bluuebunny/crossref_metadata_2025 huggingface dataset:
A gut-microbiota-muscle axis that protects against age-related motor decline by regulating mitochondrial fission inC. elegans
Authors: Dennis Nathan , Vazquez-Prada Mireya , Xue Feng , Freeman Laura M. , Karamalegos Antonis , Kudzminkaite Brigita , Brown Ian , Ezcurra Marina
Published: December 2024

Across diverse taxa, the composition of the microbiota is associated with lifelong host health. A mechanistic understanding of how microbial communities influence host physiology could lead to microbiota-based interventions for lifelong health. Here, we have developed a new host-microbiota model system utilising the model organismC. eleganscombined with a defined natural microbiota (DefNatMta) consisting of 11 bacteria isolated from wildC. elegans, to study host-microbiota interactions in a more natural setting. We show that DefNatMta colonises theC. elegansgut, forming a stable and distinct gut microbiota. Using DefNatMta, we find a gut microbiota-muscle axis by which the microbiota affects age-related motility and muscular strength and protects against age-related decline in motor function. The gut microbiota-muscle axis acts by altering metabolism and mitochondrial network dynamics in muscle, and requires dynamin-related protein 1 DRP-1, a regulator of mitochondrial fission to protect against age-related motility decline. Our study demonstrates a gut microbiota-muscle axis and microbiota-mitochondria communication affecting age-related muscle function.
Short- and long-term reconfiguration of rat prefrontal cortical networks following single doses of psilocybin
Authors: Purple Ross J. , Gupta Rahul , Thomas Christopher W. , Golden Caroline T. , Froudist-Walsh Seán , Jones Matthew W.
Published: December 2024

We quantify cellular- and circuit-resolution neural network dynamics following therapeutically relevant doses of the psychedelic psilocybin. Using chronically implanted Neuropixels probes, we recorded local field potentials (LFP) alongside action potentials from hundreds of neurons spanning infralimbic, prelimbic and cingulate subregions of the medial prefrontal cortex of freely-behaving adult rats. Psilocybin (0.3mg/kg or 1mg/kg i.p.) unmasked 100Hz high frequency oscillations that were most pronounced within the infralimbic cortex, persisted for approximately 1h post-injection and were accompanied by decreased net pyramidal cell firing rates and reduced signal complexity. These acute effects were more prominent during resting behaviour than during a sustained attention task. LFP 1-, 2- and 6-days post-psilocybin showed gradually-emerging increases in beta and low-gamma (20-60Hz) power, specific to the infralimbic cortex. These findings reveal features of psychedelic action not readily detectable in human brain imaging, implicating infralimbic network oscillations as potential biomarkers of psychedelic-induced network plasticity over multi-day timescales.
PEX1G843Dremains functional in peroxisome biogenesis but is rapidly degraded by the proteasome
Authors: Sheedy Connor J. , Chowdhury Soham P. , Ali Bashir A. , Miyamoto Julia , Pang Eric Z. , Bacal Julien , Tavasoli Katherine U. , Richardson Chris D. , Gardner Brooke M.
Published: December 2024

The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations inHsPEX1andHsPEX6disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is theHsPEX1G843Dallele, which results in a reduction of peroxisomal protein import. Here we demonstrate thatin vitrothe homologous yeast mutant,ScPex1G700D, reduces the stability of Pex1’s active D2 ATPase domain and impairs assembly with Pex6, but can still form an active AAA-ATPase motor.In vivo,ScPex1G700Dexhibits only a slight defect in peroxisome import. We generated model humanHsPEX1G843Dcell lines and show that PEX1G843Dis rapidly degraded by the proteasome, but that induced overexpression of PEX1G843Dcan restore peroxisome import. Additionally, we found that the G843D mutation reduces PEX1’s affinity for PEX6, and that impaired assembly is sufficient to induce degradation of PEX1WT. Lastly, we found that fusing a deubiquitinase to PEX1G843Dsignificantly hinders its degradation in mammalian cells. Altogether, our findings suggest a novel regulatory mechanism for PEX1/PEX6 hexamer assembly and highlight the potential of protein stabilization as a therapeutic strategy for PBDs arising from the G843D mutation and other PEX1 hypomorphs.
Network-based amyloid-beta pathology predicts subsequent cognitive decline in cognitively normal older adults
Authors: He Hengda , Razlighi Qolamreza R , Gazes Yunglin , Habeck Christian , Stern Yaakov ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2024

The deposition of amyloid-beta protein in the human brain is a hallmark of Alzheimer's disease and is related to cognitive decline. However, the relationship between early amyloid-beta deposition and future cognitive impairment remains poorly understood, particularly concerning its spatial distribution and network-level effects. Here, we employed a cross-validated machine learning approach and investigated whether integrating subject-specific brain connectome information with amyloid-beta burden measures improves predictive validity for subsequent cognitive decline. Baseline regional amyloid-beta pathology measures from positron emission tomography (PET) imaging predicted prospective cognitive decline. Incorporating structural connectome, but not functional connectome, information into the amyloid-beta measures improved predictive performance. We further identified a neuropathological signature pattern linked to future cognitive decline, which was validated in an independent cohort. These findings advance our understanding of how amyloid-beta pathology relates to brain networks and highlight the potential of network-based metrics for amyloid-beta-PET imaging to identify individuals at higher risk of cognitive decline.
Nucleosome dynamics render heterochromatin accessible in living human cells
Authors: Prajapati Hemant K. , Xu Zhuwei , Eriksson Peter R. , Clark David J.
Published: December 2024

The eukaryotic genome is packaged into chromatin, which is composed of a nucleosomal filament that coils up to form more compact structures. Chromatin exists in two main forms: euchromatin, which is relatively decondensed and enriched in transcriptionally active genes, and heterochromatin, which is condensed and transcriptionally repressed1–10. It is widely accepted that chromatin architecture modulates DNA accessibility, restricting the access of sequence-specific, gene-regulatory, transcription factors to the genome. Here, we measure genome accessibility at all GATC sites in living human MCF7 and MCF10A cells, using an adenovirus vector to express the sequence-specificdamDNA adenine methyltransferase. We find that the human genome is globally accessible in living cells, unlike in isolated nuclei. Active promoters are methylated somewhat faster than gene bodies and inactive promoters. Remarkably, both constitutive and facultative heterochromatic sites are methylated only marginally more slowly than euchromatic sites. In contrast, sites in centromeric chromatin are methylated slowly and are partly inaccessible. We conclude thatallnucleosomes in euchromatin and heterochromatin are highly dynamic in living cells, whereas nucleosomes in centromeric α-satellite chromatin are static. A dynamic architecture implies that simple occlusion of transcription factor binding sites by chromatin is unlikely to be critical for gene regulation.
A conserved role for ALG10/ALG10B and theN-glycosylation pathway in the sleep-epilepsy axis
Authors: Gill Shubhroz , Mandigo Torrey R. , Elmali Ayse Deniz , Leger Brittany S. , Yang Bo , Tran Steven , Laosuntisuk Kanjana , Lane Jacqueline M. , Bannister Dalton , Aonbangkhen Chanat , Ormerod Kiel G. , Mahama Belinda , Schuch Kelsey N. , Elya Carolyn , Akhund-Zade Jamilla , Math Suraj R. , LoRocco Nicholas C. , Seo Soobin , Maher Matthew , Kanca Oguz , Bebek Nerses , Karadeniz Derya , Senel Gulcin Benbir , Courage Carolina , Lehesjoki Anna-Elina , Winkelman John W. , Bellen Hugo J. , de Bivort Benjamin , Hart Anne C. , Littleton J. Troy , Baykan Betul , Doherty Colleen J. , Melkani Girish C. , Prober David A. , Woo Christina M. , Saxena Richa , Schreiber Stuart L. , Walker James A.
Published: December 2024

Congenital disorders of glycosylation (CDG) comprise a class of inborn errors of metabolism resulting from pathogenic variants in genes coding for enzymes involved in the asparagine-linked glycosylation of proteins. Unexpectedly to date, no CDG has been described forALG10, encoding the alpha-1,2-glucosyltransferase catalyzing the final step of lipid-linked oligosaccharide biosynthesis. Genome-wide association studies (GWAS) of human traits in the UK Biobank revealed significant SNP associations with short sleep duration, reduced napping frequency, later sleep timing and evening diurnal preference as well as cardiac traits at a genomic locus containing a pair of paralogous enzymesALG10andALG10B. Modeling Alg10 loss inDrosophila,we identify an essential role for theN-glycosylation pathway in maintaining appropriate neuronal firing activity, healthy sleep, preventing seizures, and cardiovascular homeostasis. We further confirm the broader relevance of neurological findings associated with Alg10 from humans and flies using zebrafish and nematodes and demonstrate conserved biochemical roles forN-glycosylation inArabidopsis. We report a human subject homozygous for variants in bothALG10andALG10Barising from a consanguineous marriage, with epilepsy, brain atrophy, and sleep abnormalities as predicted by the fly phenotype. Quantitative glycoproteomic analysis in ourDrosophilamodel identifies potential key molecular targets for neurological symptoms of CDGs.
Palliative Care in Geriatric Trauma: Quantitative Insight From 64 Trauma Surgeon Survey Respondent on Utilizing Specialty Palliative Care in Geriatric Trauma
Authors: Hopp Morgan J. , Comrie Cameron E. , Kang Paul T , Strand Jacob J. , Santivasi Wil L. , Hollingworth Alexzandra K. , Iskander Gaby , Weinberg Jordan , Wu Kelly L.
Published: December 2024

Background

Early specialty palliative care (SPC) involvement in geriatric trauma care improves outcomes, quality of life and healthcare utilization. However, SPC usage is inconsistent and imprecise. A knowledge gap persists in understanding surgeons’ perspectives towards SPC and barriers in geriatric trauma.

Methods

The 38-question survey was distributed through a prestigious surgical society’s membership. Subsequently, comparative analysis of responses was completed based on demographic features.

Results

64 surgeons responded (2.8%). 87.5% of respondents identified a potentially life-limiting diagnosis/prognosis and 76.6% conflicting goals of care as consult triggers. 59.4% reported comfort in addressing the palliative needs without SPC consult. The perception of limited SPC availability (54.7%) was a common barrier. 28.1% felt that patient/family resistance was the most common reason not to consult SPC.

Conclusions

Surgeons reported comfort with goals of care discussions, perceived limited SPC availability, and the perception of patient/family resistance as limitation to consultation. These data provide previously unexplored insight from trauma surgeons.
An endogenous cluster of target-directed microRNA degradation sites induces decay of distinct microRNA families
Authors: Hiers Nicholas M. , Li Lu , Li Tianqi , Sheng Peike , Wang Yuzhi , Traugot Conner M. , Yao Michael , Xie Mingyi
Published: December 2024

While much is known about miRNA biogenesis and canonical miRNA targeting, relatively less is understood about miRNA decay. The major miRNA decay pathway in metazoans is mediated through target-directed miRNA degradation (TDMD), in which certain RNAs can “trigger” miRNA decay. All known triggers for TDMD base pair with the miRNA seed, and extensively base pair on the miRNA 3′ end, a pattern that supposedly induces a TDMD-competent conformational change of Argonaute (Ago), allowing for miRNA turnover. Here, we utilized Ago1-CLASH to find that theDrosophilatranscriptKahcontains at least two triggers, a “trigger cluster”, against miR-9b and the miR-279 family. One of these triggers contains minimal/non-canonical 3′ end base pairing but is still sufficient to induce TDMD of the entire miR-279 family. We found that these clustered triggers likely lack cooperativity, the minimal 3′ pairing is required for miR-279 family turnover, and probed the in-cell RNA structure of theKahtrigger cluster. Overall, this study expands the list of endogenous triggers and the unexpectedly complex regulatory network governing miRNA degradation.
A novel and robust method for assessing mitochondrial (dys)function in healthy and diseased frozen cardiac tissue
Authors: Hu Liangyu , van Rinsum Alexia , Caliandro Rocco , Qi Xi , Fan Shuxiu , Jiang Xinyi , Massop Jur , Bekkenkamp-Grovenstein Melissa , Ott Christiane , Grune Tilman , van de Wal Melissa A.E. , Koopman Werner J.H. , Giesbers Marcel , Gladka Monika , Keijer Jaap , Zhang Deli
Published: December 2024

Cardiovascular diseases are often associated with impairment in mitochondrial function detected by reduced mitochondrial oxygen consumption using high-resolution respirometry. However, existing respirometry protocols are limited by the necessity for fresh tissue samples. This study developed a method with tailored substrate-inhibitor titration (TSIT) of mitochondrial electron transport complexes (ETC) to measure mitochondrial function in frozen cardiac samples using high-resolution respirometry. Briefly, acetyl-CoA was added to fuel the tricarboxylic acid (TCA) cycle for NADH production, enabling complex I (CI)-linked respiratory assessment. NADH was then added to measure maximum CI-linked respiratory capacity, followed by rotenone and succinate to assess complex II (CII)-linked respiratory capacity. TSIT detected mitochondrial functional differences between frozen atrial and ventricular tissue, with comparable results as measured in fresh samples. It also detected cardiac mitochondrial dysfunction across various (patho)physiological mouse models (including aging, ischemia reperfusion, obesity, and CI deficiency) as well as in frozen human donor samples, highlighting its clinical potential. Furthermore, we showed the first evidence for supercomplexes (SCs) formation between ETC-SCs and the TCA cycle metabolon, underpinning TSIT feasibility. In conclusion, we established a novel, robust, sensitive and translational method (TSIT) for assessing mitochondrial (dys)function in frozen cardiac samples from various species, enabling flexible analysis of mitochondrial function in both laboratory and clinical settings.
Male Mice Have no Sugar-preference Behavior
Authors: Pan Tao , Huang Jia-Fu , Wu Qi-Ci , Chen Yi-Xuan , Li Xiu-Min , Zhang San-Guo , Pan Yu-Tian
Published: December 2024

Sugar-preference behavior is considered to be universally innate among humans and animals. Current research on the detection and mechanisms of sugar-preference behavior largely adopts the “two-bottle choice assay”, and most experiments use male mice as the model, which has serious methodological flaws, leading to questionable conclusions. As expected, through adopting our improved experimental method, we discovered distinct sugar preferences between male and female mice: females possess an innate preference, while males do not. However, the innate sugar preference in female mice can be lost due to their long-term normal diet. Even after “training” with high-sugar food for a long time, the results still show differences between males and females. Female mice retain a significant preference for sugar, while male mice are not influenced by the training of high-sugar food and still do not evolve a sugar preference. From this, we conclude that gender determines the emergence and development of sugar preference in mice. Our results can provide researchers with a new understanding of sugar preference, which will help them fill in or even correct the gaps in the original experimental design methods to obtain more reliable conclusions.
Sex-allocation trade-offs and their genetic architecture revealed by experimental evolution
Authors: Gerchen Jörn F. , Villamil-Buenrostro Nora , Li Xinji , Le Faou Ehouarn , Pannell John R.
Published: December 2024

The theory of sex-allocation is hailed as one of evolutionary biology’s great successes. But while it has successfully predicted strategies of resource allocation to sons versus daughters under a wide range of conditions in species with separate sexes, it has been difficult to apply to hermaphroditic species because of the repeated failure to verify the fundamental assumption of a direct genetic trade-off between male and female allocations made by hermaphrodites. This assumption supposes that mutations that increase an individual’s male allocation reduce its female allocation in equal measure, yet there is almost no evidence for such ‘trade-off’ loci in hermaphroditic populations. Here, we use experimental evolution to generate wide variation in hermaphroditic sex allocation in an annual plant and demonstrate a clear trade-off between the two sexual functions within populations as well as over time, with populations evolving both increased male and reduced female allocation. Quantitative trait locus (QTL) analysis performed on multiple crosses further reveals the segregation of allelic variation at trade-off loci. Taken together, our results demonstrate a phenotypic trade-off in sex allocation in hermaphrodites and provide compelling evidence for sex-allocation trade-off loci, verifying the fundamental assumption of sex-allocation theory and securing its general applicability to both dioecious and hermaphroditic species.
Simultaneous Overexpression of Three Enzymes of Chloroplast Metabolism Fails to Improve CO2Assimilation or Biomass
Authors: Lemonnier Pauline , Wall Shellie , Gherli Hussein , Moreno-Garcia Beatriz , Afamefule Chidi , Lawson Tracy , Raines Christine A. , Lopez-Calcagno Patricia E.
Published: December 2024

Ensuring an adequate food supply amidst a growing global population and climate change challenges, necessitates innovative strategies to enhance crop productivity. Previous studies have demonstrated that the simultaneous stimulation of different photosynthesis-related processes can increase the rate of photosynthetic carbon assimilation and plant biomass. This study evaluates an approach based on modelling aimed at simultaneously increasing photosynthetic and sink capacities inNicotiana tabacumby overexpressing three key enzymes: Sedoheptulose-1,7-bisphosphatase (SBPase), Fructose-1,6-bisphosphate aldolase (FBP Aldolase), and ADP-glucose pyrophosphorylase (AGPase). Our results showed that this strategy does not significantly improve growth or carbon assimilation inNicotiana tabacumunder the tested conditions. This suggests that while the model informing our work offers a valuable framework, its application may require adjustments based on species and environmental conditions. Future research should explore these genetic modifications in species with larger sink capacities and under a range of growth conditions to fully realize the potential of photosynthetic optimization.
Exploring the help-seeking journeys for Long Covid from a health inequalities perspective: a qualitative study in England
Authors: Clutterbuck Donna , Ramasawmy Mel , Pantelic Marija , Allsopp Gail , Gabbay Mark , Hayer Jasmine , Heightman Melissa , Mu Yi , Sunkersing David , Wootton Dan , Banerjee Amitava , Alwan Nisreen A ,   STIMULATE-ICP Consortium
Published: December 2024

Background and aim

Long Covid is a health condition that continues to be challenging in terms of obtaining care and support, even in the fourth year following its emergence. This study, which forms part of the STIMULATE-ICP study in England, explores the barriers and facilitators people with Long Covid face when trying to access care, as well as experiences in relation to stigma, discrimination, and inequitable treatment.

Methods

The study was co-designed with people with lived experience of Long Covid. People attending three post-covid services in England were invited to participate by clinic staff. Twenty-three participants were interviewed about their experiences in relation to barriers and facilitators of accessing adequate care, including experiences of being treated unfairly. Interviews were analysed thematically.

Findings

Participants experienced difficulties in accessing and receiving appropriate support from primary and secondary care but generally care and support improved once participants were under the care of a Long Covid service. Positive interactions with clinicians who were knowledgeable and supportive helped to foster good patient experiences when accessing Long Covid care. Inequalities in accessing care were reported in the form of experiences of gender and race discrimination. People with previous and existing conditions reported further stigmatisation. Financial barriers to care existed and there were also difficulties faced by those who got infected with COVID-19 early in the pandemic. The impact of Long Covid on mental health was evident, as was the stigma related to mental health and the inadequacy of mental health service provision for people with Long Covid.

Some participants who worked within the National Health Service (NHS) perceived their professional position as a facilitator to accessing Long Covid care. However, some NHS employees also reported the negative impact of Long Covid on their work, the lack of employment support available, mistreatment from colleagues, and dismissal of professional knowledge.

Conclusion

Our findings highlight a range of barriers to accessing adequate Long Covid care, with women, ethnic minorities and people with co-occurring conditions experiencing intersectional stigma. We recommend a move towards a healthcare system that is sensitive to intersectional disparities in access to care and is mindful of how stigma can reinforce these inequalities. This would speak to removing barriers to care and foster a more positive experience for people living with Long Covid already disadvantaged by structural and systemic discrimination.
Anopheles mosquito exposure is associated with age, gender and bed net use in areas in Uganda experiencing varying malaria transmission intensity
Authors: Blanken Sara Lynn , Kilama Maxwell , Ramjith Jordache , Musiime Alex K. , Lanke Kjerstin , Ayo Daniel , Huijbers Kristiaan , Hofste Tom , Conrad Melissa , Krezanoski Paul , Dorsey Grant , Kamya Moses R. , Arinaitwe Emmanuel , Bousema Teun
Published: December 2024

Objectives

The number ofAnophelesmosquito bites a person receives determines the risk of acquiring malaria and the likelihood of transmitting infections to mosquitoes. We assessed heterogeneity inAnophelesbiting and associated factors in two settings in Uganda with different endemicity.

Methods

Plasmodium falciparumparasites in blood-fed indoor caughtAnophelesmosquitoes were quantified using qPCR targeting the Pf18S rRNA gene. Human DNA in dried blood spots from household occupants and mosquito blood meals was profiled using 15 short-tandem repeats (STRs) and analysed using a log-likelihood approach for matching of both single and multi-sourced blood meals and incomplete DNA profiles.

Results

The distribution of mosquito bites was non-random; school-age children (5-15 years) and adults (≥16 years) had a mosquito biting rate ratio (BRR) 1.76 (95%CI 1.27-2.44, P < 0.001) and 1.96 (95%CI 1.41-2.73, P < 0.0001) times that of children under 5 years, respectively. Biting rates were lower in bed net users (BRR: 0.80, 95%CI 0.65-0.99, P = 0.042), and higher in males (BRR: 1.30, 95%CI 1.01-1.66, P = 0.043) and individuals infected withP. falciparum(BRR: 1.42, 95%CI 1.03-1.96, P = 0.030), though the latter effect lost statistical significance in sensitivity analyses.

Conclusions

Adults and school-age children are at higher risk for receiving mosquito bites and this has implications for the relative importance of demographic populations to onward malaria transmission to mosquitoes.

Highlights

A novel statistical approach allowed us to match multi-sourced mosquito bloodmeals and partially digested mosquito bloodmeals to human individuals

Participant age consistently related to mosquito biting: adults and school-age children had a mosquito biting rate ratio that was ∼2 and ∼1.8 times that of children below 5 years, respectively

Men received more mosquito bites than women and self-reported bed net use was associated with lower mosquito exposure.

Higher mosquito biting rates were observed in individuals infected withPlasmodium falciparum
Pallidal and motor cortical interactions determine gait initiation dynamics in Parkinson’s disease
Authors: Bath Jessica E. , Louie Kenneth H. , Azgomi Hamid Fekri , Balakid Jannine P. , Presbrey Kara N. , Marks Jacob H. , Wozny Thomas A. , Wang Doris D.
Published: December 2024

Gait initiation is a fundamental human task, requiring one or more anticipatory postural adjustments (APA) prior to stepping. Deviations in amplitude and timing of APAs exist in Parkinson’s disease (PD), causing dysfunctional postural control which increases the risk of falls. The motor cortex and basal ganglia have been implicated in the regulation of postural control, however, their dynamics during gait initiation, relationship to APA metrics, and response to pharmacotherapy such as levodopa are unknown.

To address these questions, we streamed electrocorticography (ECoG) potentials from the premotor and primary motor cortices, as well as local field potentials (LFPs) from the globus pallidus in five people with PD exhibiting gait and balance dysfunction during a cued gait initiation task. Amplitude and timing of APA were evaluated with force plates and synchronized to the neural data. Subjects performed gait initiation trials under ON and LOW levodopa conditions to assess effects of medication on APA metrics and underlying neural dynamics.

All subjects demonstrated pallidal and cortical oscillatory changes during different phases of gait initiation. Grouped analysis revealed that from quiet standing to the first foot step, pallidal beta power showed stepwise decrease and broadband gamma power increases, whereas cortical potentials showed low frequency (theta, alpha, beta) power decrease during gait initiation, regardless of medication state. The pallidum and motor cortices also became increasingly coherent during gait initiation compared to quiet standing prior to APA onset. Using linear mixed models, we found that while pallidal gamma powers are predictive of APA scaling, pallidal-cortical coherence (theta, alpha, beta) and premotor-M1 gamma coherence are predictive of APA timing.

Our study is the first detailed characterization of basal-ganglia cortical circuit dynamics during human gait initiation. We identified significant pallidal motor cortical power and coherence changes that underlie the amplitude and timing of APA which appear to be independent of medication states of the study subjects. Our results provide evidence for a model where synchronized premotor and motor cortical activities transiently couple with the globus pallidus to regulate the timing of postural responses, and local pallidal activity regulate the amplitude of postural changes during gait initiation. It suggests that abnormal pallidal outflow and synchronization between the pallidum and motor cortices may be a pathophysiological mechanism underlying disordered postural response in Parkinson’s disease.
Digital healthcare in public libraries 2002-2025: a scoping review protocol
Authors: Chan Xavier , Flowers Paul , Crawford Megan
Published: December 2024

Objective

The objective of this scoping review is to explore the use of digital healthcare in public libraries within the literature.

Introduction

Accelerated by the COVID-19 pandemic, reliance on digital healthcare has grown in the past decade and will continue to play an increasingly important role in health service provision in the future, including treatment and management of health conditions. An increasing reliance on these digital technologies may exacerbate longstanding inequalities in healthcare access and socioeconomic disparities more widely. Public libraries offer an opportunity to bridge this divide to improve access to digital healthcare. A scoping review will be conducted to explore existing digital health technologies used in public libraries to inform future research.

Inclusion criteria

Published studies with adolescents and adults, focusing on digital healthcare in public libraries and conducted in any geographical location will be included in this review. Additional limiters include being published in English and conducted and published between 2002 and 2024. Grey literature sources, including theses, posters and preprints will be included in the review, where relevant.

Methods

JBI methodology for Scoping Reviews has been employed for this review. Searches will be conducted using Web of Science, SCOPUS, Pubmed, Library Information and Technology Abstracts (LISTA), Library and Information Science Abstracts(LISA), OpenDisserations and advanced Google search. Sources will be screened by two independent reviewers through 1) title and abstract screening and 2) full text screening. Data will then be charted and presented.
Performance and usability evaluation of three LDH-based malaria rapid diagnostic tests in Kédougou, Senegal
Authors: Souleymane Sambe Babacar , Zobrist Stephanie , Sheahan William , Soni Divya , Diagne Aissatou , Sarr Ibrahima , Sabene Diatta Arona , Mbacke Diaw Serigne Ousmane , Golden Allison , Slater Hannah , Jang Ihn Kyung , Roa Nerie , Pal Sampa , Diene Sarr Fatoumata , Faye Joseph , Vigan-Womas Inès , Dieye Yakou , Cisse Moustapha , Domingo Gonzalo J , Niang Makhtar
Published: December 2024

Background

The emergence ofpfhrp2/3-deleted parasites threatens histidine-rich protein 2 (HRP2)-based malaria rapid diagnostic test (RDT) performance. RDTs targetingPlasmodium falciparum(Pf) lactate dehydrogenase (LDH) may address current product limitations and improve case management.

Objectives

To evaluate the performance and usability of three LDH-based RDTs in febrile patients.

Methods

A cross-sectional diagnostic accuracy study was conducted in Kédougou, Senegal. Capillary blood was tested using the SD Bioline Ag Pf (#05FK50) and three LDH-based RDTs: BIOCREDIT Malaria Ag Pf (pLDH), BIOCREDIT Pf (pLDH/HRPII), and BIOCREDIT Pf/Pv (pLDH/pLDH) (Rapigen Inc., Republic of Korea). Venous blood was collected to repeat the BIOCREDIT RDTs and conduct microscopy. Frozen venous specimens were tested using a reference PCR assay. A quantitative multiplex malaria antigen assay measured antigen concentration. RDT performance was determined and analyzed as a function of antigen concentration distribution. Usability of thePf-only BIOCREDIT tests was evaluated using a questionnaire.

Results

154/220 participants (70%) werePf-positive by PCR. The Pf (pLDH/HRPII) test demonstrated the highest sensitivity at 78% (70.9%–84.5%); specificity was 89% (79.4%–95.6%). All RDTs performed better than microscopy (53% sensitivity). RDTs performed better when compared to antigen concentration over PCR results. Improved sensitivity of the Pf (pLDH/HRPII) test was driven by the HRP2 line. Line intensity correlated with antigen concentration. Predicted sensitivity using the analytical limit of detection (LOD) was comparable to observed sensitivity. RDTs demonstrated acceptable usability.

Conclusions

Both HRP2 and LDH contributed to the sensitivity of the best-performingPf-RDT. RDT analytical LODs can be used to predict performance in populations with known antigen concentrations.
A multi-level gene-diet interaction analysis of fish oil supplementation and 14 circulating polyunsaturated fatty acids-related traits identifies theFADSandGRP12loci
Authors: Ihejirika Susan Adanna , Chiang Alexandra Huong , Singh Aryaman , Stephen Eunice , Chen Han , Ye Kaixiong
Published: December 2024

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) among individuals but in a heterogeneous manner. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (P< 5 × 10−8) in theFADS1-FADS2gene cluster for total omega-3, omega-3%, docosapentaenoic acid (DHA), DHA% and the omega-6 to omega-3 ratio. Among the interaction signals for omega-3%, the lead SNP, rs35473591 (C>CT, CT allele frequency = 0.34), had a lower association effect size in the FOS-taking group (β = 0.35 for allele C) than that in the group without FOS (β = 0.42). Likewise, the effect sizes of associations between FOS and omega-3% varied across the three genotype groups (β = 0.45, 0.50, and 0.59, respectively, in C/C, C/CT, and CT/CT). Our gene-level aggregate and transcriptome-wide interaction analyses identified significant signals at two loci, aroundFADS1-FADS2andGRP12. The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systemic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations.
Predictors of Response to Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease Patients
Authors: Chubb Henry , Mah Douglas , Shah Maully , Lin Kimberly Y , Peng David , Hale Benjamin W , May Lindsay , Etheridge Susan , Goodyer William , Ceresnak Scott R , Motonaga Kara S , Rosenthal David N , Almond Christopher S , McElhinney Doff B , Dubin Anne M
Published: December 2024

Background

Cardiac resynchronization therapy (CRT) is an important therapeutic option in selected pediatric and congenital heart disease (CHD) patients with reduced systemic ventricular (SV) ejection fraction (EF). However, the identification of optimal responders is challenging.

Objective

To identify predictors of response to CRT in children and CHD patients at 5 large quaternary referral centers.

Methods

Patients were <21 years or had CHD; had SVEF <45%; symptomatic heart failure; and significant electrical dyssynchrony prior to CRT. Primary outcome was defined as an ordinal response at 6/12months: (1) Improved EF [≥5%], (2) Unchanged SVEF, (3) Worse SVEF. Secondary outcome utilized a propensity score-matched control cohort. Response to CRT was defined using longitudinal trajectory of SVEF up to latest follow-up.

Results

In total, 167 eligible CRT recipients were identified across the 5 centers. 150 had comprehensive data at 6/12months: 96(64%) with improved SVEF, 26(17%) unchanged, 28(19%) worsened. Mean increase in SVEF was 11% [IQR 3-21%]. On univariable ordinal regression, lower SVEF (p=0.013), biventricular circulation (p=0.022), systemic LV (p=0.021), and conduction delay to lateral wall of SV (p=0.01) were associated with positive response.

For assessment of secondary outcome, 324 controls were identified. Mean follow-up 4.2(±3.7) yrs. Almost all subgroups demonstrated improved SVEF trend with CRT, except those with systemic RV (p=0.69) or without prior single site pacemaker (p=0.20).

Conclusion

CRT in children and CHD patients frequently results in an improvement in SVEF. Those with lower SVEF, conduction delay to lateral wall of the SV and those with systemic LV are most likely to respond.

Condensed Abstract

Cardiac resynchronization therapy (CRT) is an important therapeutic option in selected pediatric and congenital heart disease (CHD) patients with reduced systemic ventricular (SV) ejection fraction (EF). However, the identification of optimal responders is challenging.

In this multicenter study, pediatric and CHD CRT recipients with heart failure and EF<45% were identified. The primary outcome was change in EF at 6/12months. Those with lower baseline SVEF, conduction delay to lateral wall of the SV and/or systemic LV were most likely to respond to CRT. When compared to propensity score-matched controls, the CRT groups also demonstrated a significantly better long-term EF trajectory.
Current etiology of hypertension in European children – role of serum uric acid
Authors: Obrycki Łukasz , Skoczyński Krzysztof , Sikorski Maksymilian , Koziej Jan , Mitoraj Kacper , Pilip Jakub , Pac Michał , Feber Janusz , Litwin Mieczysław
Published: December 2024

2.

Background

While hypertension (HT) in pediatric patients is often secondary (SH), recent trends show a rise in primary hypertension (PH), which is associated with an increasing global prevalence of obesity. Our study aimed to assess the etiology of HT and predictors of PH in a large European cohort of children referred for HT based on office blood pressure (BP) measurements.

Methods

We performed retrospective analysis of 2008 children aged 0–18 years (12.3 ± 4.9 years) diagnosed with HT. Patients were classified into white coat hypertension (WCH), PH, or SH groups based on office BP and 24-hour ambulatory BP monitoring (ABPM). Clinical, anthropometric, and biochemical data were collected to differentiate PH and SH and to identify predictors of PH.

Results

Out of 2008 patients included in the analysis, HT was confirmed in 1452 patients (556 were classified as WCH). Of 1452 patients with HT: 42.8% had PH, while 57.2% had SH, mainly secondary to renal parenchymal disease (33.2% of SH patients), post-kidney transplant HT (23.1%), aortic coarctation (15.9%) and renovascular HT (13.8%). However, PH started to be the dominant cause of HT after 13 years of age and was diagnosed in 59.1% of 13–18-year-old patients with confirmed HT. Age ≥ 13 years, obesity (BMI-SDS ≥1.65), and serum uric acid ≥ 5.5 mg/dL were identified as significant PH predictors.

Conclusions

Our study provides valuable insights into the current etiology of pediatric HT and highlights the role of uric acid level assessment in the diagnosis of PH in children.
Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome
Authors: Duran Jose S Campos , Sayed Samir , Dalalo Megan C , Mauracher Andrea A , Knight Montana S , Conrey Peyton E , Schultz Aaron B , Hay Ceire A , Lindell Robert B , Howard Christian A , Abrams Eric D , Schmitt Erica G , Thelin Martin A , Bluestein Sarah , Seroogy Christine M , Pozos Tamara C. , Thatayatikom Akaluck , Lundgren Ingrid , Gauthier Amelie , Canna Scott W , Su Helen C , Keller Michael D , Delmonte Ottavia M , Satter Lisa R Forbes , Holland Steven M , Bergerson Jenna R.E. , Leiding Jennifer W , Romberg Neil , Freeman Alexandra F , Villarino Alejandro V , Anderson Mark S , Cooper Megan A , Vogel Tiphanie P , Henrickson Sarah E
Published: December 2024

Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRDs). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-g and TNF-a secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors, and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling.
Small Extracellular Vesicles by Nucleus Pulposus Cells Maintain Niche and Cell Homeostasis via Receptor Shuffling and Metabolic Enzyme Supplements
Authors: Samanta Ankita , Yoo Mi-Jeong , Koh Jin , Lufkin Thomas , Kraus Petra
Published: December 2024

Background

Small extracellular vesicles (sEV) are a conserved mean of communication across the domains of life and lately gained more interest in mammalian non-cancerous work as non-cellular, biological therapeutic with encouraging results in recent studies of chronic degenerative diseases. The nucleus pulposus (NP) is the avascular and aneural center of an intervertebral disc (IVD), home to unique niche conditions and affected in IVD degeneration. We investigated the proteome of autologous and mesenchymal stem cell (MSC) sEVs for their potential to contribute to cell and tissue homeostasis in this niche.

Methods

We aimed to identify characteristics of NP sEVs via mass spectrometric proteome and functional enrichment analysis. We explored the proteome profile of sEVs generated by autologous parent cell lines from bovine coccygeal IVD and adipose tissue, with a focus on NP cells, using adult and fetal donors. We compared these findings to published sEV databases and MSC sEV data.

Findings

We propose several mechanisms associated with NP sEVs: 1. Membrane receptor trafficking to modify signal responses promoting niche homeostasis. 2. Cell homeostasis via proteasome delivery; 3. Redox and energy homeostasis via metabolic enzymes delivery. 4. Immunomodulation beyond an association with a serum protein corona.

Conclusion

The proteome signature of sEVs generated by NP parent cells is similar to previously published sEV data, yet with a focus on supplementing anaerobic metabolism and redox balance while contributing to the maintenance of an aneural and avascular microniche.
Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation
Authors: da Silva Araujo Mariana Gomes , Sallé Aurélie , Cahais Vincent , Renard Claire , Cuenin Cyrille , Poubel Caroline Pires , Keita Stéphane , Mosler Thorsten , Carreira Christine , Levy Gabrielle Goldman , Parres Lya , Bourova-Flin Ekaterina , Rousseaux Sophie , Khochbin Saadi , Ghantous Akram , Habazin Siniša , Pučić-Baković Maja , Cosset Erika , Lauc Gordan , Herceg Zdenko , Khoueiry Rita
Published: December 2024

Background

Epigenetic regulator genes play critical roles in controlling cell identity and are frequently disrupted in breast cancers, suggesting a key driver role in this disease and its associated phenotypes. However, specific epigenetic drivers (epidrivers) of mammary cell plasticity and their mechanistic contributions to this phenotype are poorly characterized.

Methods

To identify potential epidrivers of the emergence of mesenchymal breast cancer stem cell-like phenotypes in non-tumorigenic mammary cells, we employed a CRISPR/Cas9 loss-of-function screening strategy targeting epigenetic regulator genes. This approach was followed by an in-depth validation and characterization of epigenomic, transcriptomic, proteomic and phenotypic changes resulting from the disruption of the putative epidriver geneBAP1.

Results

Our investigation revealed that loss of the histone deubiquitinase BAP1 impacts cellular processes associated with breast cancer cell plasticity such as epithelial-to-mesenchymal transition (EMT) and actin cytoskeleton organization. In addition, we unveiled that BAP1 loss resulted in an overall less permissive chromatin and downregulated gene expression, impacting programs that control cellular glycosylation and leading to decreased glycan abundance and complexity. BAP1 rescue restored the expression of several deregulated genes in a catalytic activity-dependent manner, suggesting that BAP1-mediated cell identity and glycosylation regulation are largely dependent on its histone deubiquitinase activity.

Conclusions

Overall, our results point to BAP1 disruption as a driver of mammary cell plasticity and reveal a novel role of BAP1 as an epigenetic regulator of cellular glycosylation.
LMX1Bmissense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization
Authors: Eastman Brent , Tabuchi Nobuko , Zhang Xinrui , Spencer William C. , Deneris Evan S.
Published: December 2024

Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitoticPet1neurons that give rise to mature serotonin (5-HT) neurons; over two hundred pathogenic heterozygous mutations have been discovered in humanLMX1B,yet their impact on brain development has not been investigated. Here, we developed mouse models with differentLMX1BDNA-binding missense mutations. Missense heterozygosity broadly alteredPet1neuron transcriptomes, but expression changes converged on axon and synapse genes. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital genomic footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or no change in motif binding and accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Further, Lmx1b missense heterozygosity caused wide disruption of Lmx1b-dependent GRNs comprising diverse TFs expressed inPet1neurons. These findings reveal an unanticipated continuum of Lmx1b missense-forced perturbations onPet1neuron regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining unique insight into how TF missense mutations interfere with developing neuronal GRNs.

Significance Statement

We modeled human LMX1B missense mutations in mice to explore how they disrupt brain serotonin neuron development. Missense heterozygosity selectively impaired postnatal formation of serotonin axon arbors throughout the forebrain, notably in the hippocampus and motor cortex. DGF revealed that Lmx1b missense heterozygosity exerted a continuum of footprint changes associated with synapse and axon gene expression. Footprint changes ranged from total eliminations to partial losses and gains within thePet1neuronal epigenome. LMX1B missense mutations may cause human brain pathogenesis by selectively disrupting cis regulatory elements controlling 5-HT axon arbor formation thus impairing 5-HT delivery to presynaptic release sites.