bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between glucocorticoid administration and outcomes in patients with ARDS based on the MIMIC-III database
Authors: Lu Zhonghua , Tang Yan , Liu Mei , Cao Lijun , Chen Hu , Yu WeiLi , Sun Yun
Published: August 2024

This study aimed to investigate the association between glucocorticoid administration and outcomes in critically ill patients with ARDS using the Medical Information Mart for Intensive Care (MIMIC)-III database. Data were collected from the MIMIC-III database, which consists of critically ill participants between 2001 and 2012 in the USA. A total of 1831 adult critically ill patients with ARDS were enrolled from the MIMIC-III database. The 60-day and in-hospital mortality, were the primary endpoints. Secondary outcomes included length of stay (LOS) in the hospital and intensive care unit (ICU), 28-day ventilator-free days, ICU mortality, and 28-day mortality. A total of 1831 patients were included in the data analysis. After propensity score (PS) matching, 464 patients diagnosed with ARDS were matched between the glucocorticoid treatment and control groups. Glucocorticoids were associated with increased in-hospital mortality [hazard ratio (HR) 1.32; 95% CI 1.01–1.71; P = .039], longer ICU stay [HR 2.25; 95% CI 0.84–3.65; P = .002], and shorter ventilation-free days at 28 days in all ARDS patients [HR −2.70; 95% CI −4.28–-1.13; P = .001]. The 60-day mortality was higher in the glucocorticoid group (44.83% vs 35.34%; P = .154; HR 1.24; 95% CI 0.93–1.66). Excluding the impact of the glucocorticoid initiation time, from day 15 to day 60, mortality was significantly higher in the glucocorticoid group compared to the non-glucocorticoid group (27.16% vs 12.70%; P < .001; HR 1.75; 95% CI 1.32–2.32). Glucocorticoid administration was associated with worse 60-day and in-hospital survival, longer ICU stay, and shorter ventilator-free days on day 28 in patients with ARDS. Our findings suggest careful consideration of glucocorticoids for ARDS.
The Impact of Childhood Trauma on the Negative Symptoms of Schizophrenia
Authors: Ware Katelyn , Misiak Blazej , Hamza Eid Abo , Nalla Shahad , Moustafa Ahmed A.
Published: August 2024

Schizophrenia is a debilitating mental health disorder that imposes profound economic, societal, and personal burdens. The negative symptoms of schizophrenia (i.e., blunted affect, alogia, anhedonia, asociality, and avolition) are highly prevalent and pervasive in the psychotic disorder and pose significant resistance to available treatment options. Traumatic childhood experiences are strongly linked with the risk of developing schizophrenia. Most prior studies have primarily focused on positive symptoms of schizophrenia (e.g., hallucinations and delusions), whereas less attention has been given to negative symptoms. The current study investigated the relationship between childhood trauma (i.e., physical abuse, sexual abuse, and emotional abuse and neglect) and negative symptoms in a sample of schizophrenia outpatients and healthy controls (n = 159 participants, including 99 patients with schizophrenia). The observations from the current study revealed that schizophrenia patients experienced a significantly greater degree of childhood trauma and negative symptoms than the control individuals. The results of the current study also indicated that more severe experiences of total childhood trauma (i.e., summation of all trauma types), physical abuse, and emotional neglect may increase the risk of schizophrenia patients reporting negative symptoms. However, childhood sexual and emotional abuse was found to have no impact on the degree of negative symptoms experienced by schizophrenia patients. Implications and limitations of the current study are discussed. In conclusion, we found that the severity of overall childhood trauma, physical abuse, and emotional neglect may play an important role in increasing the likelihood of schizophrenia patients reporting negative symptoms.
Psychological Factors of Overcoming Nonchemical Addictions
Authors: Maksymova Nataliia , Hrys Antonina , Maksymov Mykola , Krasilova Yuliia , Udovenko Julia
Published: August 2024

This comprehensive study delves into the escalating issue of nonchemical addictions, spurred by technological advancements. It thoroughly examines psychological factors and intervention strategies for these addictions, focusing on their development, influence on human behavior, and psychocorrection processes. Aiming to discover effective methods for correcting and preventing addictive behavior, the study incorporates a theoretical analysis of existing scientific approaches, characterizing various nonchemical addictions such as Internet and gadget use, gambling, and others. It scrutinizes the origins, proliferation, and interplay of these addictions with an individual's psychoemotional state, lifestyle, and external environment, underscoring the destructive nature of addiction on physiological, emotional, and social levels. A key component of the research is an empirical investigation among teenagers, a highly susceptible group, to assess gadget addiction levels, causative factors, and impacts. This research not only elucidates the essence and variety of nonchemical addictions and their correlation with mental health but also provides valuable insights into prevention and overcoming strategies. The practical significance of this study lies in its potential application for recognizing addiction signs and formulating effective management programs.
Father Engagement in Home Visiting: Findings From a Continuous Quality Improvement Learning Collaborative
Authors: Treat Amy E. , Milojevich Helen , Bard David
Published: August 2024

The present study describes the efforts of a home visiting (HV) continuous quality improvement learning collaborative aimed at increasing father engagement in HV and parenting. Local implementing agencies (n = 11) delivering 3 evidence-based HV models participated in the collaborative. Each agency developed and implemented 3 rapid-cycle Plan-Do-Study-Act (PDSA) projects to increase father engagement. Specific, Measurable, Achievable, Realistic, Time-bound (SMART) aims were used to guide development of change strategies and meaningful measurement goals. HV providers collected data from enrolled families (n = 714) about fathers’ level of parenting and HV involvement. Mean father engagement scores increased 39% from the first to the second assessment and over 60% of the PDSAs met or exceeded their SMART aim goal. Data suggest that fathers are open to participating in HV and are responsive to parenting guidance. In the current paper, we share engagement strategies and lessons learned during the collaborative.
Equipping the Public Health Workforce of the Future: Evaluation of an Evidence-Based Public Health Training Delivered Through Academic-Health Department Partnerships
Authors: Mazzucca-Ragan Stephanie , Brownson Carol A. , Crouch Maurine M. , Davis Sarah , Duffany Kathleen O. , Erwin Paul C. , Leiferman Jenn A. , McCormick Lisa C. , Walker Jeffery T. , Brownson Ross C.
Published: August 2024

Objective

Maintaining a skilled public health workforce is essential but challenging given high turnover and that few staff hold a public health degree. Situating workforce development within existing structures leverages the strengths of different organizations and can build relationships to address public health challenges and health equity. We implemented and evaluated an innovative, sustainable model to deliver an established evidence-based public health (EBPH) training collaboratively among Prevention Research Centers (PRC), local and state health departments, and Public Health Training Centers (PHTC).

Design

Quantitative data: quasi-experimental, 1-group pre-post. Qualitative data: cross-sectional. Data were collected between December 2021 and August 2022.

Setting

Four US sites, each a partnership between a PRC, local or state health department, and a PHTC.

Participants

Governmental public health staff and representatives from other organizations that implement public health programs in practice settings.

Main Outcome Measures

Course participants completed a pre- and postcourse survey self-rating 14 skills on a 5-point Likert scale. Differences were analyzed using mixed effects linear models. In-depth interviews (n = 15) were conducted with course faculty and partners to understand: (1) resources contributed, (2) barriers and facilitators, (3) benefits and challenges, and (4) resources needed to sustain this model. Interviews were transcribed verbatim, and a thematic analysis identified themes.

Results

Statistically significant increases in all skills were observed from pre- to postcourse (n = 241 at post, 90% response). The skills with the largest increases were understanding economic evaluation enough to inform decision-making (mean change = 1.22, standard error [SE] = 0.05) and developing an action plan (mean change = 1.07, SE = 0.07). Facilitators to delivering the course included having a shared goal of workforce development, existing course curricula, and dedicated funding for delivering the course.

Conclusions

Collaborative delivery of the EBPH training can ameliorate the effects of high staff turnover, strengthen academic-practice relationships, and promote population-wide health and health equity.
The web of intrigue: unraveling the role of NETosis within the gut-microbiome-immune-heart axis in acute myocardial infarction and heart failure
Authors: Yasuda Tai , Deans Kate , Shankar Aditi , Chilton Robert
Published: August 2024

This review summarizes the role of NETosis, or the release of neutrophil extracellular traps (NETs), and its interplay with the gut microbiome in acute myocardial infarction (AMI) and heart failure. NETosis contributes to inflammation, thrombosis, and atherothrombosis, all central to the pathophysiology of AMI and heart failure. NETosis can be activated by inflammation and dietary factors, indicating association with metabolic conditions. In cases of heart failure, NETosis is regulated by inflammatory molecules such as C-reactive protein (CRP), and Krüppel-like factor 2 (KLF2) – a protein that plays a role in controlling inflammation, and angiotensin II. Changes in the gut microbiome are linked to the severity and recovery of cardiac injury post-AMI and heart failure progression. The microbiome’s influence extends to immune modulation and inflammatory responses, potentially affecting NETosis.
Nursing management of intracranial hypertension in adults with severe brain injury in a neurosurgery intensive care unit: a best practice implementation project
Authors: Cheng Yi-Heng , Pan Jing-Da , Guo Hui-Ling , Mou Dan , Yan Hong-Bo , Chen Qi-Li , Li Wei-Ji , Huang Feng-Ai , Zhang Bi-Xia , Qiu Xin-Yan , Lei Qing-Mei , Xu Chuan-Hui , Ling Dong-Lan
Published: August 2024

Introduction:

The nursing management of intracranial hypertension in adult patients with severe brain injury is crucial for maintaining the stability of intracranial pressure, which ultimately improves patient outcomes.

Objectives:

This project aimed to implement evidence-based practices for the nursing management of intracranial hypertension in adult patients with severe brain injury.

Methods:

This evidence implementation project was conducted in a neurosurgery intensive care unit in a large tertiary hospital in Guangzhou, China. The project was guided by the JBI Evidence Implementation Framework, which is an audit and feedback model with seven stages. The Ottawa Model of Research Use was used to identify barriers and facilitators to best practices and to develop improvement strategies.

Results:

Thirty-three nurses and 50 patients with severe brain injury participated in the baseline and follow-up audits. After project implementation, follow-up audits revealed significantly improved compliance with best practices compared with baseline. Nurses’ awareness of best practices increased (41% to 96%); nursing assessment, monitoring, and interventions related to intracranial hypertension rose significantly (from 82%, 75%, and 59% to 98%, 84%, and 87%, respectively); and patients’ optic nerve sheath diameter was notably lower (6.002±0.677 mm to 5.698±0.730 mm).

Conclusions:

The systematic integration of consistent training and education, together with the refinement of care processes and the creation of relevant tools, led to a significant improvement in awareness and adherence to best practices. Further testing of this program in more hospitals is needed.

Spanish abstract:

http://links.lww.com/IJEBH/A243
Developing the Knowledge Translation and Impact Planner (KTIPs): a resource to enhance research translation and impact in health and rehabilitation
Authors: Doig Emmah , Auld Megan , Bennett Sally
Published: August 2024

Background:

Knowledge translation (KT) is an essential skill to assist health academics to better develop, disseminate, and implement research findings to improve health care quality and impact, but many academics lack knowledge and skills in this area.

Objectives:

This study aimed to describe the KT-informed approach used to develop the Knowledge Translation and Impact Planner (KTIPs) to improve the quality of KT planning, and to examine the acceptability of the KTIPs.

Methods:

The process of developing the tool is described, including use of published literature, application of integrated KT, and consultation with end-users (n=18), including university academics, higher degree research (HDR) candidates, and experts in the KT field. The Expert Recommendations for Implementing Change (ERIC) framework was used to categorize strategies used during pilot implementation. The tool includes a comprehensive instructional guide and accompanying template that systematically takes researchers through each step of the KT process: synthesis, exchange, dissemination, and implementation, as well as guidance on planning for impact following effective KT.

Results:

Academic staff and HDR candidate stakeholders, and comprehensive advice from experts shaped development of the tool. The tool went through three rounds of concurrent feedback with different end-users. End-users confirmed its acceptability, indicating the KTIPs was adaptable, comprehensive, instructional, and facilitated development of KT and impact plans addressing varied KT goals.

Conclusion:

The KTIPs was acceptable among academic staff and HDR candidates and facilitated the KT and impact planning process. The KTIPs is freely available and is designed to be navigated, completed, and saved electronically to facilitate implementation of developed plans.

Spanish abstract:

http://links.lww.com/IJEBH/A253
Successful Electroconvulsive Therapy in Aicardi-Goutières Syndrome Presenting Psychiatric Symptoms
Authors: Arévalo Gil Manuel Ernesto , Caballero González Montserrat , Linero Ríos Nicolás Alejandro
Published: August 2024

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder that primarily affects the central nervous system and is characterized by severe intellectual and physical disabilities. Although AGS traditionally exhibits nonpsychiatric symptoms, our case challenges this norm by presenting an 18-year-old male with AGS who developed distinctive psychiatric manifestations that required hospital admission.

The patient, diagnosed with spastic cerebral palsy and thrombotic vasculopathy, displayed abrupt behavioral disturbances, insomnia, and food aversion. Standard assessments revealed basal ganglia calcifications and chilblain-like lesions, and AGS was confirmed via genetic studies that showed a mutation in the SAMHD1 gene. Despite initial treatment with aripiprazole and diazepam, psychiatric symptoms persisted. This led to the initiation of electroconvulsive therapy (ECT) with substantial success, marking its first documented use in AGS.

In conclusion, this unique case broadens the comprehension of AGS, introducing psychiatric symptoms and pioneering the successful application of ECT. The intricate interplay of neurovascular involvement, genetic nuances, and innovative treatments underscores the complexity of AGS, encouraging further exploration of its diverse clinical spectrum and evolving therapeutic strategies.
Multi-omics Analysis Reveals Biomarkers that Contribute to Biological Age Rejuvenation in Response to Therapeutic Plasma Exchange
Authors: Fuentealba Matias , Kiprov Dobri , Schneider Kevin , Mu Wei-Chieh , Kumaar Prasanna Ashok , Kasler Herbert , Burton Jordan B. , Watson Mark , Halaweh Heather , King Christina D. , Yüksel Zehra Stara , Roska-Pamaong Chelo , Schilling Birgit , Verdin Eric , Furman David
Published: August 2024

The rapid increase in the proportion of older adults worldwide poses a huge challenge for healthcare systems. Currently, age-related chronic diseases account for over 90% of annual healthcare expenditures (more than $4.1 trillion) in the US alone. Thus, new therapies to improve healthspan and reduce the burden of chronic disease are needed. Herein, we conducted a phase 3 controlled clinical trial to evaluate the biological age (BA) effects of different therapeutic plasma exchange (TPE) modalities in ambulatory individuals. We longitudinally profiled the subjects to measure changes in the epigenome, proteome, metabolome, glycome, and shifts in immune cell composition (cytomics). We demonstrate that administering TPE supplemented with intravenous immunoglobulin (IVIG) (TPE-IVIG) on a biweekly regime (two sessions in the first week, followed by a three-week break) is a robust therapy for BA rejuvenation. This intervention induced coordinated cellular and molecular ‘omics’ responses, reversed age-related immune decline, and modulated key cellular senescence-associated proteins. Integrative analysis revealed baseline biomarkers associated with successful responses, indicating that TPE-IVIG treatment benefits those with a poorer baseline health status. In summary, this is the first multi-omics study to examine the effectiveness of various TPE modalities, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation.
An empirical cross-sectional analysis of the corrections in the New York Times’ COVID-19 coverage
Authors: Haslam Alyson , Harshman Quiana , Prasad Vinay
Published: August 2024

Background

To examine the errors and corrections in the New York Times (NYT) and to assess if there is an imbalance towards overstating the pandemic severity, which may support more extreme restrictions or understating the severity.

Methods

We conducted a retrospective cross-sectional analysis of COVID-19 articles that had corrections made and reported in the NYT “corrections page”. We categorized authors in a NYT COVID-19 article as a NYT reporter, NYT other, or independent author. We calculated the number and type of corrections by author type (NYT reporter, NYT other, and independent author) and number and percentage of corrections indicating an over- or under-statement of the COVID-19 situation.

Results

There were 576 total corrections for the included 486 articles. Forty-three percent (n=245) corrections specifically pertained to COVID-19. Compared to corrections not pertaining to COVID-19, corrections pertaining to COVID-19 were less likely to be about spelling (0% vs 23.6%), locations (1.2% vs 16.3%), or title/degree (0% vs 10.6%), and more likely to be about a vaccine/vaccination (21.2% vs 0.3%), incidence/cases of conditions (12.2% vs 0.3%), or disease testing (7.8% vs 0.3%; p<0.001).

Compared to corrections not pertaining to COVID-19, corrections pertaining to COVID-19 were less likely to result in an equivocal tone (16.7% vs 88.8%), but they were more likely to both overstate (54.7% vs 8.5%) and understate (23.7% vs 2.4%) the situation in the original text (p<0.001). Ten reporters (of 346) accounted for 24% of the corrections. The reporter with the single most corrections accounted for 7% of the corrections.

Conclusions

Differential tone of the corrections suggests bias in the reporting of COVID-19 topics in a top news outlet. The reporting of unbiased information is a first step in addressing issues of misinformation in public health messaging.
Clinical Assessment of a Plasma AT(N) Panel for Alzheimer’s Disease
Authors: Collier Bradley B. , Chappell Matthew R. , Brandon Whitney C. , Le Tien , Harris Ayla B. , Volpe Joseph M. , Martone Robert , Winslow John W. , Boles Deborah , Valcour Andre , Grant Russell P.
Published: August 2024

1.

Importance

With the emergence of new therapeutics for treatment of Alzheimer’s disease, there is currently a critical need for sensitive and accurate blood-based tests to assist with the diagnosis and treatment of Alzheimer’s disease.

Objective

To determine the clinical validity of an analytically validated plasma panel for the assessment of Alzheimer’s disease.

Design, Setting, and Participants

This cross-sectional study measured biomarkers representative of the Alzheimer’s disease AT(N) framework in 200 plasma specimens acquired from the Australian Imaging, Biomarker & Lifestyle (AIBL) Study of Ageing. Specimens were obtained from amyloid PET negative subjects classified as cognitively unimpaired (n = 75) and amyloid PET positive subjects classified as having no cognitive impairment (n = 49), mild cognitive impairment (n = 26), or Alzheimer’s disease dementia (n = 50).

Exposures

Amyloid PET and plasma Aβ42/40, pTau181, and NfL.

Main Outcomes and Measures

To assess the utility of the plasma panel to assess onset and progression of Alzheimer’s disease with respect to amyloid PET results and cognitive impairment.

Results

A difference was observed for each assay with respect to amyloid status (p<0.0001). Receiver operating characteristic (ROC) analysis of clinical specimen results from validated assays produced an area-under-the-curve (AUC) of 0.941 for Aβ42/40, 0.847 for pTau181, and 0.666 for NfL (p < 0.0001 for all biomarkers). The sensitivity (96.0%) and specificity (86.7%) observed for Aβ42/40 measurements meets current recommendations for triage testing. In addition, plasma levels of pTau181 and NfL were also found to increase with worsening cognitive impairment.

Conclusions and Relevance

The clinical concordance with amyloid PET for each biomarker is consistent with the biological progression of the AD continuum. As such, the availability of this AT(N) panel will provide clinicians with a simple blood-based means to provide evidence of AD pathological changes and could help identify AD patients much faster, shorten the overall AD patient diagnostic journey, and enable earlier treatment interventions.
HuTAge: a Comprehensive Human Tissue- and Cell-specific Ageing Signature Atlas
Authors: Himori Koichi , Bingyuan Zhang , Hatta Kazuki , Matsui Yusuke
Published: August 2024

Ageing is a complex process that involves interorgan and intercellular interactions. To obtain a clear understanding of ageing, cross-tissue single-cell data resources are required. However, a complete resource for humans is not available. To bridge this gap, we developed HuTAge, a comprehensive resource that integrates cross-tissue age-related information from The Genotype-Tissue Expression project with cross-tissue single-cell information from Tabula Sapiens to provide human tissue- and cell-specific ageing molecular information.

Availability and Implementation

HuTAge is implemented within an R Shiny application and can be freely accessed athttps://igcore.cloud/GerOmics/HuTAge/home. The source code is available athttps://github.com/matsui-lab/HuTAge.

Contact

himori.koichi.b5@f.mail.nagoya-u.ac.jp
All-Diamond Boron-Doped Microelectrodes for Neurochemical Sensing with Fast-Scan Cyclic Voltammetry
Authors: Gupta Bhavna , Kepros Brandon , Landgraf Jann B. , Becker Michael F. , Li Wen , Purcell Erin K. , Siegenthaler James R.
Published: August 2024

Neurochemical sensing with implantable devices has gained remarkable attention over the last few decades. A promising area of this research is the progress of novel electrodes as electrochemical tools for neurotransmitter detection in the brain. The boron-doped diamond (BDD) electrode is one such candidate that previously has been reported for its excellent electrochemical properties, including a wide working potential, superior chemical inertness and mechanical stability, good biocompatibility and resistance to fouling. Meanwhile, limited research has been conducted on the BDD as a microelectrode for neurochemical detection. Our team has developed a freestanding, all diamond microelectrode consisting of a boron-doped polycrystalline diamond core, encapsulated in an insulating polycrystalline diamond shell, with a cleaved planar tip for electrochemical sensing. This all-diamond electrode is advantageous due to its – (1) batch fabrication using wafer technology that eliminates traditional hand fabrication errors and inconsistencies, (2) absence of metal-based wires, or foundations, to improve biocompatibility and flexibility, and (3) sp3carbon surface with resistance to biofouling, i.e. adsorption of proteins or unwanted molecules at the electrode surface in a biological environment that impedes overall electrode performance. Here, we provide findings on further in vitro testing and development of the freestanding boron-doped diamond microelectrode (BDDME) for neurotransmitter detection using fast scan cyclic voltammetry (FSCV). In this report, we elaborate on – 1) an updated fabrication scheme and work flow to generate all diamond BDDMEs, 2) slow scan cyclic voltammetry measurements of reference and target analytes to understand basic electrochemical behavior of the electrode, and 3) FSCV characterization of common neurotransmitters, and overall favorability of serotonin (5-HT) detection. The BDDME showed a 2-fold increased FSCV response for 5-HT in comparison to dopamine (DA), with a limit of detection of 0.16 µM for 5-HT and 0.26 µM for DA. These results are intended to expand on the development of the next generation BDDME and guide future in vivo experiments, adding to the growing body of literature on implantable devices for neurochemical sensing.
Material Properties Of The Embryonic Small Intestine During Buckling Morphogenesis
Authors: Gao Jenny , Martin Lucia , Loffet Elise A. , Durel John F. , Oikonomou Panagiotis , Nerurkar Nandan L.
Published: August 2024

During embryonic development, tissues undergo dramatic deformations as functional morphologies are stereotypically sculpted from simple rudiments. Formation of healthy, functional organs therefore requires tight control over the material properties of embryonic tissues during development, yet the biological basis of embryonic tissue mechanics is poorly understood. The present study investigates the mechanics of the embryonic small intestine, a tissue that is compactly organized in the body cavity by a mechanical instability during development, wherein differential elongation rates between the intestinal tube and its attached mesentery create compressive forces that buckle the tube into loops with wavelength and curvature that are tightly conserved for a given species. Focusing on the intestinal tube, we combined micromechanical testing with histologic analyses and enzymatic degradation experiments to conclude that elastic fibers closely associated with intestinal smooth muscle layers are responsible for the bending stiffness of the tube, and for establishing its pronounced mechanical anisotropy. These findings provide insights into the developmental role of elastic fibers in controlling tissue stiffness, and raise new questions on the physiologic function of elastic fibers in the intestine during adulthood.

GRAPHICAL ABSTRACT
Epigenetic clock and lifespan prediction in the short-lived killifishNothobranchius furzeri
Authors: Giannuzzi Chiara , Baumgart Mario , Neri Francesco , Cellerino Alessandro
Published: August 2024

Aging, characterized by a gradual decline in organismal fitness, is the primary risk factor for numerous diseases including cancer, cardiovascular, and neurodegenerative disorders. The inter-individual variability in aging and disease susceptibility has led to the concept of “biological age,” an indirect measure of an individual’s relative fitness. Epigenetic changes, particularly DNA methylation, have emerged as reliable biomarkers for estimating biological age, leading to the development of predictive models known as epigenetic clocks. Initially created for humans, these clocks have been extended to various mammalian species. Here we set to expand these tools for the short-lived killifish,Nothobranchius furzeri. This species, with its remarkably short lifespan and expression of canonical aging hallmarks, offers a unique model for experimental aging studies.

We developed an epigenetic clock forN. furzeriusing reduced-representation bisulfite sequencing (RRBS) to analyze DNA methylation in brain and caudal fin tissues across different ages. Our study involved generating comprehensive DNA methylation datasets and employing machine learning to create predictive models based on individual CpG sites and co-methylation modules. These models demonstrated high accuracy in estimating chronological age, with a median absolute error of 3 weeks (7.5% of median lifespan) for a clock based on methylation of individual CpG and 1.5 weeks (3.7% of median lifespan) for an eigenvector-based clock.

Our investigation extended to assessing epigenetic age acceleration in different strains and the potential resetting effect of regeneration on fin tissue. Notably, our models indicated that a shorter-lived strain has accelerated epigenetic aging and that regeneration does not reset, but may decelerate epigenetic aging. Additionally, we used longitudinal data to develop an “epigenetic timer” for direct prediction of individual lifespan based on fin biopsies and eigenvector-based method, achieving a median absolute error of 4.5 weeks in the prediction of actual age of death. This surprising result underscores the existence of intrinsic determinants of lifespan established early in life.

This study presents the first epigenetic clocks and lifespan predictors forN. furzeri, highlighting their potential as aging biomarkers and sets the stage for future research on life-extending interventions in this model organism.
CRISPR-Cas9 mediated deletions ofFvMYB46reduces fruit set and biosynthesis of flavonoids inFragaria vesca
Authors: Rai Arti , Skårn Magne Nordang , Elameen Abdelhameed , Tengs Torstein , Amundsen Mathias Rudolf , Bjorå Oskar S. , Haugland Lisa K. , Yakovlev Igor A. , Brurberg May Bente , Thorstensen Tage
Published: August 2024

Secondary metabolites produced by the phenylpropanoid pathway, which is regulated by transcription factors of the MYB family, play crucial roles in this early phase of fruit development. The MYB46 transcription factor is a key regulator of secondary cell wall structure and lignin and flavonoid biosynthesis in many plants, but little is known about its activity in flowers and berries inF. vesca. For functional analysis of FvMYB46, we designed a CRISPR-Cas9 construct with an endogenousF. vescaspecific U6-promoter for efficient and specific expression of two gRNAs targeting the first exon ofFvMYB46. This generated mutants with an in frame 81-bp deletion of the first conserved MYB-domain or an out of frame 82-bp deletion potentially knocking out the gene function. In both types of mutant plants, pollen germination and the frequency of flowers developing to mature berries was significantly reduced compared to wild type. Transcriptomic analysis of flowers demonstrated that FvMYB46 is positively regulating the expression of genes involved in pollen germination, homeostasis of reactive oxygen species (ROS) and the phenylpropanoid pathway, including secondary cell wall biosynthesis and flavonoid biosynthesis, while has a negative impact on carbohydrate metabolism. In FvMYB46-mutant flowers, the flavonols and flavan-3-olscontent, especially epicatechin, quercetin-glucoside and kaempferol-3-coumaroylhexoside were reduced, and we observed a local reduction of lignin content in anthers. Together these results suggest that MYB46 control fertility and efficient fruit set by regulating cell wall structure, flavonoid biosynthesis, carbohydrate metabolism and ROS-signaling in flowers and early fruit development inF. vesca.
Conclusions about Neural Network to Brain Alignment are Profoundly Impacted by the Similarity Measure
Authors: Soni Ansh , Srivastava Sudhanshu , Kording Konrad , Khosla Meenakshi
Published: August 2024

Deep neural networks are popular models of brain activity, and many studies ask which neural networks provide the best fit. To make such comparisons, the papers use similarity measures such as Linear Predictivity or Representational Similarity Analysis (RSA). It is often assumed that these measures yield comparable results, making their choice inconsequential, but is it? Here we ask if and how the choice of measure affects conclusions. We find that the choice of measure influences layer-area correspondence as well as the ranking of models. We explore how these choices impact prior conclusions about which neural networks are most “brain-like”. Our results suggest that widely held conclusions regarding the relative alignment of different neural network models with brain activity have fragile foundations.
HLA polymorphism impacts immune response to neoepitopes and survival in APOBEC-mutated cancers
Authors: Borzooee Faezeh , Heravi-Moussavi Alireza , Larijani Mani
Published: August 2024

APOBEC3A and APOBEC3B genome mutators drive tumor evolution and drug resistance but may also generate neoepitopes for cytotoxic T cells (CTL). Given the extensive polymorphism of Class I HLA, the CTL immunopeptidome, comprised of all 8-11mer peptides presented by an individual’s six HLA class I alleles, varies person-to-person. We predicted the genome-wide impact of APOBEC3A/B-driven mutations on the immunogenicity of the immunopeptidomes of several thousand class I HLA alleles. Analysis of several billion APOBEC3-mediated mutations revealed that HLA class I alleles vary markedly in the susceptibility of their immunopeptidome to mutations. A subset of alleles of A1-A3 and B44 supertype supported increased neoepitopes. Notably, the immunogenicity changes supported by an individual’s HLA class I alleles in response to APOBEC3 mutations predict survival in APOBEC3-mutated tumors and correlate with CTL activation. Thus, immunogenicity changes mediated by APOBEC3s impact survival, making HLA class I genotype a prognostic marker in APOBEC3-mutated tumors.
Resurrection of the Plant Immune Receptor Sr50 to Overcome Pathogen Immune Evasion
Authors: Seong Kyungyong , Wei Wei , Sent Sophie C , Vega Brandon , Dee Amanda , Ramirez-Bernardino Griselda , Kumar Rakesh , Parra Lorena , Saur Isabel ML , Krasileva Ksenia
Published: August 2024

Pathogen-driven plant diseases cause significant crop losses worldwide. The introgression of intracellular nucleotide-binding leucine-rich repeat receptor (NLR) genes into elite crop cultivars is a common strategy for disease control, yet pathogens rapidly evolve to evade NLR-mediated immunity. The NLR geneSr50protects wheat against stem rust, a devastating disease caused by the fungal pathogenPuccinia graminisf. sp.tritici(Pgt). However, mutations in AvrSr50 allowedPgtto evade Sr50 recognition, leading to resistance breakdown. Advances in protein structure modeling can enable targeted NLR engineering to restore recognition of escaped effectors. Here, we combined iterative computational structural analyses and site-directed mutagenesis to engineer Sr50 recognition of AvrSr50QCMJC, aPgteffector variant that evades wild-type Sr50 detection. Derived by molecular docking, our initial structural model identified the K711D substitution in Sr50, which partially restored AvrSr50QCMJCrecognition. Enhancing Sr50K711Dexpression via strong promoters compensated for weak recognition and restored robust immune responses. Further structural refinements led to the generation of five double and two triple receptor mutants. These engineered mutants, absent in nature, showed robust dual recognition for AvrSr50 and AvrSr50QCMJCin bothNicotiana benthamianaand wheat protoplasts. Notably, the K711D substitution was essential and synergistic with the additional substitutions for AvrSr50QCMJCrecognition, demonstrating protein epistasis. Furthermore, this single substitution altered AlphaFold 2 predictions, enabling accurate modeling of the Sr50K711D–AvrSr50 complex structure, consistent with our final structural hypothesis. Collectively, this study outlines a framework for NLR engineering to counteract pathogen adaptation and provides novel Sr50 variants with potential for stem rust resistance.
Retinoic acid breakdown is required for proximodistal positional identity during amphibian limb regeneration
Authors: Duerr Timothy Joseph , Miller Melissa , Kumar Sage , Bakr Dareen , Griffiths Jackson R. , Gautham Aditya K. , Douglas Danielle , Voss S. Randal , Monaghan James R
Published: August 2024

Regenerating limbs retain their proximodistal (PD) positional identity following amputation. This positional identity is genetically encoded by PD patterning genes that instruct blastema cells to regenerate the appropriate PD limb segment. Retinoic acid (RA) is known to specify proximal limb identity, but how RA signaling levels are established in the blastema is unknown. Here, we show that RA breakdown via CYP26B1 is essential for determining RA signaling levels within blastemas. CYP26B1 inhibition molecularly reprograms distal blastemas into a more proximal identity, phenocopying the effects of administering excess RA. We identify Shox as an RA-responsive gene that is differentially expressed between proximally and distally amputated limbs. Ablation of Shox results in shortened limbs with proximal skeletal elements that fail to initiate endochondral ossification. These results suggest that PD positional identity is determined by RA degradation and RA-responsive genes that regulate PD skeletal element formation during limb regeneration.
Insights into the role of dopamine in rhizosphere microbiome assembly
Authors: Ding Yezhang , Vogel Hunter K. , Zhai Yi , Carlson Hans K. , Andeer Peter F. , Novak Vlastimil , Kim Nakian , Bowen Benjamin P. , Golini Amber N. , Kosina Suzanne M. , Coleman-Derr Devin , Vogel John P. , Northen Trent R.
Published: August 2024

Dopamine plays a critical role in animal physiology and interactions with gut microbes. In plants, dopamine is known to function in plant defense and abiotic stress tolerance; however, its role in mediating plant-microbiome interactions remains unexplored. In this study, we observed that dopamine is one of the most abundant exometabolites with natural variation in root exudates across diverseBrachypodium distachyonlines, suggesting a potential role in rhizosphere microbial assembly. To further investigate this, we colonized ten naturalB. distachyonlines with a 16-member bacterial synthetic community (SynCom), collected paired metabolomic and 16S rRNA sequencing data, and performed an association analysis. Our results revealed that dopamine levels in root exudates were significantly associated with the abundance of six SynCom members in a hydroponic system.In vitrogrowth studies demonstrated that dopamine had a significant effect on the growth of the same six bacterial isolates. Additionally, treating soil directly with dopamine enriched Actinobacteria, consistent with both the SynCom-dopamine correlations and the isolate growth results. Collectively, our study underscores the selective influence of dopamine on rhizosphere microbial communities, with implications for precision microbiome management.
Optimizing the detection of biological signals through a semi-automated feature selection tool
Authors: Arini Gabriel Santos , Mencucin Luiz Gabriel , de Felício Rafael , Feitosa Luís Guilherme Pereira , Rezende-Teixeira Paula , Tsuji Henrique , Pilon Alan , Pinho Danielle Rocha , Costa-Lotufo Letícia Veras , Lopes Norberto Peporine , Trivella Daniela Barretto Barbosa , da Silva Ricardo Roberto
Published: August 2024

Untargeted metabolomics is often used in studies that aim to trace the metabolic profile in a broad context, with the data-dependent acquisition (DDA) mode being the most commonly used method. However, this approach has the limitation that not all detected ions are fragmented in the data acquisition process, in addition to the lack of specificity regarding the process of fragmentation of biological signals. The present work aims to extend the detection of biological signals and contribute to overcoming the fragmentation limits of the DDA mode with a dynamic procedure that combines experimental and in silico approaches. Metabolomic analysis was performed on three different species of actinomycetes using liquid chromatography coupled to mass spectrometry. The data obtained were preprocessed by the MZmine software and processed by the custom package, RegFilter. RegFilter allowed the coverage of the entire chromatographic run and the selection of precursor ions for fragmentation that were previously missed in DDA mode. Most of the ions selected by the tool could be annotated through three levels of annotation, presenting biological relevant candidates. In addition, the tool offers the possibility of creating local spectral libraries curated according to the user’s interests. Thus, the adoption of a dynamic analysis flow using RegFilter allowed for detection optimization of biological signals, previously absent in the DDA mode. In addition, this workflow enables the creation and search of in-house tailored custom libraries.
DeepReweighting: Reparameterizing Force Field under Explainable Deep Learning Framework
Authors: Zhu Junjie , Li Zhengxin , Mu Junxi , Zhong Bozitao , Chern Haifeng
Published: August 2024

The analysis and prediction of biomolecule structures is indispensable in various research fields such as protein engineering, mRNA vaccine research and targeted drug screening. Molecular dynamics (MD) simulation is currently the most commonly used and reliable tool for sampling dynamic conformation ensemble of large biomolecules. However, the force fields commonly used in MD simulations are composed of empirical parameters, and their accuracy are limited by the training set data used for parameterizing the force field.In response to these challenges, we have developed a novel force field optimization strategy based on an explainable deep learning framework, DeepReweighting, for rapid and precise force field re-parameterization and optimization. DeepReweighting demonstrates a significant increase in re-parameterization efficiency compared to traditional Monte Carlo method and exhibits greater robustness. Furthermore, DeepReweighting can rapidly re-parameterize any existing or custom differentiable parameters in the force field, providing a faster and more accurate tool for optimizing and utilizing molecular force fields.
Causal modeling in large-scale data to improve identification of adults at risk for combined and common variable immunodeficiencies
Authors: Papanastasiou Giorgos , Scutari Marco , Tachdjian Raffi , Hernandez-Trujillo Vivian , Raasch Jason , Billmeyer Kaylyn , Vasilyev Nikolay V , Ivanov Vladimir
Published: August 2024

Combined immunodeficiencies (CID) and common variable immunodeficiencies (CVID), prevalent yet substantially underdiagnosed primary immunodeficiency disorders, necessitate improved early detection strategies. Leveraging large-scale electronic health record (EHR) data from four nationwide US cohorts, we developed a novel causal Bayesian Network (BN) model to unravel the complex interplay of antecedent clinical phenotypes associated with CID/CVID. Consensus directed acyclic graphs (DAGs) were constructed, which demonstrated robust predictive performance (ROC AUC in unseen data within each cohort ranged from 0.77-0.61) and generalizability (ROC AUC across all unseen cohort evaluations ranged from 0.72-0.56) in identifying CID/CVID across diverse patient populations, created using different inclusion criteria. These consensus DAGs elucidate causal relationships between comorbidities preceding CID/CVID diagnosis, including autoimmune and blood disorders, lymphomas, organ damage or inflammation, respiratory conditions, genetic anomalies, recurrent infections, and allergies. Further evaluation through causal inference and by expert clinical immunologists substantiates the clinical relevance of the identified phenotypic trajectories within the consensus DAGs. These findings hold promise for translation into improved clinical practice, potentially leading to earlier identification and intervention for adults at risk of CID/CVID.
Disruption of outdoor activities caused by wildfires increases disease circulation
Authors: Arregui-Garcıa Beatriz , Ascione Claudio , Pera Arianna , Wang Boxuan , Stocco Davide , Carlson Colin J. , Bansal Shweta , Valdano Eugenio , Pullano Giulia
Published: August 2024

Although climate change poses a well-established risk to human health, present-day health impacts, particularly those resulting from climate-induced behavioral changes, are under-quantified. Analyzing the U.S. West Coast wildfires of September 2020, we found that poor air quality drives people indoors, increasing the circulation of airborne pathogens like COVID-19. Indoor masking rates as low as 10% can mitigate this risk, offering a clear path to enhance public health responses during wildfires.
The role of the gluteofemoral adipose tissue in cerebrovascular disease risk: evidence from a mendelian randomization and mediation analysis
Authors: Myserlis Evangelos Pavlos , Georgakis Marios K. , Parodi Livia , Mayerhofer Ernst , Rosand Jonathan , Banerjee Chirantan , Anderson Christopher D.
Published: August 2024

Objective

To explore causal associations between BMI-independent body fat distribution profiles and cerebrovascular disease risk, and to investigate potential mediators underlying these associations.

Methods

Leveraging data from genome wide association studies of BMI-independent gluteofemoral (GFAT), abdominal subcutaneous (ASAT), and visceral (VAT) adipose tissue volumes in UK Biobank, we selected variants associated with each trait, and performed univariable and multivariable mendelian randomization (MR) analyses on ischemic stroke and subtypes (large artery (LAS), cardioembolic (CES), small vessel (SVS)). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and an MRI-confirmed lacunar stroke as positive controls. For significant associations, we explored the mediatory role of four possible mediator categories in mediation MR analyses.

Results

Higher genetically proxied, BMI-independent GFAT volume was associated with decreased risk of ischemic stroke (FDR-p=0.0084), LAS (FDR-p=0.019), SVS (FDR-p<0.001), CAD (FDR-p<0.001), MRI-confirmed lacunar stroke (FDR-p=0.0053), and lower mean cIMT (FDR-p=0.0023), but not CES (FDR-p=0.749). Associations were largely consistent in pleiotropy- and sample structure-robust analyses. No association was observed between genetically proxied ASAT or VAT volumes and ischemic stroke/subtypes risk. In multivariable MR analyses, GFAT showed the most consistent independent association with ischemic stroke, LAS, and SVS. Common vascular risk factors were the predominant mediators in the GFAT-cerebrovascular disease axis, while adipose-tissue-specific adiponectin and leptin mediated a proportion of ischemic stroke and CAD risk.

Interpretation

Genetically proxied, BMI-independent higher GFAT volume is associated with reduced cerebrovascular disease risk. Although this is largely mediated by common vascular risk factor modification, targeting adipose-tissue specific pathways may provide additional cardiovascular benefit.