bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute cortical stroke alters neural activity in subthalamic nucleus, which correlates with motor disability in rats
Authors: Deng Zhengdao , Laughlin Myles MC , Kilic Ugur , Asamoah Boateng , Nuttin Bart
Published: January 2025

Objectives

We aimed to investigate the impact of acute cortical stroke (ACS) on neural activity in subthalamic nucleus (STN). We then examined the correlation between changes in STN activity and motor disability.

Methods

Forty-four Sprague-Dawley rats were used. While rats were anesthetized, we inserted electrodes in STN and induced an ACS by creating photothrombotic lesion in ipsilateral motor cortex. Local field potentials were recorded before and after ACS. The motor behavior was assessed before and after ACS using single pellet reaching task.

Results

Rats experienced significant motor disability after ACS. STN firing rate significantly decreased after ACS. Additionally, delta (0.5-4 Hz) and gamma (50-140 Hz) power significantly decreased after ACS. Furthermore, the decrease in delta mean power correlated with decreases in success rate (r =0.77,p=0.009) and first try success rate (r =0.69,p=0.028). The decreases in gamma mean power (r =0.68,p=0.029) and gamma peak power (r =0.74,p=0.015) correlated with the decrease in success rate. The decrease in gamma power significantly correlated with the decreased STN firing rate. However, decreased delta power exhibited no correlation with decreased gamma power.

Interpretation

ACS causes abnormal STN activity, which correlated with motor disability. Post-stroke STN inhibition may partially compensate for ACS. However, it could also lead to pathological consequences. This STN abnormal activity may serve as a biomarker for motor disability severity after ACS. Furthermore, our findings may provide a possibility for developing neuromodulation strategies, allowing to mitigate post-stroke motor disability through modulating abnormal STN activity.
Delineation and monitoring of the T cell repertoire of adoptive cell transfer product during the treatment of advanced melanoma
Authors: Kerr Cameron , Soleimani Shirin , Mulder David T. , Nabbi Arash , Gray Diana , Pedersen Stephanie , Sotov Valentin , Sudhaman Sumedha , Nguyen Linh , Hirano Naoto , Ohashi Pamela S. , Butler Marcus O. , Pugh Trevor J.
Published: January 2025

Background

Adoptive cell transfer (ACT) of Tumour-infiltrating lymphocytes (TIL) is an investigational treatment for solid tumours, with preliminary results showing objective clinical responses in some metastatic melanoma patients. The ability to sequence and track the T cell repertoire throughout ACT of TILs provides a method to identify T cell repertoire features associated with patients’ benefit from ACT. Identification of response biomarkers for patients receiving ACT of TILs has been limited. Conflicting evidence is observed in biomarkers such as the number of TILs in the infusion product, with some studies suggesting a relationship with response and others not. Meanwhile, certain potential biomarkers, such as the diversity of the post- infusion peripheral repertoire, have not yet been studied.

Methods

In this study, we sought to determine 1) the efficacy of using CapTCR-seq to track TILs in serial blood draws over the course of ACT immunotherapy 2) whether peripheral T cell repertoire statistics are associated with ACT response. In this study, 9 patients with cutaneous (n = 7) or mucosal (n = 2) melanoma received TIL ACT after chemotherapeutic depletion. Hybrid- capture CapTCR-seq was conducted on pre-/post-transfer peripheral blood mononuclear cells (PBMC) and cell-free DNA.

Results

Comparison between PBMC DNA, PBMC RNA, and circulating free DNA (cfDNA) repertoires demonstrated an increased presence of shared T cell clonotypes post-infusion when compared with baseline samples. Higher abundance of TIL clonotypes in the PBMC baseline and post-infusion DNA T cell repertoires and the presence of shared DNA T cell clonotypes between timepoints was seen in responders when compared with non-responders according to RECIST criteria.

Conclusion

These results demonstrate effective tracking methodologies and suggest a predictive role for baseline repertoire statistics in response to the ACT of TILs.

Trial registration

University Health Network Research Ethics Board #11-0683
Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe – first phase I/II human clinical study
Authors: van Tienen Florence H.J. , Hoeijmakers Janneke G.J. , van der Leij Christiaan , Timmer Erika , Wanders Nikki , Lindsey Patrick J. , Yi Fangzheng , Lin Fong , Kortekaas Susanne P.M. , Roelofs Helene , Westra Inge M. , Meij Pauline , Wijnen Lambert A.C.M. , de Coo Irenaeus F.M. , Smeets Hubert J.M.
Published: January 2025

Progressive myopathy and exercise intolerance significantly impair quality of life in over 50% of m.3243A>G mutation carriers, with no curative therapy currently available. We hypothesize that intra-arterial administration of autologous, mtDNA mutation-free myogenic stem cells, mesoangioblasts, can reduce mutation load, enhance oxidative phosphorylation, and improve muscle function. To test this, the tibialis anterior muscles of three m.3243A>G mutation carriers were damaged by eccentric exercise before infusion of 50 million /kg autologous mesoangioblasts into the left anterior tibial artery. The right tibialis anterior muscle served as control. Expanded mesoangioblasts had a mutation load of <15%, though culturing increased this by 7–15%. Infusion caused mild, transient discomfort without serious adverse events or vascular obstructions, as confirmed by angiography. Blood and muscle biopsies revealed no systemic or local inflammation at 24 hours and 4 weeks post-transplantation. Biopsies of the treated muscle suggested mesoangioblast migration and early signs of regeneration. This first-in-human study demonstrates that intra-arterial administration of autologous mesoangioblasts is safe, with promising, though inconclusive, evidence for muscle regeneration and mesoangioblast homing. These findings support further investigation into the therapeutic potential of mesoangioblasts for treating myopathy in m.3243A>G mutation carriers.
Recipient Cells Are the Source of Hematologic Malignancies After Graft Failure and Mixed Chimerism in Adults with SCD
Authors: Ali Mohamed A. E. , Limerick Emily M. , Hsieh Matthew M. , Upadhyaya Kalpana , Xu Xin , Phang Oswald , Mukendi Jean Pierre Kambala , Calvo Katherine R. , Lopez-Ocasio Maria , Dagur Pradeep , Fitzhugh Courtney D.
Published: January 2025

Non-myeloablative hematopoietic cell transplantation (HCT) is a curative option for individuals with sickle cell disease (SCD). Our traditional goal with this approach has been to achieve a state of mixed donor/recipient chimerism. Recently, we reported an increased risk of hematologic malignancies (HMs) in adults with SCD following graft failure or mixed chimerism. To evaluate the origin of HMs, we performed chimerism analyses of 5 patients with SCD who developed HMs after non-myeloablative HCT. DNA was extracted from sorted peripheral blood or bone marrow cells representing mature cell lineages or leukemic blasts and subjected to chimerism analysis by PCR amplification of polymorphic short tandem repeats. Unlike mature cell lineages in patients with mixed chimerism, which still showed a donor-derived fraction of cells, leukemic blast cells were found to be 99-100% recipient-derived in all patients. Non-myeloablative conditioning allows for the survival of patients’ cells that might harbor pre-leukemic clones that possess the capacity to evolve under genotoxic or environmental stress into malignancies; therefore, we have modified our HCT protocols with the goal of full donor chimerism to mitigate the risk of HM development.
Understanding Data Differences across the ENACT Federated Research Network
Authors: Wang Taowei D , Henderson Darren W , Weber Griffin M , Morris Michele , Sadhu Eugene M , Murphy Shawn N , Visweswaran Shyam , Klann Jeff G
Published: January 2025

Objective

Federated research networks, like Evolve to Next-Gen Accrual of patients to Clinical Trials (ENACT), aim to facilitate medical research by exchanging electronic health record (EHR) data. However, poor data quality can hinder this goal. While networks typically set guidelines and standards to address this problem, we developed an organically evolving, data-centric method using patient counts to identify data quality issues, applicable even to sites not yet in the network.

Materials and Methods

We distribute high-performance patient counting scripts as part of Integrating Biology at the Bedside (i2b2), which all ENACT sites operate. They produce counts of patients associated with ENACT ontology terms for each site. At the ENACT Hub, our pipeline aggregates site-contributed counts to produce network statistics, which our self-service web application, Data Quality Explorer (DQE), ingests to help sites conduct data quality investigation relative to the network.

Results

Thirteen ENACT sites have contributed their patient counts, and currently seven sites have signed up to use DQE to analyze data quality issues. We announced a call to all ENACT sites to contribute additional patient counts.

Discussion

Identifying site data quality problems relative to the network is novel. Using a metric based on evolving network statistics complements rigid data quality checks. It is adaptable to any network and has low barriers of entry, with patient counting being the sole requirement.

Conclusion

We implemented a metric for conducting data quality investigation in ENACT using patient counting and network statistics. Our end-to-end pipeline is privacy-preserving and the underlying design is generalizable.
The Pandemic Journaling Project: A new dataset of first-person accounts of the COVID-19 pandemic
Authors: Willen Sarah S. , Mason Katherine A. , Wurtz Heather M. , Karcher Sebastian
Published: January 2025

Background

The rapid global spread of the COVID-19 pandemic affected different regions, communities, and individuals in vastly different ways that interdisciplinary social scientists are well-positioned to document and investigate. This paper describes an innovative mixed-methods dataset generated by a research study that was designed to chronicle and preserve evidence of the pandemic’s divergent effects: the Pandemic Journaling Project (PJP). The dataset was generated by leveraging digital technology to invite ordinary people around the world to document the impact of the COVID-19 pandemic on their everyday lives over a two-year period (May 2020-May 2022) using text, images, and audio.

Methods and Findings

PJP’s weekly, online, bilingual (English/Spanish) journaling platform was open to anyone with access to a smartphone or computer, including teens aged 15–17 with permission of a parent or guardian. Participants first completed a baseline quantitative survey, after which they were invited to create two journal entries in response to suggested narrative prompts. In each subsequent week, participants received weekly invitations to contribute via their choice of email or SMS (text message). Each invitation included a link to that week’s journaling prompts and accompanying survey questions.

Participants could join the project at any point between May 2020 and May 2022. PJP employed a cohort design. Regardless of when they joined, all received the narrative prompts and accompanying survey questions in the same order. Participants could stop participating at any point, and they could later restart if they wished. The project welcomed any interested participant and sought to capture as broad a range of perspectives as possible, while also taking measures to include voices that might not otherwise be preserved in the historical record.

The project launched in May 2020. In the two years it operated as a weekly journaling platform, PJP generated nearly 27,000 individual journal entries from over 1,800 people in 55 countries around the world. Data from PJP’s first phase (PJP-1) are now accessible at the Qualitative Data Repository (QDR) at Syracuse University.

Conclusions

The first phase of the Pandemic Journaling Project has produced an innovative multimedia dataset that can support studies of how the COVID-19 pandemic has affected a wide range of communities across a wide range of outcomes including mental health, reproductive health, vaccine hesitancy, and trust in health professionals, among others. The dataset is available to researchers who follow established data protection protocols and procedures. These data protection measures will be in place for 25 years, through 2049, after which all PJP-1 data will become a fully accessible public archive via QDR.
Gender and mental health of adolescents: a conceptual framework developed in a Delphi study
Authors: Alaze Anita , Grosser John , Razum Oliver , Miani Céline
Published: January 2025

Objective

Adolescence is one of the most neglected developmental phases, yet there are few phases in the life course when gender socialisation is as intense. So far, no framework or theory exists that theoretically conceptualises gender norms, gender attitudes and mental health outcomes. To address this gap, we aim to develop a conceptual framework that illustrates the interplay of key constructs in the gendered pathways of health, using the Delphi technique.

Methods

We carried out a Delphi study enrolling an international panel of 21 experts from different disciplines, with 43% of the respondents completing all three survey rounds. We asked the experts to identify core constructs (first round), suggest operationalisations of the constructs (second round), and to hypothesise about their relationships (third round). Items were included, excluded or adapted according to experts’ feedback. A 70% threshold was used for consensus.

Results

The panelists consented on the following core constructs: gender norms (social environment), sex assigned at birth, gender attitudes, gender roles, competencies, and gender identity to the mental health of adolescents. They further consented on gender approaches, namely the intersectional, multidimensional and multilevel approach as well as the power relations lens. The operationalisation of the constructs in round two led to the inclusion of variables forming an intersectional lens and four social environment levels: the household, community, political and digital level. In round three, the experts formed 14 hypotheses about the relationships between the core constructs.

Conclusion

The derived conceptual framework links the interplay of six key constructs, four gender approaches and four social environment levels to adolescent mental health. Future research should validate and apply the hypothesised relationships between the constructs to disentangle the gendered pathways to (mental) health in adolescence.
More than the sum of its parts? An analysis of the factors impacting the content of antenatal care consultations in the Democratic Republic of Congo
Authors: Han Rui , Hagedorn Brittany
Published: January 2025

Background

Previous studies have shown that in lower and middle-income countries, although antenatal care (ANC) coverage has increased significantly, maternal mortality remained high due to poor quality of care. Despite established protocols, recommended actions are not consistently completed and the causes are not well understood. We sought to unpack this by analyzing direct observations of ANC consultations from the Democratic Republic of Congo (DRC).

Methods

We conducted secondary analysis of data from the Health System Strengthening for Better Maternal and Child Health Results Project (2015-2022) evaluation. We examined completion rates of twenty recommended actions for a first ANC visit. We identified contributing factors using chi-squared tests on completion rates, in samples stratified by availability of essential items and provider characteristics. We used regressions to estimate the relative importance of facility, provider, and patient characteristics in determining completion rates and the effect of availability of the essential item for different care components.

Results

We observed a statistically significant increase between baseline and endline in supply-side readiness (equipment and supplies) and quality of care for six recommended actions. While structural readiness was a significant predictor of quality, we found that provider qualifications and female gender had significant positive associations with completion rates, partially explaining the observed variation in care quality. For example, female A1 nurses prescribed tetanus vaccination for 70% of patients, male A1 nurses to 55%, and midwives to 51%. After decomposing the reasons for poor quality, we found that in addition to supply-side gaps (64% at baseline, 51% at endline), the know-do gap contributed to 30% of incompletions at baseline (21% at endline). Patient characteristics were rarely predictive of quality.

Conclusions

While supply-side gaps continue to be important barriers to service quality for ANC visits, especially preventive treatments and diagnostics, addressing these alone is inadequate. This is especially true for the physical exam, where interpersonal and behavioral barriers persist and we see evidence of gendered differences in quality of care. Interventions to improve the performance of all providers is critical to ensure that every person receives the best possible care.
A clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment
Authors: Pershad Yash , Breeyear Joseph H , Corty Robert W , Mosley Jonathan D , Giri Ayush , Roden Dan M , Edwards Todd L , Bick Alexander G
Published: January 2025

Purpose

To develop an algorithm using routine clinical laboratory measurements to identify people at risk for systematic underestimation of glycated hemoglobin (HbA1c) due to p.Val68Met glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Methods

We analyzed 122,307 participants of self-identified Black race across four large cohorts with blood glucose, HbA1c, and red cell distribution width measurements from a single blood draw. In UK Biobank, we used recursive partitioning to develop criteria for possible and likely G6PD deficiency. We validated the algorithm in NIH All of Us, Vanderbilt BioVU, and the Million Veterans Program. In Vanderbilt’s Synthetic Derivative, we created a cohort of 48,031 participants with type 2 diabetes and no genetic data to test whether predicted risk for G6PD deficiency was associated with incident diabetic retinopathy.

Results

G6PD deficiency predictions in hemizygous males showed precision/recall of 31%/81% for possible and 81%/10% for likely deficiency. In homozygous females, precision/recall was 6%/76% for possible and 34%/13% for likely deficiency. Diabetic patients with predicted possible deficiency demonstrated 1.4-fold higher 20-year retinopathy rates (14.3% vs 11.2%, P=0.003).

Conclusion

We report a simple clinical algorithm that enables healthcare systems to identify people who may benefit from G6PD genotyping and glucose-based diabetes monitoring.
Household Air Pollution Exposures Over Pregnancy and Maternal Blood Pressure Trajectories through 8 Years Postpartum: Evidence from the Ghana Randomized Air Pollution and Health Study (GRAPHS)
Authors: Kaali Seyram , Li Michelle , Mujtaba Mohamed Nuhu , Colicino Elena , Awuni Sule , Wylie Blair , Osei Musah , Tsotetsi Kholiswa , Yussif Tawfiq , Chillrud Steve , Jack Darby , Asante Kwaku Poku , Lee Alison
Published: January 2025

Background

Household air pollution is a major contributor to cardiovascular disease burden in women in Sub-Saharan Africa. However, little is known about exposures during pregnancy or the effect of clean cooking interventions on postpartum blood pressure trajectories.

Methods

The Ghana Randomized Air Pollution and Health Study (GRAPHS) randomized 1414 non-smoking women in the first and second trimesters to liquefied petroleum gas (LPG) or improved biomass stoves – vs control (traditional three-stone open fire). Personal exposure to carbon monoxide was measured at four prenatal timepoints and three times over the first postpartum year. Participants were prospectively followed with annual resting BP measurements at 2, 4, 5, 6, 7, and 8 years postpartum. We employed linear mixed effects models to determine effect of GRAPHS interventions on postpartum BP, and to examine associations between prenatal and postnatal CO and postpartum BP.

Results

LPG intervention was associated with 3.54mmHg (95% CI-5.55,-1.53) lower change in systolic BP from enrolment through 8 years postpartum, and 2.27mmHg (95% CI-3.61,-0.93) lower change in diastolic BP from enrolment through 8 years postpartum, as compared to control. In exposure-response analysis, average prenatal CO was positively associated with change in systolic BP from enrolment (β=0.71mmHg, 95% CI 0.08, 1.30, per doubling of CO)

Conclusions

LPG cookstove intervention initiated in early pregnancy and maintained through the first postpartum year was associated with lower systolic and diastolic BP trajectories through 8 years postpartum. These findings support the need to integrate clean cooking solutions into existing antenatal care packages.
Behavioral investigation of allocentric and egocentric cognitive maps in human spatial memory
Authors: Nett Laura , Guth Tim A. , Büchel Philipp K. , Rungratsameetaweemana Nuttida , Kunz Lukas
Published: January 2025

Spatial memory is a fundamental cognitive function that enables humans and other species to encode and recall the locations of items in their environments. Humans employ diverse strategies to support spatial memory, including the use of cognitive maps. Cognitive maps are mental representations of the environment that organize its content along two or more continuous dimensions. In allocentric cognitive maps, these dimensions form a Cartesian coordinate system referenced to the environment. In egocentric cognitive maps, the dimensions form a polar coordinate system centered on the subject. To better understand how humans employ allocentric and egocentric cognitive maps for spatial memory, we performed a behavioral study with a novel task designed to directly and explicitly assess both types of cognitive maps. During encoding periods, participants navigated through a virtual environment and encountered objects at different locations. During recall periods, participants aimed at remembering these locations in abstract allocentric and egocentric coordinate systems. Our results show that relationships between the objects and the environment, such as their distance to boundaries and corners, were associated with allocentric memory performance. Relationships between the objects and the participant, including their distance and orientation to the participant’s starting position, were linked to egocentric memory performance. Spatial feedback during recall supported performance within allocentric and egocentric domains, but not across domains. These findings are compatible with the notion that allocentric and egocentric cognitive maps operate as (partially) independent systems for spatial memory, each specialized in processing specific types of spatial relationships.
Protocol for the production of an Arenavirus and Hantavirus host-pathogen database: Project ArHa
Authors: Simons David , Rivero Ricardo , Guiote Ana Martinez-Checa , Gordon Harry , Milne Gregory C. , Rickard Grant , Redding David W. , Seifert Stephanie N.
Published: January 2025

1

Arenaviruses and Hantaviruses, primarily hosted by rodents and shrews, represent significant public health threats due to their potential for zoonotic spillover into human populations. Despite their global distribution, the full impact of these viruses on human health remains poorly understood, particularly in regions like Africa, where data is sparse. Both virus families continue to emerge, with pathogen evolution and spillover driven by anthropogenic factors such as land use change, climate change, and biodiversity loss. Recent research highlights the complex interactions between ecological dynamics, host species, and environmental factors in shaping the risk of pathogen transmission and spillover. This underscores the need for integrated ecological and genomic approaches to better understand these zoonotic diseases. A comprehensive, spatially and temporally explicit dataset, incorporating host-pathogen dynamics and human disease data, is crucial for improving risk assessments, enhancing disease surveillance, and guiding public health interventions. Such a dataset (ArHa) would also support predictive modelling efforts aimed at mitigating future spillover events. This paper proposes the development of this unified database for small-mammal hosts of Arenaviruses and Hantaviruses, identifying gaps in current research and promoting a more comprehensive understanding of pathogen prevalence, spillover risk, and viral evolution.

2

Strengths and Limitations of this study

This dataset combines detailed spatial and temporal information, providing a unique resource for understanding geographic and temporal trends in Arenavirus and Hantavirus host-pathogen relationships.

By explicitly quantifying sampling biases and detection efforts, the dataset allows more robust and accurate asssessments of pathogen prevalence and distribution.

The dataset offers a platform for linking ecological data with human health outcomes, supporting the identification of spillover hotspots.

The dataset relies on published material, which may vary in terms of detail, accuracy and completeness. Missing or imprecise information may limit the reliability of subsequent analyses.

The dataset will be produced as a static resource which could limit its relevance over time as emerging data will not be added.
Quantitative proteomics of infected macrophages reveals novelLeishmaniavirulence factors
Authors: Hagedorn Nicolas , Fradera-Sola Albert , Mitnacht Melina , Gold Tobias , Schleicher Ulrike , Butter Falk , Janzen Christian J.
Published: January 2025

Leishmaniasis is a major public health problem, causing diseases ranging from self-healing skin lesions to life-threatening chronic infections. Understanding howLeishmaniaparasites evade the host defense system is crucial for understanding the different manifestations of the disease and for improving diagnostic tools and drug development. We performed high-resolution proteome profiling ofLeishmaniaspp. across three species during macrophage infection and identified distinct temporal expression patterns. Clustering analysis revealed unique protein expression profiles for eachLeishmaniaspecies, whereas pairwise enrichment analysis revealed specific up- and downregulation patterns at different infection stages. Our results confirmed known virulence factors and highlighted new ones, demonstrating the utility of our dataset. We validated the dataset by showing that deletion of putativeL. mexicanavirulence factors resulted in reduced stage differentiation capacity and infectivity. This novelLeishmaniainfectome database (LInfDB) is available online for further exploration (https://butterlab.imb-mainz.de/LInfDB), providing a valuable resource for future research.
Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency
Authors: Sun Yizhe , Chou Janet , Dong Kevin , Gygi Steven P. , Gewurz Benjamin E.
Published: January 2025

X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in theSH2D1AorXIAPgenes, are characterized by the inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases in each, lymphomas occur at high rates with XLP-1 but not with XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis, in contrast to all other described congenital conditions that result in heightened susceptibility to EBV, remains a key open question. To gain insights, we cross-compared newly EBV infected versus immune stimulated B-cells from XLP-2 patients or upon XIAP CRISPR knockout, relative to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected primary human B-cells, though had no impact on proliferation of B-cells stimulated by CD40 ligand and interleukin-21 or upon established EBV-immortalized lymphoblastoid cell lines (LCLs). B-cells from XLP-2 patients or in which XIAP was depleted by CRISPR editing exhibited a markedly lower EBV transformation efficiency than healthy control B-cells. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, whose effects on transforming B-cell death were counteracted by XIAP. In the absence of XIAP, EBV infection triggered high rates of apoptosis, not seen with CD40L/IL-21 stimulation. Moreover, inflammatory cytokines are present at high levels in XLP-2 patient serum with fulminant EBV infection, which heightened apoptosis induction in newly EBV-infected cells. These findings highlight the crucial role of XIAP in supporting early stages of EBV-driven B-cell immortalization and provide insights into the absence of EBV+ lymphoma in XLP-2 patients.

Key points

XIAP loss-of-function markedly impairs EBV+ B-cells outgrowth over the first week post-infection, particularly in the presence of IFN-γ.

XIAP mutation impedes EBV-driven B-cell transformation by potentiating p53-driven caspase activation and apoptosis.
A High Throughput Assay for Measuring Secreted Protein Based on ade novoFluorescent Reporter Reveals Regulatory and Structural Insights inSalmonellaType Three Secretion System
Authors: Leach Samuel Alexander , Summers Jordan Scott , Wen Edward , Tullman-Ercek Danielle
Published: January 2025

Intracellular protein production in bacteria is limited by the need for lysis and costly purification. A promising alternative is to engineer the host organism for protein secretion. While theSalmonella entericaserovar Typhimurium (S. Typhimurium) Type 3 Secretion System (T3SS) has been utilized for protein secretion, its study and eventual applicability for recombinant protein production is constrained by the lack of high-throughput assays to quantitatively measure secretion titer. Developing such assays is challenging, as proteins must remain unfolded for secretion, limiting the use of several common reporter proteins. In this work, we develop a high-throughput secretion assay using mini-Fluorescent Activating Protein (mFAP). mFAP forms a chromophore only upon addition of an exogenous substrate, allowing secretion and subsequent fluorescence detection. We demonstrate mFAP secretion via the T3SS with an N-terminal secretion tag and show that the fluorescent signal in the secreted fraction is rapid and linear over three orders of magnitude. Using this assay, we screenS. Typhimurium strains with secretion-enhancing mutations, identifying a constitutively active strain and reveal temporally controlled secretion dynamics. We also show that this assay may be applicable to other secretion systems, providing a universal tool for tracking heterologous protein secretion.
Comprehensive analysis of 37 composts: microbial indicators for soilborne disease suppression in three plant-pathogen systems
Authors: Logo Anja , Boppré Benedikt , Fuchs Jacques , Maurhofer Monika , Oberhänsli Thomas , Thürig Barbara , Widmer Franco , Flury Pascale , Mayerhofer Johanna
Published: January 2025

Soilborne diseases pose a significant threat to crop production and their control remains a major challenge. Compost is a valuable soil amendment when it comes to suppressing soilborne pathogens, but the effectiveness of different composts varies and cannot yet be predicted. Microbial communities in compost play a key role in disease suppression, and therefore microbial taxa may serve as indicators for suppressive composts. In this study, we investigated 37 composts from seven commercial compost producers to analyze the association of their bacterial and fungal communities with disease-suppressive activity across three plant-pathogen systems: cress-Globisporanigum ultimum, cucumber-Globisporanigum ultimumand cucumber-Rhizoctonia solani. Our results underscore that compost suppressiveness is primarily pathogen-specific and, to a smaller extent, hostplant-specific. Suppressiveness was not found to be correlated to physicochemical properties or microbial activity, alpha- and beta-diversity of the composts. However, specific bacterial and a few fungal taxa were identified as potential indicators of suppression for each plant-pathogen system. Notably, forG. ultimum-suppression, bacteria from the generaLuteimonas,Sphingopyxis, andAlgoriphagusemerged as promising candidates. These findings provide a foundation for targeted microbial isolation, aiming to elucidate the role of microorganisms in compost-mediated disease suppression, and to predict and optimize suppressive activity.
Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration
Authors: Meraner Paul , Avetisyan Adel , Swift Kevin , Cheng Ya-Chen , Barria Romina , Freeman Marc R.
Published: January 2025

The Sarm1 NAD+hydrolase drives neurodegeneration in many contexts, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. VHL normally promotes O2-dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection after depletion of VHL or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to even stronger blockade of axon degeneration in mammals andDrosophila. Neuroprotection required HIF-1 DNA binding, prolonged expression, and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented the precipitous NAD+loss driven by Sarm1 activation in neurons, despite NAD+hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues hypoxia inhibits Sarm1 activity through HIF-1 driven transcriptional changes, rendering neurons less sensitive to Sarm1-mediated neurodegeneration when in a hypoxic state.

Competing interests

Marc Freeman is co-founder of Nura Bio, a biotech startup pursuing novel neuroprotective therapies including SARM1 inhibition. The remaining authors declare no competing interests.
Conditioning electrical stimulation enhances functional rewiring in a mouse model of nerve transfer to treat chronic spinal cord injury
Authors: Jara Juan Sebastián , Soliman Marwa , Bernstein Amanda , di Grazia Paola , Ferguson Adam R. , Brown Justin M. , Torres-Espín Abel , Hollis Edmund R.
Published: January 2025

Nerve transfer surgery is a state-of-the-art surgical approach to restore hand and arm function in individuals living with tetraplegia, significantly impacting daily life. While nearly a third of all individuals with chronic SCI may benefit from this intervention, variability in outcomes can limit the functional impact. A bedside-to-bench approach was taken to address the variable response of tetraplegic individuals to nerve transfer surgery. We used a hierarchical multiple factor analysis to evaluate the effects of conditioning electrical stimulation (CES) on outcomes in a mouse model of nerve transfer to treat chronic cervical spinal cord injury. We found that CES of donor nerves one week prior to nerve transfer surgery enhanced anatomical and functional measures of innervation of targeted muscles. Furthermore, CES increased the rate of recovery of naturalistic behavior. While the model has some limitations due to the small size of the rodent, our results support the use of CES as an effective approach to improve outcomes in clinical nerve repair settings.
Simultaneous EEG-PET-MRI identifies temporally coupled, spatially structured hemodynamic and metabolic dynamics across wakefulness and NREM sleep
Authors: Chen Jingyuan E. , Lewis Laura , Coursey Sean , Catana Ciprian , Polimeni Jonathan , Fan Jiawen , Dropppa Kyle , Patel Rudra , Wey Hsiao-Ying , Chang Catie , Manoach Dara , Price Julie , Sander Christin , Rosen Bruce R
Published: January 2025

Sleep entails significant changes in cerebral hemodynamics and metabolism. Yet, the way these processes evolve throughout wakefulness and sleep and their spatiotemporal dependence remain largely unknown. Here, by integrating a novel functional PET technique with simultaneous EEG-fMRI, we reveal a tightly coupled temporal progression of global hemodynamics and metabolism during the descent into NREM sleep, with large hemodynamic fluctuations emerging as global glucose metabolism declines, both of which track EEG arousal dynamics. Furthermore, we identify two distinct network patterns that emerge during NREM sleep: an oscillating, high-metabolism sensorimotor network remains active and dynamic, whereas hemodynamic and metabolic activity in the default-mode network is suppressed. These results elucidate how sleep diminishes awareness while preserving sensory responses, and uncover a complex, alternating balance of neuronal, hemodynamic, and metabolic dynamics in the sleeping brain. This work also demonstrates the potential of EEG-PET-MRI to explore neuro-hemo-metabolic dynamics underlying cognition and arousal in humans.
The First-Hand Needs of Informal Caregivers of People Living with Dementia, in Residential Care Settings: A Scoping Review
Authors: Moody Chloe , Dixon Jeremy
Published: January 2025

Background

Dementia is a terminal condition often requiring palliative care delivered in residential care settings. While informal caregivers (ICGs) are pivotal in care-based decision-making, they have higher rates of physical and mental illness than ICGs of people with other terminal conditions. Identifying the needs of ICGs of people living with dementia (PLwD) is essential, to mitigate these risks and develop effective support systems.

Objective

Our objective was to understand the first-hand experiences and needs of ICGs of PLwD receiving palliative and end-of-life care, in residential care settings.

Method

Following the JBI methodology for scoping reviews, electronic databases (APA PsychNet, the Cochrane Database of Systematic Reviews, PubMed and Web of Science) were searched in September 2024, with no publication date limitations. Thematic synthesis was conducted on the findings of eligible peer-reviewed and grey literature, written in English, and reported in accordance with the PRISMA-ScR checklist.

Results

Forty-six articles were included. There were three overarching themes: “knowledge and understanding of dementia”, “engagement in care-based decisions”, and “coping mechanisms and support for own wellbeing”. Sub-themes presented an interplay between these, demonstrating the importance of understanding dementia, the significance of such knowledge for ICGs to maintain their own wellbeing, subsequently influencing their engagement in care-based decision making.

Conclusion

Care settings must work towards compassionate and timely support for ICGs, including a stable point of contact throughout admission and should use lay language. Future studies should take a longitudinal approach to understand the evolving role of ICGs, with particular attention to cultural and ethnic needs.

What is already known on this topic

Alongside care-staff, informal caregivers play a critical role in care-based decision-making and support for people living with dementia (PLwD), but they face significant health and wellbeing challenges, with limited research on effective mechanisms to involve and support them in their role.

What this study adds

Our study highlights the interconnected challenges faced by informal caregivers of PLwD in understanding dementia, maintaining their own wellbeing, and engaging in care-based decisions for PLwD.

How this study might affect research, practice, or policy

The findings identify a need for proactive, compassionate support for informal caregivers of PLwD through navigable resources, education surrounding dementia terminology using lay-language, and consistent communication with care-staff to build trust and stability for informal caregivers.

Our scoping review highlights the need for longitudinal research on evolving informal caregiving roles and calls for further research to explore and address the diverse needs of underserved communities, to inform culturally competent policies and practices.
Protocol and Statistical Analysis Plan for the Randomized Trial of Sedative Choice for Intubation (RSI)
Authors: DeMasi Stephanie C. , Imhoff Brant , Lewis Ariel A. , Seitz Kevin P. , Driver Brian E. , Gibbs Kevin W. , Ginde Adit A , Trent Stacy A. , Russell Derek W. , Muhs Amelia L. , Prekker Matthew E , Gaillard John P. , Resnick-Ault Daniel , Stewart L. Jane , Whitson Micah R. , Van Schaik Graham W. W. , Robinson Aaron E. , Palakshappa Jessica A. , Aggarwal Neil R. , Brainard Jason C. , Douin David J. , Lyle Carolynn , Gandotra Sheetal , Lacy Aaron J. , Sherlin Kristen C. , Carlson Greta K. , Cain J. Maycee , Redman Brianne , Higgins Carrie , Withers Cori , Beach Logan L. , Gould Barbara , McIntosh Jasmine , Lloyd Bradley D. , Israel Tiffany L. , Wang Li , Rice Todd W. , Self Wesley H. , Han Jin H. , Casey Jonathan D. , Semler Matthew W. ,   the RSI investigators and the Pragmatic Critical Care Research Group
Published: January 2025

Background

Emergency tracheal intubation is a common and high-risk procedure. Ketamine and etomidate are sedative medicines commonly used to induce anesthesia for emergency tracheal intubation, but whether the induction medication used affects patient outcomes is uncertain.

Research Question

Does the use of ketamine for induction of anesthesia decrease the incidence of death among adults undergoing emergency tracheal intubation, compared to the use of etomidate?

Study Design and Methods

The Randomized trial of Sedative choice for Intubation (RSI) is a pragmatic, multicenter, unblinded, parallel-group, randomized trial being conducted in 14 sites (6 emergency departments and 8 intensive care units) in the United States. The trial compares ketamine vs etomidate for induction of anesthesia among 2,364 critically ill adults undergoing emergency tracheal intubation. The primary outcome is all-cause, 28-day in-hospital mortality. The secondary outcome is the incidence of cardiovascular collapse during intubation, a composite of hypotension, receipt of vasopressors, and cardiac arrest. Enrollment began on April 6, 2022, and is expected to conclude in 2025.

Interpretation

The RSI trial will provide important data on the effects of ketamine vs etomidate on death and other outcomes for critically ill adults undergoing emergency tracheal intubation. Specifying the protocol and statistical analysis plan before the conclusion of enrollment increases the rigor, reproducibility, and interpretability of the trial.

Trial Registry

ClinicalTrials.gov; No.:NCT05277896; URL:www.clinicaltrials.gov

Take-Home Points

Study Question

Does use of ketamine for induction of anesthesia during emergency tracheal intubation decrease the incidence of death, compared with use of etomidate?

Results

This manuscript describes the protocol and statistical analysis plan for the Randomized trial of Sedative choice for Intubation (RSI) comparing ketamine vs etomidate for induction of anesthesia for emergency tracheal intubation.

Interpretation

Prespecifying the full statistical analysis plan before completion of enrollment increases rigor, reproducibility, and transparency of the trial results.
The AMPKα2/PHF2 axis is critical for turning over lipid droplets during muscle stem cell fate
Authors: Cicciarello Delia , Mouradian Sandrine , Pitchecanin Mélodie , Jarassier William , Kneppers Anita , Mounier Rémi , Schaeffer Laurent , Scionti Isabella
Published: January 2025

Lipid metabolism is a key process required for muscle stem cell (MuSCs) function during regenerative myogenesis. However, the molecular pathway responsible of such regulation is still unknown. Studies of lysine demethylase PHF2 have reported its critical role in lipid metabolism in pathological processes, although there are no data regarding its role during MuSC fate transition. Here we show that PHF2 controls lipid droplet homeostasis in MuSCs during regenerative myogenesis, by promoting the contact between lipid droplets and mitochondria. Consistently, in absence of PHF2, myocytes accumulate lipid droplets, leading to mitochondrial dysfunction and impaired regeneration. Interestingly, such phenotype is rescued by AMPKα2-PHF2 phospho-mimetic mutant expression. Our findings provide evidence that PHF2 is part of AMPKα2 signaling and underscore the critical role of AMPKα2/PHF2 axis in regulating lipid droplets homeostasis during MuSC fate.
circAβ-a RNA encoded Aβ175—the hidden driver of β-amyloid plaque formation and deposition in sporadic Alzheimer’s disease
Authors: Mo Dingding , Zhao Yi , Liu Yuxuan , Brosius Juergen , Xiao Gelei
Published: January 2025

Mechanisms that trigger Aβ production in sporadic Alzheimer’s disease are still obscure. We recently reported the expression of a human circular RNA (circAβ-a) encoded Aβ peptide precursor variant (Aβ175). Presently, we demonstrated that AAV9 virus-expressed circAβ-a gave rise to extensive extracellular Aβ plaque depositions and microglial activation in mouse brain; this recapitulates critical pathogenic hallmarks within a sporadic AD mouse model. Specifically developed antibodies detected robust endogenous Aβ175 expression in HEK293 cells and hNSC-derived human neurons, underscoring the potential of Aβ175 as a salient Aβ precursor. Furthermore, we detected high levels of Aβ175 oligomers in young-adult human brains. In intermediate and old-age human brain samples, accumulation of soluble Aβ175 pentamers was reduced and Aβ175 oligomers were components of most insoluble Aβ plaques in older human brain. We propose a causal relationship between human circAβ-a RNA expression, dysregulation of Aβ175 oligomer processing/aggregation and Aβ plaque accumulation in sporadic AD.
Empowering sustainability: green entrepreneurial orientation, innovative strategies, culture and operational performance
Authors: Adiguzel Zafer , Sonmez Cakir Fatma
Published: January 2025

Purpose

The research purpose is to investigate the impact of green entrepreneurial orientation (GEO) on operational performance (OP) in renewable energy companies, with a particular focus on the mediating roles of green innovation strategy (GIS) and green innovation culture (GIC).

Design/methodology/approach

Data were collected through interactive surveys with 338 middle and senior managers of renewable energy companies prioritizing sustainability. The relationships between variables were analyzed using SmartPLS and Jamovi software, which facilitates structural equation modeling.

Findings

The analysis revealed that GEO had a significant positive impact on both GIS and GIC, followed by OP. It is supported by the hypotheses that mediating variables GIS and GIC positively influence OP, and their important role in transforming entrepreneurial efforts into operational success is confirmed.

Research limitations/implications

The research is limited to renewable energy companies and findings may not be generalizable to other sectors. Future research could expand the scope to include different industries and geographic contexts. Additionally, dimensional research studies can provide deeper insights into the long-term effects of GEO, GIS and GIC on OP.

Practical implications

The findings suggest that renewable energy companies should encourage a strong entrepreneurial orientation towards green practices. Emphasizing innovation strategies and developing a green culture within organizations can lead to improved OP, supporting overall sustainability goals.

Originality/value

The research provides a comprehensive framework for understanding the drivers of OP in the renewable energy sector, providing a new perspective by combining GEO with innovation strategies and cultural elements. The originality of the research lies in the application of these concepts to an industry where sustainability is very important.