bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement of Spontaneous Locomotor Activity in a Murine Model of Duchenne Muscular Dystrophy by N-Acetylglucosamine Alone and in Combination with Prednisolone
Authors: Satoh Masahiko. S. , St-Pierre Guillaume , Rancourt Ann , Fillion Maude , Sato Sachiko
Published: August 2024

N-acetylglucosamine (GlcNAc) is an endogenous compound whose intracellular concentration is closely associated with the biosynthesis of acetyllactosamine-rich N-linked oligosaccharides. These oligosaccharides interact with mammalian lectin galectin-3, mediating cell surface receptor dynamics as well as cell-to-cell and cell-to-extracellular matrix interactions. Our previous and recent studies suggest that GlcNAc, in conjunction with galectin-3, augments muscle regenerationin vitro. We have also demonstrated that intraperitoneal GlcNAc administration improves muscle strength in a murine model of Duchenne muscular dystrophy (DMD) (mdxmice). Here, we show that oral administration of GlcNAc significantly improves the spontaneous locomotor activity of mdx mice. Administering GlcNAc at concentrations of 0.6, 1.2, 1.8, and 2.4 g/kg body weight per day for 35 days significantly improved nocturnal spontaneous locomotor activity at all those doses, with the 1.2 g/kg body weight dose reducing damages of extensor digitorum longus muscle by nearly 50%. While consecutive forced exercises, including horizontal and downhill treadmill running, reduced GlcNAc-promoted locomotor activity, treatment with 0.6 and 1.2 g/kg body weight treatment results in increased spontaneous locomotor activity. These results suggest that GlcNAc enhances overall muscle health, likely through promoting muscle repair/regeneration rather than preventing damage formation. Notably, co-administration of GlcNAc with prednisolone, a corticosteroid commonly used in DMD patients, further enhanced spontaneous locomotor improvement inmdxmice compared to prednisolone alone. These findings suggest that GlcNAc has the potential to improve the clinical status of DMD patients, either as a monotherapy or in combination with corticosteroids.
Simultaneous GCaMP imaging and focal recording of tonic and phasic synapses: Probing short-term plasticity within a defined microenvironment
Authors: Xing Xiaomin , Wu Chun-Fang
Published: August 2024

Key point summary

We developed a protocol for stable simultaneous focal recording and GCaMP imaging on identified motor synaptic boutons in theDrosophilaneuromuscular preparation with minimized muscular movements in extended concentration ranges of extracellular Ca2+and Sr2+.

This approach directly demonstrated temporal correlation between the dynamics of cytosolic residual Ca2+and activity-dependent synaptic plasticity in tonic and phasic synapses.

Our data demonstrated presynaptic GCaMP signals markedly lagged behind and poorly correlated with the concurrent transmitter release, but reliably indicated the immediate states of short-term plasticity. GCaMP’sphysical-chemicalproperties allow information extraction on cytosolic Ca2+levels during facilitation and depression phases.

The decay phase of GCaMP signal often coincided with lingering vesicular releases after stimulation, more pronounced in phasic than tonic synapses and exaggerated in Sr2+-containing saline. Lingering releases were coupled with the tendency of asynchronous transmission.

GCaMP fluorescence has been widely used to monitor intracellular Ca2+. However, the physiological significance of the GCaMP signal in presynaptic terminals remains to be further elucidated. We investigated how the dynamics of GCaMP signals correlates with the activity dependence of short-term plasticity in synaptic transmission. We devised a local manipulation protocol that minimizes interference from muscular contraction during simultaneous Ca2+imaging and focal recording at theDrosophilalarval neuromuscular junction (NMJ), where the tonic and phasic excitatory synapses can be compared side-by-side. By confining the local ionic microenvironment, this protocol enabled stable measurements across extended concentration ranges of Ca2+or Sr2+in saline. Compared to tonic synapses, phasic synapses displayed stronger GCaMP signals, along with faster facilitation and more severe depression. Upon repetitive stimulation (40 Hz), facilitation of transmission occurred during or immediately prior to the early rising phase (0.25 s) of the GCaMP signal, which could subsequently convert into a depression phase of transmission decline, most evident during a steeper and longer rise of GCaMP signals in higher Ca2+saline. Typically, deepest depression occurred when GCaMP signals rose to a plateau. Phasic synapses with stronger GCaMP signal and deeper depression, more often exhibited lingering post-stimulation releases. In both tonic and phasic synapses, replacing Ca2+with Sr2+induced extreme asynchronous transmission coupled with post-stimulation lingering releases during the decay of GCaMP signals. Further applications of this focal recording-local manipulation protocol may help to probe additional mechanisms underlying synaptic transmission and plasticity.
Proteome structuring of crown-of-thorns starfish
Authors: Yunchi Zhu , Zuhong Lu
Published: August 2024

This data report presents the proteome structuring of the crown-of-thorns starfish (COTS,Acanthaster planci) using the ColabFold system. The resulting dataset includes 31,743 predicted protein structures, covering 60.4% of residues with confident predictions and 35.5% with very high confidence. A preliminary structural bioinformatics analysis was conducted using post-AlphaFold methods, including fast structure clustering, ligand transplanting, and structure-based Gene Ontology (GO) annotation, which identified potential functions for previously uncharacterized proteins. These findings contribute to a deeper understanding of COTS biology and provide valuable data for developing biocontrol methods to mitigate the impact of COTS outbreaks on coral reefs.
Actin Polymerization Status Regulates Tendon Homeostasis through Myocardin-Related Transcription Factor-A
Authors: West Valerie C. , Owen Kaelyn , Inguito Kameron L. , Ebron Karl Matthew M. , Reiner Tori , Mirack Chloe E. , Le Christian , Marqueti Rita de Cassia , Snipes Steven , Mousavizadeh Rouhollah , Elliott Dawn M. , Parreno Justin
Published: August 2024

The actin cytoskeleton is a potent regulator of tenocyte homeostasis. However, the mechanisms by which actin regulates tendon homeostasis are not entirely known. This study examined the regulation of tenocyte molecule expression by actin polymerization via the globular (G-) actin-binding transcription factor, myocardin-related transcription factor-a (MRTF). We determined that decreasing the proportion of G-actin in tenocytes by treatment with TGFβ1 increases nuclear MRTF. These alterations in actin polymerization and MRTF localization coincided with favorable alterations to tenocyte gene expression. In contrast, latrunculin A increases the proportion of G-actin in tenocytes and reduces nuclear MRTF, causing cells to acquire a tendinosis-like phenotype. To parse out the effects of F-actin depolymerization from regulation by MRTF, we treated tenocytes with cytochalasin D. Similar to latrunculin A treatment, exposure of cells to cytochalasin D increases the proportion of G-actin in tenocytes. However, unlike latrunculin A treatment, cytochalasin D increases nuclear MRTF. Compared to latrunculin A treatment, cytochalasin D led to opposing effects on the expression of a subset of genes. The differential regulation of genes by latrunculin A and cytochalasin D suggests that actin signals through MRTF to regulate a specific subset of genes. By targeting the deactivation of MRTF through the inhibitor CCG1423, we verify that MRTF regulates Type I Collagen, Tenascin C, Scleraxis, and α-smooth muscle actin in tenocytes. Actin polymerization status is a potent regulator of tenocyte homeostasis through the modulation of several downstream pathways, including MRTF. Understanding the regulation of tenocyte homeostasis by actin may lead to new therapeutic interventions against tendinopathies, such as tendinosis.
Sustainablein situextraction of microalgae-derived terpenoids using functionalized silica microparticles
Authors: Overmans Sebastian , Gallo Adair , Mishra Himanshu , Lauersen Kyle J.
Published: August 2024

Chlamydomonas reinhardtiiis a green microalga that has been genetically engineered to produce heterologous terpenoid metabolites. While this green biochemical approach for producing high-value chemicals holds tremendous potential, the currentin situextraction methods, utilizing traditional solvents such as dodecane and perfluorinated chemicals, present separation challenges, unfavorable economics, and risk of cell toxicity. Here, we develop a low-cost solvent-free approach based on silanized silica particles to fill the technology gap. We determine the feasibility and specificity of three differently coated (C11, C16, C18) silica particles to extract nine terpenoid metabolites fromC. reinhardtiicultures during cultivation. The results reveal that the extraction efficiencies of functionalized particles, particularly those coated with C18, demonstrated high potential as an alternative to traditional extraction methods. While the extraction efficiencies of coated microparticles are for most compounds lower than those observed for dodecane-based extractions, it holds higher potential for larger-scale cultivations where the use of dodecane is restricted due to its flammability and tendency to form emulsions. In addition, the present study provides insights into the optimization of particle-to-culture volume ratio, particle saturation, and the required number of product elution steps, and proves the feasibility of an upscaled extraction of the sesquiterpenoid patchoulol as a representative metabolite in 5 L hanging bag reactors. This study paves the way for a circular bioprocess where product capture with traditional solvent overlays is impractical due to the formation of emulsions, and at the same time allows for an easy product recovery (solid-liquid separation) and reuse of functionalized particles over numerous cycles.
Women’s experiences and acceptability of self-administered, home delivered, intravaginal 5-Fluorouracil cream for cervical precancer treatment in Kenya
Authors: Adewumi Konyin , Kachoria Aparna Ghosh , Adoyo Everlyn , Rop Mercy , Owaya Antony , Tang Jennifer H , Rahangdale Lisa , Mungo Chemtai
Published: August 2024

BACKGROUND

Innovative strategies are essential to meet the World Health Organization’s 90/70/90 cervical cancer elimination targets, aiming for 90% access to precancer treatment globally by 2030. In low-and middle-income countries (LMICs) where most cervical cancer cases occur, access to precancer treatment is severely limited. Scalable solutions like self-administered topical therapies can help close this gap. In a recent Phase I trial (ClinicalTrials.govNCT05362955), we demonstrated safety and adherence to self-administered intravaginal 5% 5-Fluorouracil (5FU) cream as an adjuvant therapy for cervical precancer among women living with HIV (WLWH) in rural Kenya. To understand women’s experiences with self-administered 5FU, we evaluated the acceptability of this intervention among trial participants.

METHODS

All 12 participants from the Phase I trial completed a structured questionnaire and in-depth semi-structured interviews in their preferred language, focusing on their experiences with 5FU self-administration, challenges faced, and overall acceptability of the intervention, including whether they would use it again or recommend it to someone who needed it. Quantitative data were analyzed using descriptive statistics. In the qualitative study, acceptability was defined as “the perception that a given treatment is agreeable, palatable, or satisfactory.” A thematic analysis was conducted using five dimensions of acceptability: content, complexity, comfort, delivery, and credibility.

RESULTS

The mean age was 43.9 years (SD 4.4), and seven (58%) had primary education or less. While some participants reported feelings of uncertainty when they started using 5FU, at the end of the study, all 12 participants strongly agreed that the cream was safe and were confident they used it correctly. Most participants (91.7%) experienced no discomfort with the vaginal applicator, and most reported using tampons overnight after 5FU use, as recommended. Qualitative findings revealed that favorable perceptions of self-administered 5FU were driven by its ease of use, the discrete nature of the treatment, and the comfort of home application. The main challenges included correctly measuring the study drug, finding a private place at home to self-administer, and the need to use condoms during treatment. Compared to their previous ablation or excision treatments, participants found 5FU to be less painful, and all would prefer a self-administered treatment instead of a procedure if it were an option.

CONCLUSION

Self-administered intravaginal 5FU as an adjuvant treatment for cervical precancer among women living with HIV in Kenya was highly acceptable. Randomized studies of 5FU and other topical therapies in LMICs are needed to evaluate their use in closing the current precancer treatment gaps in these settings.
Cross-Institutional European Evaluation and Validation of Automated Multilabel Segmentation for Acute Intracerebral Hemorrhage and Complications
Authors: Nawabi Jawed , Baumgärtner Georg Lukas , Schulze-Weddige Sophia , Dell’Orco Andrea , Morotti Andrea , Mazzacane Federico , Kniep Helge , Schlunk Frieder , Böhmer Maik FH , Akkurt Burak Han , Orth Tobias , Sofie Weissflog Jana , Schumann Maik , Sporns Peter B. , Scheel Michael , Hanning Uta , Fiehler Jens , Penzkofer Tobias
Published: August 2024

Purpose

To evaluate a nnU-Net-based deep learning for automated segmentation of intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and perihematomal edema (PHE) on noncontrast CT scans.

Materials and Methods

Retrospective data from acute ICH patients admitted at four European stroke centers (2017-2019), along healthy controls (2022-2023), were analyzed. nnU-Net was trained (n=775) using a 5-fold cross-valiadtion approach, tested (n=189), and seperatly validated on internal (n=121), external (n=169), and diverse ICH etiologies (n=175) datasets. Interrater-validated ground truth served as the reference standard. Lesion detection, segmentation, and volumetric accuracy were measured, alongside time efficiency versus manual segmentation.

Results

Test set results revealed high nnU-Net accuracy (median Dice Similartiy Coefficient (DSC): ICH 0.91, IVH 0.76, PHE 0.71) and volumetric correlation (ICH, IVH: r=0.99; PHE: r=0.92). Sensitivities were high (ICH, PHE: 99%; IVH: 97%), with IVH detection specificities and sensitivities >90% for volumes up to 0.2 ml. Anatomical-specific metrics showed higher performance for lobar and deep hemorrhages (median DSC 0.90 and 0.92, respectively) and lower for brainstem (median DSC 0.70). Concurrent hemorrhages did not affect accuracy, p> 0.05. Across validation sets, segmentation precision was consistent, especially for ICH (median DSC 0.85-0.90), with PHE slightly lower (median DSC 0.61-0.66) and IVH best in the second and third set (median DSC 0.80). Average processing time was 18.2 seconds versus 18.01 minutes manually.

Conclusion

The nnU-Net provides reliable, time-efficient ICH, IVH, and PHE segmentation, validated across various clinical settings, with excellent anatomical-specific performance for lobar and deep hemorrhages. It shows promise for enhancing clinical workflow and research initiatives.
Discovery of natural compounds as novel FMS-like tyrosine kinase-3 (FLT3) therapeutic inhibitors for the treatment of acute myeloid leukemia: anin silicoapproach
Authors: Das Uddalak , Lavanya C , Uttarkar Akshay , Kumar Jitendra , Niranjan Vidya
Published: August 2024

FLT3 mutations, observed in approximately 30-35% of Acute Myeloid Leukemia (AML) cases, drive leukemic proliferation and survival pathways, presenting a significant challenge in clinical management. To address this therapeutic need, we employed a comprehensive computational approach integrating pharmacophore screening, molecular docking, ADMET analysis, and molecular dynamics simulations to identify potent inhibitors targeting FLT3. Utilizing ligand-based pharmacophore models generated from experimentally proven FLT3 inhibitors from BindingDB, we screened over 400,000 natural compounds from the COCONUT database. Hits identified through pharmacophore screening underwent further evaluation via Lipinski and Golden triangle criteria to ensure drug-like properties. Molecular docking against the FLT3 receptor, combined with ADMET analyses, facilitated the prioritization of lead compounds. Subsequently, three promising candidates were subjected to molecular dynamics simulations to assess binding stability. Our findings reveal three top- performing compounds, demonstrating robust and stable binding affinity and favorable ADMET characteristics. These compounds hold promise as potential scaffolds or leads for developing novel FLT3 inhibitors in AML therapy.
Sustained fertility from first-wave follicle oocytes that pause their growth
Authors: Soygur Bikem , Gaylord Eliza A. , Foecke Mariko H. , Cincotta Steven A. , Horan Tegan S. , Wood Anna , Cohen Paula E. , Laird Diana J.
Published: August 2024

Ovulation results from the cyclical recruitment of non-renewing, quiescent oocytes for growth. Therefore, the primordial follicles that are established during development from an oocyte encapsulated by granulosa cells are thought to comprise the lifelong ovarian reserve1–4. However, using oocyte lineage tracing in mice, we observed that a subset of oocytes recruited for growth in the first juvenile wave remain paused for many months before continuing growth, ovulation, fertilization and development into healthy offspring. This small subset of genetically-labeled fetal oocytes, labeled with Sycp3-CreERT2, is distinguished by earlier entry and slower dynamics of meiotic prophase I. While labeled oocytes were initially found in both primordial follicles and growing follicles of the first wave, they disappeared from primordial follicles by puberty. Unexpectedly, these first-wave labeled growing oocytes persisted throughout reproductive lifespan and contributed to offspring at a steady rate beyond 12 months of age, suggesting that follicles can pause mid-growth for extended periods then successfully resume. These results challenge the conclusion from lineage tracing of granulosa cells that first-wave follicles make a limited contribution to fertility5and furthermore suggest that growth-paused oocytes comprise a second and previously unrecognized ovarian reserve.
Nationwide melanoma registry databases in real-world settings: a scoping review protocol
Authors: Yang Songchun , Deng Dilan , Lin Wenrui , Chen Xiaozhen , Zhao Shuang , Lu Lixia , Xiao Yi , Shen Minxue , Chen Mingliang , Chen Xiang , Su Juan
Published: August 2024

Introduction

A patient registry database is an important tool to address a wide range of research questions. Several countries have established nationwide melanoma registry databases. However, there is no report on summarising and comparing these databases. This scoping review aims to answer a broad question on how contemporary nationwide melanoma registry databases were conducted across different countries.

Methods

The proposed scoping review will follow the guidelines described by the Joanna Briggs Institute manual for evidence synthesis and results will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews guideline. PubMed, Embase, Web of Science,ClinicalTrials.gov, and Google will be parallelly and independently searched by two reviewers. We will include nationwide melanoma databases with the aim of continuously and systematically collecting medical records and other relevant information about melanoma patients under routine conditions. The reference list of all included publications will also be screened for additional literature. The literature search will be limited to records after the year 2000 and in English. Two reviewers will independently review the selected literature for information extraction according to a predefined extraction guidance sheet. For databases without relevant literature introductions, we will try contacting the main researchers of the database via email for detailed information. We will provide a brief descriptive analysis of the collected data.

Expected results and implications

This scoping review will provide an extensive description of how contemporary nationwide melanoma databases were conducted. Findings have the potential to enhance the understanding of melanoma registry databases among researchers in related fields and promote subsequent international collaborations that aim at promoting the clinical practice of melanoma.

STRENGTHS AND LIMITATIONS OF THIS STUDY

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This is the first scoping review protocol of summarizing contemporary nationwide melanoma databases globally.

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Targeted online surveys through email enable us to have a more comprehensive understanding of the latest situation of current databases.

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We expect to answer a broad question on how contemporary nationwide melanoma registry databases were conducted across different countries.

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Potentially missing relevant databases that have not been insufficiently reported is a limitation of the present scoping review.
New Eye Tracking Metrics System: The Value in Early Diagnosis of Autism Spectrum Disorder
Authors: Wang Raymond Kong , Kwong Kenneth , Liu Kevin , Kong Xue-Jun
Published: August 2024

Background

Eye tracking (ET) is emerging as a promising early and objective screening method for autism spectrum disorders (ASD), but it requires more reliable metrics with enhanced sensitivity and specificity for clinical use.

Methods

This study introduces a suite of novel ET metrics: Area of Interest (AOI) Switch Counts (ASC), Favorable AOI Shifts (FAS) along self-determined pathways, and AOI Vacancy Counts (AVC). These metrics were applied to toddlers and preschoolers diagnosed with ASD. The correlation between these new ET metrics and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) scores was assessed using linear regression. Sensitivity and specificity of the cut-off scores were also evaluated to predict diagnosis.

Results

Our findings indicate significantly lower FAS and ASC and higher AVC (P<0.05) in children with ASD compared to their non-ASD counterparts within this high-risk cohort. There were no significant differences in total fixation time or pupil size (p > 0.05). Additionally, FAS was negatively correlated with ADOS-2 total scores and the social affect (SA) subscale (p < 0.05). Among these new ET metrics, AVC yielded the best sensitivity (88-100%) and specificity (80-88%) with a cut-off score of 0.305-0.306, followed by FAS and ASC for distinguishing ASD from non-ASD for diagnosis.

Conclusions

This study confirms the utility of innovative ET metrics—FAS, AVC, and ASC, which exhibit markedly improved sensitivity and specificity, enhancing ASD screening and diagnostic processes.
Neurocognitive Functioning is Impaired in Perinatally HIV-Infected Youth
Authors: Welikson Tamara , Sarma Manoj K. , Keller Margaret , Sayre James , Walot Irwin , Michalik David E. , Hayes Judy , Nielsen-Saines Karin , Deville Jaime , Kovacs Andrea , Operskalski Eva , Church Joseph A. , Thomas M. Albert , Ventura Joseph
Published: August 2024

Background

The present study examined neurocognitive differences between Perinatally HIV (PHIV)-infected-youth and age and gender matched healthy controls. Despite early, long-term anti-viral treatment (ART), significant neurocognitive deficiencies remain for PHIV-infected-youth reaching adulthood compared to controls.

Methods

Participants were assessed with a comprehensive neuropsychological battery. An Overall Neurocognitive Composite Score and a Global Deficit Score (GDS) were created. Sleep, depression, and developmental level of intellectual functioning were also examined.

Results

PHIV-youth performed more poorly than controls in all neurocognitive domains. Very large effect sizes were observed for the Overall Neurocognitive Composite Score and GDS. PHIV-infected-youth appear to be significantly more depressed compared to controls, but there were no differences in amount or type of sleep observed.

Conclusion

Despite early, long-term anti-viral treatment (ART), neurocognitive deficiencies remain for PHIV-infected-young-adults. The verbal learning domain was significantly impaired with implications for functioning. The PHIV-infected-youth were also depressed and not receiving treatment for depression.
Low-cost generation of clinical-grade layperson-friendly pharmacogenetic passports using oligonucleotide arrays
Authors: Lanting Pauline , Warmerdam Robert , Slager Jelle , Brugge Harm , Ochi Taichi , Benjamins Marloes , Lopera-Maya Esteban , Jankipersadsing Soesma , Gelderloos-Arends Jody , Teuben Daphne , Hendriksen Dennis , Charbon Bart , Johansson Lennart , Munnink Thijs Oude , de Boer-Veger Nienke ,   Lifelines NEXT,   LifeLines Cohort Study, Wilffert Bob , Swertz Morris , Touw Daan , Deelen Patrick , Knoers Nine , Dekens Jackie , Franke Lude
Published: August 2024

Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual’s genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. Pharmacogenetic information is most often obtained using special assays, making it expensive and time-consuming to generate. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing, and lowering the barrier to generating PGx information prior to first prescription.

Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a novelCYP2D6copy number variant calling tool, foregoing the need to use separate PCR-based copy number detection. Ultimately, we returned 1227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.
Comorbidity trajectories before and after the diagnosis of heart failure: a UK Biobank cohort study
Authors: MacGowan Hugo , Brown Oliver I , Drozd Michael , Walker Andrew MN , Giannoudi Marilena , Straw Sam , Paton Maria F , Gierula John , McGinlay Melanie , Griffin Kathryn J , Witte Klaus K , Kearney Mark T , Cubbon Richard M
Published: August 2024

Background

Heart Failure (HF) is frequently associated with multiple comorbidities. We aimed to define their trajectory of accrual to identify opportunities for disease prevention.

Methods

We identified all participants in the UK Biobank cohort study diagnosed with HF prior to enrolment or during follow-up, who had disease occurrence data available from both primary and secondary care records (n=9,824). We established the time between diagnosis of HF and 16 common comorbidities to determine the rate and sequence of comorbidity accrual in relation to HF. Stratified analyses considered associations with sex and age at diagnosis of HF.

Findings

In chronological sequence, HF was the median fourth diagnosis for men and women. As the age at HF diagnosis increased, HF came later in the sequence of diseases (median second in under 50s to fifth in those aged 80-90). In all age strata, comorbidities accumulated for over a decade before HF and this accelerated in the years immediately before HF. The median time between comorbidity and HF diagnoses ranged from depression preceding HF by 10.7 years to dementia proceeding HF by 0.7 years; all comorbidities presented earlier in women. Atrial fibrillation/flutter was the commonest disease to immediately precede HF, followed by hypertension, cancer, myocardial infarction and osteoarthritis.

Interpretation

HF is most often diagnosed in people with established multimorbidity. There is a protracted window of opportunity during which interventions to prevent HF could be applied, often in disease contexts where this is not routine care, such as cancer and osteoarthritis.

Funding

British Heart Foundation (RG/F/22/110076)
Study of Compliance of Law on Healthy and Balanced Diets by Schools in a District of New Delhi, India
Authors: Singh Raja , Dada Rima , Frank Arthur L
Published: August 2024

There has been a steep increase in incidence of complex life style diseases. An unhealthy diet, alcohol consumption, tobacco consumption and high stress levels are major contributory factors. While action may be directed at dealing with all these points by various mechanisms, the issue of resolving unhealthy diets in schools, and the compliance of its related legal framework is discussed in this paper. In 2020, the Indian food regulatory organisation passed a regulation assuring school children are provided food that meets the standards of safety and a balanced diet. To this end, there has been consideration making sure foods with high trans/saturated fat and with added sodium and sugar do not form part of the diet of school children. All exposures to such foods, direct or indirect, have been prohibited and schools have been made accountable together with other local agencies. To understand compliance with this regulation, information from 49 public-run schools in a district of India’s capital New Delhi were collected and reported. The implementation and compliance status in these schools has been dismal with 24% being, for example, the maximum compliance for a single factor related to implementation of ‘Eat Right Campus’ campaign and similar or lower levels of compliance for other factors related to advertisement of unhealthy foods. The status of implementation and compliance of the food regulations for schools can inform policy and future actions required in this area. The creation of laws regarding regulation of schools must be followed by thorough implementation in order to deal with issues of rising global childhood obesity and other clinical manifestations (in the form of other lifestyle diseases) of unhealthy diets among children now and during adulthood.
Perceptions about the Use of Virtual Assistants for Seeking Health Information among Caregivers of Young Childhood Cancer Survivors
Authors: Sezgin Emre , Jackson Daniel I. , Kaufman Kate , Skeens Micah , Gerhardt Cynthia A. , Moscato Emily L.
Published: August 2024

Purpose

This study examined the perceptions of caregivers of young childhood cancer survivors (YCCS) regarding the use of virtual assistant (VA) technology for health information seeking and care management. The study aim was to understand how VAs can support caregivers, especially those from underserved communities, in navigating health information related to cancer survivorship.

Methods

A qualitative study design was employed, involving semi-structured interviews and focus groups with ten caregivers of YCCS from metropolitan, rural and Appalachian regions, recruited from a large pediatric academic medical center in the Midwest. A web-based VA prototype was tested with caregivers, who provided feedback on its usability, utility, and feasibility. Data were analyzed using thematic analysis to identify key themes related to caregivers’ interactions with and perceptions of the VA technology.

Results

We identified four major themes: Interface and Interaction, User Experience, Content Relevance, and Trust. Caregivers expressed preferences for multimodal interactions, emphasized the need for accurate and relevant health information, and highlighted the importance of trust and confidentiality. The VA was perceived as a valuable tool for quickly accessing information, reducing the cognitive and emotional burden on caregivers. VAs were perceived to provide tailored support for managing specific health needs of YCCS.

Conclusions

VAs hold promise as a support tool for caregivers of YCCS, particularly in underserved communities. By offering personalized, reliable, and easily accessible information, VAs were perceived to support caregivers to manage health conditions and ease the caregiving tasks.
How Alzheimer’s Aβ propagates and triggers tau pathology in intact neurons
Authors: Sasahara Tomoya , Shoko Hongo , Ito Mika , Takino Naomi , Muramatsu Shin-ichi , Kakita Akiyoshi , Hoshi Minako
Published: August 2024

Alzheimer’s disease begins with Aβ accumulation, progresses to tau aggregates and results in widespread neurodegeneration1-3. Simultaneous propagation of Aβ aggregates from very limited to wide and distant brain regions is one of the outstanding events in the early stage. Here, we demonstrate that the neurovascular unit4,5comprising capillaries and pericytes, the machinery supplying oxygen and glucose to neurons, is also the machinery for propagating effector molecules that impose Alzheimer’s pathologies on intact neurons. We discovered two distinct signaling cascades, one activated in capillary endothelial cells and the other in pericytes. At the origin of either cascade, we identified amylospheroid (ASPD)6,7, a highly toxic 30-mer assembly of Aβ, and its sole target NKAα38, a neuron-specific isoform of Na+,K+-ATPase9,10but present in endothelial cells and pericytes. In endothelial cells, ASPD binding to NKAα3 releases angiotensin II, which increases β-secretase in intact neurons, causing a huge increase of Aβ42and resultant accumulation. In pericytes, ASPD binding to NKAα3 releases an unknown effector molecule that activates δ-secretase in intact neurons, further augmenting Aβ42and producing pathogenic tau1-368fragment. Thus, Aβ and tau pathologies are directly linked. Stopping the signaling cascades near the origin by inhibiting ASPD-NKAα3 interaction8may provide a new therapeutic approach.
Age Dependent Integration of Cortical Progenitors Transplanted at the Adult CSF-Brain Interface
Authors: Pothayee Nikorn , Greene Gretchen , Jahanipour Jahandar , Jie Hyesoo , Tao-Cheng Jung-Hwa , Petrus Emily , Maric Dragan , Koretsky Alan P.
Published: August 2024

There has been renewed interest in neural transplantation of cells and tissues for brain repair. Recent studies have demonstrated the ability of transplanted neural precursor cells and in vitro grown organoids to mature and locally integrate into host brain neural circuitry. Much effort has focused on how the transplant behaves and functions after the procedure, but the extent to which the host brain can properly innervate the transplant, particularly in the context of aging, is largely unexplored. Here we report that transplantation of rat embryonic cortical precursor cells into the cerebrospinal fluid-subventricular zone (CSF-SVZ) of adult rat brains generates a brain-like tissue (BLT) at an ectopic site. This model allows for the assessment of long-range connectivity and cellular interactions between the transplant and the host brain as a function of host age. The transplanted precursor cells initially proliferate, then differentiate, and develop into mature BLTs, which receive supportive cellular components from the host including blood vessels, microglia, astrocytes, and oligodendrocytes. There was integration of the BLT into the host brain which occurred at all ages studied, suggesting that host age does not affect the maturation and integration of the transplant-derived BLT. Long-range axonal projections from the BLT into the host brain were robust throughout the different aged recipients. However, long-distance innervation originating from the host brain into the BLT significantly declined with age. This work demonstrates the feasibility and utility of integrating new neural tissue structures at ectopic sites into adult brain circuits to study host-transplant interactions.
Engineering Intercellular Communication using M13 Phagemid and CRISPR-based Gene Regulation for Multicellular Computing inEscherichia coli
Authors: Kusumawardhani Hadiastri , Zoppi Florian , Avendaño Roberto , Schaerli Yolanda
Published: August 2024

Engineering multicellular consortia, where information processing is distributed across specialized cell types, offers a promising strategy for implementing sophisticated biocomputing systems. However, a major challenge remains in establishing orthogonal intercellular communication, or “wires”, within synthetic bacterial consortia. In this study, we address this bottleneck by integrating phagemid-mediated intercellular communication with CRISPR-based gene regulation for multicellular computing in syntheticE. coliconsortia. We achieve intercellular communication by regulating the transfer of single guide RNAs (sgRNAs) encoded on M13 phagemids from sender to receiver cells. Once inside the receiver cells, the transferred sgRNAs mediate gene regulation via CRISPR interference. Leveraging this approach, we successfully constructed one-, two-, and four-input logic gates. Our work expands the toolkit for intercellular communication and paves the way for complex information processing in synthetic microbial consortia, with diverse potential applications, including biocomputing, biosensing, and biomanufacturing.
Colonisation lags predict sympatric diversity in birds
Authors: Reijenga Bouwe R. , Etienne Rampal S. , Murrell David J. , Pigot Alex L.
Published: August 2024

Ecological communities are assembled over time, suggesting a crucial role for evolutionary history in determining the diversity of species assemblages. Indeed, differences in the build-up of sympatric diversity across space, time and clades may reflect variation in the historical patterns of speciation and thus time available for colonisation. However, quantifying the role of evolutionary history is challenging and thus its potential effects have received far less attention than the effects of ecological limits to diversity. Here we use a dynamic model of assembly by allopatric speciation, colonisation, and local extinction to test how evolutionary history predicts variation in sympatric diversity across clades of passerine birds. We show that the clade-specific history of speciation strongly impacts the build-up of sympatry over time, and that phylogenetic tree shape statistics are key predictors of differences in sympatric diversity between clades. Within clades the proportion of species that are sympatric is highest in old, species-poor, and phylogenetically balanced clades. These historical factors all promote the average age of extant species, providing more time for species to expand their geographic distributions and colonise communities. We further show that phylogenetic patterns in community structure frequently interpreted as evidence that community assembly is limited by the saturation of ecological niche space can be explained simply by the lag-time to colonisation following speciation. Our results show that the macroevolutionary history of speciation and assembly time is essential in explaining variation in the structure and diversity of ecological communities.
Genetic suppression interactions are highly conserved across genetic backgrounds
Authors: Paltenghi Claire , van Leeuwen Jolanda
Published: August 2024

Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature sensitive alleles ofSEC17, TAO3, andGLN1in three genetically diverse natural isolates of the budding yeastSaccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four yeast strains, although the extent to which a suppressor could rescue the temperature sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.
Inhibition of IAPs induces programmed cell death and inflammatory signaling in patient-derived metastatic breast cancer organoids
Authors: Wächtershäuser Kaja Nicole , Schneider Jana V. , Gessner Alec , Andrieux Geoffroy , Kur Ivan , Duschek Nadine , Weigert Andreas , Boerries Melanie , Rieger Michael A. , Stelzer Ernst H.K. , Pampaloni Francesco , van Wijk Sjoerd J.L.
Published: August 2024

Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects therapy success and remains a major challenge. Representative and translational models to understand, manipulate and cultivate advanced BC and to model PCD resistance are therefore urgently required. Smac mimetics are promising compounds to circumvent apoptosis resistance and are able to induce caspase-independent necroptosis, a lytic and inflammatory mode of PCD. Here, we apply primary, patient-derived human mammary organoids (hMOs) to investigate alternative forms of PCD to overcome apoptosis resistance. Using time lapse brightfield with immunofluorescent confocal microscopy, biochemistry and gene expression analysis, we demonstrate that Smac mimetics induce apoptosis in primary hMOs. By mimicking apoptosis resistance via caspase inhibition, hMOs undergo necroptosis, associated with expression and secretion of inflammatory mediators. Inhibition of linear ubiquitination by the LUBAC inhibitor HOIPIN-8 prevents necroptosis, as well as the expression and release of inflammatory mediators in hMOs. Our findings demonstrate that primary hMOs are effective models to model, study and manipulate PCD responses and inflammation in in primary BC organoids and open new therapeutic screening options for chemotherapy-resistant BC.
Comprehensive Database of Circular Permutations: Systematic Detection and Analysis Using Deep Learning
Authors: Hu Yue , Huang Bin
Published: August 2024

This study presents a comprehensive approach to detect circular permutations in Protein Data Bank up to date (PDB, 287081 proteins which sequence length is under 800 up to 20240101). We systematically analyzed the Protein Data Bank (PDB) to identify circular permutations, leveraging FoldSeek and MMseqs2 for structural and sequence similarity searches. The 143756535 candidate pairs were filtered by some threshold for corresponding analysis. TM-align, icarus or plmCP was used to align protein structures and refine detection accuracy, while facilitated the precise identification of circular permutations. Finally, we got 20801 candidate circular permutation pairs and 3351 circular permutation proteins(https://github.com/YueHuLab/Circular-permutation-in-PDB). Our methodology provides a robust framework for uncovering circular permutations in protein databases, enhancing our understanding of protein structural variations and evolutionary adaptations.
RNA order regulates its interactions with zwitterionic lipid bilayers
Authors: Singh Akhil Pratap , Prabhu Janak , Vanni Stefano
Published: August 2024

RNA-lipid interactions directly influence RNA activity, which plays a crucial role in developing new applications in medicine and biotechnology. However, while specific preferential behaviors between RNA and lipid bilayers have been identified experimentally, their molecular origin remains unexplored. Here we use molecular dynamics simulations to investigate the interaction between RNA and membranes composed of zwitterionic lipids at the atomistic level. Our data reproduce and rationalize previous experimental observations, including that short-chain RNAs rich in guanine have higher affinity for gel-phase membranes compared to RNA sequences rich in other nucleotides and that RNA prefers gel-phase membranes to fluid bilayers. Our simulations reveal that RNA order is a key molecular determinant of RNA-zwitterionic phospholipid interactions. Our data provides a wealth of information at the atomic level that will help accelerating research on RNA-lipid assemblies for task-specific applications such as designing lipid-based nanocarriers for RNA delivery.
Gaze reflects confidence in explicit decisions while relying on a distinct computational mechanism
Authors: Stern Yonatan , Netzer Ophir , Koren Danny , Zvilichovsky Yair , Hertz Uri , Salomon Roy
Published: August 2024

The eyes are considered a ‘window’ into the mind, shedding light on the cognitive processes leading to explicit decisions. Yet, eye movements are also a distinct oculomotor decision that is the outcome of an independent cognitive system. When exploring novel environments, the convergence and divergence of gaze and explicit decisions highlights the eyes’ dual role. However, the computational mechanisms underlying this interplay and its contribution to adaptative behavior remains unclear. Combining virtual reality based associative learning paradigms with computational modeling across one exploratory and two pre-registered experiments (Total N = 115), we examine learning as multi-system process encompassing explicit decisions and ocular expectations. The two exhibited a partial overlap in their learning. On the one hand, participants’ explicit predictions about target location and their subsequent anticipatory gaze direction robustly converged, and gaze reveals the latent probability of the explicit choice. Moreover, gaze exhibited computational hallmarks of confidence, reflecting an oculomotor assessment of the explicit prediction. On the other hand, ocular and explicit decisions consistently diverged indicating an independent computation reflected in gaze. Although the two systems learn and ascribe value similarly, they utilize different decision mechanisms. Oculomotor decisions were less driven by choice consistency across trials enabling increased exploration. Under uncertainty explicit and oculomotor decisions tended to diverge, enabling a hedging of one’s decision. These findings highlight how together, explicit and oculomotor systems’ learning enables adaptive embodied behavior.

Significance Statement

The eyes often reveal additional information beyond one’s explicit decision, offering a ‘window into the mind’ (e.g., leading poker players to wear sunglasses). Yet, eye movements are the product of a distinct system, occasionally diverging from explicit decisions. However, what additional information is conveyed by gaze, and what leads to its occasional divergence remain unclear. Using virtual reality and computational modeling, this study demonstrates a partial overlap between the two. Generally, they robustly converge, and gaze reflects a confidence-like assessment of explicit decisions. Yet they also diverge due to distinct decision mechanisms. Their divergence enables a ‘hedging’ of one’s decision under uncertainty. This demonstrates a multimodal decision process, where different action systems make overlapping but independent choices.