bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of natural compounds as novel FMS-like tyrosine kinase-3 (FLT3) therapeutic inhibitors for the treatment of acute myeloid leukemia: anin silicoapproach
Authors: Das Uddalak , Lavanya C , Uttarkar Akshay , Kumar Jitendra , Niranjan Vidya 
Published: August 2024

ABSTRACTFLT3 mutations, observed in approximately 30-35% of Acute Myeloid Leukemia (AML) cases, drive leukemic proliferation and survival pathways, presenting a significant challenge in clinical management. To address this therapeutic need, we employed a comprehensive computational approach integrating pharmacophore screening, molecular docking, ADMET analysis, and molecular dynamics simulations to identify potent inhibitors targeting FLT3. Utilizing ligand-based pharmacophore models generated from experimentally proven FLT3 inhibitors from BindingDB, we screened over 400,000 natural compounds from the COCONUT database. Hits identified through pharmacophore screening underwent further evaluation via Lipinski and Golden triangle criteria to ensure drug-like properties. Molecular docking against the FLT3 receptor, combined with ADMET analyses, facilitated the prioritization of lead compounds. Subsequently, three promising candidates were subjected to molecular dynamics simulations to assess binding stability. Our findings reveal three top- performing compounds, demonstrating robust and stable binding affinity and favorable ADMET characteristics. These compounds hold promise as potential scaffolds or leads for developing novel FLT3 inhibitors in AML therapy.
Sustained fertility from first-wave follicle oocytes that pause their growth
Authors: Soygur Bikem , Gaylord Eliza A. , Foecke Mariko H. , Cincotta Steven A. , Horan Tegan S. , Wood Anna , Cohen Paula E. , Laird Diana J. 
Published: August 2024

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

ABSTRACTIntroductionA patient registry database is an important tool to address a wide range of research questions. Several countries have established nationwide melanoma registry databases. However, there is no report on summarising and comparing these databases. This scoping review aims to answer a broad question on how contemporary nationwide melanoma registry databases were conducted across different countries.MethodsThe proposed scoping review will follow the guidelines described by the Joanna Briggs Institute manual for evidence synthesis and results will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews guideline. PubMed, Embase, Web of Science,ClinicalTrials.gov, and Google will be parallelly and independently searched by two reviewers. We will include nationwide melanoma databases with the aim of continuously and systematically collecting medical records and other relevant information about melanoma patients under routine conditions. The reference list of all included publications will also be screened for additional literature. The literature search will be limited to records after the year 2000 and in English. Two reviewers will independently review the selected literature for information extraction according to a predefined extraction guidance sheet. For databases without relevant literature introductions, we will try contacting the main researchers of the database via email for detailed information. We will provide a brief descriptive analysis of the collected data.Expected results and implicationsThis scoping review will provide an extensive description of how contemporary nationwide melanoma databases were conducted. Findings have the potential to enhance the understanding of melanoma registry databases among researchers in related fields and promote subsequent international collaborations that aim at promoting the clinical practice of melanoma.STRENGTHS AND LIMITATIONS OF THIS STUDY➢This is the first scoping review protocol of summarizing contemporary nationwide melanoma databases globally.➢Targeted online surveys through email enable us to have a more comprehensive understanding of the latest situation of current databases.➢We expect to answer a broad question on how contemporary nationwide melanoma registry databases were conducted across different countries.➢Potentially missing relevant databases that have not been insufficiently reported is a limitation of the present scoping review.
New Eye Tracking Metrics System: The Value in Early Diagnosis of Autism Spectrum Disorder
Authors: Wang Raymond Kong , Kwong Kenneth , Liu Kevin , Kong Xue-Jun 
Published: August 2024

AbstractBackgroundEye tracking (ET) is emerging as a promising early and objective screening method for autism spectrum disorders (ASD), but it requires more reliable metrics with enhanced sensitivity and specificity for clinical use.MethodsThis study introduces a suite of novel ET metrics: Area of Interest (AOI) Switch Counts (ASC), Favorable AOI Shifts (FAS) along self-determined pathways, and AOI Vacancy Counts (AVC). These metrics were applied to toddlers and preschoolers diagnosed with ASD. The correlation between these new ET metrics and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) scores was assessed using linear regression. Sensitivity and specificity of the cut-off scores were also evaluated to predict diagnosis.ResultsOur findings indicate significantly lower FAS and ASC and higher AVC (P<0.05) in children with ASD compared to their non-ASD counterparts within this high-risk cohort. There were no significant differences in total fixation time or pupil size (p > 0.05). Additionally, FAS was negatively correlated with ADOS-2 total scores and the social affect (SA) subscale (p < 0.05). Among these new ET metrics, AVC yielded the best sensitivity (88-100%) and specificity (80-88%) with a cut-off score of 0.305-0.306, followed by FAS and ASC for distinguishing ASD from non-ASD for diagnosis.ConclusionsThis study confirms the utility of innovative ET metrics—FAS, AVC, and ASC, which exhibit markedly improved sensitivity and specificity, enhancing ASD screening and diagnostic processes.
Neurocognitive Functioning is Impaired in Perinatally HIV-Infected Youth
Authors: Welikson Tamara , Sarma Manoj K. , Keller Margaret , Sayre James , Walot Irwin , Michalik David E. , Hayes Judy , Nielsen-Saines Karin , Deville Jaime , Kovacs Andrea , Operskalski Eva , Church Joseph A. , Thomas M. Albert , Ventura Joseph 
Published: August 2024

AbstractBackgroundThe present study examined neurocognitive differences between Perinatally HIV (PHIV)-infected-youth and age and gender matched healthy controls. Despite early, long-term anti-viral treatment (ART), significant neurocognitive deficiencies remain for PHIV-infected-youth reaching adulthood compared to controls.MethodsParticipants were assessed with a comprehensive neuropsychological battery. An Overall Neurocognitive Composite Score and a Global Deficit Score (GDS) were created. Sleep, depression, and developmental level of intellectual functioning were also examined.ResultsPHIV-youth performed more poorly than controls in all neurocognitive domains. Very large effect sizes were observed for the Overall Neurocognitive Composite Score and GDS. PHIV-infected-youth appear to be significantly more depressed compared to controls, but there were no differences in amount or type of sleep observed.ConclusionDespite early, long-term anti-viral treatment (ART), neurocognitive deficiencies remain for PHIV-infected-young-adults. The verbal learning domain was significantly impaired with implications for functioning. The PHIV-infected-youth were also depressed and not receiving treatment for depression.
Low-cost generation of clinical-grade layperson-friendly pharmacogenetic passports using oligonucleotide arrays
Authors: Lanting Pauline , Warmerdam Robert , Slager Jelle , Brugge Harm , Ochi Taichi , Benjamins Marloes , Lopera-Maya Esteban , Jankipersadsing Soesma , Gelderloos-Arends Jody , Teuben Daphne , Hendriksen Dennis , Charbon Bart , Johansson Lennart , Munnink Thijs Oude , de Boer-Veger Nienke ,   Lifelines NEXT,   LifeLines Cohort Study, Wilffert Bob , Swertz Morris , Touw Daan , Deelen Patrick , Knoers Nine , Dekens Jackie , Franke Lude 
Published: August 2024

AbstractPharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual’s genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. Pharmacogenetic information is most often obtained using special assays, making it expensive and time-consuming to generate. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing, and lowering the barrier to generating PGx information prior to first prescription.Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a novelCYP2D6copy number variant calling tool, foregoing the need to use separate PCR-based copy number detection. Ultimately, we returned 1227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.
Comorbidity trajectories before and after the diagnosis of heart failure: a UK Biobank cohort study
Authors: MacGowan Hugo , Brown Oliver I , Drozd Michael , Walker Andrew MN , Giannoudi Marilena , Straw Sam , Paton Maria F , Gierula John , McGinlay Melanie , Griffin Kathryn J , Witte Klaus K , Kearney Mark T , Cubbon Richard M 
Published: August 2024

AbstractBackgroundHeart Failure (HF) is frequently associated with multiple comorbidities. We aimed to define their trajectory of accrual to identify opportunities for disease prevention.MethodsWe identified all participants in the UK Biobank cohort study diagnosed with HF prior to enrolment or during follow-up, who had disease occurrence data available from both primary and secondary care records (n=9,824). We established the time between diagnosis of HF and 16 common comorbidities to determine the rate and sequence of comorbidity accrual in relation to HF. Stratified analyses considered associations with sex and age at diagnosis of HF.FindingsIn chronological sequence, HF was the median fourth diagnosis for men and women. As the age at HF diagnosis increased, HF came later in the sequence of diseases (median second in under 50s to fifth in those aged 80-90). In all age strata, comorbidities accumulated for over a decade before HF and this accelerated in the years immediately before HF. The median time between comorbidity and HF diagnoses ranged from depression preceding HF by 10.7 years to dementia proceeding HF by 0.7 years; all comorbidities presented earlier in women. Atrial fibrillation/flutter was the commonest disease to immediately precede HF, followed by hypertension, cancer, myocardial infarction and osteoarthritis.InterpretationHF is most often diagnosed in people with established multimorbidity. There is a protracted window of opportunity during which interventions to prevent HF could be applied, often in disease contexts where this is not routine care, such as cancer and osteoarthritis.FundingBritish Heart Foundation (RG/F/22/110076)
Study of Compliance of Law on Healthy and Balanced Diets by Schools in a District of New Delhi, India
Authors: Singh Raja , Dada Rima , Frank Arthur L 
Published: August 2024

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

AbstractPurposeThis study examined the perceptions of caregivers of young childhood cancer survivors (YCCS) regarding the use of virtual assistant (VA) technology for health information seeking and care management. The study aim was to understand how VAs can support caregivers, especially those from underserved communities, in navigating health information related to cancer survivorship.MethodsA qualitative study design was employed, involving semi-structured interviews and focus groups with ten caregivers of YCCS from metropolitan, rural and Appalachian regions, recruited from a large pediatric academic medical center in the Midwest. A web-based VA prototype was tested with caregivers, who provided feedback on its usability, utility, and feasibility. Data were analyzed using thematic analysis to identify key themes related to caregivers’ interactions with and perceptions of the VA technology.ResultsWe identified four major themes: Interface and Interaction, User Experience, Content Relevance, and Trust. Caregivers expressed preferences for multimodal interactions, emphasized the need for accurate and relevant health information, and highlighted the importance of trust and confidentiality. The VA was perceived as a valuable tool for quickly accessing information, reducing the cognitive and emotional burden on caregivers. VAs were perceived to provide tailored support for managing specific health needs of YCCS.ConclusionsVAs hold promise as a support tool for caregivers of YCCS, particularly in underserved communities. By offering personalized, reliable, and easily accessible information, VAs were perceived to support caregivers to manage health conditions and ease the caregiving tasks.
How Alzheimer’s Aβ propagates and triggers tau pathology in intact neurons
Authors: Sasahara Tomoya , Shoko Hongo , Ito Mika , Takino Naomi , Muramatsu Shin-ichi , Kakita Akiyoshi , Hoshi Minako 
Published: August 2024

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

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

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