bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergency Management During Telehealth
Authors: Rauzi Michelle R. , Olivos Maegan E. , Currier Deborah L. , Abbate Lauren M. , Lum Hillary D. , Stevens-Lapsley Jennifer E.
Published: October 2023

The COVID-19 pandemic rapidly expanded telehealth utilization, spurring interest in patient safety and emergency procedures during treatment. The purpose of this report was to present safety procedures within a Veterans Affairs (VA)-affiliated telehealth physical therapy program treating medically complex older adults. Staff completed organizational and clinic-specific training for emergency procedures; these procedures were iteratively adapted through safety event debriefings and weekly meetings. Twenty-one individuals participated in the program. Clinicians completed 317 and 122 individual and group sessions, respectively, and reported 17 safety events. Four case examples highlight how safety procedures were adapted to mitigate risk and respond to emergencies.
Telehealth Adoption Among Rehabilitation Specialists
Authors: Terrell Evelyn Abrahante , Rafols Jose
Published: October 2023

This article aims to provide virtual care solutions to address social determinants of health and expand access to care for underserved populations. The article highlights virtual care enhancements and strategies to extend the geographic reach of clinicians into home and community settings for greater health equity. It supports the use of telehealth in meeting the health care needs of underserved communities facing barriers to access, as well as provides integrated and coordinated high-quality care. Finally, this article describes an organization's telehealth journey and offers practical guidance for clinicians on how to successfully implement and scale telehealth services.
Teleassessment of Balance and Gait Outcome Measures in Older Adults
Authors: Jasper Amie , Chamberlain Deborah , Lazaro Rolando
Published: October 2023

Introduction:

This article systematically reviews the reliability and validity of balance and gait outcome measures obtained by teleassessment in older adults.

Methods:

Two reviewers searched electronic databases for articles published from 2010 to 2022. Included studies were appraised for quality.

Results:

Six articles were reviewed. Reliability was found to be low to good, and validity was acceptable, with some concerns with bias during testing.

Discussion:

There is evidence to support the use of certain balance and gait outcome measures in teleassessment of the older adult population if the individuals have appropriate electronic devices for telecommunication, good Internet connectivity, and adequate technological knowledge.
Defying Stereotypes
Authors: Mulcahy Julie , Beresford Lauren S. , DeLaRosby Anna
Published: October 2023

Poor technological proficiency is a barrier to engaging with digital health for older adults, preventing providers from recommending digital health tools to patients aged 60+years. Effect of age and gender on engagement with a digital physical therapy application was assessed over 5883 episodes. The 60+ age group had 78% increased odds of engagement compared with the 20-29 years age group. The 60+ age group performed 64% to 101% more workouts per week. Women aged 60+ years were significantly more engaged than other demographics. Patients using app-based physical therapy are highly engaged. Age and gender do not appear to preclude engagement with digital physical therapy.
Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate
Authors: Garcia Sarah , Askew Robert L. , Kavcic Voyko , Shair Sarah , Bhaumik Arijit K. , Rose Edna , Campbell Stephen , May Nicolas , Hampstead Benjamin M. , Dodge Hiroko H. , Heidebrink Judith L. , Paulson Henry L. , Giordani Bruno
Published: October 2023

Background:

Early detection is necessary for the treatment of dementia. Computerized testing has become more widely used in clinical trials; however, it is unclear how sensitive these measures are to early signs of neurodegeneration. We investigated the use of the NIH Toolbox-Cognition (NIHTB-CB) and Cogstate-Brief computerized neuropsychological batteries in the identification of mild cognitive impairment (MCI) versus healthy older adults [healthy control (HC)] and amnestic (aMCI) versus nonamnestic MCI (naMCI). Exploratory analyses include investigating potential racial differences.

Methods:

Two hundred six older adults were diagnosed as aMCI (n = 58), naMCI (n = 15), or cognitively healthy (HC; n = 133).

Results:

The NIH Toolbox-CB subtests of Flanker, Picture Sequence Memory, and Picture Vocabulary significantly differentiated MCI from HC. Further, subtests from both computerized batteries differentiated patients with aMCI from those with naMCI. Although the main effect of race differences was noted on tests and in diagnostic groups was significant, there were no significant race-by-test interactions.

Conclusions:

Computer-based subtests vary in their ability to help distinguish MCI subtypes, though these tests provide less expensive and easier-to-administer clinical screeners to help identify patients early who may qualify for more comprehensive evaluations. Further work is needed, however, to refine computerized tests to achieve better precision in distinguishing impairment subtypes.
Anterior Quadratus Lumborum Block at Lateral Supra-Arcuate Ligament vs Lateral Quadratus Lumborum Block for Postoperative Analgesia after Laparoscopic Colorectal Surgery: A Randomized Controlled Trial
Authors: Shi Rong , Shao Peiqi , Hu Jinge , Li Huili , Wang Yun
Published: October 2023

BACKGROUND:

Quadratus lumborum block (QLB) has been found to be advantageous for laparoscopic colorectal surgery. This study hypothesized that preoperative anterior QLB at lateral supra-arcuate ligament (QLB-LSAL) would decrease postoperative opioid usage and offer improved analgesia within the context of multimodal analgesia compared with lateral QLB (LQLB) for laparoscopic colorectal surgery.

STUDY DESIGN:

In this randomized controlled trial, 82 American Society of Anesthesiologists physical status I to III class colorectal cancer patients undergoing laparoscopic radical resection were enrolled and randomly assigned to receive either LQLB or QLB-LSAL (0.375% ropivacaine 0.3 mL/kg bilaterally for each group). The primary outcomes were the total intravenous morphine equivalent consumption at 24 hours postoperatively.

RESULTS:

Intravenous morphine equivalent consumption at 24 hours postoperatively was significantly reduced in the QLB-LSAL group compared with that in the LQLB group with per-protocol analysis (29.2 ± 5.8 vs 40.5 ± 9.6 mg, p < 0.001) and intention-to-treat analysis (29.6 ± 6.1 vs 40.8 ± 9.5 mg, p < 0.001). Time to first patient-controlled analgesia request was notably longer in the QLB-LSAL group than that in the LQLB group (10.4 ± 3.9 vs 3.7 ± 1.5 hours, p < 0.001).

CONCLUSIONS:

Preoperative bilateral ultrasound-guided QLB-LSAL reduces morphine usage and extends the duration until the first patient-controlled analgesia demand within the framework of multimodal analgesia when compared with LQLB after laparoscopic colorectal surgery.
The human immune checkpoint molecule, HLA-G2, induces tolerance in monocytes and dendritic cells via upregulation of PD-L1
Authors: Takahashi Ami , Kuroki Kimiko , Maeda Naoyoshi , Nieda Mie , Maenaka Katsumi
Published: October 2023

Human leukocyte antigen (HLA)-G is a non-classical HLA class I immunomodulatory molecule with restricted expression in the placenta, thymus and regulatory T cells. The spliced isoforms of HLA-G include an α2 domain-deleted isoform, HLA-G2, which specifically binds to the immune checkpoint leukocyte immunoglobulin-like receptor B2 (LILRB2), to suppress immune responses in myelomonocytic cells. We previously reported the structural and receptor binding characteristics of recombinant HLA-G2 protein and its immunosuppressive effects on inflammation in mouse models. However, the function and the mechanism of action of HLA-G2 on human immune cells have not been elucidated.

In the present study, we demonstrate the immunosuppressive effect of HLA-G2 on human CD14-positive monocytic cells. HLA-G2 induced the production of the immunosuppressive cytokine, IL-10, and stimulated IL-6/STAT3/indoleamine-2,3-dioxygenase signaling by binding to LILRB2. HLA-G2 binding to LILRB2 also down-regulated cell surface expression of HLA-DR and CD86. Unexpectedly, HLA-G2 up-regulated cell surface expression of PD-L1 in both CD14-positive monocytic cells and interferon-induced dendritic cells (IFN-DCs). This observation suggests HLA-G2/LILRB2 signaling promotes PD-L1 expression. Furthermore, HLA-G2 treatment of IFN-DCs suppressed T cell proliferation in mixed lymphocyte reactions. These findings provide novel insights into the modulation of human immune responses of tolerogenic myelomonocytic cells induced by HLA-G2 binding to LILRB2, and suggest that targeting the HLA-G2-LILRB2 interaction could be a novel approach for immune checkpoint therapy.

Significance statement

During pregnancy, HLA-G isoforms are expressed by fetal trophoblasts to suppress maternal immune responses. Among various HLA-G isoforms, the HLA-G2 homodimer has been expected as an immunosuppressive biologic targeting myelomonocytic antigen-presenting cells via leukocyte immunoglobulin-like receptor B2. We previously reported significant immunosuppressive effects of HLA-G2 in autoimmune mouse models. Here, we first demonstrate that HLA-G2 isoform induces tolerogenic phenotypes of human peripheral immune cells by significantly upregulating an immune checkpoint molecule, PD-L1. Monocyte-derived dendritic cells stimulated by HLA-G2 suppressed T cell proliferation in mixed lymphocyte reactions. These results suggest that HLA-G2 can be a novel candidate for immune checkpoint therapy.
Longevity and frailty and their associated factors in the prognosis of coronary heart disease in a Latin American cohort
Authors: Dulcey Sarmiento Luis Andres , Acevedo Peña Diego Andrey , Castillo Goyeneche Silvia Fernanda , Arias Anderson Felipe , Estévez Gómez María Juliana , Gomez Jaime , Hernandez Carlos , Theran Leon Juan Sebastián , Caltagirone Raimondo , Blanco Edgar , Ciliberti María , Calderon Amaya Silvia Yulieth , Gutierrez Emily , Lizcano Angie , Amaya Maria Camila , Lobo Diego , Estupiñan Francisco Mora
Published: October 2023

Introduction

to study the characteristics of the anamnestic history, the clinical course, as well as the nature of medical care for elderly patients with acute myocardial infarction (MI) and evaluate their impact on the prognosis of the disease.

Material and methods

the study included patients aged 60 years or older, survivors of acute myocardial infarction and registered in the database of the Hospital Universitario de los Andes in Merida, Venezuela (n=410). During the 2013-2018 study, a five-year prospective observation of patients with an assessment of their vital status was conducted. For the statistical processing of the data obtained, the Statistica V10.0 application package (StatSoft Inc.) was used.

Results

the analysis showed that 90% of the patients had a history of comorbid pathology. The presence of an atypical manifestation of myocardial infarction lengthened the prehospital stage of medical care for patients who were late in seeking medical attention (120 [49; 311.5] minutes), as well as the longest time until the first medical contact (26.5 [20; 40] minutes (p = 0.005)). One-fifth of patients were treated for acute MI in complementary hospitals, where the level of in-hospital mortality among elderly patients reached 65.7%, three times higher than the same figure in specialized cardiology departments (19, 7%, p< 0.001).

Conclusion

The main factors influencing long-term post-infarction in elderly patients were isolated systolic arterial hypertension, diabetes mellitus, renal dysfunction, previous myocardial infarction and acute stroke.
OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records
Authors: Chen Qingwen , Dwaraka Varun B. , Carreras-Gallo Natàlia , Mendez Kevin , Chen Yulu , Begum Sofina , Kachroo Priyadarshini , Prince Nicole , Went Hannah , Mendez Tavis , Lin Aaron , Turner Logan , Moqri Mahdi , Chu Su H. , Kelly Rachel S. , Weiss Scott T. , Rattray Nicholas J.W , Gladyshev Vadim N. , Karlson Elizabeth , Wheelock Craig , Mathé Ewy A. , Dahlin Amber , McGeachie Michae J. , Smith Ryan , Lasky-Su Jessica A.
Published: October 2023

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype,EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to modelEMRAgewith DNA-methylation (DNAm) and multiple omics, generatingDNAmEMRAgeandOMICmAge,respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies,OMICmAgehas the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.
BUMBLE BEE RESPONSES TO CLIMATE AND LANDSCAPES: INVESTIGATING HABITAT ASSOCIATIONS AND SPECIES ASSEMBLAGES ACROSS GEOGRAPHIC REGIONS IN THE UNITED STATES OF AMERICA
Authors: Christman Morgan E. , Spears Lori R. , Burchfield Emily K. , Pearse William D. , Strange James P. , Ramirez Ricardo A.
Published: October 2023

Bumble bees are integral pollinators of native and cultivated plant communities, but species are undergoing significant changes in range and abundance on a global scale. Climate change and land cover alteration are key drivers in pollinator declines; however, limited research has evaluated the cumulative effects of these factors on bumble bee assemblages. This study tests bumble bee responses to climate and land use by modeling 1) occupancy (presence/absence); 2) species richness; 3) species-specific habitat requirements; and 4) assemblage-level responses across geographic regions. We integrated richness, abundance, and distribution data for 18 bumble bee species with site specific bioclimatic, landscape composition, and landscape configuration data to evaluate the effects of multiple environmental stressors on bumble bee assemblages throughout 433 agricultural fields in Florida, Indiana, Kansas, Kentucky, Maryland, South Carolina, Utah, Virginia, and West Virginia from 2018 to 2020. Increased prevalence of attractive crops was associated with increased bumble bee presence, while higher maximum temperature of warmest month and unattractive crops were linked to bumble bee absences. Bumble bee species richness was positively correlated with attractive crops and elevation but declined with precipitation of the wettest month. Moreover, species richness increased as maximum temperature of warmest month approached 29°C but declined at they rose to 36°C, suggesting a potential temperature threshold around 33°C. Distinct east vs. west groupings emerged when evaluating species-specific habitat associations, prompting a detailed evaluation of bumble bee assemblages by geographic region. Overall, climate and land use combine to drive bumble bee occupancy and assemblages, but how those processes operate is idiosyncratic and spatially contingent across regions. From these findings, we suggested regionally specific management practices to best support rich bumble bee assemblages in agroecosystems. Results from this study contribute to a better understanding of climate and landscape factors affecting bumble bees and their habitats throughout the USA.
Reliability of dynamic causal modelling of resting state magnetoencephalography
Authors: Jafarian Amirhossein , Assem Melek Karadag , Kocagoncu Ece , Lanskey Juliette H , Williams Rebecca , Cheng Yun-Ju , Quinn Andrew J , Pitt Jemma , Raymont Vanessa , Lowe Stephen , Singh Krish D , Woolrich Mark , Nobre Anna C , Henson Richard N , Friston Karl J , Rowe James B
Published: October 2023

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magneto-electroencephalography under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting state magneto-electroencephalography (MEG) data from two sessions, acquired two weeks apart, from a cohort with high between-subject variance arising from Alzheimer’s disease. Our focus is not on the effect of disease, but on the predictive validity of the methods implicit in their reliability, which is crucial for future studies of disease progression and drug intervention. To assess the predictive validity of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the ‘quality’ of the models) with vs. without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the predictive validity of DCM parameters at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, between-epochs; (ii) within-subject between-session and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of ‘reliability’ and the conditional dependency among inferred model parameters. Our analyses confirm the predictive validity and reliability of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders.

Abstract Figure
An optimized high-yield protocol for expression and purification of monomeric full-length BAX protein
Authors: Chen Yiyang , Gelles Jesse D. , Mohammed Jarvier N. , Chipuk Jerry Edward
Published: October 2023

Diverse developmental signals and pro-death stresses converge on regulation of the mitochondrial pathway of apoptosis. BAX, a pro-apoptotic BCL-2 effector, directly forms proteolipid pores in the outer mitochondrial member to activate the mitochondrial pathway of apoptosis. BAX is a viable pharmacological target for various human diseases, and increasing efforts have been made to study the molecular regulation of BAX and identify small molecules selectively targeting BAX. However, generating large quantities of monomeric and functionally-competent BAX has been challenging due to its aggregation-prone nature. Additionally, there is a lack of detailed and instructional protocols available for investigators who are not already familiar with recombinant BAX production. Here, we present a comprehensive high-yield protocol for expressing, purifying, and storing functional recombinant BAX protein. We utilize an intein-tagged BAX construct and employ a two-step chromatography strategy to capture and purify BAX, and provide example standard assays to observe BAX activation. We also highlight best practices for handling and storing BAX to effectively preserve its quality, shelf-life, and function.
Functional Tissue Units in the Human Reference Atlas
Authors: Bidanta Supriya , Börner Katy , Herr Bruce W. , Nagy Marcell , Gustilo Katherine S. , Bajema Rachel , Maier Libby , Molontay Roland , Weber Griffin
Published: October 2023

Functional tissue units (FTUs) form the basic building blocks of organs and are important for understanding and modeling the healthy physiological function of the organ and changes during disease states. In this first comprehensive catalog of FTUs, we document the definition, physical dimensions, vasculature, and cellular composition of 22 anatomically correct, nested functional tissue units (FTUs) in 10 healthy human organs. The catalog includes datasets, illustrations, an interactive online FTU explorer, and a large printable poster. All data and code are freely available. This is part of a larger ongoing international effort to construct a Human Reference Atlas (HRA) of all cells in the human body.
Quantifying and mitigating recorder-induced variability in ecological acoustic indices
Authors: Luna-Naranjo David , Martínez Juan D. , Sánchez-Giraldo Camilo , Daza Juan M. , López José D.
Published: October 2023

Due to the complexity of soundscapes, Ecological Acoustic indices (EAI) are frequently used as metrics to summarize ecologically meaningful information from audio recordings. Recent technological advances have allowed the rapid development of many audio recording devices with significant hardware/firmware variations among brands, whose effects in calculating EAI have not yet be determined. In this work, we show how recordings of the same landscape with different devices effectively hinder reproducibility and produce contradictory results. To address these issues, we propose a preprocessing pipeline to reduce EAI variability resulting from different hardware without altering the target information in the audio. To this end, we tested eight EAI commonly used in soundscape analyses. We targeted three common cases of variability caused by recorder characteristics: sampling frequency, microphone gain variation, and frequency response. We quantified the difference in the probability density functions of each index among recorders according to the Kullback-Leibler divergence. As a result, our approach reduced up to 75% variations among recorders from different brands (AudioMoth and SongMeter) and identified the conditions in which these devices are comparable. In conclusion, we demonstrated that different devices effectively affect EAI and show how these variations can be mitigated.

Graphical Abstract

Highlights

Addressing recorder-induced biases in acoustic indices for improved reproducibility.

Proposing an effective method to mitigate recorder-related biases.

Evaluating pipeline proposed performance via acoustic index distribution analysis.
A comprehensive neuroanatomical survey of theDrosophilaLobula Plate Tangential Neurons with predictions for their optic flow sensitivity
Authors: Zhao Arthur , Nern Aljoscha , Koskela Sanna , Dreher Marisa , Erginkaya Mert , Laughland Connor W. , Ludwigh Henrique , Thomson Alex , Hoeller Judith , Parekh Ruchi , Romani Sandro , Bock Davi D. , Chiappe Eugenia , Reiser Michael B.
Published: October 2023

Flying insects exhibit remarkable navigational abilities controlled by their compact nervous systems.Optic flow, the pattern of changes in the visual scene induced by locomotion, is a crucial sensory cue for robust self-motion estimation, especially during rapid flight. Neurons that respond to specific, large-field optic flow patterns have been studied for decades, primarily in large flies, such as houseflies, blowflies, and hover flies. The best-known optic-flow sensitive neurons are the large tangential cells of the dipteran lobula plate, whose visual-motion responses, and to a lesser extent, their morphology, have been explored using single-neuron neurophysiology. Most of these studies have focused on the large, Horizontal and Vertical System neurons, yet the lobula plate houses a much larger set of ‘optic-flow’ sensitive neurons, many of which have been challenging to unambiguously identify or to reliably target for functional studies. Here we report the comprehensive reconstruction and identification of the Lobula Plate Tangential Neurons in an Electron Microscopy (EM) volume of a wholeDrosophilabrain. This catalog of 58 LPT neurons (per brain hemisphere) contains many neurons that are described here for the first time and provides a basis for systematic investigation of the circuitry linking self-motion to locomotion control. Leveraging computational anatomy methods, we estimated the visual motion receptive fields of these neurons and compared their tuning to the visual consequence of body rotations and translational movements. We also matched these neurons, in most cases on a one-for-one basis, to stochastically labeled cells in genetic driver lines, to the mirror-symmetric neurons in the same EM brain volume, and to neurons in an additional EM data set. Using cell matches across data sets, we analyzed the integration of optic flow patterns by neurons downstream of the LPTs and find that most central brain neurons establish sharper selectivity for global optic flow patterns than their input neurons. Furthermore, we found that self-motion information extracted from optic flow is processed in distinct regions of the central brain, pointing to diverse foci for the generation of visual behaviors.
Improved science communication and student gains from an undergraduate biomedical research experience
Authors: Ward Donna , Han Yueh-Ying , Qoyawayma Christopher , Dukes April , McClendon T. Brooke , Manni Michelle L.
Published: October 2023

Summer research experiences expose undergraduate students to biomedical research in a laboratory or clinical setting, but often do not incorporate formal learning on scientific communication. Proper written and oral communication of science is essential to succeed in biomedical fields. This study examined whether participation in a science communication series (SCS) would increase gains in research and written communication abilities among students participated in the University of Pittsburgh School of Medicine Department of Pediatrics Summer Research Internship Program. Surveys were administered at the beginning and end of the program to evaluate their summer undergraduate research experience (SURE). Positive personal and professional gains in research and communication skills were identified through participation in both SURE and SCS. Participation in the SCS also significantly improved the quality and presentation of research abstracts. Focused learning in science communication during SUREs would improve undergraduate students’ personal and professional abilities in biomedical research and medicine.
Ribosomal S6 kinase 1 regulates ‘inflammaging’ via the senescence secretome
Authors: Gallage Suchira , Irvine Elaine E. , Pedroni Silvia M.A. , Barragan Avila Jose Efren , Khadayate Sanjay , Pombo Joaquim , Brookes Sharon , Heide Danijela , Dharmalingham Gopuraja , Choudhury Agharul I. , Herranz Nicolás , Vernia Santiago , Heikenwalder Mathias , Gil Jesús , Withers Dominic J.
Published: October 2023

Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream effector S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the broad range of age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). While both cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, the specific role of S6K1 signalling in these processes has not been determined. Here, focussing on mouse liver, a key target tissue for the beneficial metabolic effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showedin vivo thatS6K1deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1ý and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by loss of S6K could contribute to explain the beneficial effects of inhibiting this pathway on healthspan and lifespan.
OPUS-Rota5: A Highly Accurate Protein Side-chain Modeling Method with 3D-Unet and RotaFormer
Authors: Xu Gang , Luo Zhenwei , Yan Yaming , Wang Qinghua , Ma Jianpeng
Published: October 2023

Accurate protein side-chain modeling is crucial for protein folding and design. This is particularly true for molecular docking as ligands primarily interact with side chains. A protein structure with large errors in side chains has limited usage such as in drug design. Previous research on AlphaFold2 (AF2) predictions of GPCR targets indicates that the docking of natural ligands back on AF2-predicted structures has limited successful rate presumably due to large errors in side chains. Here, we introduce a two-stage side-chain modeling approach called OPUS-Rota5. It leverages a modified 3D-Unet to capture the local environmental features including ligand information of each residue, and then employs RotaFormer module to aggregate various types of feature. Evaluation on three test sets, including recently released targets from CAMEO and CASP15, reveals that side chains modeled by OPUS-Rota5 are significantly more accurate than those predicted by other methods. We also employ OPUS-Rota5 to refine the side chains of 25 GPCR targets predicted by AF2 and then performed docking of their natural ligands back with a significantly improved successful rate. Such results suggest that OPUS-Rota5 could be a valuable tool for molecular docking, particularly for targets with relatively accurate predicted backbones, but not side chains.
The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T-cell recognition by targeting CIITA
Authors: Maaßen Fabienne , Le-Trilling Vu Thuy Khanh , Betke Luisa , Bracht Thilo , Schuler Corinna , Bayer Malte , Belter Antonia , Becker Tanja , Katschinski Benjamin , Frappier Lori , Sitek Barbara , Fleischhauer Katharina , Trilling Mirko
Published: October 2023

Human cytomegalovirus (HCMV) is a relevant pathogen especially for individuals with impaired immunity. Harnessing potent immune antagonists, HCMV circumvents sterile immunity. Given that HCMV prevents the upregulation ofhuman leukocyte antigen(HLA)-DP and HLA-DR, we screened a library of HCMV genes by co-expression with the HLA class II (HLA-II)-inducing transcription coordinatorclass II transactivator(CIITA). We identified the latency regulator pUS28 as interaction factor and potent viral antagonist of CIITA-driven expression of CD74, HLA-DR, HLA-DM, HLA-DQ, and HLA-DP. Both wt-pUS28 and a mutant incapable to induce G-protein-coupled signaling (R129A), but not a mutant lacking the C-terminus, drastically reduced the CIITA protein abundance post-transcriptionally. While control CD4+ T cells from HCMV-seropositive individuals vigorously responded to CIITA-expressing cells decorated with HCMV antigens, pUS28 expression was sufficient to inhibit HLA-II induction and immune recognition by HCMV-specific CD4+ T cells. Our data uncover a mechanism employed by HCMV to evade HLA-II-mediated recognition by CD4+ T cells.
MOAL: Multi-Omic Analysis at Lab. A simplified methodology workflow to make reproducible omic bioanalysis
Authors: Dumont Florent , Ponsardin Emy , Bernadat Guillaume , Cohen-Kaminsky Sylvia
Published: October 2023

Omic data research projects are still developing today, but analysis suffers from not having a standardized workflow for biostatistics and functional integration steps that we gather here as bioanalysis. To make bioanalysis more reproducible and accessible, we created MOAL (Multi-Omic Analysis at Lab), an R package including a omic() function that automates most classical tasks. We reproduced in one go the results of a published dataset starting from unfiltered available data confirming the capabilities to automate the production of omic bioanalysis using MOAL.
The genetic architecture of protein interaction affinity and specificity
Authors: Bendel Alexandra M. , Faure André J. , Klein Dominique , Shimada Kenji , Kempf Georg , Cavadini Simone , Lehner Ben , Diss Guillaume
Published: October 2023

Proteins function in crowded cellular environments in which they must bind to specific target proteins but also avoid binding to many other off-target proteins. In large protein families this task is particularly challenging because many off-target proteins have very similar structures. How this specificity of physical protein-protein interactions in cellular networks is encoded and evolves is not very well understood. Here we address the question of specificity-encoding by comprehensively quantifying the effects of all mutations in one protein, JUN, on its binding to all other members of a protein family, the 54 human basic leucine zipper transcription factors. Fitting a global thermodynamic model to the data reveals that most affinity changing mutations equally affect JUN’s propensity to bind to all its interaction partners. Mutations that alter the specificity of binding are much rarer. These specificity-altering mutations are, however, distributed throughout the JUN interaction interface. JUN’s interaction specificity is encoded by both positive determinants that promote on-target interactions and negative determinants that prevent off-target interactions. Indeed, about half of the specificity-defining residues in JUN have dual functions and both promote on-target binding and prevent off-target binding. Whereas nearly all mutations that alter specificity are pleiotropic and also alter the affinity of binding to all interaction partners, the converse is not true with mutations outside of the interface able to tune affinity without affecting specificity. Our results provide the first global view of how mutations in a protein affect binding to all its potential interaction partners and reveal the distributed encoding of specificity and affinity in an interaction interface. They also show how the modular architecture of coiled-coils provides an elegant solution to the challenge of optimising specificity and affinity in a large protein family.
A novel approach to identify cross-identity peptides between Epstein-Barr virus and central nervous system proteins in Guillain-Barré syndrome and multiple sclerosis
Authors: do Patrocínio Helmut Kennedy Azevedo , Fiúza Tayná da Silva , Oliveira Jonas Ivan Nobre , Rodrigues-Neto João Firmino , Jerônimo Selma Maria Bezerra , de Souza Gustavo Antônio , Lima João Paulo Matos Santos
Published: October 2023

Background

Guillain-Barré Syndrome (GBS) and multiple sclerosis are autoimmune diseases associated with an immune system attack response against peripheral and central nervous system autoantigens, respectively. Given the potential of Epstein-Barr virus (EBV) as a risk factor for both multiple sclerosis and GBS, the present study aimed to identify crucial residues among potential EBV CD4+ T lymphocyte epitopes and nervous system proteins.

Methods

Public databases (Allele Frequency Net Database, Immune Epitope Database, Genevestigator and Protein Atlas) were used to select proteins abundant in the nervous system, EBV immunogenic proteins, and HLA haplotypes. Computational tools were employed for predicting HLA-binding peptides and immunogenicity. For this, we developed immuno-cross, a Python tool (https://github.com/evoMOL-Lab/immuno-cross) to compare residue identity among nonamers.

Results

We found ten proteins from the nervous system and 28 from EBV, which were used for predicting the binding peptides of 21 common HLAs in the world population. A total of 1411 haplotypes were distributed among 51 pairs of HLAs. Simulations were performed to determine whether nonamers from the EBV and nervous system proteins targeted TCR-contact residues. Then, three selection criteria were used, based on the relevance of each contact in the TCR-peptide-MHC interaction. The primary contact has to be located at position P5, and the positions P2, P3, and P8 were weighed as secondary, and P4, P6, and P7 were considered tertiary. Nonamers of EBV proteins and myelin proteins were combined in pairs and compared based on predefined selection criteria. The Periaxin protein had the highest number of nonamers pairs among PNS proteins, with 35 pairs. Four nonamers pairs from APLP1, two from CNP, and two from MBP bind to alleles of the haplotype DR-15.

Conclusions

The new approach proposed herein revealed that peptides derived from nervous system and EBV proteins share identical residues at critical contact points, which supports molecular mimicry. These findings suggest cross-reactivity between them and that the nonamer pairs identified with this approach have the potential to be an autoantigen. Experimental studies are needed to validate these findings.
Acute toxicity effects of pesticides on predatory snout mites (family Bdellidae)
Authors: Knapp Rosemary A. , Mata Luis , McDougall Robert , Yang Qiong , Hoffmann Ary A. , Umina Paul A.
Published: October 2023

Predatory mites biologically control a range of arthropod crop pests and are often central to agricultural IPM strategies globally. Conflict between chemical and biological pest control has prompted increasing interest in selective pesticides with fewer off-target impacts on beneficial invertebrates, including predatory mites. However, the range of predatory mite species included in standardised pesticide toxicity assessments does not match the diversity of naturally-occurring species contributing to biocontrol, with most testing carried out on species from the family Phytoseiidae. Here, we aim to bridge this knowledge gap by investigating the impacts of 22 agricultural pesticides on the predatory snout miteOdontoscirus lapidaria(Kramer) (family Bdellidae). Using internationally standardised testing methodologies, we identified several active ingredients with minimal impact onO. lapidariamortality, includingBacillus thuringiensis, nuclear polyhedrosis virus, flonicamid, afidopyropen, chlorantraniliprole and cyantraniliprole, which may therefore be good candidates for IPM strategies utilising both chemical and biological control. Importantly, we reveal differences between Bdellidae and Phytoseiidae in responses to a number of chemicals, including the miticides diafenthiuron and abamectin, highlighting the risk of making generalisations around acute toxicity based on tests with one beneficial mite family. We also explored the impacts of several pesticides on a second Bdellidae species and found differences in the response to chlorpyrifos compared withO. lapidaria, further highlighting the taxon-specific nature of non-target toxicity effects.
Pervasive polygenicity of complex traits inflates false positive rates in transcriptome-wide association studies
Authors: Liang Yanyu , Nyasimi Festus , Im Hae Kyung
Published: October 2023

Transcription-wide association studies (TWAS) and related methods (xWAS) have been widely adopted in genetic studies to understand molecular traits as mediators between genetic variation and disease. However, the effect of polygenicity on the validity of these mediator–trait association tests has largely been overlooked. Given the widespread polygenicity of complex traits, it is necessary to assess the validity and accuracy of these mediator–trait association tests. We found that for highly polygenic target traits, the standard test based on linear regression is inflated, leading to greatly increased false positives rates, especially in large sample sizes. Here, we show the extent of the inflation as a function of the underlying GWAS sample size and polygenic heritability of the target trait. To address this inflation, we propose an effective variance control method, similar to genomic control, but which allows for a different correction factor for each gene. Using simulated and real data, as well as theoretical derivations, we show that our method yields calibrated false positive rates, outperforming existing approaches. We further demonstrate that methods analogous to TWAS that associate genetic predictors of mediating traits with target traits suffer from similar inflation issues. We advise developers of genetic predictors for molecular traits (including polygenic risk scores, PRS) to compute and provide the necessary inflation parameters to ensure proper false positive control. Finally, we have updated our PrediXcan software package and resources to facilitate this correction for end users.
Duox activation inDrosophilaMalpighian tubules stimulates intestinal epithelial renewal through a countercurrent flow
Authors: Liu Zhonggeng , Zhang Hongyu , Lemaitre Bruno , Li Xiaoxue
Published: October 2023

The gut must perform a dual role of protecting the host against toxins and pathogens while harboring mutualistic microbiota. Previous studies suggested that the NADPH oxidase Duox contributes to intestinal homeostasis inDrosophilaby producing reactive oxygen species (ROS) in the gut that stimulate epithelial renewal. We find instead that ROS generated by Duox in the Malpighian tubules leads to the production of Upd3, which enters the gut and stimulates stem cell proliferation. We describe for the first time inDrosophilathe existence of a countercurrent flow system, which pushes tubule-derived Upd3 to the anterior part of the gut and stimulates epithelial renewal at a distance. Thus, our paper clarifies the role of Duox in gut homeostasis and describes the existence of retrograde fluid flow in the gut, collectively revealing a fascinating example of inter-organ communication.
Establishment of the Meyer-Overton correlation in an artificial membrane without protein
Authors: Matsumoto Atsushi , Uesono Yukifumi
Published: October 2023

Background

The potency of anesthetics with various structures increases exponentially with lipophilicity, which is the Meyer-Overton (MO) correlation discovered over 120 years ago. The MO correlation was also observed with various biological effects and various chemicals, including alcohols; thus, the correlation represents a fundamental relationship between chemicals and organisms. The MO correlation was explained by the lipid and protein theories, although the debate has not been resolved and the principle remains unknown.

Methods

The gentle hydration method was used to form giant unilamellar vesicles (GUVs) consisting of high- and low-melting phospholipids and cholesterol in the presence ofn-alcohols (C2-C12). Confocal fluorescence microscopy was used to determine the percentage of GUVs with domains in relation to the concentrations ofn-alcohols.

Results

n-Alcohols inhibited the domain formation of GUVs, and the half inhibitory concentration (IC50) in the aqueous phase decreased exponentially with increasing chain length (lipophilicity). In contrast, the membrane concentrations of alcohols for the inhibition, which is a product of the membrane-water partition coefficient and the IC50values, remained constant irrespective of the chain length.

Conclusions

The MO correlation is established in artificial lipid membrane, which supports the lipid theory. When alcohols reach the same critical concentration in the membrane, similar biological effects appear irrespective of the chain length, which is the principle underlying the MO correlation.

Summary Statement

n-Alcohols inhibit the domain formation of giant unilamellar vesicles according to the Meyer-Overton correlation.
Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation
Authors: Carter Zorana , Creamer Declan , Kouvidi Katerina , Grant Chris M.
Published: October 2023

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since no stress sensitivity has been reported in deletion mutants. We show here that Btn2 and Hsp42 are required for oxidant tolerance and act to sequestering misfolded proteins into defined PQC sites following ROS exposure. We have used the Sup35 translation termination factor as a model oxidized protein to show that protein aggregation is elevated and widespread in mutants lacking Btn2 and Hsp42. Oxidant-induced prion formation is also elevated in sequestrase mutants consistent with the idea that Btn2 and Hsp42 function to sequester oxidatively damaged Sup35, thus preventing templating to form its heritable prion form. Taken together, our data identify protein sequestration as key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.
Developing oak buds produce volatile emissions in response to herbivory by freshly hatched caterpillars
Authors: Graham Jessica L. , Staudt Michael , Buatois Bruno , Caro Samuel P.
Published: October 2023

Plant responses to damage by insectivorous herbivores is well documented in mature leaves. The resulting herbivore-induced plant volatiles (HIPVs) protect the plant by attracting carnivorous arthropods and even some insectivorous vertebrates, to parasitize or consume the plant invaders. However, very little is known about plant production of HIPVs in developing buds, particularly when herbivorous insects are too small to be considered a prey item. It is additionally unclear whether plants respond differently to generalist and specialist chewing insects that overlap in distribution. Therefore, we compared HIPV production of Downy oak (Quercus pubescensWilld.) buds infested with freshly hatched caterpillars ofTortrix viridana(specialist) andOperophtera brumata(generalist), against uninfested buds. Of the compounds identified in both years of the experiment, we found that (Z)-hex-3-enyl acetate, (E)-β-ocimene, acetophenone, linalool, (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), methyl salicylate,α-copaene,α-humulene, (E)-caryophyllene, and (E,E)-α-farnesene were higher in infested buds compared to controls. We found no difference in HIPV production between the specialist and the generalist herbivores. Production of HIPVs was also associated with leaf damage, with higher HIPV production in more severely attacked buds. Thus, our study shows that oak trees already start responding to insect herbivory before leaves are developed, by producing compounds similar to those found in damaged mature leaves. Future work should focus on how Downy oak may benefit from initiating alarm cues at a time when carnivorous arthropods and insectivorous vertebrates are unable to use herbivorous insects as host or food.