bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polyunsaturated fatty acids and their endocannabinoid-related metabolites activity at human TRPV1 and TRPA1 ion channels expressed in HEK-293 cells
Authors: Abate Atnaf A , Santiago Marina J , Garcia-Bennett Alf , Connor Mark 
Published: September 2024

ABSTRACTBackgroundPolyunsaturated fatty acids (PUFAs), particularly Omega-3 (ω-3) and Omega-6 (ω-6) PUFAs, may exert neuroprotective effects via the endocannabinoid system (ECS) and are promoted as brain health supplements. However, despite their potential role in endocannabinoid biosynthesis, the impact of PUFAs on ion channels such as TRPV1 and TRPA1, which are modulated by endocannabinoids, remains incompletely understood. Furthermore, the potentialin vitroactions of ω-6 to ω-3 PUFA combined in the ratios available in supplements remains uncertain. Therefore, the objective of this study is to evaluate the functional activity of individual PUFAs, their combination in a specific ratio, and their endocannabinoid-related derivatives on TRPV1 and TRPA1 ion channels.MethodologyWe employed a fluorescent Ca-sensitive dye in HEK-293 Flp-In T-REx cells expressing human TRPV1, TRPA1, or an empty vector to measure changes in intracellular calcium concentration ([Ca2+]i).ResultsCapsaicin and certain PUFA derivatives such as DHEA, γ-LEA and AEA stimulate TRPV1 activity directly, whereas EPA, DHA, γ-LA, and their 9:3:1 ratio triggered TRPV1 response via a mechanism dependent on prior exposure to phorbol ester. Similarly, cinnamaldehyde and selected PUFA derivatives such as EPEA, DHEA, γ-LEA, 2-AG, 2-AG ether and AEA triggered TRPA1 response, with EPA, DHA, γ-LA, and the 9:3:1 ratio showing significant effects at higher concentrations.ConclusionsPUFAs alone and their combined form in 9:3:1 ratio stimulate TRPA1 activity, whereas their metabolites trigger both TRPV1 and TRPA1 response. These findings suggest new avenues to explore for research into potential mechanisms underlying the neurological benefits of PUFAs and their metabolites.
Skeletal Metastasis of Prostate Cancer Is Augmented by Activation of EphA2 Noncanonical Signaling and Ligand-Deficient Bone Microenvironment
Authors: Lingerak Ryan , Petty Aaron , Shi Xiaojun , Kim Soyeon , Lin Hebei , Hsieh Jer-Tsong , Tang Dean , Stiles Bangyan , Wald David , Varambally Sooryanarayana , Chinnaiyan Arul M. , Lee Zhenghong , Morrissey Colm , Wang Bingcheng 
Published: September 2024

AbstractEphA2, a member of Eph family receptor tyrosine kinases (RTKs), is overexpressed in multiple types of solid human tumors, particularly at the late stages. However, whether and how it drives specific malignant processes remain elusive. We report that EphA2 is elevated during prostate cancer (PCa) progression in multiple syngeneic murine models. Interestingly, human metastatic PCa specimens from two Rapid Autopsy Programs showed selective overexpression of EphA2 in metastasis to the bone, but not to the lymph nodes or viscera. Serine 897 phosphorylation that mediates the pro-oncogenic, noncanonical signaling by EphA2 was also upregulated in bone metastasis. Analysis of human datasets shows EphA2 overexpression is associated with skeletal but not visceral metastases. Ephrin-A1, a major cognate ligand for EphA2, is lost in PCa bone metastasis, which is correlated with poor prognosis. Further, the bone microenvironment is unique in expressing little of the fiveEFNAgenes, providing permissive microenvironment for bone colonization. S897A mutation that ablates EphA2 noncanonical signaling, suppressed PCa development. Restoration of ephrin-A1 expression in PC-3, a model cell line for double negative prostate cancer derived from bone metastasis and devoid of ephrin-As, profoundly changed global tyrosine phosphorylation profiles, inhibited basal ERK and Src activities in vitro, and suppressed tumor development in the bone. Together these results demonstrate EphA2 overexpression and concomitant loss of ligands in PCa lead to activation of noncanonical signaling that is sustained in ephrin-A1-deficient skeletal milieu to promote bone metastasis.
Loss-of-function of RNA-binding protein PRRC2B causes translational defects and congenital cardiovascular malformation
Authors: Das Debojyoti , Khor Eng-Soon , Jiang Feng , He Jiali , Kawakami Yui , Wainwright Lindsey , Hollinger Jared , Geiger Joshua , Liu Huan , Meng Fanju , Porter George A. , Jin Zhenggen , Murphy Patrick , Yao Peng 
Published: September 2024

AbstractAlternative splicing generates variant forms of proteins for a given gene and accounts for functional redundancy or diversification. A novel RNA-binding protein,Pro-richCoiled-coil Containing Protein2B(PRRC2B), has been reported by multiple laboratories to mediate uORF-dependent and independent regulation of translation initiation required for cell cycle progression and proliferation. We identified two alternative spliced isoforms in human and mouse hearts and HEK293T cells, full-length (FL) and exon 16-excluded isoform ΔE16. A congenital heart disease-associated human mutation-mimicry knock-in of the equivalent variant in the mouse genome leads to the depletion of the full-lengthPrrc2bmRNA but not the alternative spliced truncated form ΔE16, does not cause any apparent structural or functional disorders. In contrast, global genetic inactivation of the PRRC2B gene in the mouse genome, nullifying both mRNA isoforms, caused patent ductus arteriosus (PDA) and neonatal lethality in mice. Bulk and single nucleus transcriptome profiling analyses of embryonic mouse hearts demonstrated a significant overall downregulation of multiple smooth muscle-specific genes inPrrc2bmutant mice resulting from reduced smooth muscle cell number. Integrated analysis of proteomic changes inPrrc2bnull mouse embryonic hearts and polysome-seq and RNA-seq multi-omics analysis in human HEK293T cells uncover conserved PRRC2B-regulated target mRNAs that encode essential factors required for cardiac and vascular development. Our findings reveal the connection between alternative splicing regulation of PRRC2B, PRRC2B-mediated translational control, and congenital cardiovascular development and disorder. This study may shed light on the significance of PRRC2B in human cardiovascular disease diagnosis and treatment.Discovery bullet pointsPRRC2B has two alternative splicing isoforms, full-length and exon 16-skipped (ΔE16) mRNAs in humans and mice.Full-lengthPrrc2bKO mice show no apparent cardiac phenotypes, while double KO of full-length and ΔE16 causes patent ductus arteriosus and neonatal lethality in mice.Multi-omics analyses ofPrrc2bdouble KO mice suggest changes in SMC cell abundance and dysregulation of translation of specific proteins in E18.5 embryos.CRISPR-Cas9-mediated KO ofPRRC2Bin human cells reduces the translation of heart and valve development-related mRNAs.
Synergizing Health Strategies: Exploring the Interplay of Treatment and Vaccination in an Age-Structured Malaria Model
Authors: Hridoy Mahmudul Bari , Peace Angela 
Published: September 2024

AbstractMalaria remains a persistent global challenge, particularly prevalent in tropical regions of Africa, Asia, and South America. According to the World Health Organization’s (WHO) World Malaria Report 2023, there were approximately 249 million reported malaria cases in 2022 across 85 endemic countries, resulting in over half a million deaths. Progress towards global malaria eradication through antimalarial drugs has been slow, with case numbers increasing since 2015. Dihydroartemisinin (DHA), artesunate, and artemether, derivatives of artemisinin, are crucial components of modern antimalarial treatment. However, resistance to these drugs and their partners in Artemisinin Combination Therapy (ACT) has emerged in Southeast Asia, Africa, and South America. In 2021, the WHO recommended widespread use of the RTS,S malaria vaccine among children in endemic regions. To address these challenges, we develop an extended SEIR age-structured model incorporating malaria vaccination for children, drug-sensitive and drug-resistant strains, and interactions between human hosts and mosquitoes. Our research focuses on evaluating how malaria vaccination coverage influences disease prevalence and transmission dynamics. We derive the basic, intervention, and invasion reproduction numbers for both strains and conduct sensitivity analysis to identify key parameters affecting infection prevalence. Our findings reveal that model outcomes are primarily influenced by scale factors that reduce transmission and natural recovery rates for the resistant strain, as well as by drug treatment and vaccination efficacies, and mosquito death rates. Numerical simulations indicate that while treatment reduces the malaria disease burden, it also increases the proportion of drug-resistant cases. Conversely, higher vaccination efficacy correlates with lower infection cases for both strains. These results suggest that a synergistic approach, involving both vaccination and treatment, could effectively decrease the overall proportion of the population that is infected.
Maternal Diet Quality and BMI as Predictors of Human Milk Composition and Exclusive Breastfeeding Duration
Authors: Cetinkaya Hatice , Valentine Christina J. , Dingess Kelly A. , Ollberding Nicholas J. , Summer Suzanne S. , Meredith Nathan A. , Maria Sarah D. , Morrow Ardythe L. , Nommsen-Rivers Laurie A. 
Published: September 2024

AbstractBackgroundPoor diet quality and high body mass index (BMI) contribute to inflammation, which may influence human milk composition and exclusive breastfeeding (EBF) duration.ObjectiveWe evaluated maternal diet and prepregnancy BMI as predictors of human milk C-reactive protein (CRP) and long chain fatty acid concentrations (%LCFA), and EBF duration.MethodsWe utilized the Global Exploration of Human Milk Study-Cincinnati subset (n=114), where healthy dyads continued follow-up if ≥75% of feeds were breastmilk at 4 weeks postpartum. We computed a Dietary Inflammatory Index (DII) from diet recalls obtained between 4-13 weeks postpartum, where higher score indicates a more proinflammatory diet. Milk CRP and fatty acid analyses were performed on week 4 milk. We compared milk CRP across 4 combinations of DII×BMI using the Kruskal Wallis test, with BMI categorized as normal versus elevated (<25 versus>25 kg/m2), and DII split at the median. Linear regression was used to examine DII and BMI as predictors of %LCFA. Logistic regression was used to examine DII tertiles and BMI as predictors of EBF duration.ResultsMilk CRP concentrations differed across DII×BMI groups (p=0.009): the low DII/normal BMI group had the lowest milk CRP (n=30, median [Q1, Q3], 64.3 [38.2, 121.4] ng/mL) versus all other groups (n=70, 124.1 [71.2, 181] ng/mL,p=0.022). Lower milk %LCFA was predicted by higher DII score (β±SE = -0.68 ± 0.21,p=0.002, n=103) and higher BMI (β±SE = -0.13 ± 0.01,p=0.043, n=114). Having the highest DII tertile and elevated BMI lowered the odds of EBF at week 6 (OR [95% CI]: 0.26 [0.07, 0.85]) compared to the referent group (low or medium DII, normal BMI).ConclusionsMilk CRP concentrations were lowest in women with a more anti-inflammatory diet and normal BMI. Both higher BMI and proinflammatory diet predict lower milk %LCFA and lower EBF prevalence at week 6.
Domain specific Memory Impairments in Bipolar Mania: Insights from a Tertiary Care Study
Authors: Kumar Mohit , Kumar Sanjay , Khusboo  , Maqbool Masood , Singh Vinit Kumar , Soni Amit Kumar 
Published: September 2024

AbstractBackgroundCognitive deficits in bipolar affective disorder (BPAD), particularly during manic episodes, are well-documented. However, research on domain-specific memory impairments in bipolar mania is limited, especially in the Indian subcontinent. This study aimed to assess memory impairments in patients with bipolar mania using the Postgraduate Institute Memory (PGI-Memory) Scale and to highlight domain-specific deficits compared to healthy controls.MethodsThis cross-sectional study was conducted at Tertiary Care Centre in North India. Twenty patients diagnosed with bipolar mania and twenty age, sex and education-matched healthy controls between age 18 to 40 were recruited. Memory functions were assessed using the PGI-Memory scale, focusing on immediate, recent, remote, long-term memory, and associative memory. Mental control and working memory were also evaluated.ResultsBoth groups were matched in terms of age, sex, and education. the mean (sd) age for bipolar mania group was 27.2 (4.14) years. Patients with bipolar mania demonstrated significant deficits in various memory domains, including immediate, recent, remote, long-term, and associative memory, as well as in visual reproduction and recognition tasks. In contrast, their working memory performance was comparable to that of the control group. The largest deficits were observed in long-term memory (d =2.37) and visual reproduction (d=2.30).ConclusionsBipolar mania is associated with widespread memory impairments, particularly in long-term and associative memory, which may contribute to difficulties in emotional regulation and daily functioning. These findings emphasize the importance of considering memory impairments in the diagnosis and management of BPAD. Further studies are required to investigate the neurobiological foundations of these impairments and to develop specific interventions.
Integrating health care and early years support for children and young people living in deprivation: A cost effectiveness analysis of a novel integrated clinic in Birmingham, UK
Authors: Melyda Melyda , Monahan Mark , Bird Chris , Roberts Tracy , Harper Lorraine , Litchfield Ian 
Published: September 2024

AbstractBackgroundIncreased use of emergency and secondary care by children and young people, especially in deprived populations, drive increased costs in health and social care systems in rich country settings, without necessarily delivering quality care.AimTo assess the potential cost-effectiveness of the Sparkbrook’s Children Zone (SCZ), a pilot clinic for children and young people which integrates health and early years support in a highly deprived area of Birmingham, the UK’s second city, compared with standard primary care.MethodsA decision-analytic model taking healthcare and partial social care perspective was developed using best available, though limited, evidence from aggregated data of an ongoing pilot, published literature, expert opinions and assumptions. Effectiveness was measured as proportion of patients attending the emergency department. Deterministic and probabilistic sensitivity analyses were performed to assess the impact of parameter uncertainties.ResultsThe integrated SCZ clinic may potentially be cost-effective based on this preliminary model-based analysis. The SCZ had lower proportion of patients attending emergency department, 0.017 compared with 0.029 for standard primary care, reducing proportion of emergency department visits by 0.012. The average cost of SCZ was £66.22 compared with £110.36 for standard primary care, leading to a cost-saving of £44.08 per patient. This potential reduction in total costs resulting from fewer referrals to children’s social care and secondary medical services, including the emergency department. Extensive sensitivity analysis supported the indications that the intervention was likely to be cost-effective.ConclusionThe SCZ pilot shows potential in integrating health and social care within a community setting, with Its early years services likely enhancing the cost-effectiveness of the SCZ compared to standard primary care. Further robust data and trial evaluation are essential to confirm these findings, ensuring the scalability and sustainability of such programs.
Neighborhood deadwood and yard rewilding modulate commensal microbiota and inflammatory signals among urbanites
Authors: Roslund Marja I. , Uimonen Laura , Kummola Laura , Cerrone Damiano , Ojala Ann , Luukkonen Anna , Holopainen Ella , Korhonen Aku , Penttilä Reijo , Venäläinen Martti , Haveri Hanna , Rajaniemi Juho , Laitinen Olli H. , Sinkkonen Aki ,   the BIWE research group
Published: September 2024

AbstractBackgroundGlobal ecosystem deprivation is linked to reduced microbial diversity and diminished immunological resilience. Urban rewilding and decomposing plant matter have been suggested to reverse this deprivation and support human health.MethodsWe rewilded 21 urban private yards with vegetation and deadwood. Control yards (15) were analyzed for comparison. We collected microbial samples and used vegetation and deadwood inventories, landcover data and questionnaires to determine the effects of rewilding and living environment on skin and salivary microbiota, gene pathways and cytokine levels (IL-6, IL-10). Samples were collected before the rewilding in summer and three months later in autumn.FindingsRewilding preserved skin microbial richness in comparison to control group, including previously health-associated Alpha- and Gammaproteobacteria, despite the normal seasonal decline and less outdoor time in autumn. Deadwood abundance within 200-m radii associated directly to beta diversity of skin microbiota and Gammaproteobacterial taxonomies.In saliva, deadwood was directly associated with the diversity of functional gene pathways, which in turn was negatively associated with pleiotropic IL-6 levels. Rewilding was associated with a decrease in L-histidine degradation and an increase in Mycobacteriaceae.InterpretationSince both yard rewilding and neighborhood deadwood preserved rich commensal microbiota and reduced pro-inflammatory signals, decomposing plant matter, not just plant richness, seems to be crucial for ecosystem services that contribute to health. Since deadwood abundance was associated to reduced pro-inflammatory signals, it may be a suitable indicator of environment supporting immunological resilience.Our findings provide an incentive for future strategic investments for planetary health.FundingStrategic Research council Finland.
Predicting Common Pathway Signatures Between DNA Methylation and Post Translational Modification in Type II Diabetes & Parkinson’s Disease Using Heterogeneous Data Integration
Authors: Biswas First Saikat , Mitra Second Pabitra , Rao Third Krothapalli Sreenivasa 
Published: September 2024

AbstractThe complex diseases, namely, Type 2 Diabetes Mellitus (T2DM) and Parkinson’s Disease (PD), are extensively studied due to their prevalence in a large population group. Between these two diseases, T2DM is denoted as the zero index disease in a patient, which may lead to PD in a more advanced clinical stage. Both of these diseases may occur due to abrupt DNA methylation of genes. Likewise, both diseases may occur in a patient due to protein misfolding. Our study proposes a novel framework for building two disease-specific heterogeneous networks by integrating different tissue-based transcriptomics, epigenetics, epistasis, and PPI-based topological information. We predict the missing links between the DNA methylation and Post-Translational Modification (PTMs) associated with protein aggregation. Next, we have predicted the common signature of the prevalence of linked patterns in both diseases, further validated by relevant biological evidence.
Leveraging Pretrained Vision Transformers for Automated Cancer Diagnosis in Optical Coherence Tomography Images
Authors: Ray Soumyajit , Lee Cheng-Yu , Park Hyeon-Cheol , Nauen David W. , Bettegowda Chetan , Li Xingde , Chellappa Rama 
Published: September 2024

AbstractThis study presents a novel approach to brain cancer detection based on Optical Coherence Tomography (OCT) images and advanced machine learning techniques. The research addresses the critical need for accurate, real-time differentiation between cancerous and noncancerous brain tissue during neurosurgical procedures. The proposed method combines a pre-trained Vision Transformer (ViT) model, specifically DiNOV2, with a convolutional neural network (CNN) operating on Grey Level Co-occurrence Matrix (GLCM) texture features. This dual-path architecture leverages both the global context capture capabilities of transformers and the local texture analysis strengths of GLCM + CNNs. The dataset comprised OCT images from 11 patients, with 5,831 B-frame slices used for training and validation, and 1,610 slices for testing. The model achieved high accuracy in distinguishing cancerous from noncancerous tissue, with 99.7% ± 0.1% accuracy on the training dataset, 99.4% ± 0.1% on the validation dataset and 94.9% accuracy on the test dataset. This approach demonstrates significant potential for achieving and improving intraoperative decision-making in brain cancer surgeries, offering real-time, high-accuracy tissue classification and surgical guidance.
Multi-omics integration prioritizes potential drug targets for multiple sclerosis
Authors: Jiang Yuan , Liu Qianwen , Stridh Pernilla , Kockum Ingrid , Olsson Tomas , Alfredsson Lars , Diaz-Gallo Lina Marcela , Jiang Xia 
Published: September 2024

AbstractBackground and ObjectivesMultiple sclerosis (MS) is a chronic autoimmune disease with limited treatment options. Thus, drug discovery and repurposing are essential to enhance treatment efficacy and safety.MethodsWe obtained summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma proteins and 1,443 brain proteins, a genome-wide association study (GWAS) of MS susceptibility with 14,802 cases and 26,703 controls, and expression quantitative trait loci (eQTL) for 8,000 genes in peripheral blood and 16,704 genes in brain tissue. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization (SMR) to determine causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing SMR, HEIDI, and colocalization analyses were considered potential drug targets. We further conducted pathway annotations, protein-protein interaction (PPI) network analysis, and examined mRNA levels of these targets.ResultsWe identified hundreds of MS-associated proteins in plasma and brain, confirming the causal roles of 18 proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also discovered intricate PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. Combining expression data, we identified two targets adhering to the central dogma of molecular biology.DiscussionWe prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for drug discovery and repurposing in MS.