bluuebunny/crossref_metadata_2025_split huggingface dataset:
SOD1-ALS-Browser: a web-utility for investigating the clinical phenotype inSOD1amyotrophic lateral sclerosis
Authors: Spargo Thomas P , Opie-Martin Sarah , Hunt Guy P , Kalia Munishikha , Khleifat Ahmad Al , Topp Simon D , Shaw Christopher E , Al-Chalabi Ammar , Iacoangeli Alfredo 
Published: March 2023

AbstractObjectiveVariants in the superoxide dismutase (SOD1) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear thatSOD1-linked ALS presents a highly variable age at symptom onset and disease duration.MethodsHere we describe an open access web-tool for comparative phenotype analysis in ALS:https://sod1-als-browser.rosalind.kcl.ac.uk/. The tool contains a built-in dataset of clinical information from 1,383 people with ALS harbouring aSOD1variant resulting in one of 162 unique amino acid sequence alterations, and from a non-SOD1comparator ALS cohort of 13,469 individuals. We present two examples of analyses possible with this tool, testing how the ALS phenotype relates toSOD1variants which alter amino acid residue hydrophobicity, and distinct variants at the 94thresidue of SOD1 which has six variants sampled at the same position.Results and conclusionsThe tool provides immediate access to the datasets and enables bespoke analysis of phenotypic trends associated with different gene variants, including the option for users to upload their own datasets for integration with the server data. The tool can be used to studySOD1-ALS as well as an analytical framework to study the differences between other user-uploaded ALS groups and our large reference database ofSOD1and non-SOD1ALS. The tool is designed to be useful for clinicians and researchers, including those without programming expertise, and is highly flexible in the analyses that can be conducted.
BDNF, inflammatory and oxidative levels in treatment-naïve ADHD children treated with methylphenidate: An open cohort protocol
Authors: de Lucca Marina Silva , Tonon Laira Lopes , Ferreira Jordânia Alves , Cabral Bárbara Silva , Raimundo Cleuberton Kenedy Oliveira , Cardoso Sílvia Almeida , de Miranda Débora Marques 
Published: March 2023

AbstractThe attention-deficit hyperactivity disorder (ADHD) has a complex etiology, involving the interaction between biological, genetic, and environmental factors. The ADHD pathophysiology remains unknown even though there are hypotheses that inflammatory, hormonal, oxidative and neurotrophic factors are associated. This clinical trial aims to evaluate the contribution of brain derived neurotrophic factor (BDNF), inflammatory and oxidative levels before and after 12 and 24 weeks of methylphenidate use.MethodsPatients will be screened upon their entry into Child and Adolescent Psychiatry Teaching Outpatient Clinic of the Medical Course at the Federal University of Viçosa in Minas Gerais, Brazil. One hundred and fifty ADHD treatment-naïve children of both sexes, between 6–14 years old, will be invited to participate, after the ADHD diagnosis by an experienced psychiatrist and the child fulfilling the inclusion criteria. Children and their caregivers will answer questionnaires regarding mental health and the children will undergo neuropsychological tests, physical, nutritional and activity assessment, in addition to blood sampling at baseline, 12 and 24 weeks of methylphenidate use respectively.DiscussionThis clinical trial intends to verify how the pharmacological treatment changes the plasma BDNF, inflammatory and oxidative levels in treatment-naïve Brazilian children diagnosed for ADHD.Trial RegistrationSubmitted for registration on Brazilian Registry of Clinical Trials (ReBEC). Trial identifier: 13612Registry name: Níveis de neurotrofina, perfil inflamatório e oxidativo em crianças com TDAH tratadas com metilfenidato.
Epigenetic, psychological, and EEG changes after a 1-week retreat based on mindfulness and compassion for stress reduction: Study protocol of a cross-over randomized controlled trial
Authors: Diez Gustavo G. , Martin-Subero Ignacio , Zangri Rosaria M. , Kulis Marta , Andreu Catherine , Blanco Ivan , Roca Pablo , Cuesta Pablo , García Carola , Garzón Jesús , Herradón Carlos , Riutort Miguel , Baliyan Shishir , Venero César , Vázquez Carmelo 
Published: March 2023

AbstractIntroductionThe main objective of the study will be to evaluate the effects of two widely used standardized mindfulness-based programs [Mindfulness-Based Stress Reduction (MBSR) and Compassion Cultivation Training (CCT)], on epigenetic, neurobiological, psychological, and physiological variables.MethodsThe programs will be offered in an intensive retreat format in a general population sample of healthy volunteer adults. During a 7-day retreat, participants will receive MBSR and CCT in a crossover design where participants complete both programs in random order. After finishing their first 3-day training with one of the two programs, participants will be assigned to the second 3-day training with the second program.The effects of the MBSR and CCT programs, and their combination, will be measured by epigenetic changes (i.e., DNA methylation biomarkers), neurobiological and psychophysiological measures (i.e., EEG resting state, EKG, respiration patterns, and diurnal cortisol slopes), self-report questionnaires belonging to different psychological domains (i.e., mindfulness, compassion, well-being, distress, and general functioning), and stress tasks (i.e., an Arithmetic Stress Test and the retrieval of negative autobiographical memories). These measures will be collected from both groups on the mornings of day 1 (pre-program), day 4 (after finishing the first program and before beginning the second program), and day 7 (post-second program). We will conduct a 3-month follow-up using only the set of self-report measures.DiscussionThis study aims to shed light on the neurobiological and psychological mechanisms linked to meditation and compassion in the general population. The protocol was registered atclinicaltrials.gov(Identifier:NCT05516355; August 23, 2022).
Early life exposure to cigarette smoke primes lung function and DNA methylation changes atCyp1a1upon exposure later in life
Authors: Onuzulu Chinonye Doris , Lee Samantha , Basu Sujata , Comte Jeannette , Hai Yan , Hizon Nikho , Chadha Shivam , Fauni Maria Shenna , Kahnamoui Shana , Xiang Bo , Halayko Andrew J. , Dolinsky Vernon W. , Pascoe Christopher , Jones Meaghan J. 
Published: March 2023

AbstractPrenatal and early life exposure to cigarette smoke (CS) have repeatedly been shown to induce stable, long-term changes in DNA methylation (DNAm) in offspring. It has been hypothesized that these changes might be functionally related to the known outcomes of prenatal and early life CS exposure, which include impaired lung development, altered lung function and increased risk of asthma and wheeze. However, to date, few studies have examined DNAm changes induced by prenatal CS in tissues of the lung, and even fewer have attempted to examine the specific influences of prenatal versus early postnatal exposures. Here, we have established a mouse model of CS exposure which isolates the effects of prenatal and early postnatal CS exposures in early life. We have used this model to measure the effects of prenatal and/or postnatal CS exposures on lung function and immune cell infiltration as well as DNAm and expression ofCyp1a1, a candidate gene previously observed to demonstrate DNAm differences upon CS exposure in humans. Our study revealed that exposure to CS prenatally and in the early postnatal period cause long-lasting differences in offspring lung function, gene expression and lungCyp1a1DNAm, which wane over time but are reestablished upon re-exposure to CS in adulthood. This study creates a testable mouse model which can be used to investigate the effects of prenatal and early postnatal CS exposures and will contribute to the design of intervention strategies to mediate these detrimental effects.
Spatial and temporal transcriptomics of SHH-medulloblastoma with chromothripsis identifies multiple genetic clones that resist to treatment and lead to relapse
Authors: Kats Ilia , Schreiber Hannah Sophia , Simovic Milena , Sant Pooja , Mallm Jan-Philipp , Li Albert , Velmurugan Pravin , Weil Sophie , Devens Frauke , Sill Martin , Jugold Manfred , Moustafa Mahmoud , Abdollahi Amir , Winkler Frank , Korshunov Andrey , Pfister Stefan M , Stegle Oliver , Ernst Aurélie 
Published: March 2023

AbstractPaediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the determinants of their aggressiveness and the molecular makeup of chromothriptic medulloblastoma are not well understood. Here, we applied spatial transcriptomics to profile a cohort of 13 chromothriptic and non-chromothriptic medulloblastomas from the same molecular subgroup. Our data reveal a higher extent of spatial intra-tumour heterogeneity in chromothriptic medulloblastomas, which is associated with increased proliferation and stemness, but lower immune infiltration and differentiation. Spatial mapping of genetic subclones of the same tumour identify a regionally distinct architecture and clone-specific phenotypic features, with distinct degrees of differentiation, proliferation and immune infiltration between clones. We conducted temporal profiling of 11 patient-derived xenografts from chromothriptic medulloblastomas, covering the transition from the minimal residual disease stage to treatment-resistant regrown tumours. In chromothriptic medulloblastoma, an ecosystem of cells from multiple genetic clones resisting treatment and leading to relapse highlighted the importance of multi-clone interplay. Finally, we identified a potential role for tumour microtubes in treatment resistance in chromothriptic medulloblastoma, suggesting cell network communication as a putative target.HighlightsBiological insightsMedulloblastomas with chromothripsis are characterised by higher spatial intra-tumour heterogeneity, proliferation and stemness, but lower immune infiltration and differentiation, as compared with non-chromothriptic medulloblastomasSpatially aware genetic clone assignment identifies phenotypic features such as degree of differentiation, proliferation and immune infiltration enriched in specific clonesCells from distinct genetic clones resist to treatment and give rise to relapse in patient-derived xenografts of medulloblastoma with chromothripsisTumour microtubes point to putative molecular processes implicated in treatment resistance in chromothriptic medulloblastomaTechnological advancesValidation of the spatial representation of patient-derived xenograft models, providing novel insights into the faithfulness of such models to study cancerSpatial mapping of clones based on spatial transcriptomics and copy-number variant profiling
Internal Translation of p53 Oncoproteins During Integrated Stress Response Confers Survival Advantage on Cancer Cells
Authors: López-Iniesta Maria José , Lacerda Rafaela , Ramalho Ana Catarina , Parkar Shrutee N. , Marques-Ramos Ana , Pereira Bruna , Miyawaki Lina , Fujita Jun , Hrstka Roman , Romão Luísa , Candeias Marco M 
Published: March 2023

Abstractp53is the most known and studied tumour suppressor gene. Yet we have recently shown thatp53is also a proto-oncogene, as it encodes the Δ160p53 oncoprotein. Integrated stress response (ISR) is a survival pathway frequently activated in cancers, marked by the phosphorylation of eukaryotic initiation factor 2alpha (eIF2α) and a defined reprogramming in mRNA translation. Here we identified ISR as a powerful trigger of p53 oncogene, leading to the induction of not only Δ160p53 but also Δ133p53, another protein variant of thep53gene. Upon ISR the two isoforms were translated internally from p53 full-length (FL) transcript through an internal regulator of expression site (IRES) located in the vicinity of codon 160. Frameshift mutations upstream of codons 133 and 160 demonstrated that FLp53 protein synthesis is not required for making Δ133p53 and Δ160p53. Instead, targeting IRES(160) with an antisense oligo was sufficient to efficiently and specifically impair the expression of these isoforms without affecting FLp53 levels. This in turn averted ISR’s protective program culminating in cancer cell cycle arrest and death. Mechanistically, FLp53 showed 3 times more affinity to Δ160p53 than to other isoforms, Δ40p53 or Δ133p53. During ISR Δ160p53 localized to the nucleus and strongly inhibited FLp53-mediated activation of pro-apoptotic genep53 upregulated modulator of apoptosis(PUMA). Our results uncover a new branch of the ISR network essential for cancer cell survival and growth and establish the proof of concept for a new strategy to target cancer.
PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease
Authors: Thakore Pratish , Yamasaki Evan , Ali Sher , Solano Alfredo Sanchez , Labelle-Dumais Cassandre , Gao Xiao , Chaumeil Myriam M. , Gould Douglas B. , Earley Scott 
Published: March 2023

AbstractNeurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report aCol4a1mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K+(Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of agedCol4a1mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.One-sentence summaryPI3K inhibition rescues neurovascular coupling defects in cerebral small vessel disease.
Ecosystem connectivity and configuration can mediate instability at a distance in metaecosystems
Authors: Tadiri Christina P. , Negrín Dastis Jorge O. , Cristescu Melania E. , Gonzalez Andrew , Fussmann Gregor F. 
Published: March 2023

AbstractEcosystems are connected by flows of nutrients and organisms. Changes to connectivity and nutrient enrichment may destabilise ecosystem dynamics far from the nutrient source. We used gradostats to examine the effects of trophic connectivity (movement of consumers and producers) versus nutrient-only connectivity in different metaecosystem configurations (linear vs dendritic) on dynamics ofDaphnia pulex(consumers) and an algae (resources). We found that peak population size and instability (coefficient of variation; CV) ofDaphniapopulations increased as distance from the nutrient input increased, but were lower in metaecosystems connected by all trophic levels compared to nutrient-only connected systems and in dendritic systems compared to linear ones. We examined the effects of trophic connectivity (i.e. how many trophic levels are moving rather than one or the other) using a generic model to qualitatively assess patterns of ecosystem dynamics. Our model predicted increased population sizes and fluctuations in ecosystems with nutrient connectivity, with this pattern being more pronounced in linear rather than dendritic systems. These results confirm that connectivity may propagate and even amplify instability over a metaecosystem to communities far from the source disturbance, and suggest a pathway for future experiments, that recreate conditions closer to those found in natural systems.
Management factors influenceSalmonellapersistence in reused poultry litter over three successive flocks
Authors: Woyda Reed , Oladeinde Adelumola , Endale Dinku , Strickland Timothy , Lawrence Jodie Plumblee , Abdo Zaid 
Published: March 2023

AbstractSalmonellainfections are a leading cause of bacterial food-borne illness worldwide. Infections are highly associated with the consumption of contaminated food, and in particular, chicken meat. Understanding how management practices and environmental factors influenceSalmonellapopulations in broiler chicken production may aid in reducing the risk of food-borne illness in humans. Utilizing whole genome sequencing with antimicrobial and heavy metal resistance, virulence factor and plasmid identification, we have characterized the genetic diversity ofSalmonella entericaisolates (n = 55) obtained from broiler chicken litter.S. entericaisolates were recovered from the litter of broiler chickens over three consecutive flocks in four broiler houses on a single integrated farm in Georgia, USA. The chickens were raised under a newly adopted “No Antibiotics Ever” program and copper sulfate was administered via drinking water.In-silicoserovar prediction identified threeS. entericaserovars: Enteritidis (n = 12), Kentucky (n = 40) and Senftenberg (n = 3). Antimicrobial susceptibility testing revealed that only oneS. Kentucky isolate was resistant to streptomycin, while the remaining isolates were susceptible to all antibiotics tested. Metal resistance operons, including copper and silver, were identified chromosomally and on plasmids in serovar Senftenberg and Kentucky isolates, respectively. Serovar Kentucky isolates harboring metal resistance operons were the onlySalmonellaisolates recovered from the litter of third flock cohort. These results suggest the addition of copper sulfate to drinking water may have selected forS.Kentucky isolates harboring plasmid-borne copper resistance genes and may explain their persistence in litter from flock to flock.ImportanceSalmonellafoodborne illnesses are the leading cause of hospitalizations and deaths, resulting in a high economic burden on the healthcare system. Globally, chicken meat is one of the highest consumed meats and is a predominant source of foodborne illness. The severity ofSalmonellainfections depends on the presence of antimicrobial resistance genes and virulence factors. While there are many studies which have investigatedSalmonellastrains isolated from post-harvest chicken samples, there is a gap in our understanding of the prevalence and persistence ofSalmonellain pre-harvest and in particular their makeup of antibiotic resistance genes, virulence factors and metal resistance genes. The objective of this study was to determine how on-farm management practices and environmental factors influenceSalmonellapersistence, as well as the antimicrobial resistance genes and virulence factors they harbor. In this study we demonstrate that broiler chickens raised without antibiotics are less likely to harbor antibiotic resistance, however the practice of adding acidified copper sulfate to drinking water may select for strains carrying metal resistant genes.
Sordarin bound eEF2 unlocks spontaneous forward and reverse translocation on CrPV IRES
Authors: Ou Zheren , Petrov Alexey 
Published: March 2023

ABSTRACTThe Intergenic Region Internal Ribosome Entry Sites (IGR IRESs) ofDiscistroviridaepromote protein synthesis without initiation factors, with IRES translocation by elongation factor 2 (eEF2) being the first factor catalyzed reaction. Here, we developed a system that allows for the observation of intersubunit conformation of eukaryotic ribosomes at the single-molecule level. We use it to follow translation initiation and subsequent translocation of the cricket paralysis virus IRES (CrPV IRES). We observed that pre-translocation 80S-IRES ribosomes spontaneously exchanged between non-rotated and semi-rotated conformations but predominantly occupied a semi-rotated conformation. In the presence of eEF2, ribosomes underwent forward and reverse translocation. Both reactions were eEF2 concentration dependent, indicating that eEF2 promoted both forward and reverse translocation. The antifungal sordarin, stabilizes eEF2 on the ribosome after GTP hydrolysis in an extended conformation. 80S-CrPV IRES-eEF2-sordarin complexes underwent multiple rounds of forward and reverse translocations per eEF2 binding event. In the presence of sordarin, GTP hydrolysis or phosphate release were not required for IRES translocation. Together, these results suggest that in the presence of sordarin, eEF2 promotes the mid and late stages of CrPV IRES translocation by unlocking ribosomal movements, with mid and late stages of translocation being thermally driven.
Eye proteome ofDrosophila melanogaster
Authors: Kumar Mukesh , Has Canan , Lam-Kamath Khanh , Ayciriex Sophie , Dewett Deepshe , Bashir Mhamed , Poupault Clara , Schuhmann Kai , Knittelfelder Oskar , Raghuraman Bharath Kumar , Ahrends Robert , Rister Jens , Shevchenko Andrej 
Published: March 2023

AbstractTheDrosophila melanogastereye is a popular model to elucidate the molecular mechanisms that underlie the structure and function of the eye as well as the causes of retinopathies. For instance, theDrosophilaeye has been used to investigate the impacts of ageing and environmental stresses such as light-induced damage or dietary deficiencies. Moreover, large-scale screens have isolated genes whose mutation causes morphological and functional ocular defects, which includes key components of the phototransduction cascade. However, the proteome of theDrosophilaeye is poorly characterized. Here, we used GeLC-MS/MS to quantify 3516 proteins he adultDrosophila melanogastereye and provide a generic and expandable resource for further genetic, pharmacological, and dietary studies.
Microglia play beneficial roles in multiple experimental seizure models
Authors: Shelton-Gibbs Synphane , Benderoth Jordan , Gaykema Ronald P. , Straub Justyna , Okojie Kenneth A. , Uweru Joseph O. , Lentferink Dennis H. , Rajbanshi Binita , Cowan Maureen N. , Patel Brij , Campos-Salazar Anthony Brayan , Perez-Reyes Edward , Eyo Ukpong B. 
Published: March 2023

AbstractSeizure disorders are common, affecting both the young and the old. Currently available antiseizure drugs are ineffective in a third of patients and have been developed with a focus on known neurocentric mechanisms, raising the need for investigations into alternative and complementary mechanisms that contribute to seizure generation or its containment. Neuroinflammation, broadly defined as the activation of immune cells and molecules in the central nervous system (CNS), has been proposed to facilitate seizure generation, although the specific cells involved in these processes remain inadequately understood. The role of microglia, the primary inflammation-competent cells of the brain, is debated since previous studies were conducted using approaches that were less specific to microglia or had inherent confounds. Using a selective approach to target microglia without such side effects, we show a broadly beneficial role for microglia in limiting chemoconvulsive, electrical, and hyperthermic seizures and argue for a further understanding of microglial contributions to contain seizures.