bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Morbidity, Mortality, and Hospital Utilization Among Endoscopic Retrograde Cholangiopancreatography–related Hospitalizations
Authors: Kilani Yassine , Madi Mahmoud Y. , Alsakarneh Saqr , Puelo Priscila Castro , Aldiabat Mohammad , Syrilan Kym Yves , Ferreira Mariana Nunez , Gonzalez Mosquera Daniel Alejandro , Sohail Amir H. , Numan Laith , Kim Marina , Kiwan Wissam
Published: September 2024

Objective:

We aimed to assess the hospital frailty risk score on the inpatient mortality, morbidity, and health care resource utilization among endoscopic retrograde cholangiopancreatography (ERCP)-related hospitalizations.

Background:

Data regarding the inpatient mortality, morbidity, and health care resource utilization of ERCP among frail individuals remain limited.

Materials and Methods:

Using the Nationwide Inpatient Sample, we compared the odds of inpatient mortality and morbidity of ERCP-related hospitalizations among individuals with low frailty scores, intermediate frailty scores (IFSs), and high frailty scores (HFSs).

Results:

Overall, 776,025 ERCP-related hospitalizations were recorded from 2016 to 2020. 552,045 had a low frailty score, whereas 217,875 had an IFS, and 6105 had an HFS. Frail individuals had a 5-fold increase in mortality [IFS: adjusted odds ratio (aOR) = 4.81, 95% CI: 3.77-6.14; HFS: aOR = 4.62, 95% CI: 2.48-8.63]. An IFS was associated with a 24% increase in post-ERCP pancreatitis (aOR = 1.25, 95% CI: 1.11-1.41), a 3-fold increase in post-ERCP bleeding (aOR = 2.59, 95% CI: 1.82-3.67), and a 2-fold increase in post-ERCP duct perforation (aOR = 1.91, 95% CI: 1.38-2.64). Frail individuals experienced higher odds of in-hospital morbidity, including secondary sepsis, respiratory failure, acute kidney injury, cerebrovascular accidents, deep vein thrombosis, and pulmonary embolism.

Conclusions:

In summary, our study presents strong evidence in support of using the hospital frailty risk score as an index to predict mortality and morbidity during ERCP-related hospitalizations. Additional caution is warranted in the management of frail individuals undergoing ERCP.
The regulatory effect and mechanism of traditional Chinese medicine on the renal inflammatory signal transduction pathways in diabetic kidney disease: A review
Authors: Li Xiaoxia , Ma Guoping , Liu Jin , Zhang Guoqiang , Ma Kexin , Ding Baozhu , Liang Wenjie , Gao Weifang
Published: September 2024

Inflammatory injury is a critical factor in the occurrence and development of diabetic kidney disease (DKD). Signal transduction pathways such as the nuclear factor kappa beta (NF-κB), mitogen-activated protein kinase (MAPK), NOD-like receptor protein 3, and Smads are important mechanisms of inflammatory kidney injury in DKD, and the NF-κB pathway plays a key role. The inflammatory factor network formed after activation of the NF-κB pathway connects different signaling pathways and exacerbates renal inflammatory damage. Many traditional Chinese medicine compounds, single agents, effective components and active ingredients can regulate the expression of key molecules in the signaling pathways associated with inflammatory injury, such as transforming growth factor-β activated kinase 1, NF-κB, p38MAPK, NOD-like receptor protein 3, and Smad7. These treatments have the characteristics of multiple targets and have multiple and overlapping effects, which can treat DKD kidney inflammation and injury through multiple mechanisms and apply the “holistic concept” of traditional Chinese medicine.
Indications for testosterone therapy in men
Authors: Grossmann Mathis
Published: September 2024

Purpose of review

Testosterone replacement therapy for men with organic hypogonadism due to medical disease of the hypothalamic-pituitary-testicular (HPT) axis is uncontroversial. In these men, testosterone replacement replaces the deficient hormone and relieves the signs and symptoms of androgen deficiency. In contrast, the role of testosterone treatment in middle-aged or older men who have clinical features consistent with androgen deficiency accompanied by reductions in serum testosterone but lack identifiable HPT axis disease, a scenario sometimes referred to as ‘functional’ or ‘late onset’ hypogonadism, has been uncertain.

Recent findings

Three large randomized controlled clinical trials, discussed in this review, have reported new data regarding short-term to medium-term benefits and risks of testosterone therapy in such middle-aged and older men, including effects on sexual function, vitality, cognition and mood, glucose metabolism, physical function, hematologic parameters, as well as bone, cardiovascular and prostate health.

The findings of these trials allow for a more nuanced, personalized approach to testosterone therapy in such men. However, long-term benefits and risk of testosterone therapy (beyond 3–4 years) remain unknown.
Anxiety of Patients Undergoing Magnetic Resonance Imaging (MRI): The Effectiveness of Guided Mental Imagery
Authors: Shojaie Atena , Amiri Houshang , Dehesh Tania , Bagherian Behnaz
Published: September 2024

Background:

Since magnetic resonance imaging (MRI) is an extensively used and fundamental diagnostic imaging method and anxiety is one of the most important confounding factors in its performance, using guided imagery is recommended.

Objective:

This study aimed to assess the effectiveness of guided imagery on the anxiety of patients undergoing MRI in 2023.

Methods:

88 patients were randomly assigned to intervention and control groups. The intervention group listened to the nature-based guided imagery audio file during their scan, and the control group did not receive any intervention. Data were collected using demographic information and the Spielberger Anxiety Questionnaire before and after the scan.

Results:

There was no significant difference between the 2 groups before the intervention regarding demographic data and anxiety. In the intervention group, the mean anxiety decreased from 104.0 ± 14.6 to 92.4 ± 9.0, showing a significant reduction in the level of anxiety in both subscales (state and trait) and the total score (P < 0.001), compared with the control group and before the intervention.

Conclusion:

The results showed that using guided imagery could decrease anxiety levels in patients undergoing MRI. Since patients' anxiety is one of the most important nursing diagnoses, performing cognitive methods, including guided imagery, as a simple, safe, inexpensive, and effective intervention should be considered.
Identification of Key Genes and Signaling Pathways in Microtia by the Analysis of Transcriptomics
Authors: Shang Qiaoli , He Leren
Published: September 2024

Microtia is a common, complex congenital birth defect in the world. According to the degree of deformity, microtia can be divided into several types. However, it is unclear whether the different degrees of microtia share a common underlying mechanism. In this study, the transcriptomic profiles of auricular cartilage tissues from mild and severe deformities and controls were detected by RNA-seq technology. Relative mRNA abundances were compared and assessed for their function and putative involvement in microtia. A total of 1058, 1648, and 1150 differentially expressed genes (DEGs) were identified in MIC-Ⅱ-vs-NOR, MIC-Ⅲ-vs-NOR, and MIC-Ⅲ-vs-MIC-Ⅱ groups, respectively. Further bioinformatics analysis revealed that some DEGs displayed potential associations with microtia. In the lobular type microtia (MIC-Ⅱ), the changed biological processes mainly enriched in mitosis. And in the conchal type microtia (MIC-Ⅲ), the changed biological processes were not only enriched in mitosis but also in migration. In addition, we also found that the dysregulation of the key genes IL-6 and COMP and key signaling pathway PI3K-AKT signaling pathway were associated with the development of microtia. This study was a report on the transcriptomic detection and bioinformatics analysis of auricular samples of different degrees of microtia. Through this study, we initially explored the correlation of different degrees of microtia pathogenesis, but further research is still needed to confirm these mechanisms.
Assessment of twelve echovirus virus-neutralisation assays in Europe: recommendations for harmonisation of non-polio enterovirus sero-surveillance studies
Authors: Couderé Karen , Benschop Kimberley S.M. , Koen Gerrit , van Eijk Hetty , Harvala Heli , Bailly Jean-Luc , Bessaud Maël , Kamau Everlyn , Simon Isabelle , Joffret Marie-Line , Nikolaeva-Glomb Lubomira , Georgieva Irina , Stoyanova Asya , Diedrich Sabine , Böttcher Sindy , Cabrerizo Maria , Tabain Irena , Hruškar Željka , Stevanović Vladimir , Susi Petri , Hietanen Eero , Palminha Paula , Rainetová Petra , Baicus Anda , Kristensen Maartje , Pajkrt Dasja , Murk Jean-Luc , Wolthers Katja C. ,   European non-polio enterovirus network
Published: September 2024

Non-polio enteroviruses (NPEV) cause significant disease worldwide. Population-based sero-surveillance, by measuring antibodies against specific NPEV types, provides additional information on past circulation and the prediction for future upsurges. Virus neutralisation assays (VNA), the current method of choice for measuring NPEV type specific antibodies, are not entirely standardised. Via the European Non-Polio Enterovirus Network, we organised a VNA quality assessment in which twelve laboratories participated. We provided five echovirus (E) types (E1, E18, E30 G2, E30 G6 and E6) and intravenous immunoglobulins (IVIG) as a sample for the NPEV VNA quality assessment. Differences in VNA protocols and neutralising Ab (nAb) titres were found between the participating laboratories with geometric coefficients of variation ranging from 10.3–62.9 %. Mixed-effects regression analysis indicated a small but significant effect of type of cell line used. Harmonisation of cell line passage number, however, did not improve variation between laboratories. Calibration by making use of a reference sample, reduced variation between laboratories but differences in nAb titres remained higher than two log2 dilution steps. In conclusion, sero-surveillance data from different laboratories should be compared with caution and standardised protocols are needed.
A comparative genomic and phenotypic study of Vibrio cholerae model strains using hybrid sequencing
Authors: Lorentzen Øyvind M. , Bleis Christina , Abel Sören
Published: September 2024

Next-generation sequencing methods have become essential for studying bacterial biology and pathogenesis, often depending on high-quality, closed genomes. In this study, we utilized a hybrid sequencing approach to assemble the genome of C6706, a widely used Vibrio cholerae model strain. We present a manually curated annotation of the genome, enhancing user accessibility by linking each coding sequence to its counterpart in N16961, the first sequenced V. cholerae isolate and a commonly used reference genome. Comparative genomic analysis between V. cholerae C6706 and N16961 uncovered multiple genetic differences in genes associated with key biological functions. To determine whether these genetic variations result in phenotypic differences, we compared several phenotypes relevant to V. cholerae pathogenicity like genetic stability, acid sensitivity, biofilm formation and motility. Notably, V. cholerae N16961 exhibited greater motility and reduced biofilm formation compared to V. cholerae C6706. These phenotypic differences appear to be mediated by variations in quorum sensing and cyclic di-GMP signalling pathways between the strains. This study provides valuable insights into the regulation of biofilm formation and motility in V. cholerae.
Subnational tailoring of malaria interventions for strategic planning and prioritization: experience and perspectives of five malaria programs
Authors: Onyango Letitia , Ouédraogo-Ametchie Ghislaine , Ozodiegwu Ifeoma , Galatas Beatriz , Gerardin Jaline
Published: September 2024

In the context of high malaria burden and insufficient resources, several national malaria programs (NMPs) used subnational tailoring (SNT) as a tool for evidence-informed decision-making on their national malaria strategic plans and funding requests. The SNT process included the formation of an SNT team, determination of criteria for targeting interventions, data assembly and review, stratification, application of targeting criteria to determine preliminary plans, mathematical modeling, finalization of intervention plans, and monitoring and evaluation of the eventual implemented plan, all under the leadership of the NMP. Analysis steps of SNT were supported by the World Health Organization (WHO) and other partners. As SNT was a new approach, this study used semi-structured interviews to understand the perspectives and experiences of personnel from five NMPs (Burkina Faso, Ghana, Guinea, Nigeria, and Togo) that undertook SNT between 2019 and 2023. Participants reported that SNT outputs were used to inform national strategic plans and prioritized plans, that the process incentivized improvements in data collection and data quality, and that NMPs were strongly motivated to grow their capacity to conduct more steps of the SNT analysis process internally. Major challenges included the lack of resources available to implement the full strategic plans as well as challenges with data quality and alignment of stakeholders. Participants reported a moderate to strong sense of ownership over the process and were eager to extend, adapt, and reuse the SNT process in the future. Among countries supported by WHO, SNT was well-accepted and allowed NMPs to successfully use evidence to inform their decision-making, advocate for themselves, and mobilize resources.
Effects of cladribine on intrathecal and peripheral B and plasma cells
Authors: Allen-Philbey Kimberley , Stephenson Sophie , Doody Gina , MacDougall Amy , Aboulwafaali Mohammad , Ammoscato Francesca , Andrews Michael , Gnanapavan Sharmilee , Giovannoni Gavin , Grigoriadou Sofia , Hickey Alaco , Holden David W. , Lock Helen , Papachatzaki Maria , Redha Iman , Baker David , Tooze Reuben , Schmierer Klaus
Published: September 2024

Background

Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis. However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited.

Objectives

The CLADRIPLAS study examined the effect of cladribine on peripheral and intrathecal B and plasma cell biology in people with MS.

Methods

Thirty-eight people with progressive MS ineligible for- or rejecting-treatment with licenced therapies were recruited and supplied a baseline lumbar puncture. Those exhibiting gadolinium-enhancing or new/enlarging T2 magnetic resonance imaging lesions and/or elevated neurofilament levels were offered subcutaneous cladribine (Litak®). Seven people were eligible; one person died before treatment, and only five completed the first year of treatment. Twenty-two ineligible people were willing to provide a repeat lumbar puncture twelve months later.

Results

The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band (cOCB) result between the cladribine-treated and untreated group. This is probably explained by microarray andin vitrostudies, which demonstrated that plasmablasts and notably long-lived plasma cells are relatively resistant to the cytotoxic effect of cladribine compared to memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation.

Discussion

CLADRIPLAS indicates that cOCB are not rapidly eliminated in most people with MS. This may be explained by the relative lack of direct cytotoxic action of cladribine on long-lived plasma cells.
SMART MRS: A Simulated MEGA-PRESS Artifacts Toolbox for GABA-edited MRS
Authors: Bugler Hanna , Shamaei Amirmohammad , Souza Roberto , Harris Ashley D.
Published: September 2024

Purpose

To create a Python-based toolbox to simulate commonly occurring artifacts for single voxel Gamma-Aminobutyric Acid (GABA)-edited Magnetic Resonance Spectroscopy (MRS) data.

Methods

The toolbox was designed to maximize user flexibility and contains artifact, applied, input/output (I/O), and support functions. The artifact functions can produce spurious echoes, eddy currents, nuisance peaks, line broadening, baseline contamination, linear frequency drifts, and frequency and phase shift artifacts. Applied functions combine or apply specific parameter values to produce recognizable effects such as lipid peak and motion contamination. I/O and support functions provide additional functionality to accommodate different kinds of input data (MATLAB FID-A .mat files, nifti-mrs files), which vary by domain (time vs. frequency), collection type (edited vs. non-edited) and scale.

Results

Users may provide some or all of the required artifact function parameter values which will result in artifacts of different appearances. Visual assessment confirms the resemblance of simulated compared toin vivoproduced artifacts.

Conclusion

Our pip installable Python artifact simulated toolboxSMART_MRSis meant to enhance the diversity and quality of existing simulated edited-MRS data and is complementary to existing MRS simulation software.
Halfpipe: a tool for analyzing metabolic labeling RNA-seq data to quantify RNA half-lives
Authors: Müller Jason M. , Altendorfer Elisabeth , Freier Susanne , Moos Katharina , Mayer Andreas , Tresch Achim
Published: September 2024

We introduce Halfpipe, a tool for analyzing RNA-seq data from metabolic RNA labeling experiments. Its main features are the absolute quantification of 4sU-labeling-induced T>C conversions in the data as generated by SLAM-seq, calculating the proportion of newly synthesized transcripts, and estimating subcellular RNA half-lives. Halfpipe excels at correcting critical biases caused by typically low labeling efficiency. We measure and compare the RNA metabolism in the G1 phase and during the mitosis of synchronized human cells. We find that RNA half-lives of constantly expressed RNAs are similar in mitosis and G1 phase, suggesting that RNA stability of those genes is constant throughout the cell cycle. Our estimates correlate well with literature values and with known RNA sequence features. Halfpipe is freely available athttps://github.com/IMSBCompBio/Halfpipe
The linear correlation between genome size and the size of the non-transcribing region
Authors: Zhang-Ren Chen
Published: September 2024

Background

The genome sizes of organisms vary widely (C-value paradox). There are non-transcribing regions in the genome that neither encode proteins nor RNA entities. There are several hypotheses about the function of these regions: one suggests that they are unannotated functional areas, while another views them as genomic isolation zones that reduce mutations in coding regions.

Method

Statistical analysis was conducted on the transcribing regions (including areas annotated as genes and transcribed pseudogenes) and non-transcribing regions, protein-coding regions (Coding sequence, CDS), and genome sizes using annotation files from 63,866 species genomes in the NCBI RefSeq database.

Results

There is a significant linear relationship between the size of non-transcribing genomic regions and overall genome size across species, with varying proportional coefficients among different phyla (realms for viruses). As genome size increases, the proportion of non-transcribing regions gradually rises, eventually approaching a linear proportional limit, resembling one arm of hyperbolic functions. Eukaryotes show high linear correlation, with the highest in Streptophyta and the lowest in Apicomplexa. In eukaryotes, the size of the coding region increases with genome size, but the increasing trend diminishes (proportionally decreases). In non-eukaryotes, the size of the coding region maintains a linear relationship with genome size.

Conclusion

The size of non-transcribing region in species may be subject to some strict quantitative control mechanism, showing that genome and non-transcribing genome sizes increase proportionally with the expansion of the transcribing genome, indicating a strict balance between expansion and energy conservation. The proportion of non-transcribed genomes in eukaryotes is conservative (although the sequences are not), and the presence of non-transcribing genomes has significant implications for the evolution or survival of species. Thus, I propose a new hypothesis about the non-transcribing genome, that it is a space for generating new genes from scratch, and the different proportional coefficients among phyla are due to their different positions in energy transfer.

Graphic Abstract
A lymphoid tissue chemokine checkpoint prevents loss of CD8+T cell functionality
Authors: Altenburger Lukas M. , Claudino Carvoeiro Daniela , Dehio Philippe , Zhou Jianwen , Laura Chiara , Katoch Mitali , Krüger Caroline , Barreto de Albuquerque Juliana , Pfenninger Petra , Martínez Magdaleno Jose , Abe Jun , Mehling Matthias , Dengjel Jörn , Iannacone Matteo , Gheinani Ali Hashemi , Stein Jens V.
Published: September 2024

The generation of effector CD8+T cells (TEFF) requires activation of naive CD8+T cells (TN) by dendritic cells (DCs) within lymphoid tissue. To date, it remains elusive how the duration of TN-DC interactions and integration of activation signals are controlledin vivo. Here, we report that lymphoid stroma-secreted ligands for CCR7 constrained interaction duration by gradually inducing CD8+T cell release from DCs. At late time points of interactions, CCR7 ligands repositioned the F-actin-promoting factor DOCK2 away from the DC interface to enable CD8+T cell detachment, proliferation onset and acquisition of cytotoxicity. Lack of CCR7 signaling, as duringex vivoactivation or in chronically inflamed lymphoid tissue, caused sustained T cell-DC interactions, and generated dysfunctional TEFFwith high expression of inhibitory receptors, impaired antimicrobial activity, and poor recall responses. In sum, our findings uncover that lymphoid stromal chemokines act as built-in “disruptors” of T cell-DC interactions for long-term preservation of TEFFfunctionality.
Multi-generational biotic stress increases the rate of spontaneous epimutations in a ROS1-dependent manner
Authors: Zhang Zhilin , Parker Adam Hannan , Symeonidi Aikaterini , Wilkinson Samuel W. , Stassen Joost H. M. , Smith Lisa M. , Ton Jurriaan , Johannes Frank
Published: September 2024

Mistakes in the maintenance of CG methylation are a source of spontaneous epimutations in plants that can be inherited across generations. The extent to which these stochastic events are affected by prolonged exposure to biotic and abiotic stress remains poorly characterized. Here, we grew Arabidopsis Mutation Accumulation (MA) lines for 12 generations in the presence of two biotic stressors:Pseudomonas syringae(Pst) and salicylic acid (SA). We found that multi-generational exposure to Pst and SA led to an 18%-32% and 23%-61% increase in the genome-wide epimutation rate, respectively. These rate increases were mainly targeted to subsets of genes characterized by low steady-state methylation (LM), on average, and a lack of transcriptional responsiveness to stress. We show that these effects are mediated by the DNA demethylaseRepressor of Silencing 1(ROS1). Loss of ROS1 not only buffers transcriptional responses to biotic stress, but also stabilizes epimutation rates, particularly in LM genes, rendering them insensitive to environmental perturbations. Taken together, our data demonstrates that stress can induce heritable epimutations and highlights a ROS1-mediated link between transcriptional plasticity and DNA methylation maintenance fidelity over generations.
CanDrivR-CS: A Cancer-Specific Machine Learning Framework for Distinguishing Recurrent and Rare Variants
Authors: Francis Amy , Campbell Colin , Gaunt Tom
Published: September 2024

Motivation

Missense variants play a crucial role in cancer development, and distinguishing between those that frequently occur in cancer genomes and those that are rare may provide valuable insights into important functional mechanisms and consequences. Specifically, if common variants confer growth advantages, they may have undergone positive selection across different patients due to similar selection pressures. Moreover, studies have demonstrated the significance of rare mutations that arise as resistance mechanisms in response to drug treatment. This highlights the importance of understanding the role of both recurrent and rare variants in cancer. In addition to this, most existing tools for variant prediction focus on distinguishing variants found in normal and disease populations, often without considering the specific disease contexts in which these variants arise. Instead, they typically build predictors that generalise across all diseases. Here, we introduceCanDrivR-CS, a set of cancer-specific gradient boosting models designed to distinguish between rare and recurrent cancer variants.

Results

We curated missense variant data from the International Cancer Genome Consortium (ICGC). Cancer-type-specific models significantly outperformed a baseline pan-cancer model, achieving a maximum leave-one-group-out cross-validation (LOGO-CV) F1 score of up to 90% forCanDrivRSKCM (Skin Cutaneous Melanoma)and 89% forCanDrivR-SKCA (Skin Adenocarcinoma), compared to 79.2% for the baseline model. Notably, DNA shape properties consistently ranked among the top features for distinguishing recurrent and rare variants across all cancers. Specifically, recurrent missense variants frequently occurred in DNA bends and rolls, potentially implicating regions prone to DNA replication errors and acting as mutational hotspots.

Availability and Implementation

All training and test data, and Python code are available in ourCanDrivR-CSGitHub repository:https://github.com/amyfrancis97/CanDrivR-CS.
Discovering Governing Equations of Biological Systems through Representation Learning and Sparse Model Discovery
Authors: Sadria Mehrshad , Swaroop Vasu
Published: September 2024

Understanding the governing rules of complex biological systems remains a significant challenge due to the nonlinear, high-dimensional nature of biological data. In this study, we present CLERA, a novel end-to-end computational framework designed to uncover parsimonious dynamical models and identify active gene programs from single-cell RNA sequencing data. By integrating a supervised autoencoder architecture with Sparse Identification of Nonlinear Dynamics, CLERA leverages prior knowledge to simultaneously extract related low-dimensional embeddings and uncovers the underlying dynamical systems that drive the processes. Through the analysis of both synthetic and biological datasets, CLERA demonstrates robust performance in reconstructing gene expression dynamics, identifying key regulatory genes, and capturing temporal patterns across distinct cell types. CLERA’s ability to generate dynamic interaction networks, combined with network rewiring using Personalized PageRank to highlight central genes and active gene programs, offers new insights into the complex regulatory mechanisms underlying cellular processes.
Integrative Modeling of Protein-Polypeptide Complexes by Bayesian Model Selection using AlphaFold and NMR Chemical Shift Perturbation Data
Authors: Benavides Tiburon L. , Montelione Gaetano T.
Published: September 2024

Protein-polypeptide interactions, including those involving intrinsically-disordered peptides and intrinsically-disordered regions of protein binding partners, are crucial for many biological functions. However, experimental structure determination of protein-peptide complexes can be challenging. Computational methods, while promising, generally require experimental data for validation and refinement. Here we presentCSP_Rank, an integrated modeling approach to determine the structures of protein-peptide complexes. This method combines AlphaFold2 (AF2) enhanced sampling methods with a Bayesian conformational selection process based on experimental Nuclear Magnetic Resonance (NMR) Chemical Shift Perturbation (CSP) data and AF2 confidence metrics. Using a curated dataset of 108 protein-peptide complexes from the Biological Magnetic Resonance Data Bank (BMRB), we observe that while AF2 typically yields models with excellent consistency with experimental CSP data, applying enhanced sampling followed by data-guided conformational selection routinely results in ensembles of structures with improved agreement with NMR observables. For two systems, we cross-validate the CSP-selected models using independently acquired nuclear Overhauser effect (NOE) NMR data and demonstrate how CSP and NMR can be combined using our Bayesian framework for model selection.CSP_Rankis a novel method for integrative modeling of protein-peptide complexes and has broad implications for studies of protein-peptide interactions and aiding in understanding their biological functions.
Single-Session Feasibility of a Wearable Music-based Rhythmic Auditory Stimulation Device to Improve Walking in Knee Osteoarthritis
Authors: Yang Yiwen , Okamura Michele , Kim Ehyun , Kumar Deepak
Published: September 2024

Objective

We examined the single-session feasibility of a wearable device to deliver a closed-loop music-based rhythmic auditory stimulation (RAS) walking intervention in people with knee osteoarthritis (OA).

Methods

Fifteen participants with knee OA (age 70.0 ± 8.6 years; BMI 29.4±5.9 kg/m2; 10 women) complete a supervised 30-minute walking session using a wearable music-based RAS device. The device included shoe-worn inertial sensors, headphones, and a proprietary algorithm embedded in a touchscreen control unit. The algorithm continuously assessed users’ gait and adjusted the tempo of the selected music to encourage improvements in gait quality. Spatiotemporal gait measures were collected using separate inertial sensors during the session. We examined change in gait during the session, participant’s report of exertion, and participant-reported acceptability.

Results

On average, participants showed ∼12%, 30%, and 15% increases in cadence, gait speed, and stride length, respectively without worsening variability or symmetry from before to during the RAS session. Of the 15 participants, 9/15, 11/15, and 9/15 showed ≥ 10% increase in cadence, gait speed, and stride length, respectively. Rating of Perceived Exertion was on average 13.3 (range 12-15). There were no serious adverse events and small increase in knee pain that resolved at the end of the session. Participants were highly accepting of the device and willing to use it at home for longer periods.

Conclusion

A single-session feasibility study of a wearable closed-loop music-based RAS device in people with knee OA demonstrated increases in cadence and gait speed while safely walking at a moderate exercise intensity under supervision.
A quantitative approach to evidence triangulation: development of a framework to address rigour and relevance
Authors: Shapland Chin Yang , Bell Joshua A. , Borges Maria-Carolina , Goncalves Soares Ana , Davey Smith George , Gaunt Tom R. , Lawlor Deborah A. , McGuinness Luke A. , Tilling Kate , Higgins Julian P.T.
Published: September 2024

Triangulation is an approach to strengthening causal inference by integrating evidence from multiple sources. Most studies using triangulation have qualitatively examined whether different studies agree upon the presence of a causal effect, rather than estimated the effect by quantitatively integrating results. Here, we develop a framework for quantitative triangulation. We first address how to relate study specific research questions to an overall target causal question (relevance), and then assess the directions and magnitudes of bias in each study (rigour), before combining the results using meta-analysis adjusted for the biases.

We illustrate our framework by triangulating evidence from randomized controlled trials (RCTs), Mendelian randomization (MR) and conventional multivariable regression (MVR) to estimate the effect of beta-carotene on coronary heart disease (CHD) and cardiovascular disease (CVD). Five RCTs and one MR study showed little evidence of a causal relationship between beta-carotene and CHD (relative risk (RR)=1.00 with 95% CI=0.98 to 1.01 and RR=1.02 with 95% CI=0.98 to 1.07, respectively). 13 MVR studies indicated that high intake of beta-carotene reduces CHD risk (RR=0.83 with 95% CI0.76 to 0.91). After applying our framework, the three study designs agreed that there is little evidence of an effect of beta-carotene intake on the risk of CHD (RR=1.01 with 95% CI=0.99 to 1.02). Findings were similar for CVD.

Our framework shows how to address rigour and relevance quantitatively when triangulating evidence from different study designs. We highlight the importance of explicitly defining the target and study-specific research questions.
Plasma proteomics reveals the potential causal impact of extracellular matrix proteins on abdominal aortic aneurysm
Authors: Khodursky Samuel , Yuan Shuai , Spin Joshua M. , Tsao Philip S. , Levin Michael G. , Damrauer Scott M.
Published: September 2024

Background

Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous associated loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAA have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAA.

Methods

Causal inference was performed using two-sample Mendelian randomization (MR). For AAA, we utilized recently published summary statistics from a multi-population genome-wide association (GWAS) meta-analysis including 39,221 individuals with, and 1,086,107 individuals without AAA from 14 cohorts. We used protein quantitative trait loci (pQTLs) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2,783 plasma proteins for possible causal effects on AAA using two-sample MR with inverse variance weighting and common sensitivity analyses to evaluate the MR assumptions. Bayesian colocalization and gene ontology (GO) enrichment analyses provided additional insights.

Results

MR identified 90 plasma proteins associated with AAA at FDR<0.05, with 25 supported by colocalization analysis. Among those supported by both MR and colocalization were previously experimentally validated proteins such as PCSK9 (OR 1.3; 95%CI 1.2-1.4; P<1e-10), LTBP4 (OR 3.4; 95%CI 2.6-4.6; P<1e-10) and COL6A3 (OR 0.6; 95%CI 0.5-0.7; P<1e-6). GO analysis revealed enrichment of proteins found in extracellular matrix (ECM, OR 7.8; P<1e-4), some with maximal mRNA levels in aortic tissue. Bi-directional MR suggested plasma level changes were not caused by liability to AAA itself. We then investigated whether variants responsible for expression changes in the aorta also influenced plasma levels and AAA risk. Colocalization analysis showed that an aortic expression quantitative trait locus (eQTL) for COL6A3, and a splicing quantitative trait locus (sQTL) for LTBP4 colocalized with their respective plasma pQTLs and AAA signals (posterior probabilities 0.84 and 0.89, respectively).

Conclusions

Our results highlight proteins and pathways with potential causal effects on AAA, providing a foundation for future functional experiments. These findings suggest a possible causal pathway whereby genetic variation affecting ECM proteins expressed in the aortic wall cause their levels to change in blood plasma, influencing development of AAA.
Linguistic Dynamics: Women vs. the General Population in Reddit’s ADHD Discussions
Authors: Rahman Muhammad Mahbubur
Published: September 2024

Understanding how language reflects the experiences of individuals with attention-deficit/hyperactivity disorder (ADHD) is important for developing targeted support strategies. This research investigates the linguistic patterns exhibited in discussions within women-centric and general ADHD population on Reddit, exploring how gender influences language use. By analyzing language, the study uncovers unique linguistic patterns and illuminates how women with ADHD express themselves, share experiences, and seek support compared to the general ADHD population. By leveraging deep learning-based embedding, clustering and named entity recognition, the study conducts a comprehensive analysis. Results reveal that women with ADHD emphasize themes like “ADHD Awareness and Diagnosis” and “Emotional Well-being”. Conversely, the general population highlights “Medication and Treatment”, and “Work and Academic Challenges”. Statistical tests confirm significant differences in both linguistics and emotional expression between the two groups, emphasizing the importance of gender considerations in understanding ADHD language nuances and tailoring interventions accordingly.
Effect of Beta Blockers on Exercise Capacity, Diastolic Function, and Quality of Life in Patients with Heart Failure with Preserved Ejection Fraction: A Secondary Analysis of INDIE-HFpEF and RELAX
Authors: Weigel Frank R. , Miller Alexandria , Patel Vaiibhav , Haas Garrie , Smith Sakima
Published: September 2024

Background

The use of beta blockers in patients with heart failure with preserved ejection fraction (HFpEF) is common, with about 75% of patients in recent landmark clinical trials on beta blockers. Though the implementation of this medication class is routine, there is sparse data to support their use. Furthermore, beta blocker effects on exercise capacity, diastolic function, and quality of life in HFpEF patients is unclear.

Methods

A retrospective cohort study was completed using patient-level data from two prior randomized trials. Cohorts were generated based on beta blocker use at the time of trial enrollment, demographic information was compared. Primary outcomes assessed were exercise capacity, diastolic function, and quality of life metrics. The results of baseline testing were utilized to avoid potential bias from each trial’s intervention.

Results

After multivariate linear regression, HFpEF patients on beta blockers had no difference in exercise capacity (peak VO2 (mL/kg/min): 12.5 vs 13.5, P=0.933), diastolic function (average E/e’: 16 vs 14, P=0.125; left atrial volume index (mL/m2): 47 vs 42, P=0.665; peak tricuspid regurgitation velocity (m/s): 2.85 vs 2.70, P=0.165), or quality of life survey scores (KCCQ: 54 vs 60, P=0.206; MLHFQ 44 vs 48, P=0.762) compared to those not taking beta blockers.

Conclusions

In this secondary analysis of patient-level data, there was no association with beta blocker use and worsened exercise capacity, diastolic function, or quality of life in HFpEF patients. Randomized controlled trials are necessary to definitively determine the clinical and functional impact of beta blockers in HFpEF.

RESEARCH PERSPECTIVE

In this secondary analysis or INDIE-HFpEF and RELAX, there was no significant association with beta blocker use and worsened exercise capacity, diastolic dysfunction, or quality of life in HFpEF patients.

With little available evidence to suggest clinical or functional benefits from implementation of beta blockers in HFpEF, randomized controlled trials are warranted to more definitively evaluate the potential effects of this medication class.

Evaluating unique HFpEF phenotypes with different comorbidity profiles would provide specific insights that could be translated to the clinical management of HFpEF patients.
Solid-State Nanopore Real Time Assay for Monitoring Cas9 Endonuclease Reactivity
Authors: Chau Chalmers C. , Weckman Nicole E. , Thomson Emma E. , Actis Paolo
Published: September 2024

The field of nanopore sensing is now moving beyond nucleic acid sequencing. An exciting new avenue is the use of nanopore platforms for the monitoring of biochemical reactions. Biological nanopores have been used to investigate the dynamics of enzymatic reactions but solid-state nanopore approaches have lagged. This is partially due to the necessity of using higher salt conditions (e.g.4M LiCl) to improve the signal-to-noise ratio. These conditions are often incompatible with monitoring biological activities such as restriction enzyme and CRISPR-Cas9 endonuclease activities, as their abilities to digest DNA are largely abolished under high salt conditions. We pioneered a polymer electrolyte based solid-state nanopore approach that can maintain a high signal-to-noise ratio even at a physiologically relevant salt concentration. Based on this, we report monitoring the endonuclease activities at physiological salt conditions in real time with a polymer electrolyte nanopore. We successfully monitor the dsDNA cleavage activity of the restriction enzyme SwaI in in a range of digestion buffers and the off-target activity of CRISPR-Cas9 RNP endonuclease in the presence of single base pair mismatches. This approach enables solid-state nanopore technology for the dynamic monitoring of biochemical reactions at single molecule resolution.
Biological oscillations without genetic oscillator or external forcing
Authors: Vandenbroucke Vincent , Henrion Lucas , Delvigne Frank
Published: September 2024

Oscillators play a crucial role in biological systems, enabling complex behaviors such as cell division and circadian cycles. As a result, researchers have been studying both natural and synthetic genetic oscillators. Interestingly, oscillating cellular behaviors are often linked to biological oscillators. In a previous study [1], we discovered sustained oscillations related to phenotypic switching in different cellular systems and gene circuits, without any external forcing. These oscillations were associated with the induction of slow-growing phenotypes. In this paper, we aim to understand when and why such phenotypic instabilities can arise, leading to oscillations in cell populations. To achieve this, we developed a simple mathematical model of a stress phenotype and solved it analytically to determine the range of operating conditions in continuous culture for which the gene expression should not reach a stable equilibrium. This range of conditions is expected to exhibit an unstable biological behavior, which we verified in Bacillus subtilis cultures. Our findings demonstrate that oscillations can occur in the absence of genetic oscillators or external forcing, departing from the classical Monod model. While we explain this phenomenon for the stress response in continuous culture, it is likely that similar unexpected behavior can occur in any long-term culture where there is environmental feedback connecting the inducer and the cellular system considered.
Endosymbionts impact ladybird predation rates of aphids in a temperature-dependent manner
Authors: Thomsen Katrine Bitsch , Ross Perran A. , Gill Alex , Yang Qiong , Stelmach Monica , Callahan Ashley , Ørsted Michael , Hoffmann Ary A. , Kristensen Torsten N.
Published: September 2024

Aphids are worldwide pests causing major economic losses to growers. Current management strategies rely heavily on pesticides, but some effective pesticides are being withdrawn and the efficiency of remaining pesticides is also decreasing as aphids build up resistance. Biological control using predators can provide a sustainable alternative to pesticides under some circumstances, while the deliberate introduction of facultative bacterial endosymbionts that induce host fitness costs and reduce plant virus transmission provides another potential future strategy to combat aphid pests. However, new control options should not be antagonistic, with the concern that the effectiveness of biocontrol might be altered by endosymbiont presence in hosts. We, therefore, tested if predation by two aphidophagous ladybirds,Adalia bipunctataandHarmonia conformis, on the green peach aphid,Myzus persicae, and the oat aphid,Rhopalosiphum padi, was affected by transinfectedRickettsiella viridisand both native and transinfectedRegiella insecticolaendosymbionts at different temperatures. The predation rate of aphids infected by either endosymbiont was higher at 14 ° C than the rate for uninfected aphids of both species, but the opposite pattern was apparent at 20 °C and for one host-endosymbiont combination at 26 °C. Overall, the results showed that higher temperatures increased predation, while differences between intermediate and low temperatures were species-dependent. No transmission of endosymbionts from aphid to ladybird through predation was detected. These findings point to a lack of consistent effects of the investigated endosymbionts on predation rates in these major aphid pests. The temperature dependence of endosymbiont-predation interactions suggests that the impact of seasonal climate should be considered when assessing the potential of endosymbionts in a biological control setting.

HIGHLIGHTS

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Aphid endosymbiont effects on ladybird predation rates are temperature-dependent

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Ladybird predation rate of aphids increases as temperature rises

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Prey (aphid) endosymbionts are not transferred to predators (ladybirds)
TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice
Authors: Zolkiewski L. , Simon M. , Harrison J. , Vizor L. , Ireson E. , Moir L. , Yon M. , Beresford L. , Rodrigues A. , Hill S. , Hawkins J. , Bentley L. , Cox R. D. , Dumbell R.
Published: September 2024

Adipose tissue distribution in the body is an indicator of metabolic disease risk, independent of body mass index (BMI), and is indirectly measured by waist-hip-ratio (WHR). T-Box transcription factor-15 (TBX15) has been implicated in regulation of adipose distribution in multiple human and mouse studies, and theTBX15-WARS2genome-wide association study locus has been associated with BMI-adjusted-WHR signals in multiple investigations. As a potential mediator of this signal, we investigated the role ofTbx15using heterozygous and homozygous mouse knockout models to determine if loss of this gene alters adipose physiology, and to identify the transcriptional network regulated byTbx15in adipose tissue and preadipocyte cells. In a metabolic phenotyping experiment we provided either low fat diet (LFD) or high fat diet (HFD) to male and female heterozygousTbx15+/-and wildtypeTbx15+/+mice from weaning and maintained for 24 weeks. OnlyTbx15+/-mice maintained on LFD weighed less than wildtype LFD controls, and female LFDTbx15+/-mice had lower fat mass overall. We found that in LFDTbx15+/-mice, multiple visceral fat depots weighed less than wildtype controls, and this was maintained when corrected for body mass for both gonadal and mesenteric visceral adipose depots. When comparing adipocyte size in multiple adipose depots, some reduction in number of larger adipocytes was detected in the perirenal adipose tissue of female HFDTbx15+/-vsTbx15+/+mice, mesenteric adipose tissue from female LFDTbx15+/-vsTbx15+/+mice and male HFDTbx15+/-vsTbx15+/+mice. RNA-sequencing of subcutaneous (inguinal) adipose tissues from 12-week old male and female knockoutTbx15-/-,Tbx15+/-andTbx15+/+mice raised on a standard chow diet identified 897 upregulated genes and 2328 downregulated genes in femaleTbx15-/-mice compared toTbx15+/+mice. We then combined this dataset with TBX15 ChIP-sequencing data from mouse preadipocyte 3T3-L1 cells overexpressingTBX15to identify acredible setof genes directly regulated by TBX15. These 52 genes were enriched for B- and T-cell receptor signalling, JAK-STAT signalling and haematopoietic cell lineage pathways; suggesting a direct regulatory role for TBX15 in these pathways in adipose tissue. Together, these data highlight a role for TBX15 in regulation of differential adipose tissue expansion, particularly under low caloric conditions. Further, we identify a potentially important role for TBX15 in the well described adipocyte-immune cell crosstalk associated with obesity and type 2 diabetes mellitus.