal activity and producing phytohormones previously isolated from Yok Don National Park, Vietnam. The genome contained 6,191,946 bp with 47.3% GC content, 5,791 CDSs, 116 RNAs, 101 CAZymes, and 13 BGCs. It showed the highest values of both ANI (95.07%) and dDDH (72.6%) to those of B. formosus NF2 (CP018145). The genome sequence will provide useful information for further studies on the functional gene and application of B. formosus YSY-2.2.
Computational Modeling of Ternary Complex Formation and Targeted Protein Degradation Mediated by Molecular Glues
Authors: Izaguirre Jesus A , Wu Yujie , McDargh Zachary , Palpant Timothy , Razavi Asghar M , Trovato Fabio , Koh Cheryl , Xu Huafeng
Published: January 2025

We introduce GlueMap, a computational toolkit to discover and optimize molecular glues. GlueMap integrates structural and pharmacodynamic modeling, molecular dynamics (MD), and machine learning (ML) for modeling targeted protein degradation (TPD) mediated by molecular glues (MGs). GlueMap accurately models the structural ensemble of ternary complexes, predicts their thermodynamic stabilities, and evaluates downstream effects such as ubiquitination and degradation efficiency. We validated GlueMap’s capabilities through two case studies: CRBN-dependent degradation of GSPT1 and DDB1-dependent degradation of CDK12. For CRBN-GSPT1, GlueMap successfully recovered known molecular glue degraders and identified novel candidates through prospective virtual screening, leveraging ternary complexes derived from extensive MD simulation. In the DDB1-CDK12 system, we observed strong correlations between ternary complex stability, quantified by binding free energy calculations, and degradation efficiency, though notable exceptions highlighted the importance of considering structural dynamics of the ternary complex in the context of the cullin ring ligase. Through a supervised variational autoencoder (VAE) model combined with attention-based regression, GlueMap demonstrates high accuracy in predicting degradation potency from structural features. By integrating structural, thermodynamic, and ubiquitination metrics, GlueMap provides a multi-criteria approach to rational MG design, distinguishing it from traditional screening methods that rely primarily on docking scores. These results illustrate that GlueMap may provide mechanistic insights and accelerate molecular glue discovery and optimization across diverse protein targets.
TRANSCRIPTOMIC ANALYSIS OF THE RELATIONSHIP BETWEEN PANCREATIC DUCTAL ADENOCARCINOMA STROMAL SUBTYPES AND NEURAL INVASION
Authors: Yildizhan Saliha E. , Demir Ihsan E. , Sever Elif Arik , Zeybek Didem Karakas , Sezerman O. Ugur , Ceyhan Güralp O.
Published: January 2025

We investigated the association between pancreatic ductal adenocarcinoma (PDAC) subtypes and neural invasion (NI) status in order to assess what factors influence the inter-tumor heterogeneity of NI. We built single-sample classifiers for prominent subtype schemes using multiple approaches. We predicted the subtype labels of samples with known NI status using the classifiers based on pairwise gene expression comparisons, which were consistently the best-performing models. These classifiers were made available in a Shiny app (https://salihaey.shinyapps.io/pcsubtypes/). Stromal subtypes were found to be most significantly associated with NI, with activated stroma being enriched in neuro-invasive samples. We compared the results of differential expression and gene set enrichment analyses between NI and stromal subtypes from both bulk and single-cell RNA-seq data, which revealed a prominent role of myCAFs and common signatures between activated stroma and NI (e.g., ECM remodeling and TGFβ signaling) as well as signatures that changed in divergent directions for activated stroma and NI (e.g., iCAF markers). Our study presents support for the clinical implications of PDAC stromal subtypes by revealing their association with NI incidence, while providing biological insights into the interactions between diverse genetic programs that influence NI emergence.
Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer
Authors: Galloway A. , Hofstede B. Ter , Walsh Alex J.
Published: January 2025

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted treatments currently available. TNBC cells participate in metabolic symbiosis, a process that optimizes tumor growth by balancing metabolic processes between glycolysis and oxidative phosphorylation through increased activity by the enzyme lactate dehydrogenase B (LDHB). Metabolic symbiosis allows oxidative cancer cells to function at a similar rate as glycolytic cancer cells, increasing overall metabolic activity and proliferation. Here, fluorescence lifetime imaging microscopy (FLIM) is used to analyze the metabolism of TNBC cells with inhibition of LDHB using a multiphoton microscope to measure the fluorescent lifetimes of two metabolic coenzymes, NAD(P)H and FAD. LDHB is inhibited via an indole derivative known as AXKO-0046 in varying concentrations. Understanding how TNBC cell metabolism changes due to LDHB inhibition will provide further insight into metabolic symbiosis and potential new TNBC treatment options.
Interpretable adenylation domain specificity prediction using protein language models
Authors: Adduri Abhinav K. , McNutt Andrew T. , Ellington Caleb N. , Suraparaju Krish , Fang Nan , Yan Donghui , Krummenacher Benjamin , Li Sitong , Bodden Camilla , Xing Eric P. , Behsaz Bahar , Koes David , Mohimani Hosein
Published: January 2025

Natural products have long been a rich source of diverse and clinically effective drug candidates. Non-ribosomal peptides (NRPs), polyketides (PKs), and NRP-PK hybrids are three classes of natural products that display a broad range of bioactivities, including antibiotic, antifungal, anticancer, and immunosuppressant activities. However, discovering these compounds through traditional bioactivity-guided techniques is costly and time-consuming, often resulting in the rediscovery of known molecules. Consequently, genome mining has emerged as a high-throughput strategy to screen hundreds of thousands of microbial genomes to identify their potential to produce novel natural products. Adenylation domains play a key role in the biosynthesis of NRPs and NRP-PKs by recruiting substrates to incrementally build the final structure. We propose MASPR, a machine learning method that leverages protein language models for accurate and interpretable predictions of A-domain substrate specificities. MASPR demonstrates superior accuracy and generalization over existing methods and is capable of predicting substrates not present in its training data, or zero-shot classification. We use MASPR to develop Seq2Hybrid, an efficient algorithm to predict the structure of hybrid NRP-PK natural products from microbial genomes. Using Seq2Hybrid, we propose putative biosynthetic gene clusters for the orphan natural products Octaminomycin A, Dityromycin, SW-163B, and JBIR-39.
Deciphering Features of Metalloprotease Cleavage Targets Using Protein Structure Prediction
Authors: Chung Dae sun , Park Jongkeun , Choi Won Jong , Seong Do Young , Hong Dongwan
Published: January 2025

Metalloproteases are a class of enzymes that utilize metal ions within their active sites to catalyze the hydrolysis of peptide bonds in proteins. Among these, ADAM10 (A Disintegrin and Metalloproteinase 10), a member of the ADAM family, plays a crucial role in mediating intracellular signaling by cleaving specific substrates, thereby influencing a variety of physiological and pathological processes. The mechanisms underlying the activity of ADAM10 present significant opportunities for the development of novel therapeutic strategies aimed at disease intervention. However, the information available to identify the substrate and cleavage sites of ADAM10 is still insufficient. Therefore, it is essential to identify and classify the features of substrates and to elucidate cleavage sites through experimental approaches. However, these studies across numerous proteins present significant challenges.

To address the promise of these investigations, we developed a model that leverages protein structure prediction to decipher substrate features, classify substrates, and predict cleavage sites. Through the analysis of predicted protein complexes between ADAM10 and its substrates using PDB files, we evaluated protein-protein interaction (PPI) data, the structural information of cleavage sites, and the spatial relationships between the cleavage sites and metal ions.

Finally, we present a computational model that effectively classifies substrates and accurately predicts cleavage sites in this study. Our study demonstrates the potential for application not only to ADAM10 but also to other members of the ADAM family and, more broadly, to additional metalloproteases. By leveraging computed protein structural information, our approach offers a novel perspective for substrate classification.
Testing for divergence in a plant symbiont across two natural environmental gradients
Authors: Chang Chang-Yu , Topping-Brown Terrence , Rud Jazmine L. , Calvert McCall B. , Bencosme Gerardo , Robinson Linda J. , Wood Corlett W.
Published: January 2025

Microbes dominate the biological diversity found in natural landscapes. Yet, studies of microbial population differentiation across environmental gradients have been surprisingly scarce. In this study, we tested for phenotypic and genetic divergence in rhizobia bacteria (genusSinorhizobium) associated with the legumeMedicago lupulinaacross two environmental gradients: an elevation gradient in the Appalachian Mountains and an urbanization gradient in Philadelphia. Common garden experiments inMedicago sativarevealed that symbiotic traits differed significantly between high- and low-elevation rhizobia populations, but not between urban and suburban populations. Nitrogen supplementation erased the trait differences between low- and high-elevation populations, consistent with the hypothesis that these differences arise from the nitrogen that rhizobia provide. In contrast to symbiotic traits, free-living growth traits showed minimal differentiation across gradients. To test the hypothesis that greater gene flow constrains phenotypic divergence in the urbanization gradient, we compared the strength of isolation by distance in the core and accessory genomes across the two gradients. Contrary to our expectation, isolation by distance was significantly stronger in the urbanization gradient in both the core and accessory genomes. These results suggest that our focal elevation gradient imposed stronger divergent selection on rhizobia than our focal urbanization gradient. Together, this study highlights the need for a holistic understanding of microbial evolution with regard to the traits across life stages, molecular evolution across genomic levels, and evolutionary processes across environmental gradients.
Non-invasive eDNA reveals the ecological and genetic status of the Western Capercaillie (Tetrao urogallus aquitanicus) in the Eastern Pyrenees
Authors: Buso Pauline , Paris Céleste , Canal Manon , Tassaint Morgane , Daniello Sylvain , Gibert Anaïs , Palme Rupert , Macho-Maschler Sabine , Llauro Christel , Jacob Gwenaël , Delorme-Hinoux Valérie , Bertrand Joris A. M. , Rey Olivier
Published: January 2025

The Anthropocene era is expected to bring about significant biodiversity and habitat loss for many species. These geographical changes, whether driven by climatic or anthropogenic factors, are likely to lead to considerable alterations in population size, structure, and genetic diversity. Monitoring natural populations is therefore essential to assess these impacts and enable informed conservation strategies for threatened species. The Western Capercaillie (Tetrao urogallus, L. 1758) has a widespread distribution in Boreal forests but fragmented in mountainous regions of the Palearctic, and is locally threatened by climate change, habitat destruction, and human disturbance. Our study focused on the eastern population of the subspeciesT. u. aquitanicus,which is endemic to the Pyrenees mountains. The monitoring of this population has relied on direct methods and no genetic information had been generated so far. Here, we conducted a molecular study based on 229 non-invasive samples (faeces) to assess the ecological and genetic status of local population in the Catalan Nature Reserves of the Pyrénées-Orientales (Occitanie region, France). At the individual level, we assessed multi-locus genotypes, sexing, levels of inbreeding, stress level (Fecal Corticosterone Metabolites; FCMs) and diet. At the population level, we assessed sex ratio, genetic diversity and structure. We identified 62 individuals with a balanced sex ratio and estimated a census size of 79 individuals [95%CI = 68–92] in the study area. Genetic diversity was low and suggested significant inbreeding levels. FCM levels were lower in birds of areas considered as disturbed by humans and metabarcoding approach indicated a geographical structuring of diet composition at the reserve scale, with individuals exhibiting feeding behavior upon only one or few plant species. Our estimate of population census size was higher with figures assessed from lek counts, and the genetic approach provided additional insights on this population, establishing a baseline that will support conservation management plans.
Periodic Obstacles Regulate Membrane Tension Propagation to Enable Localized Mechanotransduction
Authors: Català-Castro Frederic , Bonilla-Quintana Mayte , Sanfeliu-Cerdán Neus , Rangamani Padmini , Krieg Michael
Published: January 2025

Forces applied to cellular membranes lead to transient membrane tension gradients. The manner in which membrane tension propagates away from the stimulus into the membrane reservoir has emerged as a key property in cellular adaptation, mechanotransduction, and thus organismal physiology. However, it remains unclear whether tension propagation in membranes is actively regulated or is a passive property and how it depends on the cell type. Here, we combined membrane nanorheology with time-shared optical traps and mathematical modeling to investigate plasma membrane tension propagation in culturedCaenorhabditis elegansmechanosensory neurons using a dual tether extrusion assay. Our results showed that, surprisingly, the propagation of tension was restricted to 30 μm in the neurites and traveled quickly, at speeds exceeding 120 μm/s. Although membrane lipid properties had minimal impact, tension propagation strongly relied on the intact actin and microtubule cytoskeleton. In particular, the organization of theα/β-spectrin network and the MEC-2 stomatin condensates acted as barriers, limiting the spread of tension. A biophysical model for tension propagation suggests that obstacle density and arrangement play a key role in controlling the propagation of mechanical information. Our findings suggest that restricting membrane tension propagation in space and time enables precise localized signaling. This localization may facilitate the recruitment of mechanosensitive ion channels and allow a single neuron to process mechanical signals in multiple distinct domains, thus expanding its computational capacity.
New insights into thecis-regulation of theCFTRgene in pancreatic cells
Authors: Blotas Clara , Le Nabec Anaïs , Collobert Mégane , Bulcaen Mattijs , Carlon Marianne S. , Férec Claude , Moisan Stéphanie
Published: January 2025

Background

Spatial organization of the genome is fundamental for ensuring accurate gene expression. This process depends on the communication between gene promoters and distalcis-regulatory elements (CREs), which together make up 8% of the human genome and are supported by the chromatin structure. It is estimated that over 90% of disease-associated variants are located in the non-coding region of the genome and may affect CRE. For thecystic fibrosis transmembrane conductance regulator(CFTR)gene, a complete understanding of tissue-specificCFTRexpression and regulation is missing, in particular in the pancreas. Mechanistic insights into tissue-specific expression may provide clarity on the clinical heterogeneity observed in Cystic Fibrosis and CFTR-related disorders.

Methods

To understand the role of 3D chromatin architecture in establishing tissue-specific expression of theCFTRgene, we mapped chromatin interactions via circular chromosome conformation capture (4C) and epigenomic regulation through H3K27ac and DNase Hypersensitive site I (DHS) in Capan-1 pancreatic cells. Candidate regulatory regions are validated by luciferase reporter assay and CRISPR-knock out.

Results

We identified active regulatory regions not only around theCFTRgene but also outside the topologically associating domain (TAD). By performing functional assays, we validated our targets and revealed a cooperative effect of the −44 kb, −35 kb, +15.6 kb and 37.7 kb regions, which share common predicted transcription factor (TF) motifs. Comparative 3D genomic analysis and functional assays using the Caco-2 intestinal cell line revealed the presence of tissue-specific CREs.

Conclusion

By studying the chromatin architecture of theCFTRlocus in Capan-1 cells, we demonstrated the involvement of multiple CREs upstream and downstream of theCFTRgene. We also extend our analysis to compare intestinal and pancreatic cells and provide information on the tissue-specificity of CRE. These findings highlight the importance of expanding the search for causative variants beyond the gene coding sequence but also by considering the tissue-specific 3D genome.
Atomic Force Microscopy reveals differences in mechanical properties linked to cortical structure in mouse and human oocytes
Authors: Bulteau Rose , Barbier Lucie , Lamour Guillaume , Lemseffer Yassir , Verlhac Marie-Hélène , Tessandier Nicolas , Labrune Elsa , Lenz Martin , Terret Marie-Emilie , Campillo Clément
Published: January 2025

Cell mechanical properties regulate biological processes such as oocyte development. Cortical tension is regulated via actomyosin cortex remodeling to ensure optimal oocyte quality. However, the evolution of other mechanical parameters and their relationship with cortex structure remain poorly understood in mammalian oocytes. In this work, we propose a methodology combining multiple mechanical parameters measured through Atomic Force Microscopy to investigate the relationship between oocyte mechanical properties and cortex organization. By studying mouse oocytes at various stages of development, along with engineered ones with specific cortex organization, we demonstrate that a thin actin cortex corresponds to stiff oocytes while a thick one is associated with softer oocytes. We further reveal that maternal age, a critical factor for fertility, affects mouse oocytes mechanics correlating with alterations in their cortex structure. Finally, we show that the evolution of mechanical properties differs between human and mouse oocyte development, highlighting species-specific differences in cortex organization.