bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the barriers and enablers to outbreak reporting in the Asia-Pacific region: a mixed-methods study protocol
Authors: Talwar Amish , Katz Rebecca , Kirk Martyn D. , Housen Tambri
Published: December 2024

Introduction

The COVID-19 pandemic has raised concerns about the global capacity for timely outbreak reporting. However, gaps remain in our understanding of barriers and enablers to outbreak reporting, particularly at the local level. Field epidemiology training program (FETP) fellows often participate in the outbreak reporting process as part of both their training and the public health roles they assume after graduating; they therefore represent a potentially valuable source of information for better understanding these barriers and enablers. This study will investigate the barriers and enablers to outbreak reporting through a mixed methods approach that will encompass a review of the existing literature as well as surveying and interviewing FETP trainees and graduates from the Asia-Pacific region.

Methods

This study will begin with a scoping review of the literature to identify existing evidence of barriers and enablers to outbreak reporting. Based on our findings from the scoping review, we will administer a survey to FETP trainees and graduates from the World Health Organization Western Pacific and South-East Asian Regions and conduct interviews with a subset of survey respondents to investigate the survey findings in more detail. We will summarise and compare the survey results according to various country-level economic and political indicators, and we will employ thematic analysis to evaluate the interview responses. Based on the findings from the scoping review, survey, and interviews, we will construct a model to comprehensively describe the various barriers and enablers to outbreak reporting.

Discussion

This study will contribute to our understanding of the determinants of outbreak reporting across several geographic, political, and economic contexts by eliciting the viewpoints and experiences of persons involved with outbreak reporting, particularly at the local level. This information will help improve the outbreak reporting process, allowing for more timely reporting and helping prevent future outbreaks from becoming pandemics.
Making a Case for an Autism-Specific Multimorbidity Index: A Comparative Cohort Study
Authors: Sosenko Filip , Nijhof Dewy , McKernan Ward Laura , Cairns Deborah , Hughes Laura , Rydzeswka Ewelina
Published: December 2024

Autistic people experience challenges in healthcare, including disparities in health outcomes and multimorbidity patterns distinct from the general population. This study investigated the efficacy of existing multimorbidity indices in predicting COVID-19 mortality among autistic adults and proposes a bespoke index, the ASD-MI, tailored to their specific health profile. Using data from the CVD-COVID-UK/COVID-IMPACT Consortium, encompassing England’s entire population, we identified 1,027 autistic adults hospitalized for COVID-19, among whom 62 died due to the virus. Employing logistic regression with 5-fold cross-validation, we selected diabetes, coronary heart disease, and thyroid disorders as predictors for the ASD-MI, outperforming the Quan Index, a general population-based measure, with an AUC of 0.872 versus 0.828, respectively. Notably, the ASD-MI exhibited better model fit (pseudo-R2 0.25) compared to the Quan Index (pseudo-R2 0.20). These findings underscore the need for tailored indices in predicting mortality risks among autistic individuals. However, caution is warranted in interpreting results, given the limited understanding of morbidity burden in this population. Further research is needed to refine autism-specific indices and elucidate the complex interplay between long-term conditions and mortality risk, informing targeted interventions to address health disparities in autistic adults. This study highlights the importance of developing healthcare tools tailored to the unique needs of neurodivergent populations to improve health outcomes and reduce disparities.
EFFICACY OF STEVIA REBAUDIANA BERTONI ON LEVELS OF GCF GLUCOSE AND BIO-MARKERS IN DIABETIC PATIENTS WITH PERIODONTITIS-A SPLIT MOUTH RANDOMIZED CONTROLLED TRIAL
Authors: Chandra Rampalli Viswa , Komaravelli Nandini , Reddy Aileni Amarendhar
Published: December 2024

Aim & Objectives

The aim of the present study was to evaluate the effect of Stevia rebaudiana bertoni on GCF glucose levels and GCF bio-markers in diabetic patients with periodontitis.

Patients and methods

19 subjects were participated in the study. Randomly, a quadrant was allotted as test site for placing Stevia gel and other quadrant was allotted as a control site for placing placebo in the gingival sulcus having PD≥ 5mm after performing thorough scaling and root planing. GCF samples was collected using sterile paper strips at baseline i.e., after scaling and root planing, 3 months and 6 months using intra-crevicular superficial method. GCF samples was eluted from the strips by placing them in Eppendorf® tubes that contained 500 micro-litre of buffer and will be stored at -80℃ until analysis was done. The levels of GCF glucose and GCF bio-markers was evaluated by using commercially available ELISA kit.

Results

Stevia gel was effective in decreasing the GCF glucose and increasing ghrelin levels in diabetic patients with periodontitis. There was significant difference in clinical parameters in both test and control groups.

Conclusion

This study concluded that application of Stevia gel in gingival crevice may be of value in controlling diabetes and periodontitis at a time.
A mixed methods study exploring food insecurity and diet quality in households accessing food clubs in England
Authors: Ziauddeen Nida , Taylor Elizabeth , Alwan Nisreen A , Richards Fran , Margetts Barrie , Lloyd Tim , Disegna Marta , Mason Naomi , Taheem Ravita , Smith Dianna
Published: December 2024

Background

Food clubs are a higher-agency food aid intervention that charge a small fee for a set number of items. Some incorporate longer-term solutions such as budgeting support and cooking skills. These are in place in England to help address inadequate reliable access to affordable, nutritious food. We used a convergent parallel mixed methods design to describe the food insecurity households accessing food clubs experience and to assess diet quality and wellbeing at the start and after at least three months of using food clubs in the South of England.

Methods

Participants accessing food clubs in Wessex from March 31 to November 3, 2022 were recruited after providing informed consent. They completed a survey at recruitment that collected data on diet and health. Food security was assessed using the modified six-item US Department of Agriculture (USDA) food security survey module, and wellbeing using the short form Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). Follow-up surveys were conducted after participants used the clubs for at least three months. Participants were invited to take part in a semi-structured interview.

Results

Of the 90 participants recruited at baseline, 52% were aged 35–54 years, 74% were female, 81% were of White ethnicity, and 71% reported having at least one dependent child. Food security status was calculated in 69 participants who answered all six questions of the USDA module, with 42% reporting low and 43% very low food security. Among participants with follow-up (n=52), low food security was 41% and very low food security was 18% at follow-up.

Eleven participants were interviewed. Two themes explored impact and experiences of food club. Impact illustrated how participants consumed a more varied diet, experienced less financial pressure, and improved health, wellbeing and social interaction. Experiences of food clubs explored limitations of time and food range at clubs, developing a sense of community and overcoming stigma.

Conclusion

This study is the first in the UK to explore potential diet, food security and wellbeing impacts of food clubs. Ongoing impact evaluation will enable optimisation of interventions for the populations they serve, such as inviting other organisations/groups to attend/be available for members.
Longitudinal Evolution of Diffusion Metrices in the Cerebello-Thalamo-Cortical Tract After MRgFUS Thalamotomy for Essential Tremor
Authors: Upadhyay Neeraj , Daamen Marcel , Purrer Veronika , Borger Valeri , Schmeel Carsten , Krauß Jonas , Maurer Angelika , Radbruch Alexander , Wüllner Ullrich , Boecker Henning
Published: December 2024

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) targets the ventral intermediate nucleus hub region within the cerebello-thalamo-cortical tract (CTCT). Understanding the microstructural changes in the CTCT over time and their link to tremor improvement is crucial from a tremor-network perspective. We retrospectively analyzed tremor scores, lesion characteristics, and diffusion MRI-derived CTCT microstructural measures in 27 ET patient’s pre-treatment (T0), at 1 month (T2), and 6 months (T3) post-MRgFUS. Using probabilistic tractography, we created an average CTCT mask for assessing fractional anisotropy (FA), axial (AD), mean (MD), and radial diffusivity (RD) measures across time points. Significant tremor reduction was observed at T2 and T3. The Linear mixed effect analyses showed significant time effects for FA, MD, and AD. Relative to baseline, post-hoc comparisons showed a significant decrease of FA and AD at lesion site only for T2. Instead, there was a significant increase in AD and MD at T3 compared to T2 at lesion site, and remotely near the motor cortex. Lesion size and FA changes in the CTCT at T2 showed only trend-level correlations with tremor outcome. Stronger associations were observed for the thalamic lesion-tract overlap at T2, which were even more robust at T3. Dynamic microstructural changes suggest early axonal disruption at the lesion site and subsequent reorganization, with remote CTCT changes potentially indicating chronic degeneration. Meanwhile, microstructural measures show limited predictive value for longer-term tremor outcome compared with macroanatomical lesion-CTCT overlap. Yet, advanced diffusion imaging protocol could increase the sensitivity to predict MRgFUS clinical outcome.
Vertebrobasilar Dolichoectasia Future Aspects: A Meta-analysis of Clinical Features and Treatment Strategies
Authors: Shaheen Nour , Ortega-Gutierrez Santiago , Samaniego Edgar A , Mastorakos Panagiotis , Gooch Michael Reid , Jabbour Pascal , Flouty Oliver , Dlouhy Kathleen , Zanaty Mario
Published: December 2024

Background

Dolichoectatic Vertebrobasilar fusiform aneurysm (DVBFAs) presents a clinical challenge due to its complex anatomical features and associated neurological complications. This meta-analysis evaluates the clinical outcomes of endovascular treatment (EVT), open surgery, and conservative management for VBDA.

Methods

A systematic review of the PubMed, Scopus, and Web of Science databases was conducted to identify studies reporting on radiologically confirmed DVBFAs. Clinical outcomes were assessed using the modified Rankin Scale (mRS) and mortality rates. Meta-regression was performed to identify potential predictors of treatment outcomes.

Results

Ten studies with 219 patients were analyzed. Of the cohort, 58.4% underwent EVT, 24.6% received open surgery, and 16.9% were managed conservatively. The overall proportion of patients achieving a good clinical outcome (mRS <3) was 46.8%, with EVT showing the highest proportion at 59.4%, compared to 32.3% for open surgery and 24.7% for conservative management (p = 0.0145). The overall mortality rate was 25.98%, with EVT having the lowest mortality rate at 10.06%, followed by open surgery at 44.44% and conservative management at 63.30% (p = 0.0004). Subgroup analyses revealed statistically significant differences between treatment approaches in clinical outcomes and mortality.

Conclusion

EVT appears to provide better clinical outcomes for DVBFAs, though mortality rates remain high across all treatment modalities. The absence of significant differences in subgroup analysis suggests the need for further randomized controlled trials (RCTs) of EVT vs. conservative management to establish definitive treatment guidelines.
Learning from and improving upon high-throughput screens for protein fitness with Generative AI - Application to BBB-crossing AAV design
Authors: Kashyap Ayan , Soniya Kumari , Anubhooti  , Kandavel Subhalakshmi , Avadhani Kruthika , Kanishka Siva , Sharma Manasvi , Chodavarapu Prasad
Published: December 2024

Deep Science is enabling high-throughput experimentation (HTE) to design novel biological entities with desired properties. E.g., blood-brain-barrier (BBB) crossing adeno-associated virus (AAV) vectors, needed for systemic delivery of gene therapies to brain cells, have been identified through innovative directed evolution assays such as M-CRE-ATE and TRACER. But, even these high-throughput experiments are only able to explore a miniscule portion of the large design space of biological entities. In this paper, we introduce autograd based maximization of protein fitness (AutoMaxProFit) to learn from and improve upon protein designs generated with high-throughput screens. Using a transformer based generative AI network and protein language models, we improve upon the design of a variant previously discovered through HTE, to yield 2x better enrichment in brain endothelial cells, as estimated by molecular dynamics (MD) simulations. This shows that Deep Tech models can learn from the observations generated by Deep Science experiments and go on to find more optimal design candidates for application in Biopharma.
Salience Network Segregation and Symptom Profiles in Psychosis Prodrome Subgroups
Authors: Iyer Aditya , Stanford William , Dayan Eran , Xavier Rose Mary
Published: December 2024

Background

Understanding neurobiological similarities between individuals with prodromal psychosis symptoms can improve early identification and intervention strategies. Here, we aimed to (i) identify neurobiologically similar groups by integrating resting-state functional connectivity and prodromal symptom data and (ii) discern discriminating symptom profiles and brain connectivity patterns in the identified sub-groups.

Methods

Our sample (N=922) was extracted from the Philadelphia Neurodevelopmental Cohort and included individuals ages 12-21 years with fMRI and self-reported psychopathology data. Analyses were conducted separately for youth and early adults. We first constructed a two-layer network using pair-wise similarity distances between participants based on resting-state functional connectivity and prodromal positive psychosis symptoms. We then performed community detection via a multiplex stochastic block model to identify subject clusters.

Results

We identified 2 blocks or communities for both the youth (n=458 and 179) and early adult (n=173 and 112) groups. Connection parameter estimates of the neuroimaging layer were nearly identical between blocks for both age groups whereas there was significant variation for the symptom layer. Psychopathology symptom and brain system segregation profiles were consistent across age groups. The youth block (n=458) with higher salience network segregation values had higher mean scores for prodromal symptoms. However, the early adult block (n=173) with lower salience network segregation had higher mean prodromal scores.

Conclusions

By integrating global similarities in brain connectivity and prodromal symptoms, we identified distinct subgroups. These groups show differences in symptom profiles and network segregation in youth and early adults, indicating significant variations in developmental paths for psychosis spectrum.
Spatial mRNA profiling using Rapid Amplified Multiplexed-FISH (RAM-FISH)
Authors: Banerjee Tirtha Das , Raine Joshua , Mathuru Ajay S. , Chen Kok Hao , Monteiro Antónia
Published: December 2024

Localizing multiple RNA molecules simultaneously in intact tissues and organs is valuable for gaining insights into possible gene-regulatory interactions underlying cell differentiation. Existing technologies for multiplexed RNA localization are expensive, computationally complex, have elaborate sample preparation steps, have size limitations, and require weeks of processing time. This limits the widespread use of such techniques in most labs. Here we describe a cost-effective methodology, Rapid Amplified Multiplexed-FISH (or RAM-FISH), based on Hybridization Chain Reaction 3.0 for localizing dozens of transcripts in the same sample. This methodology achieves multiplexing by localizing 3 genes per cycle to detect 30 or more genes within a few days. The method can be applied to fixed tissue sections, entire organs, or whole organisms such as larvalDanio rerio, without extensive sample preparation steps. The automation used here can also be adapted to perform other amplification-based FISH. Here, we demonstrate its utility, flexibility, and versatility for gene expression analysis in two very different types of samples,Bicyclus anynanabutterfly larval wings and intact 10-day-oldDanio reriofish larvae.
Reciprocal nutritional benefits in a sponge-seagrass association
Authors: Cardini U. , Montilla L.M. , Zapata-Hernández G. , Berlinghof J. , Guarcini E. , Furia M. , Margiotta F. , Meador T.B. , Wild C. , Fraschetti S. , Olivé I.
Published: December 2024

Sponges commonly form associations within seagrass meadows, but their potential impact on seagrass productivity and nutrient cycles remains poorly understood. This study investigates the association between the demospongeChondrilla nuculaand the Mediterranean seagrassPosidonia oceanicain two sampling occasions during the plant growth (spring) and senescence (autumn) seasons at a small inlet near Naples, Italy, where the sponge grows conspicuously within the seagrass bed. We found a non-linear relationship between the benthic cover of the sponge and the seagrass, with higherC. nuculacover linked to intermediateP. oceanicacover, suggesting spatial dependence.P. oceanicashowed higher net primary production (NPP) in spring, whileC. nuculawas net heterotrophic in spring but exhibited slightly positive NPP in autumn. NPP remained stable when the two organisms were associated, regardless of the season.C. nuculaconsistently contributed inorganic nutrients to the association in the form of phosphate, ammonium, and substantial nitrate, recycling nutrients that potentially benefitedP. oceanicain its growth season. In return, the seagrass consistently provided dissolved organic carbon, which aided sponge nutrition in spring. These findings suggest reciprocal benefits in the interaction betweenC. nuculaandP. oceanica, with nutrient exchange facilitating a facultative mutualism that potentially supports and stabilizes the productivity of the seagrass ecosystem.

SIGNIFICANCE STATEMENT

This study provides a novel exploration of the reciprocal interactions between the demospongeChondrilla nuculaand the Mediterranean seagrassPosidonia oceanica, revealing a facultative mutualism mediated by nutrient exchange. Our findings show a non-linear spatial dependence between sponge and seagrass cover and demonstrate the sponge’s substantial contributions of inorganic nutrients (phosphate, ammonium and conspicuous nitrate) to the seagrass, particularly during its productive spring season. In return,P. oceanicasupplies dissolved organic matter, aiding sponge nutrition. This study uniquely quantifies these reciprocal nutrient exchanges across the plant growth and senescence seasons, demonstrating how such interactions stabilize net primary production and support ecosystem functioning. These insights address a critical gap in understanding the role of sponge-seagrass associations in nutrient cycling, highlighting their significance for the resilience, productivity, and metabolic balance of coastal ecosystems under changing environmental conditions.
Phase reset dynamics of memory encoding
Authors: Colyer Ryan A. , Kahana Michael J.
Published: December 2024

Human and animal studies have implicated oscillatory reset following a behaviorally relevant stimulus in learning and memory function. Here we asked whether phase reset predicts the dynamics of memory encoding for subsequently recalled and forgotten items. Our dataset comprised 188 neurosurgical patients (99 male, 89 female) who studied lists of common words for a subsequent delayed free recall test. We observed significant 3–21 Hz overall phase reset widespread throughout the brain in the 125–500 ms interval following stimulus presentation for both subsequently recalled and forgotten items. We found that the increased recalls of the primacy effect correlated significantly and exclusively with theta phase reset from 3–7 Hz throughout the brain. When controlling for serial position effects and examining the phase consistency differences of subsequently recalled and forgotten items, we identified both a theta (3–6 Hz) and an alpha (9–14 Hz) component of phase reset. Examined separately, early list items revealed a significant theta phase reset difference, while later list items revealed a significant alpha phase reset difference for subsequently recalled items. In regional analyses, the lateral temporal cortex exhibited a significant theta phase reset difference, while the prefrontal cortex revealed both a significant theta and a significant alpha phase reset difference for subsequently recalled items. These findings support the view that oscillatory reset serves an important role in encoding new episodic associations, and reveal differing oscillatory mechanisms across theta and alpha bands for serial position effects of phase reset versus serial position controlled subsequent recall.

Significance Statement

In 188 neurosurgical patients we examined the relationship of memory function with oscillatory phase consistency in response to word encoding events in a delayed free recall task. We innovated a new approach to computing a phase consistency score with robustness across sample size differences. Using this method, we showed a significant serial position correlate across subjects with primacy regions exhibiting a clear increase in theta phase consistency (3–7 Hz). After controlling for serial position effects, we also observed a significant effect of both increased theta phase consistency (3–6 Hz) and increased alpha phase consistency (9–14 Hz) for subsequently recalled versus forgotten items. This improves our understanding of the multi-faceted role of frequency-specific phase resetting in episodic memory encoding.
DISTRIBUTION OF LIVING (ROSE BENGAL STAINED) BENTHIC FORAMINIFERA IN COPANO, ARANSAS, AND REDFISH BAYS, CENTRAL TEXAS COAST
Authors: Barrera Anna , Lowery Christopher M.
Published: December 2024

A combination of human development and climate change have the potential to impact ecosystems in the ecologically, economically, and culturally important bays of the Texas Coastal Bend in the northwestern Gulf of Mexico. To determine the extent to which potential impacts are becoming actual impacts, population studies are necessary. Here, we report populations for living benthic foraminifera from three bays collected in May 2023 and 2024. We find the bays largely dominated byAmmonia, a shift from the last complete census carried out by Frances Parker and colleagues in 1951 during a multiyear drought. We see no correlation between predominance facies and salinity within our samples, although we only record a salinity range of 25-30 PSU, a small fraction of the possible range of ∼10-40 PSU in these bays. We do observe a relationship between sediment grain size and predominance facies, withAmmoniamore common in finer grained environments.
Antibodies disrupt bacterial adhesion by ligand mimicry and allosteric interference
Authors: Hvorecny Kelli L. , Interlandi Gianluca , Veth Tim S. , Aprikian Pavel , Manchenko Anna , Tchesnokova Veronika L. , Dickinson Miles S. , Quispe Joel D. , Riley Nicholas M. , Klevit Rachel E. , Magala Pearl , Sokurenko Evgeni V. , Kollman Justin M.
Published: December 2024

A critical step in infections is the attachment of many microorganisms to host cells using lectins that bind surface glycans, making lectins promising antimicrobial targets. Upon binding mannosylated glycans, FimH, the most studied lectin adhesin of type 1 fimbriae inE. coli, undergoes an allosteric transition from an inactive to an active conformation that can act as a catch-bond. Monoclonal antibodies that alter FimH glycan binding in various ways are available, but the mechanisms of these antibodies remain unclear. Here, we use cryoEM, mass spectrometry, binding assays, and molecular dynamics simulations to determine the structure-function relationships underlying antibody-FimH binding. Our study reveals four distinct antibody mechanisms of action: ligand mimicry by an N-linked, high-mannose glycan; stabilization of the ligand pocket in the inactive state; conformational trapping of the active and inactive states; and locking of the ligand pocket through long-range allosteric effects. These structures reveal multiple mechanisms of antibody responses to an allosteric protein and provide blueprints for new antimicrobial that target adhesins.
CD4 Co-Receptor Regulates Sex-Specific NK Cell Responses to AcuteToxoplasma gondiiInfection
Authors: Roy Tathagato , Bernstein Leah , Keplinger Hunter K. , Fisk Kaatje , Ng Sai K. , Denton Stephen L. , Gigley Jason P.
Published: December 2024

Immunity toToxoplasma gondii(T. gondii) is sexually dimorphic in humans and mice, with females having higher morbidity and mortality during immune dysfunction and HIV-AIDS. The mechanisms underlying these sex differences are unclear. We investigated how a lack of CD4+ T cells (CD4 co-receptor KO) impactedT. gondiisurvival in mice. Female CD4 co-receptor KO mice succumbed toT. gondiimuch faster than males. To dissect why female CD4 co-receptor KO mice died faster, we tested their NK cell responses to acuteT. gondiiinfection compared to males. Although in wild-type (WT) animals, both sexes had similar increases in total NK cells and IFNγ + NK cells, infected CD4 co-receptor KO female mice had 50% fewer IFNγ+ NK cells than infected WT female mice. Infected male CD4 co-receptor KO had a similar increase in IFNγ+ NK cells as WT male mice. Since CD4 co-receptor deficient mice still have functional helper T cells that are CD4−, we next tested survival and NK cell responses in female and male MHCII deficient (MHCIIKO) animals, which completely lack helper CD4+T cells. Surprisingly, survival, NK cell numbers, and IFNγ+ NK cells were not significantly different between WT or MHCIIKO female and male mice. These results suggest CD4 co-receptor expression is required for survival via optimal NK cell responses during acuteT. gondiiinfection only in female mice and not in male mice. Our findings reveal an unappreciated sexual dimorphic role of CD4 co-receptor expression in regulating NK cell responses to acuteT. gondiiinfection.
Combination of live attenuated and adenovirus-based vaccines completely protects interferon gamma (IFNγ) knockout mice against pneumonic plague
Authors: Hendrix Emily K. , Sha Jian , Kilgore Paul B. , Neil Blake H. , Chopra Ashok K.
Published: December 2024

Two live attenuated vaccines (LAVs), LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their efficacy and immune responses in wild type (WT) and interferon gamma (IFNγ) knockout (KO) mice in a C57BL/6 background. While LMA and LMP are triple deletion mutants ofYersinia pestisCO92 strain, Ad5-YFV incorporates three protective plague immunogens. An impressive 80-100% protection was observed in all vaccinated animals against highly lethal intranasal challenge doses of parentalY. pestisCO92. All vaccinated mice generated robust humoral and cellular immune responses. The immunized WT mice showed overall better antibody responses in both serum and bronchoalveolar lavage fluid with much higher percentages of polyfunctional T cell populations. On the other hand, vaccinated IFNγ KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen specific T cells and memory T cells. In addition, depletion of IFNγ and tumor necrosis factor alpha (TNFα) from immunized WT mice prior to and during infection did not reduce protection against pulmonaryY. pestisCO92 challenge. These data demonstrated a dispensable nature of IFNγ in mediating protection by the aforementioned vaccines. This is the first detailed immunogenicity study of two plague LAVs administered either alone or in combination with an Ad5-YFV vaccine in a prime-boost immunization strategy in IFNγ KO mice. Further, by combining advantages of live-attenuated and adenovirus-based vaccines, augmentation of generalized immune responses were observed which could be beneficial in providing long-lasting immunity in the host.
Default mode and motor networks facilitate early learning of implicit motor sequences: a multimodal MR spectroscopy and fMRI study
Authors: Hendrikse Joshua , Brooks Emily , Wallis Sarah , Curtin Dylan , Rogasch Nigel C. , Yücel Murat , Biabani Mana , Stagg Charlotte J , Bellgrove Mark , McIntyre Richard , Suo Chao , Coxon James
Published: December 2024

Learning new motor skills is a fundamental process that involves the sequencing of actions. Skill develops with practice and time, and manifests as performance that is fast and accurate. Although we know that learning can occur through animplicitprocess in the absence of conscious awareness, and across multiple temporal scales, the precise neural mechanisms mediating implicit motor sequence learning remain poorly understood. Similarly, the capacity for interventions with known influence on learning and memory, such as cardiovascular exercise, to facilitate implicit learning is yet to be clearly established. Here, we investigated the neuroplasticity of implicit motor sequence learning and the effect of acute exercise priming. Healthy adults (39.5% female) aged 22.55 ± 2.69 years were allocated to either a high-intensity exercise (HIIT) group (n = 16) or to a very low-intensity control group (n = 17). Following exercise, participants performed a serial reaction time task. MR spectroscopy estimates of sensorimotor gamma-aminobutyric acid (GABA) were acquired before and after exercise, and during task performance, and resting-state fMRI was acquired at the end of the protocol. We show that early stages of learning are linked to default mode network connectivity, while the overall degree of learning following sustained practice is associated with motor network connectivity. Sensorimotor GABA concentration was linked to the early stages of learning, and GABA concentration was modulated following HIIT, although the two were not related. Overall, via integration of multiple neuroimaging modalities we demonstrate that interactions between hippocampal and motor networks underlieimplicitmotor sequence learning.

Key points summary

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Motor learning occurs across different temporal scales and can arise implicitly in the absence of conscious awareness.

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Explicitmotor learning is linked to the brain’s primary inhibitory neurotransmitter, GABA, and interactions across motor and hippocampal networks.

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Whether these same neural mechanisms are implicated inimplicitlearning is unclear. Similarly, the capacity to influence learning via priming with cardiovascular exercise is yet to be clearly established.

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We show that early implicit learning is underpinned by default mode network connectivity and sensorimotor GABA concentration, while total learning following sustained practice is linked to motor network connectivity. We also found that HIIT exercise elevated sensorimotor GABA concentration, but not the magnitude of implicit learning.

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Overall, our results highlight shared involvement of default mode and motor networks in implicit motor sequence learning.
SPE-CZE-MS quantifies zeptomole concentrations of phosphorylated peptides
Authors: Serrano Lia R. , Mellors J. Scott , Thompson J. Will , Lancaster Noah M. , Robinson Margaret Lea , Overmyer Katherine A. , Quarmby Scott T. , Coon Joshua J.
Published: December 2024

Capillary zone electrophoresis (CZE) is gaining attention in the field of single-cell proteomics for its ultra-low-flow and high-resolution separation abilities. Even more sample-limited yet rich in biological information are phosphoproteomics experiments, as the phosphoproteome composes only a fraction of the whole cellular proteome. Rapid analysis, high sensitivity, and maximization of sample utilization are paramount for single-cell analysis. Some challenges of coupling CZE analysis with mass spectrometry analysis (MS) of complex mixtures include 1. sensitivity due to volume loading limitations of CZE and 2. incompatibility of MS duty cycles with electrophoretic timescales. Here, we address these two challenges as applied to single-cell equivalent phosphoproteomics experiments by interfacing a microchip-based CZE device integrated with a solid-phase-extraction (SPE) bed with the Orbitrap Astral mass spectrometer. Using 225 phosphorylated peptide standards and phosphorylated peptide-enriched mouse brain tissue, we investigate microchip-based SPE-CZE functionality, quantitative performance, and complementarity to nano-LC-MS (nLC-MS) analysis. We highlight unique SPE-CZE separation mechanisms that can empower fit-for-purpose applications in single-cell-equivalent phosphoproteomics.
Plant-induced transcriptional plasticity diverges between generalist and specialist herbivores
Authors: Wu Jun , Lin Zhimou , Li Guomeng , Yu Wenyuan , Zhang Yangzhi , Kou Yishuo , Peng Pengshuai , He Tingfen , Wang Yu , Zhan Shuai , Simon Jean-Christophe , Hogenhout Saskia A. , Chen Yazhou
Published: December 2024

Most herbivores are specialized on particular host plants but some are generalists that can exploit distinct hosts. Generalists may have evolved adaptive transcriptional plasticity to cope with the defenses of the different hosts. However, the fundamental differences in plant-induced transcriptional plasticity between generalists and specialists remain poorly understood. Here, we investigated transcriptional plasticity of the generalist aphidMyzus persicaeand two specialist aphids,Brevicoryne brassicaeandRhopalosiphum padi, by transferring them betweenBrassica napus(a host forB. brassicaebut not forR. padi) andZea mays(a host forR. padibut not forB. brassicae), both suitable hosts forM. persicae. Generalist and specialist aphids exhibited transcriptional plasticity coordinately in response to different plant species, but their gene expression patterns often diverged. Generalists suppressed plant-defense salicylic acid (SA) signaling in the host plants, while specialist aphids provoked it in nonhost plants. SA signaling had limited effects on gene expression in the generalist aphids, but significantly shaped transcriptional responses of the specialists. These findings underscore the fundamental differences in plant-induced transcriptional plasticity between generalists and specialists and highlight the critical role of plasticity directionality in insect adaptation.

Significance statement

Most insects specialize in feeding on just a few specific plants, but some generalists can thrive on many plant species. This study compares the gene expression of green peach aphidMyzus persicae, a generalist, with two specialist aphids in response to different types of plants. Generalists showed adaptive plasticity in their gene responses, while specialists often exhibited opposite gene expression changes. Interestingly, generalists appeared to suppress plant defense signals like salicylic acid, while specialists tended to trigger them. These findings highlight how gene expression plasticity enables generalists to adapt and survive, providing new insights into the evolution of insect-plant interactions.
Single-cell mass spectrometry reveals heterogeneous triterpenic acid accumulation in apple callus-derived cells
Authors: Laezza Carmen , Heinicke Sarah , Wurlitzer Jens , D’Amelia Vincenzo , Caputi Lorenzo , Rigano Maria M. , O’Connor Sarah E.
Published: December 2024

The use of plant cell cultures for large scale production of natural compounds, although promising, has been hindered by their genetic instability and heterogeneity. Here, we show how single cell mass spectrometry can be used to characterize the natural product profile of a callus culture at a highly resolved level. We identify and quantify triterpenic acids in a population of callus cells derived from Annurca apple (Malus pumila Miller cv Annurca) leaf. The analysis demonstrated that a high degree of metabolic heterogeneity exists in the cell population, with the levels of detected metabolites varying significantly across the callus cells. This metabolic heterogeneity was underpinned by variable expression levels of key biosynthetic genes in the single cells. The application of an abiotic stress, near ultraviolet radiation (NUV), to the callus culture resulted in increased levels of triterpenic acids. Single cell mass spectrometry analysis revealed that after treatment, a larger percentage of callus cells produced detectable amounts of these metabolites, ultimately resulting in a more homogeneous production of the metabolites. Furthermore, it showed that intracellular concentrations of ursolic acid derivatives can reach more than 100 mM. Single cell mass spectrometry analyses provide a starting foundation for understanding the molecular mechanisms responsible for metabolic heterogeneity in plant cell cultures, which could in turn facilitate efforts to improve these cell cultures for commercial purposes.
LSD1 demethylase inhibition prevents cardiac fibrosis in both ischemic and congenital diseases in mice and pig models
Authors: Arnaud Denis , Lambert Virginie , Benoîst David , Martin Amandine , Gauthier Jean , Pucéat Michel
Published: December 2024

Fibrosis is part of a clinical burden in cardiovascular diseases. The pathological process has been the subject of intensive research with still mitigated therapeutic options. Recently chromatin modifiers have turned out to be potential drugs to modulate fibrosis. Here, in order to address the question of pharmacological inhibition of fibrosis, we used both a mouse model of myocardial infarction with left ventricular fibrosis and a more clinically relevant pig model of right ventricular failure featuring interstitial fibrosis. Treatment of these diseased animal models with an inhibitor of the Lysine Demethylase 1 (LSD1) significantly prevented both left and right ventricular failure in both the mouse and the pig, respectively. This was revealed by a significant recovery of left ventricular function post-myocardial infarction in the mouse and a limitation of remodeling of the pig right ventricle, thus preserving its function. Fibrosis was significantly decreased in both mouse and pig hearts, which likely account for improvement in ventricular function. We thus provide evidence of the beneficial effect of LSD1 inhibitors in cardiac fibrosis and of the use of such drugs to preserve ventricular function in both ischemic and congenital heart diseases.

NEW & NOTEWORTHY

Drugs to prevent cardiac fibrosis has been the subject of intensive research with limited outcomes. This work inspired by oncology, provides evidence that an epigenetic modifier which targets the process of epithelial-to-mesenchymal transition turns out to be an efficient inhibitor of fibrosis for both ischemic and non-ischemic myocardial diseases.
Two-fold Red Excess (TREx): A simple and novel digital color index that enables non-invasive real-time health assessment of green-leaved as well as anthocyanin-rich crops
Authors: Agarwal Avinash , de Jesus Colwell Filipe , Galvis Viviana Andrea Correa , Hill Tom R. , Boonham Neil , Prashar Ankush
Published: December 2024

Background

Digital color indices provide a reliable means for assessing plant health status by enabling real-time estimation of chlorophyll (Chl) content, and are thus adopted widely for crop monitoring. However, as all prevalent leaf color indices used for this purpose have been developed using green-leaved plants, they do not perform reliably for anthocyanin (Anth)-rich red-leaved varieties. Hence, the present study investigates digital color indices for six types of leafy vegetables with different levels of Anth to identify congruent trends that could be implemented universally for non-invasive crop monitoring irrespective of species and leaf Anth content. For this, datasets from three digital color spaces, viz., RGB (Red, Green, Blue), HSV (Hue, Saturation, Value), andL*a*b*(Lightness, Redness-greenness, Yellowness-blueness), as well as various derived plant color indices were compared with SPAD Chl meter readings and Anth/Chl ratio ofn= 320 leaf samples.

Results

While most digital color features and indices presented abrupt shifts between Anth-rich and green-leaved samples, the newly-developed color index Two-fold Red Excess (TREx) as well as the color feature R showed very strong correlation with SPAD readings (R2> 0.84), and did not exhibit any deviation due to leaf Anth content. Moreover, both parameters could predict SPAD values reliably (R2> 0.75). Further, logarithmic decline of G/R and Augmented Green-Red Index (AGRI) with increasing Anth/Chl ratio (R2> 0.82) revealed that relative Anth content affected digital color indices markedly by shifting the R:G balance until the Anth/Chl ratio reached a certain threshold.

Conclusion

The present study provides the first in-depth assessment of variations in RGB-based digital color indices due to high leaf Anth contents, and uses the data for Anth-rich as well as green-leaved crops belonging to different species to develop a universal digital color index TREx that can be used as a reliable alternative to handheld Chl meters for rapid high-throughput monitoring of green-leaved as well as red-leaved crop varieties.
Computational prediction of cyclotides fromViola odorataas potential inhibitors against the neuraminidase ofStreptococcus pneumoniae
Authors: Sankar Sreejanani , Sahoo Ajaya Kumar , Baskaran Shanmuga Priya , Babu R. , Srivastava Smita , Samal Areejit
Published: December 2024

Cyclotides are naturally occurring peptides characterized by a cyclic cystine knot, which provides them with exceptional structural stability. In addition to their stability, cyclotides exhibit diverse therapeutic activities including antimicrobial, antiviral and antitumor activities, making them promising candidates in drug discovery. However, computational studies aimed at identifying cyclotide-based inhibitors for infectious diseases remain limited. To this end, we conducted a virtual screening of cyclotides from an Indian medicinal plantViola odoratato identify potential inhibitors against a bacterial pathogen causing respiratory infections. We compiled a library of 93 cyclotides by retrieving their structures from public domain or predicting them using the AlphaFold server. We then docked these cyclotides against the neuraminidase protein ofStreptococcus pneumoniaeand analyzed the interacting residues and binding energies to identify top five potential inhibitors namely, kalata S, kalata B1, cycloviolacin O15, vodo L12, and cycloviolacin O36. Thereafter, we performed molecular dynamics simulations of the protein-cyclotide complexes, and observed that the cyclotides remained stable within the complex. Altogether, this study is the first computational effort to identify potential cyclotide inhibitors against bacterial pathogen causing respiratory diseases, which can be further pursued for experimental validation to develop novel therapeutic agents for respiratory infections.
Dominant negativeADA2mutations cause ADA2 deficiency in heterozygous carriers
Authors: Wouters Marjon , Ehlers Lisa , Van Eynde Wout , Kars Meltem Ece , Delafontaine Selket , Kienapfel Verena , Dzhus Mariia , Schrijvers Rik , De Haes Petra , Struyf Sofie , Bucciol Giorgia , Itan Yuval , Bolze Alexandre , Voet Arnout , Hombrouck Anneleen , Moens Leen , Ogunjimi Benson , Meyts Isabelle
Published: December 2024

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in theADA2gene. DADA2 carriers harbor a single pathogenic variant inADA2and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients’ phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.

Graphical abstract
Intestinal somatic mutations in inflammatory bowel disease patients are enriched in very early onset IBD and primary immunodeficiency genes
Authors: Hidding Iwan J. , Vich Vila Arnau , Hu Shixian , Bourgonje Arno R. , van Gijn Marielle , Maassen W.T.K. , van der Vries Gerben B. , Ruigrok Renate A.A.A. , Andreu-Sánchez Sergio , Jansen Bernadien H. , van Dullemen Hendrik M. , Visschedijk Marijn C. , Dijkstra Gerard , Swertz Morris A. , van Diemen Cleo C. , Festen Eleonora A.M. , Weersma Rinse K. , Imhann Floris
Published: December 2024

The genetic predisposition of Inflammatory bowel disease (IBD) in the germline is well-established, while the potential role of somatic mutations in IBD remains underexplored. We aim to identify somatic mutations in intestinal mucosa and study their potential role in IBD pathogenesis. We identified somatic mutations using 538 intestinal biopsies and 268 blood samples from 268 IBD patients and 51 intestinal biopsies from 19 non-IBD controls. Mutations were called from RNA-seq data and whole exome sequencing data using Mutect2 software. Pathogenicity of mutations was predicted using the Variant Interpretation Pipeline. Mutation frequency and patterns were compared between IBD and controls, and within IBD-subgroups, considering both inflammation status and tissue of origin. IBD-affected tissue exhibited a significantly higher burden of somatic mutations compared to controls (p=0.02), with a striking enrichment for predicted likely pathogenic or pathogenic (pLP-P) mutations (p=2.07e-09). Notably, within IBD biopsies, pLP-P mutations were enriched in very early onset-IBD (VEO-IBD) genes (p≤2.2e-16) and primary immune deficiency (PID) genes (p≤2.2e-16), showing a 5.5-fold increase compared to non-IBD. Inflamed tissue showed an increase in mutations in PID and IBD-GWAS associated genes. Additionally, we identified pathogenic mutations in many IBD genes, such as the stop-gained mutation (c.517C>T) inHPS1, and many pLP-P mutations across the JAK-STAT pathway. Our analysis reveals widespread accumulation of pLP-P somatic mutations in IBD-affected tissue compared to non-IBD controls, with significant enrichment in genes that cause monogenic VEO-IBD. These findings suggest that somatic mutations can contribute to the initiation and perpetuation of inflammation in IBD.