bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer’s disease plasma biomarkers
Authors: Chen Yijun , Zeng Xuemei , Lee Jihui , Sehrawat Anuradha , Lafferty Tara K. , Boslett James J. , Klunk William E. , Pascoal Tharick A. , Villemagne Victor L. , Cohen Annie D. , Lopez Oscar , Yates Nathan A. , Karikari Thomas K. 
Published: March 2024

ABSTRACTINTRODUCTIONThe reliability of plasma Alzheimer’s disease (AD) biomarkers can be compromised by protease-induced degradation. This limits the feasibility of conducting plasma biomarker studies in environments that lack the capacity for immediate processing and appropriate storage of blood samples. We hypothesized that blood collection tube supplementation with protease inhibitors can improve the stability of plasma biomarkers at room temperatures (RT). This study conducted a comparative analysis of blood biomarker stability in traditional ethylenediaminetetraacetic acid (EDTA) tubes versus BD™ P100 collection tubes, the latter being coated with a protease inhibitor cocktail. The stability of six plasma AD biomarkers was evaluated over time under RT conditions.METHODSWe evaluated three experimental approaches. In Approach 1, pooled plasma samples underwent storage at RT for up to 96 hours. In Approach 2, plasma samples isolated upfront from whole blood collected into EDTA or P100 tubes were stored at RT for 0h or 24h before biomarker measurements. In Approach 3, whole blood samples were collected into paired EDTA or P100 tubes, followed by storage at RT for 0h or 24h before isolating the plasma for analyses. Biomarkers were measured with Single Molecule Array (Simoa) and immunoprecipitation-mass spectrometry (IP-MS) assays.RESULTSBoth the IP-MS and Simoa methods revealed that the use of P100 tubes significantly improved the stability of Aβ42 and Aβ40 across all approaches. Additionally, the Aβ42/Aβ40 ratio levels were significantly stabilized only in the IP-MS assay in Approach 3. No significant differences were observed in the levels of plasma p-tau181, GFAP, and NfL for samples collected using either tube type in any of the approaches.CONCLUSIONSupplementation of blood collection tubes with protease inhibitors could reduce the protease-induced degradation of plasma Aβ42 and Aβ40, and the Aβ ratio for IP-MS assay. This has crucial implications for preanalytical procedures, particularly in resource-limited settings.
Fetal-maternal interactions with gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome
Authors: Moreno María de Lourdes , González-Rovira María , Martínez-Pancorbo Cristina , Martín-Cameán María , Nájar-Moyano Ana María , Romero Mercedes , de la Hoz Esther , López-Beltrán Cristina , Mellado Encarnación , Bartha José Luis , Brodin Peter , Rodríguez-Herrera Alfonso , Sainz-Bueno José Luís , Sousa Carolina 
Published: March 2024

AbstractThe increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a lifecourse perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant’s solid diet after birth. We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. 119 pregnant women with different gluten diets and gestational ages were recruited. GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. The study shows evidence, for the first time, of the fetal exposure to gluten immunogenic peptides, and establish a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a closed-loop circuit entailing fetal swallowing of GIP contained in AF, and its subsequent excretion through the fetal kidneys. The study adds important new information to understanding the coeliac exposome.
Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations
Authors: Stenton Sarah L. , Pejaver Vikas , Bergquist Timothy , Biesecker Leslie G. , Byrne Alicia B. , Nadeau Emily , Greenblatt Marc S. , Harrison Steven , Tavtigian Sean , Radivojac Predrag , Brenner Steven E. , O’Donnell-Luria Anne ,   ClinGen Sequence Variant Interpretation Working Group
Published: March 2024

ABSTRACTPurposeTo investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations.MethodsMissense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools able to reach PP3_Strong and BP4_Moderate evidence strengths (BayesDel, MutPred2, REVEL, and VEST4). The numbers of variants at each evidence strength were analyzed across disease-associated genes and genome-wide.ResultsFrom a median of 75.5 rare (≤1% allele frequency) missense variants in disease-associated genes per proband, a median of one reached PP3_Strong, 3-5 PP3_Moderate, and 3-5 PP3_Supporting. Most were allocated BP4 evidence (median 41-49 per proband) or were indeterminate (median 17.5-19 per proband). Extending the analysis to all protein-coding genes genome-wide, the number of PP3_Strong variants increased approximately 2.6-fold compared to disease-associated genes, with a median per proband of 1-3 PP3_Strong, 8-16 PP3_Moderate, and 10-17 PP3_Supporting.ConclusionA small number of variants per proband reached PP3_Strong and PP3_Moderate in 3,424 disease-associated genes, and though not the intended use of the recommendations, also genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as Pathogenic or Likely Pathogenic by ACMG/AMP rules.
COVID-19 Vaccination Booster Uptake Is Related to End of Pandemic Perception: Population-Based Survey in Four Provinces in Indonesia
Authors: Maula Ahmad Watsiq , Indriani Citra , Arisanti Risalia Reni , Testamenti Vincentius Arca , Praptiningsih Catharina Yekti , Merril Rebecca , Ansariadi  , Wahyono Tri Yunis Miko , Hidajah Atik Choirul , Ahmad Riris Andono 
Published: March 2024

AbstractGlobal COVID-19 booster vaccination uptake has been low, particularly in low-middle-income countries (LMICs). However, studies on the determinants of COVID-19 booster vaccination remain limited, especially in LMIC settings. This study aims to describe the determinants of COVID-19 booster vaccination uptake in an LMIC context. We analyzed data from a cross-sectional survey that was conducted in September 2022 in four provinces in Indonesia. Participants (n=2,223) were recruited using multiple-stage cluster sampling. Multivariable logistic regression analysis was used to identify factors associated with booster vaccination status. The proportion of COVID-19 booster vaccination among fully vaccinated adults was 29.5%, while fear of transmission (12.4%) and perceived risk of getting a COVID-19 infection (33.5%) were low. Multivariable analysis showed that people living on Java Island (aOR: 2.45, 95% CI: 1.87-3.24), living in the urban area (aOR: 2.04, 95% CI: 1.60-2.61), being an employee in the formal sector (aOR: 3.99, 95% CI: 1.93 - 8.58), experiencing a side effect from previous vaccination (aOR: 1.71, 95% CI: 1.40-2.09), having a history of SARS-COV2 infection (aOR: 2.10, 95%CI: 1.27-3.50), having perception on the upcoming new wave of COVID-19 (aOR: 1.37, 95% CI: 1.07 -1.76), and believing the pandemic has not ended (aOR: 1.29, 95% CI: 1.01, 1.64) were associated with booster shot uptake. Low educational level (aOR: 0.6, 95% CI: 0.39-0.93) inhibited booster vaccination uptake. Current booster dose coverage was considerably lower than the primary vaccination dosage. The low booster vaccination uptake in four provinces was associated with a belief the pandemic has no longer, which might hinder the catch up of wide-population target coverage and COVID-19 control for reduced disease severity and hospitalization. Thus, efforts need to be prioritized in reaching the COVID-19 vulnerable population, which includes elderly and those with comorbidities.
International consensus on fluoride programmes for Early Childhood Caries prevention in early education settings
Authors: Abuhaloob Lamis , Conay David I , Blokland Alex , Ross Al 
Published: March 2024

AbstractBackgroundThe World Health Organisation has set out a clear priority for the implementation of interventions to reduce the burden of Early Childhood Caries (ECC), a global public health problem affecting over 500 million children around the world and having a substantial impact on child well-being and health system expenditure.The aim of this study was to assess and develop international expert consensus on the evidence for fluoride-based interventions in early-year education settings (kindergartens/nursery and primary schools) for reducing ECC and to synthesise clear programme-level recommendations with regard to ECC prevention in this setting.MethodsA systematic overview of systematic reviews, trials, and observational studies was performed to identify and critically appraise the available evidence on the effectiveness and cost-effectiveness of fluoride-based interventions in early-years education settings to prevent ECC.This was followed by a three-stage modified Delphi panel study (n= 21) consisting of: round 1, an online survey to gather opinions on safety, effectiveness and feasibility of interventions; round 2, an iterative survey to consider collated group opinion and gather feedback on review findings; and finally, an online workshop with presentations and facilitated in-depth, recorded group discussions.ResultsThere was high-quality evidence and consensus on delivering supervised toothbrushing in kindergartens (nurseries) and primary/elementary schools; this is safe and cost-effective, shows greater benefit to more disadvantaged children, helps child social development, and is feasible in high and low/middle-income countries. There was more moderate support for the effectiveness and cost-effectiveness of fluoride varnish application in this setting (especially where supervised toothbrushing with fluoride is in place). It was agreed that policy makers should prioritise at-risk groups where resources are limited, and that systemic fluoride interventions (Fluoride tablets, drops, milk, and salt) in this setting are no longer a priority.ConclusionSupervised toothbrushing with fluoridated toothpaste is the most effective, cost-effective, feasible and safest mechanism for children in early education settings. Universal coverage is preferred but where resources are limited targeting based on need is indicated. Panel consensus is that it remains appropriate in water fluoridated areas and is largely feasible in low/middle-income countries.
Depressive Symptoms and its Associated Factors among Health Care Workers in Saint Paul’s Hospital Millennium Medical College, Ethiopia
Authors: Tesema Melese Bahiru , Woldeamanue Berhanu Teshome , Mekonen Eyoel Berhane , Melese Kidest Getu 
Published: March 2024

AbstractBackgroundDepression is a mental disorder that presents with a depressed mood, loss of pleasure or interest, decrease in energy, feeling of guilt or low self-worth, disturbed sleep, loss of appetite, and poor-concentration. Healthcare professionals are more susceptible to depression because they face higher amounts of professional stress in their job and academic lives. However, there is limited knowledge regarding health professionals’ level of depressive disorder in Ethiopia. This study aimed to assess the prevalence of depression and associated factors among health professionals, at Saint Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia.MethodsWe conducted an institution-based cross-sectional study among 439 randomly selected health care worker using interviewer-administered patient health questionnaire-9 from April to May 2023. Ordinal logistic regression was performed to identify predictors of depressive disorder.ResultThe overall prevalence of depressive symptoms among health care workers was 56.5% (95% CI (51.8%, 61.1%)). There were reports of mild (35%), moderate (13%) and severe (9%) depression, respectively. Marital status of being single (AOR=7.78, 95%CI: 1.123, 49.01), history of childhood abuse (AOR=2.57, 95%CI:1.49, 4.42), history of suicidal attempt (AOR=2.66, 95%CI:1.25,5.67), having history of stressful life event (AOR=1.527, 95%CI: 1.02,2.3), back pain over the past 30 days (AOR=2, 95%CI: 1.30,3.11), working for more than 8 hours (AOR=3.03, 95%CI: 1.12,8.24), and having experience of 5-10 year (AOR=4, 95%CI: 1.05,15.27) and 10-15 years (AOR= 4.24, 95%CI: 1.08,16.58) and poor social support (AOR= 2.09, 95%CI: 1.09,3.99) were statistically associated with increased level of depressive disorder.ConclusionHealthcare professionals’ higher rate of depression was due to the higher work load, childhood abuse, history of stressful life, back pain, and poor social support. Thus, the hospital or ministry of health should give special attention to health care workers who has high work load, childhood abuse, history of stressful life, back pain, and poor social support to reduce the burden of depressive disorder among health professionals. Furthermore, early depression screening and treatment in hospitals is needed.
Human Anterior Insular Cortex Encodes Multiple Electrophysiological Representations of Anxiety-Related Behaviors
Authors: Lee A Moses , Sturm Virginia E , Dawes Heather , Krystal Andrew D , Chang Edward F 
Published: March 2024

AbstractAnxiety is a common symptom across psychiatric disorders, but the neurophysiological underpinnings of these symptoms remain unclear. This knowledge gap has prevented the development of circuit-based treatments that can target the neural substrates underlying anxiety. Here, we conducted an electrophysiological mapping study to identify neurophysiological activity associated with self-reported state anxiety in 17 subjects implanted with intracranial electrodes for seizure localization. Participants had baseline anxiety traits ranging from minimal to severe. Subjects volunteered to participate in an anxiety induction task in which they were temporarily exposed to the threat of unpredictable shock during intracranial recordings. We found that anterior insular beta oscillatory activity was selectively elevated during epochs when unpredictable aversive stimuli were being delivered, and this enhancement in insular beta was correlated with increases in self-reported anxiety. Beta oscillatory activity within the frontoinsular region was also evoked selectively by cues-predictive of threat, but not safety cues. Anterior insular gamma responses were less selective than gamma, strongly evoked by aversive stimuli and had weaker responses to salient threat and safety cues. On longer timescales, this gamma signal also correlated with increased skin conductance, a measure of autonomic state. Lastly, we found that direct electrical stimulation of the anterior insular cortex in a subset of subjects elicited self-reported increases in anxiety that were accompanied by enhanced frontoinsular beta oscillations. Together, these findings suggest that electrophysiologic representations of anxiety- related states and behaviors exist within anterior insular cortex. The findings also suggest the potential of reducing anterior insular beta activity as a therapeutic target for refractory anxiety-spectrum disorders.
Integrating mechanism-based T cell phenotypes into a model of tumor-immune cell interactions
Authors: Tangella Neel , Cess Colin G. , Ildefonso Geena V. , Finley Stacey D. 
Published: March 2024

ABSTRACTInteractions between cancer cells and immune cells in the tumor microenvironment influence tumor growth and can contribute to the response to cancer immunotherapies. It is difficult to gain mechanistic insights into the effects of cell-cell interactions in tumors using a purely experimental approach. However, computational modeling enables quantitative investigation of the tumor microenvironment, and agent-based modeling in particular provides relevant biological insights into the spatial and temporal evolution of tumors. Here, we develop a novel agent-based model (ABM) to predict the consequences of intercellular interactions. Furthermore, we leverage our prior work that predicts the transitions of CD8+ T cells from a naïve state to a terminally differentiated state using Boolean modeling. Given the detailed incorporated to predict T cell state, we apply the integrated Boolean-ABM framework to study how the properties of CD8+ T cells influence the composition and spatial organization of tumors and the efficacy of an immune checkpoint blockade. Overall, we present a mechanistic understanding of tumor evolution that can be leveraged to study targeted immunotherapeutic strategies.
Exploring the causal role of the human gut microbiome in endometrial cancer: a Mendelian randomization approach
Authors: Fryer Ella , Hatcher Charlie , Knight Rochelle , Wade Kaitlin 
Published: March 2024

ABSTRACTEndometrial cancer presents a major public health issue, particularly in post-menopausal women. Whilst there are known risk factors for the disease, including oestrogen and obesity, these factors do not fully explain risk variability in cancer outcomes. The identification of novel risk factors may aid in better understanding of endometrial cancer development and, given the link with oestrogen metabolism, obesity and the risk of various cancers, the gut microbiome could be one such risk factor. Mendelian randomization (MR), a method that reduces biases of conventional epidemiological studies (namely, confounding and reverse causation) by using genetic variants to proxy exposures, was used to investigate the effect of gut microbial traits on endometrial cancer risk. Whilst our initial analyses showed that the presence of an unclassified group of bacteria in theErysipelotrichaceaefamily increased the risk of oestrogen-dependent endometrial cancer (odds ratio (OR) per approximate doubling of the genetic liability to presence vs absence: 1.13; 95% CI: 1.01, 1.26; P=0.03), subsequent sensitivity analyses, including colocalisation, suggested these findings were unlikely reflective of causality. This work highlights the importance of using a robust MR analysis pipeline, including sensitivity analyses to assess the validity of causal effect estimates obtained using MR.
IMPROVING ALPHAFOLD2 PERFORMANCE WITH A GLOBAL METAGENOMIC & BIOLOGICAL DATA SUPPLY CHAIN
Authors: Munsamy Geraldene , Bohnuud Tanggis , Lorenz Philipp 
Published: March 2024

AbstractScaling laws suggest that more than a trillion species inhabit our planet but only a miniscule and unrepresentative fraction (less than 0.00001%) have been studied or sequenced to date. Deep learning models, including those applied to tasks in the life sciences, depend on the quality and size of training or reference datasets. Given the large knowledge gap we experience when it comes to life on earth, we present a data-centric approach to improving deep learning models in Biology: We built partnerships with nature parks and biodiversity stakeholders across 5 continents covering 50% of global biomes, establishing a global metagenomics and biological data supply chain. With higher protein sequence diversity captured in this dataset compared to existing public data, we apply this data advantage to the protein folding problem by MSA supplementation during inference of AlphaFold2. Our model, BaseFold, exceeds traditional AlphaFold2 performance across targets from the CASP15 and CAMEO, 60% of which show improved pLDDT scores and RMSD values being reduced by up to 80%. On top of this, the improved quality of the predicted structures can yield better docking results. By sharing benefits with the stakeholders this data originates from, we present a way of simultaneously improving deep learning models for biology and incentivising protection of our planet’s biodiversity.
Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder
Authors: Szente Laszlo , Balla Gyula Y , Varga Zoltan K , Toth Blanka , Biro Laszlo , Balogh Zoltan , Hill Matthew N , Toth Mate , Mikics Eva , Aliczki Mano 
Published: March 2024

AbstractTraumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of PTSD, we characterized distinct resilient and susceptible subpopulations based on generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing supervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Susceptible subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) neuronal prefrontal, hippocampal and amygdalar hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.HighlightsWe assessed endocannabinoid and neuroplasticity correlates of PTSD susceptibilityPosttrauma generalized fear strength separates susceptible and resilient individualsSusceptible individuals show altered endocannabinoid levels in the fear circuitryNeuroplasticity and endocannabinoid gene expression patterns predict susceptibility