bluuebunny/crossref_metadata_2025 huggingface dataset:
Rational Choice as an Empirical and Normative Model of Political Behavior
Authors: Chong Dennis
Published: September 2023

Rational choice theory is both a normative and empirical model of behavior. The model predicts (or prescribes) how individuals will (or should) choose from alternative courses of action given their objectives and beliefs about the instrumental relationship between those alternatives and their goals. The economic version of the theory assumes perfect, unbounded, or substantive rationality, while bounded rationality assumes that peoples’ decision-making procedures and the quality of their decisions will vary by the demands of the problem and the abilities, goals, and motivations of the decision-maker. This chapter explores the economic and the psychological rationality of political choice by evaluating the attitudes and behavior of citizens against this normative and empirical model in various decision-making contexts. It assesses the degree to which people pursue their self-interest, whether and when individuals can make good decisions with limited information, the circumstances in which beliefs are updated and information is processed rationally, and the consistency and coherence of preferences across alternative framings of issues.
Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence
Authors: Davidson Michael , Carpenter William T
Published: September 2023

Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate’s questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient’s quality of life. Patients’ profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered.
Region-specific changes in brain activity and memory after continuous positive airway pressure therapy in obstructive sleep apnea: a pilot high-density electroencephalography study
Authors: D’Rozario Angela L , Kao Chien-Hui , Phillips Craig L , Mullins Anna E , Memarian Negar , Yee Brendon J , Duffy Shantel L , Cho Garry , Wong Keith K H , Kremerskothen Kyle , Chapman Julia , Haroutonian Carla , Bartlett Delwyn J , Naismith Sharon L , Grunstein Ron R
Published: September 2023

Study Objectives

Limited channel electroencephalography (EEG) investigations in obstructive sleep apnea (OSA) have revealed deficits in slow wave activity (SWA) and spindles during sleep and increased EEG slowing during resting wakefulness. High-density EEG (Hd-EEG) has also detected local parietal deficits in SWA (delta power) during NREM. It is unclear whether effective continuous positive airway pressure (CPAP) treatment reverses regional SWA deficits, and other regional sleep and wake EEG abnormalities, and whether any recovery relates to improved overnight memory consolidation.

Methods

A clinical sample of men with moderate-severe OSA underwent sleep and resting wake recordings with 256-channel Hd-EEG before and after 3 months of CPAP. Declarative and procedural memory tasks were administered pre- and post-sleep. Topographical spectral power maps and differences between baseline and treatment were compared using t-tests and statistical nonparametric mapping (SnPM).

Results

In 11 compliant CPAP users (5.2 ± 1.1 hours/night), total sleep time did not differ after CPAP but N1 and N2 sleep were lower and N3 was higher. Centro-parietal gamma power during N3 increased and fronto-central slow spindle activity during N2 decreased (SnPM < 0.05). No other significant differences in EEG power were observed. When averaged specifically within the parietal region, N3 delta power increased after CPAP (p = 0.0029) and was correlated with the change in overnight procedural memory consolidation (rho = 0.79, p = 0.03). During resting wakefulness, there were trends for reduced delta and theta power.

Conclusions

Effective CPAP treatment of OSA may correct regional EEG abnormalities, and regional recovery of SWA may relate to procedural memory improvements in the short term.
Dizziness Directly Influences Postconcussion Symptoms and Is Predictive of Poorer Mental Health in UK Military Personnel: A Retrospective Analysis
Authors: Denby Emma , Dempster Tammy , White Toni , Brockman Katherine , Ellis Henrietta , Dharm-Datta Shreshth , Wilkinson David , Brunger Helen
Published: September 2023

Objective:

To investigate the contribution of dizziness to postconcussion symptoms, depression, and anxiety symptoms.

Setting:

Mild traumatic brain injury (mTBI) service, Defence Medical Rehabilitation Centre, Stanford Hall.

Participants:

Two hundred eighty-three UK military personnel from the Royal Navy, Royal Airforce, Royal Marines, and British Army.

Design:

A retrospective analysis of data from the Ministry of Defence medical records database.

Main measures:

Sixteen-item Rivermead Post Concussion Symptoms Questionnaire, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire-9, The Dizziness Handicap Inventory.

Results:

Injuries from sports or falls were the most common mechanism of mTBI, accounting for 23%, respectively. Chi-square analysis indicated that individuals with dizziness and postconcussion symptoms (PCS) had greater severity of PCS, depression, and anxiety than those with PCS alone. Mediation analysis showed dizziness directly and independently influenced the severity of PCS, despite the indirect effects of mediating depression and anxiety symptoms.

Conclusion:

Comorbid dizziness and PCS were predictive of poorer mental health compared with PCS alone. In addition, dizziness directly influenced the severity of PCS irrespective of the indirect effects of mental health symptoms. These observations suggest that treating dizziness with vestibular rehabilitation may improve PCS and mental health.
Clinical Features and Follow-up of Referred Children and Young People With Long COVID
Authors: Weakley Kathryn E. , Schikler Allegra , Green Julianne V. , Blatt Daniel B. , Barton Shanna M. , Statler Victoria A. , Feygin Yana , Marshall Gary S.
Published: September 2023

Background:

Patient-level data on the clinical features and outcomes of children and young people referred for possible long coronavirus disease (COVID) can guide clinicians on what to expect in managing patients and advising families.

Methods:

A Post-Acute COVID Clinic for persons <21 years of age was established in October 2020. Intake was standardized and management was tailored to presenting symptoms. Data were abstracted from the charts of all patients evaluated through December 2021, and the study cohort consisted of patients who had a history of confirmed severe acute respiratory syndrome coronavirus 2 infection, had ≥1 symptom persisting for ≥12 weeks and had no pre-existing diagnosis that explained the symptoms. A structured follow-up interview was conducted in early 2022.

Results:

A total of 104 patients were referred, 81 of whom met inclusion criteria. The median age was 14 years (interquartile range, 13–16), and most were female, White/Caucasian and had commercial health insurance. Patients reported previously good health but over half reported moderate-to-severe disability at their first visit. Two clusters of presenting symptoms—fatigue with multiple symptoms, and fatigue and headache with cardiopulmonary symptoms—were identified. Extensive routine testing did not affirm alternative diagnoses. Incident conditions—most commonly anxiety, depression and/or panic disorder; migraines; and autonomic dysfunction—were diagnosed on clinical grounds. Telephone interviews (N = 55) revealed that 78% of patients were improved by about 6 months.

Conclusions:

Within the limits of a single-center, referral-based, observational cohort, this study provides reassurance to patients and parents in that most cases of long COVID were self-limited. Extensive evaluations may be more useful in ruling out alternative diagnoses than in affirming specific physiologic disturbances.
Nighttime Sleep and Respiratory Disturbances in Individuals Receiving Methadone to Treat Opioid Use Disorder
Authors: Finlay Myles , Erwin Julie A. , Skeiky Lillian , Hansen Devon A. , Layton Matthew E. , Quock Raymond , Van Dongen Hans P. A. , Wilson Marian
Published: September 2023

Opioids are a leading cause of drug overdose deaths in the United States. Methadone used as medication for opioid use disorder (MOUD) reduces drug cravings and promotes abstinence. However, individuals in methadone-based MOUD treatment commonly report subjective sleep complaints and are at risk for respiratory depression from opioids. We investigated nighttime sleep and respiratory function in eight individuals (six women, two men; ages 31–68 years) in their first 90 days of methadone-based MOUD treatment. Participants underwent overnight cardiorespiratory polysomnography. Sleep and respiratory variables were characterized with descriptive statistics for comparison to reference data from similarly aged healthy adults. Although participants spent 8.1 ± 0.3 hours (mean ± SD) in bed, their total sleep time was only 6.8 ± 1.3 hours. They exhibited longer sleep latency and intermittent wakefulness. Sleep structure was irregular, with disrupted sleep cycles. Participants also displayed a decreased amount of N1 sleep and an increased amount of N3 sleep, compared with reference data. Participants showed respiratory depression, with an average apnea–hypopnea index of 16.5 ± 8.9 events per hour. Central sleep apneas comprised 69.1% ± 20.9% of the respiratory events. A Cheyne–Stokes-like breathing pattern, consisting of 30-second cycles of three central sleep apneas, was observed in 75% of participants. Our results suggest that individuals early in methadone-based MOUD treatment experience disordered sleep and respiratory disturbances. Such nighttime physiological changes may have serious long-term health consequences and contribute to unintended overdose rates. Identifying and treating MOUD individuals with sleep apnea could reduce risk of death.
“We Don't Want to Screen for the Sake of Screening”
Authors: Cordova-Ramos Erika G. , Burke Judith , Sileo Nicole , McGean Maggie , Torrice Vanessa , Mantri Saaz , Parker Margaret G. , Drainoni Mari-Lynn
Published: September 2023

Background:

Low uptake of social determinants of health (SDH) screening and referral interventions within neonatal intensive care units (NICUs) is partly due to limited understanding of the best procedures to integrate this practice into routine clinical workflows.

Purpose:

To examine the feasibility and acceptability of an SDH screening and referral intervention in the NICU from the perspective of neonatal nurses; and to identify factors affecting implementation outcomes.

Methods:

We conducted 25 semistructured interviews with NICU nurses. We used the Promoting Action on Research Implementation in Health Services (PARiHS) framework to guide interview questions and codebook development for directed content analysis. Themes were mapped onto the 3 PARiHS domains of context, evidence, and facilitation.

Findings:

Analysis yielded 8 themes. Context: Nurses felt that stressors experienced by NICU families are magnified in a safety net environment. Nurses shared varying viewpoints of the roles and responsibilities for social care in the NICU, and feared that scarcity of community resources would make it difficult to address families' needs. Evidence: The intervention was perceived to increase identification of adverse SDH and provision of resources; and to potentially jump-start better caregiver and infant health trajectories. Facilitation: Procedures that improved acceptability included dynamic training and champion support, regular feedback on intervention outcomes, and strategies to reduce stigma and bias.

Conclusion:

We identified contextual factors, concrete messaging, and training procedures that may inform implementation of SDH screening and referral in NICU settings.
Nurse practitioner education: Uniting the 2021 essentials with The Core Competencies on Disability Health Care Education
Authors: Kronk Rebecca , Lucas Denise , Williams Susan
Published: September 2023

People with disabilities (PWD) are the largest minority group in the world, making up 16% of the world's population, an estimated 1.3 billion people. People with disabilities die earlier, have poorer health outcomes, and are more affected by emergencies and natural disasters. Factors contributing to health inequities can be characterized as socioeconomic, political, involve social determinants of health, include higher risk factors, and display a wide spectrum of health system barriers. Too often, health care training programs exclude specific standards for disability training. By mapping the new American Association of Colleges of Nursing (AACN) The Essentials: Core Competencies for Professional Education with The Core Competencies for Disability Health Care Education, we can provide a synergistic relationship that will prepare future advanced practice nurses to provide effective care to people with disabilities across the lifespan and in every delivery care system.
Predicting Persistent Opioid Use after Hand Surgery: A Machine Learning Approach
Authors: Baxter Natalie B. , Ho Allister Z. , Byrd Jacqueline N. , Fernandez Anne C. , Singh Karandeep , Chung Kevin C.
Published: September 2023

Background:

The aim of this study was to evaluate the use of machine learning to predict persistent opioid use after hand surgery.

Methods:

The authors trained 2 algorithms to predict persistent opioid use, first using a general surgery data set and then using a hand surgery data set, resulting in 4 trained models. Next, the authors tested each model’s performance using hand surgery data. Participants included adult surgery patients enrolled in a cohort study at an academic center from 2015 to 2018. The first algorithm (Michigan Genomics Initiative model) was designed to accommodate patient-reported data and patients with or without prior opioid use. The second algorithm (claims model) was designed for insurance claims data from patients who were opioid-naive only. The main outcome was model discrimination, measured by area under the receiver operating curve (AUC).

Results:

Of 889 hand surgery patients, 49% were opioid-naive and 21% developed persistent opioid use. Most patients underwent soft-tissue procedures (55%) or fracture repair (20%). The Michigan Genomics Initiative model had AUCs of 0.84 when trained only on hand surgery data, and 0.85 when trained on the full cohort of surgery patients. The claims model had AUCs of 0.69 when trained only on hand surgery data, and 0.52 when trained on the opioid-naive cohort of surgery patients.

Conclusions:

Opioid use is common after hand surgery. Machine learning has the potential to facilitate identification of patients who are at risk for prolonged opioid use, which can promote early interventions to prevent addiction.
Biomarker-confirmed suboptimal adherence to isoniazid preventive therapy among children with HIV in western Kenya
Authors: Onyango Dickens Otieno , van der Sande Marianne A.B. , Yuen Courtney M. , Were Joyce , Mecha Jerphason , Njagi Lilian N. , Panpradist Nuttada , Matemo Daniel , Leon Daniel , Lutz Barry , Kinuthia John , John-Stewart Grace , Lacourse Sylvia M.
Published: September 2023

Objectives:

The aim of this study was to assess the level and correlates of biomarker-confirmed adherence to isoniazid (INH) preventive therapy (IPT) among children with HIV (CLHIV).

Design:

This prospective cohort study assessed adherence among CLHIV on IPT in public sector HIV clinics from 2019 through 2020.

Methods:

Adherence was assessed by pill counts or caregiver or self-reports, and urine biomarkers (in-house dipstick and Isoscreen). Both urine biomarker tests detect INH metabolites within 48 h of ingestion. Consistent adherence was defined as having positive results on either biomarker at all visits. Correlates of biomarker-confirmed nonadherence at each visit were evaluated using generalized estimating equations. The in-house dipstick was validated using Isoscreen as the reference.

Results:

Among 97 CLHIV on IPT with adherence assessments, median age was 10 years (IQR 7–13). All were on ART at IPT initiation (median duration 46 months [IQR 4–89]); 81% were virally suppressed (<1000 copies/ml). At all visits, 59% (n = 57) of CLHIV reported taking at least 80% of their doses, while 39% (n = 38) had biomarker-confirmed adherence. Viral nonsuppression (adjusted risk ratio [aRR] = 1.65; 95% confidence interval [95% CI] 1.09–2.49) and the sixth month of IPT use (aRR = 2.49; 95% CI 1.34–4.65) were independent correlates of biomarker-confirmed nonadherence at each visit. Sensitivity and specificity of the in-house dipstick were 98.1% (94.7–99.6%) and 94.7% (88.1–98.3%), respectively, versus Isoscreen.

Conclusion:

Biomarker-confirmed adherence to IPT was sub-optimal and was associated with viral nonsuppression and duration of IPT. Urine dipstick testing may be useful in assessing adherence to IPT in clinical care.
Common antiretroviral combinations are associated with somatic depressive symptoms in women with HIV
Authors: Parra-Rodriguez Luis , O’Halloran Jane , Wang Yuezhe , Jin Wei , Dastgheyb Raha M. , Spence Amanda B. , Sharma Anjali , Gustafson Deborah R. , Milam Joel , Weber Kathleen M. , Adimora Adaora A. , Ofotokun Igho , Fischl Margaret A. , Konkle-Parker Deborah , Maki Pauline M. , Xu Yanxun , Rubin Leah H.
Published: September 2023

Objective:

While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms.

Design:

Analysis of longitudinal data from the Women's Interagency HIV Study.

Methods:

Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment.

Results:

The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group.

Conclusions:

Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression.
Viral blips and virologic failures following mpox vaccination with MVA-BN among people with HIV
Authors: Raccagni Angelo Roberto , Diotallevi Sara , Lolatto Riccardo , Lucente Maria Francesca , Candela Caterina , Gianotti Nicola , Trentacapilli Benedetta , Canetti Diana , Castagna Antonella , Nozza Silvia
Published: September 2023

Objectives:

The study aim was to evaluate whether mpox vaccination with modified vaccinia Ankara-Bavarian Nordic (MVA-BN) may be associated with viral blips or confirmed virologic failures (CVF) in people with HIV (PWH) receiving antiretroviral therapy and the associated factors.

Design:

PWH who received MVA-BN, with HIV-RNA less than 50 copies/ml, and CD4+ lymphocytes at least 200 cells/μl in the 6 months prior to vaccination and at least 1 HIV-RNA determination within 3 months from vaccination.

Methods:

The primary outcome was occurrence of viral blips (1 HIV-RNA ≥50 copies/ml) and CVF (1 HIV-RNA ≥1000 copies/ml or ≥2 consecutive HIV-RNA ≥50 copies/ml) following MVA-BN. Changes in CD4+ and CD4+/CD8+ were secondary outcomes. Residual viremia was defined as detectable HIV-RNA less than 50 copies/ml. PWH already vaccinated against smallpox received single-dose MVA-BN. Mann--Whitney rank-sum test or chi-square/Fisher's test applied.

Results:

Overall, 187 PWH were included: 147 received two doses of MVA-BN, 40 single-dose. Six viral blips [incidence rate = 1.59/100-person months of follow-up (PMFU), 95% confidence interval (95% CI) = 0.58–3.47], and three CVFs [incidence rate = 0.80/100-PMFU (95% CI = 0.16–2.33)] were observed. Two CVFs occurred at second dose with presence of detectable HIV-RNA following first one, with high compliance to antiretroviral therapy (ART). PWH with viral blips or CVFs had, prior to first vaccination, more frequently residual viremia [77% (n = 7) versus 35% (n = 62), P = 0.01]. No differences in ART (P = 0.42) and number of MBA-BN doses (P = 0.40) was found. In two cases of CVFs, ART was changed; all VBs resolved within 1 month.

Conclusion:

Although rare, viral blips and CVFs following MVA-BN vaccination among PWH receiving ART were identified. Close monitoring of HIV-RNA during mpox vaccination should be encouraged.
CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation
Authors: Mei Shuai , Zhou Li , Ma Xiaozhu , Wuyun Qidamugai , Chen Chen , Cai Ziyang , Yan Jiangtao , Ding Hu
Published: September 2023

Aims

Circular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, making them attractive therapeutic agents for various vascular diseases. SMAD family is a downstream mediator of the canonical TGFβ signalling pathway and has been considered a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. Therefore, this study aimed to identify a functional circRNA derived from the SMAD family and elucidate its potential as an effective therapeutic agent for vascular proliferative diseases.

Methods and Results

We initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed VSMC proliferation and phenotype switchingin vitroevidenced by morphological assays and ameliorated arterial injury-induced neointima formationin vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 (WDR76) to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated p53γ signalling pathway, and finally suppressed VSMC proliferation and phenotype switching.

Conclusion

Our study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.
The more symptoms the better? Covid-19 vaccine side effects and long-term neutralizing antibody response
Authors: Dutcher Ethan G. , Epel Elissa S. , Mason Ashley E. , Hecht Frederick M. , Robinson James E. , Drury Stacy S. , Prather Aric A.
Published: September 2023

Protection against SARS-CoV-2 wanes over time, and booster uptake has been low, in part because of concern about side effects. We examined the relationships between local and systemic symptoms, biometric changes, and neutralizing antibodies (nAB) after mRNA vaccination. Data were collected from adults (n = 364) who received two doses of either BNT162b2 or mRNA-1273. Serum nAB concentration was measured at 1 and 6 months post-vaccination. Daily symptom surveys were completed for six days starting on the day of each dose. Concurrently, objective biometric measurements, including skin temperature, heart rate, heart rate variability, and respiratory rate, were collected. We found that certain symptoms (chills, tiredness, feeling unwell, and headache) after the second dose were associated with increases in nAB at 1 and 6 months post-vaccination, to roughly 140-160% the level of individuals without each symptom. Each additional symptom predicted a 1.1-fold nAB increase. Greater increases in skin temperature and heart rate after the second dose predicted higher nAB levels at both time points, but skin temperature change was more predictive of durable (6 month) nAB response than of short-term (1 month) nAB response. In the context of low ongoing vaccine uptake, our convergent symptom and biometric findings suggest that public health messaging could seek to reframe systemic symptoms after vaccination as desirable.
Integrated single-cell multiome analysis reveals muscle fiber-type gene regulatory circuitry modulated by endurance exercise
Authors: Rubenstein Aliza B. , Smith Gregory R. , Zhang Zidong , Chen Xi , Chambers Toby L. , Ruf-Zamojski Frederique , Mendelev Natalia , Cheng Wan Sze , Zamojski Michel , Amper Mary Anne S. , Nair Venugopalan D. , Marderstein Andrew R. , Montgomery Stephen B. , Troyanskaya Olga G. , Zaslavsky Elena , Trappe Todd , Trappe Scott , Sealfon Stuart C.
Published: September 2023

Endurance exercise is an important health modifier. We studied cell-type specific adaptations of human skeletal muscle to acute endurance exercise using single-nucleus (sn) multiome sequencing in human vastus lateralis samples collected before and 3.5 hours after 40 min exercise at 70% VO2max in four subjects, as well as in matched time of day samples from two supine resting circadian controls. High quality same-cell RNA-seq and ATAC-seq data were obtained from 37,154 nuclei comprising 14 cell types. Among muscle fiber types, both shared and fiber-type specific regulatory programs were identified. Single-cell circuit analysis identified distinct adaptations in fast, slow and intermediate fibers as well asLUM-expressing FAP cells, involving a total of 328 transcription factors (TFs) acting at altered accessibility sites regulating 2,025 genes. These data and circuit mapping provide single-cell insight into the processes underlying tissue and metabolic remodeling responses to exercise.
Biallelic non-productive enhancer-promoter interaction precedes imprinted expression ofKcnk9during mouse neural commitment
Authors: Rojas Cecilia Rengifo , Cercy Jil , Perillous Sophie , Gonthier-Guéret Céline , Montibus Bertille , Maupetit-Méhouas Stéphanie , Espinadel Astrid , Dupré Marylou , Hong Charles C. , Hata Kenichiro , Nakabayashi Kazuhiko , Plagge Antonius , Bouschet Tristan , Arnaud Philippe , Vaillant Isabelle , Court Franck
Published: September 2023

How constitutive allelic methylation at imprinting control regions (ICRs) interacts with other levels of regulation to drive timely parental allele-specific expression along large imprinted domains remains partially understood. To gain insight into the regulation of thePeg13-Kcnk9domain, an imprinted domain with important brain functions, during neural commitment, we performed an integrative analysis of the epigenetic, transcriptomic and cis-spatial organisation in an allele-specific manner in a mouse stem cell-based model of corticogenesis that recapitulates the control of imprinted gene expression during neurodevelopment. We evidence that despite an allelic higher-order chromatin structure associated with the paternally CTCF-boundPeg13ICR, the enhancer-Kcnk9promoter contacts can occur on both alleles, although they are only productive on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side, and suggests a more nuanced role for allelic CTCF binding at some ICRs.
Peds1 deficiency in zebrafish results in myeloid cell apoptosis and exacerbated inflammation
Authors: Arroyo Ana B. , Tyrkalska Sylwia D. , Bastida-Martínez Eva , Monera-Girona Antonio J. , Cantón-Sandoval Joaquín , Bernal-Carrión Martín , García-Moreno Diana , Elías-Arnanz Montserrat , Mulero Victoriano
Published: September 2023

Plasmalogens are glycerophospholipids with a vinyl ether bond that confers unique properties. Recent identification of the gene encoding PEDS1, the desaturase generating the vinyl ether bond, enables evaluation of the role of plasmalogens in health and disease. Here, we report that Peds1-deficient zebrafish larvae display delayed development, increased basal inflammation, normal hematopoietic stem and progenitor cell emergence, and cell-autonomous myeloid cell apoptosis. In a sterile acute inflammation model, Peds1-deficient larvae exhibited impaired inflammation resolution and tissue regeneration, increased interleukin-1β and NF-κB activities, and elevated ROS levels at the wound site. Abnormal immune cell recruitment, neutrophil persistence, and fewer but predominantly pro-inflammatory macrophages was observed. Chronic skin inflammation worsened in Peds1-deficient larvae but was mitigated by exogenous plasmalogen, which also alleviated hyper-susceptibility to bacterial infection, as did pharmacological inhibition of caspase-3 and colony-stimulating factor 3-induced myelopoiesis. Overall, our results highlight an important role for plasmalogens in myeloid cell biology and inflammation.

Keypoints

Plasmalogens are crucial for cell autonomous survival, recruitment and activation of neutrophils and macrophages.

Plasmalogen production aids inflammation resolution, while supplementation reduces inflammation and boosts bacterial clearance.
StableMate: a statistical method to select stable predictors in omics data
Authors: Deng Yidi , Mao Jiadong , Choi Jarny , Lê Cao Kim-Anh
Published: September 2023

Identifying statistical associations between biological variables is crucial to understand molecular mechanisms. Most association studies are based on correlation or linear regression analyses, but the identified associations often lack reproducibility and interpretability due to the complexity and variability of omics datasets, making it difficult to translate associations into meaningful biological hypotheses.

We developed StableMate, a regression framework to address these challenges through a process of variable selection across heterogenous datasets. Given datasets from different environments, such as experimental batches, StableMate selects environment-agnostic (stable) and environment-specific predictors in predicting the response of interest. Stable predictors represent robust functional dependencies with the response, and can be used to build regression models that make generalizable prediction in unseen environments.

We applied StableMate to 1) RNA-seq data of breast cancer to discover genes that consistently predict estrogen receptor expression across disease status, 2) metagenomics data to identify microbial signatures that show persistent association with colon cancer across study cohorts and 3) scRNA-seq data of glioblastoma to discern signature genes associated with development of pro-tumour microglia regardless of cell location.

Our case studies demonstrate that StableMate is adaptable to regression and classification analyses and achieves comprehensive characterisation of biological systems for different omics data types.
A qualitative evaluation of treatment fidelity alongside a pilot trial of a novel therapy for pediatric IBD
Authors: Olson Jenny L. , Castillo Gisell , Palumbo Amelia , Harrison Megan , Singleton Ruth , Lalu Manoj M. , Fergusson Dean A. , Stintzi Alain , Mack David R. , Presseau Justin
Published: September 2023

Background

Process evaluations conducted alongside clinical trials can improve understanding of treatment fidelity and provide contextual knowledge to aide interpretations of trial outcomes. We adopted a multiple-goals perspective to investigate treatment fidelity in two related pilot clinical trials of an adjuvant treatment for pediatric-onset Inflammatory Bowel Disease. This included a focus on barriers and enablers of performing trial-specific activities and of integrating those activities into daily life.

Methods

We interviewed a sub-sample of participants of the Resistant Starch in Pediatric Inflammatory Bowel Disease (NCT04522271) and Optimized Resistant Starch in Inflammatory Bowel Disease pilot trials (NCT04520594) and their caregivers (N=42). The trials examined the effects of personalized food-derived resistant starches as an adjuvant therapy on intestinal microbiome functioning. Codes were identified inductively though conventional content analysis and then mapped to personal projects units of analysis, to explore how participants navigated between activities.

Results

Three themes were identified. The first described the potential impact of living with inflammatory bowel disease and taking prescribed medications. The second described characteristics of trial-specific activities that might impact on their enactment, including perceived difficulty, and challenges following procedures or using trial materials. The third described the integration of trial-specific activities with school, work, household demands, and social, and extracurricular activities.

Conclusions

Adjusting to living with inflammatory bowel disease and managing its treatment can impact trial participation. Integrating trial-related activities into daily life can be challenging, which could heighten perceptions of goal conflict. Findings can inform interpretations of trial outcomes and development of strategies for trial optimization and implementation of the adjuvant therapy into clinical practice.
Exposure ofMycobacterium tuberculosisto human alveolar lining fluid shows temporal and strain-specific adaptation to the lung environment
Authors: Allué-Guardia Anna , Garcia-Vilanova Andreu , Schami Alyssa M. , Olmo-Fontánez Angélica M. , Hicks Amberlee , Peters Jay , Maselli Diego J. , Wewers Mark D. , Wang Yufeng , Torrelles Jordi B.
Published: September 2023

Upon infection,Mycobacterium tuberculosis(M.tb) reaches the alveolar space and comes in close contact with human alveolar lining fluid (ALF) for an uncertain period of time prior to its encounter with alveolar cells. We showed that homeostatic ALF hydrolytic enzymes modify theM.tbcell envelope, drivingM.tb-host cell interactions. Still, the contribution of ALF duringM.tbinfection is poorly understood. Here, we exposed 4M.tbstrains with different levels of virulence, transmissibility, and drug resistance (DR) to physiological concentrations of human ALF for 15-min and 12-h, and performed RNA sequencing. Gene expression analysis showed a temporal and strain-specific adaptation to human ALF. Differential expression (DE) of ALF-exposedvs.unexposedM.tbrevealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE genes were detected at 12-h post-ALF exposure, with DR-M.tbstrain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated in all strains post-ALF exposure. These results indicate thatM.tb-ALF contact drives initial metabolic and physiologic changes inM.tb, with potential implications in infection outcome.

IMPORTANCE

Tuberculosis, caused by airborne pathogenMycobacterium tuberculosis(M.tb), is one of the leading causes of mortality worldwide. Upon infection,M.tbreaches the alveoli and gets in contact with human alveolar lining fluid (ALF), where ALF hydrolases modify theM.tbcell envelope driving subsequentM.tb-host cell interactions. Still, the contributions of ALF during infection are poorly understood. We exposed 4M.tbstrains to ALF for 15-min and 12-h and performed RNA sequencing, demonstrating a temporal and strain-specific adaptation ofM.tbto ALF. Interestingly, genes associated with cholesterol degradation were highly upregulated in all strains. This study shows for the first time that ALF drives global metabolic changes inM.tbduring the initial stages of the infection, with potential implications in disease outcome. Biologically relevant networks and common and strain-specific bacterial determinants derived from this study could be further investigated as potential therapeutic candidates.
Femora Nutrient Foramina and Aerobic Capacity in Giant Extinct Xenarthrans
Authors: Varela Luciano , Tambusso P. Sebastián , Fariña Richard A.
Published: September 2023

Nutrient foramina are small openings in the periosteal surface of long bones that traverse the cortical layer and reach the medullary cavity. They are important for the delivery of nutrients and oxygen to bone tissue, and are crucial for the repair and remodeling of bones over time. The nutrient foramina in the femur’s diaphysis are related to the energetic needs of the femur, and have been shown to be related to the maximum metabolic rate (MMR) of taxa. Here, we investigate the relationship between nutrient foramen size and body mass as a proxy to the aerobic capacity of taxa in living and extinct xenarthrans, including living sloths, anteaters, and armadillos, as well as extinct xenarthrans such as glyptodonts, pampatheres, and ground sloths. Sixtynine femora were sampled, including 19 from extant taxa and 50 from extinct taxa. We obtained the blood flow index (Qi) based on foramina area and performed PGLS and phylogenetic ANCOVA in order to explore differences among mammalian groups. Our results show that among mammals, taxa commonly associated with lower metabolism like marsupials and living xenarthrans showed relatively smaller foramina, while the foramina of giant extinct xenarthrans like ground sloths and glyptodonts overlapped with non-xenarthran placentals. Consequently, Qiestimations indicated aerobic capacities comparable to other placental giant taxa like elephants or some ungulates. Furthermore, the estimation of the MMR for fossil giant taxa showed similar results, with almost all taxa showing high values except for those for which strong semi-arboreal or fossorial habits have been described. Moreover, the results are compatible with the diets predicted for extinct taxa, which indicate a strong consumption of grass similar to ungulates and in contrast to the folivorous or insectivorous diets of extant xenarthrans. The ancestral reconstruction of the MMR values indicated a lack of a common pattern for all xenarthrans, strongly supporting the occurrence of low metabolic rates in extant forms due to their particular dietary preferences and arboreal or fossorial habits. Our results highlight the importance of considering different evidence beyond the phylogenetic position of extinct taxa, especially when extinct forms are exceptionally different from their extant relatives. Future studies evaluating the energetic needs of giant extinct xenarthrans should not assume lower metabolic rates for these extinct animals based solely on their phylogenetic position and the observations on their extant relatives.
Comparative genomics reveals the diversity of CRISPR-Cas systems among neonatal sepsis causing group BStreptococcus agalactiae
Authors: Ghate Sudeep D , Rao R. Shyama Prasad , Shastry Rajesh P , Pinto Deepak , Shetty Praveenkumar
Published: September 2023

The pathogenStreptococcus agalactiae, or Group BStreptococcus(GBS) infection is the leading cause of neonatal sepsis and meningitis in neonates. In this study, we aimed to investigate the occurrence and diversity of the CRISPR-Cas system inS. agalactiaegenomes using computational biology approaches. A total of 51 out of 52 complete genomes (98.07%) ofS. agalactiaepossess CRISPR arrays (75 CRISPR arrays) with 17 strains possessing multiple CRISPR arrays. There were only two CRISPR-Cas systems – type II-A system and type I-C system inS. agalactiaestrains. RNA secondary structure analysis through direct repeat analysis showed that the analyzed strains could form stable secondary structures. The 16S rRNA phylogeny exhibited clustering of the strains into three major clades grouped on the type of CRISPR-Cas system. The anti-CRISPRs that contribute to CRISPR-Cas system diversity and prevent genome editing were also detected. These results provide valuable insights into elucidating the evolution, diversity, and function of CRISPR/Cas elements in this pathogen.
Mechanical imbalance between normal and transformed cells drives epithelial homeostasis through cell competition
Authors: Gupta Praver , Kayal Sayantani , Tanimura Nobuyuki , Pothapragada Shilpa P. , Senapati Harish K. , Devendran Padmashree , Fujita Yasuyuki , Bi Dapeng , Das Tamal
Published: September 2023

Cell competition in epithelial tissue eliminates transformed cells expressing activated oncoproteins to maintain epithelial homeostasis. Although the process is now understood to be of mechanochemical origin, direct mechanical characterization and associated biochemical underpinnings are lacking. Here, we employ tissue-scale stress and compressibility measurements and theoretical modeling to unveil a mechanical imbalance between normal and transformed cells, which drives cell competition. In the mouse intestinal epithelium and epithelial monolayer, transformed cells get compacted during competition. Stress microscopy reveals an emergent compressive stress at the transformed loci leading to this compaction. A cell-based self-propelled Voronoi model predicts that this compressive stress originates from a difference in the collective compressibility of the competing populations. A new collective compressibility measurement technique named gel compression microscopy then elucidates a two-fold higher compressibility of the transformed population than the normal population. Mechanistically, weakened cell-cell adhesions due to reduced junctional abundance of E-cadherin in the transformed cells render them collectively more compressible than normal cells. Taken together, our findings unveil a mechanical basis for epithelial homeostasis against oncogenic transformations with implications in epithelial defense against cancer.
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion
Authors: Aleksandrova Elena V. , Wu Kelvin J. Y. , Tresco Ben I. C. , Syroegin Egor A. , Killeavy Erin E. , Balasanyants Samson M. , Svetlov Maxim S. , Gregory Steven T. , Atkinson Gemma C. , Myers Andrew G. , Polikanov Yury S.
Published: September 2023

The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacteriumThermus thermophilusand report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.
An adapted method for Cas9-mediated editing reveals the species-specific role of β-glucoside utilization driving competition betweenKlebsiellaspecies
Authors: d. H. Almási Éva , Knischewski Nele , Osbelt Lisa , Muthukumarasamy Uthayakumar , Mouali Youssef El , Vialetto Elena , Beisel Chase L. , Strowig Till
Published: September 2023

Cas9-based gene editing tools have revolutionized genetics, enabling the fast and precise manipulation of diverse bacterial species. However, widely applicable genetic tools for non-model gut bacteria are unavailable. Here, we present a two-plasmid Cas9-based system designed for gene deletion and knock-in complementation in three members of theKlebsiella oxytocaspecies complex (KoSC), which we applied to study the genetic factors underlying the role of these bacteria in competition againstKlebsiella pneumoniae. The system allowed efficient and precise editing via enhanced lambda Red expression and functionally-validated complementation with the use of universal ‘bookmark’ targets inK. oxytoca, Klebsiella michiganensis, andKlebsiella grimontii. We revealed that the carbohydrate permease CasA is critical inex vivoassays forK. pneumoniaeinhibition byK. oxytocabut is neither sufficient nor required forK. michiganensisandK. grimontii. Thus, the adaptation of state-of-the-art genetic tools to KoSC allows the identification of species-specific functions in microbial competition.

* Importance

Cas9-based gene editing tools have revolutionized bacterial genetics, yet, their application to non-model gut bacteria is frequently hampered by various limitations. We utilized a two-plasmid Cas9-based system designed for gene deletion inKlebsiella pneumoniaeand demonstrate after optimization its utility for gene editing in three members of theKlebsiella oxytocaspecies complex (KoSC) namelyK. oxytoca, K. michiganensisandK. grimontii. We then adapted a recently developed protocol for functional complementation based on universal ‘bookmark’ targets applicable to all tested species. In summary, species specific adaptation of state-of-the-art genetic tools allow efficient gene deletion and complementation in types strains as well as natural isolates of KoSC members to study microbial interactions.