Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M‐mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M‐mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M‐mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c‐MET and p53), next‐generation sequencing and comparative genomic hybridization array. Forty‐nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M‐mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M‐mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.
Subsequent Surgery for Loss of Motion After Anterior Cruciate Ligament Reconstruction Does Not Influence Function at 2 Years: A Matched Case-Control Analysis

Background: Loss of motion (LOM) remains a common complication after anterior cruciate ligament (ACL) reconstruction and can be detrimental to patient outcomes after surgery. LOM is multifactorial, but nonsurgical and surgical solutions to this complex problem are available. A paucity of quality data exists evaluating clinical outcomes after the surgical treatment of patients with LOM after ACL reconstruction. Hypothesis: Patients undergoing surgical lysis of adhesions and manipulation under anesthesia for LOM after ACL reconstruction will exhibit decreased function, lower outcome scores, and delayed time of release to play when compared with matched controls without LOM. Study Design: Cohort study; Level of evidence, 3 Methods: A database of 1572 patients undergoing ACL reconstruction was sampled from 2013 to 2017 to identify a total of 58 patients (LOM group [n = 29] vs matched control group [n = 29]). Group comparisons were examined for patients requiring a second surgical procedure for LOM versus matched controls after ACL reconstruction for differences in surgical timing, self-reported International Knee Disability Committee scores, objective function at release to play, and subjective knee function at 2 years with the Single Assessment Numeric Evaluation. The risk of a type I error was set at α = . 05 for all statistical analyses. Results: Patients who underwent lysis of adhesions and manipulation under anesthesia for LOM after ACL reconstruction exhibited no differences in Single Assessment Numeric Evaluation knee function at 2 years when compared with matched controls (85.8 ± 14.9 vs 88.0 ± 10.8, P = .606). All patients met release-to-play criteria. Only International Knee Disability Committee scores (P = .046) and single-legged hop testing (P = .050) reached statistically significant differences, with higher scores in the control group. There was no difference in the time to release to play (P = .034) or level of participation (P = .180) between the control and surgical groups. Subjective function scores at 2 years were not significantly different between groups. Tourniquet time during the index ACL reconstruction was shorter in the control group (P = .034). Conclusion: The findings of this study suggest that patients who undergo surgical treatment for LOM after ACL reconstruction can release to play at similar times but display relative deficits in single-legged-hop symmetry and lower self-reported function when compared with matched controls. Longer surgical times may increase the risk for LOM after ACL reconstruction. Registration: NCT03704376 (ClinicalTrials.gov identifier)
Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltage-gated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies. SIGNIFICANCE STATEMENT Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures. FXS is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein, and the neuronal hyperexcitability observed in the absence of FMRP likely results from its ability to regulate the expression and activity of voltage-gated ion channels. Here we find that FMRP serves as a key translational regulator of the voltage-gated calcium channel Cav2.3 under basal conditions and following activity. Cav2.3 impacts cellular excitability and calcium signaling, and the alterations in channel translation and expression observed in the absence of FMRP could contribute to the neuronal hyperactivity that underlies FXS.
Role of MCC/Eisosome in Fungal Lipid Homeostasis

One of the best characterized fungal membrane microdomains is the MCC/eisosome. The MCC (membrane compartment of Can1) is an evolutionarily conserved ergosterol-rich plasma membrane domain. It is stabilized on its cytosolic face by the eisosome, a hemitubular protein complex composed of Bin/Amphiphysin/Rvs (BAR) domain-containing Pil1 and Lsp1. These two proteins bind directly to phosphatidylinositol 4,5-bisphosphate and promote the typical furrow-like shape of the microdomain, with highly curved edges and bottom. While some proteins display stable localization in the MCC/eisosome, others enter or leave it under particular conditions, such as misbalance in membrane lipid composition, changes in membrane tension, or availability of specific nutrients. These findings reveal that the MCC/eisosome, a plasma membrane microdomain with distinct morphology and lipid composition, acts as a multifaceted regulator of various cellular processes including metabolic pathways, cellular morphogenesis, signalling cascades, and mRNA decay. In this minireview, we focus on the MCC/eisosome’s proposed role in the regulation of lipid metabolism. While the molecular mechanisms of the MCC/eisosome function are not completely understood, the idea of intracellular processes being regulated at the plasma membrane, the foremost barrier exposed to environmental challenges, is truly exciting.
Thrombectomy for acute ischemic stroke in nonagenarians compared with octogenarians

Introduction Multiple randomized trials have shown that endovascular thrombectomy (EVT) leads to improved outcomes in acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Elderly patients were poorly represented in these trials, and the efficacy of EVT in nonagenarian patients remains uncertain. Methods We performed a retrospective cohort study at a single center. Inclusion criteria were: age 80–99, LVO, core infarct <70 mL, and salvageable penumbra. Patients were stratified into octogenarian (80–89) and nonagenarian (90–99) cohorts. The primary outcome was the ordinal score on the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included dichotomized functional outcome (mRS ≤2 vs mRS ≥3), successful revascularization, symptomatic intracranial hemorrhage (ICH), and mortality. Results 108 patients met the inclusion criteria, including 79 octogenarians (73%) and 29 nonagenarians (27%). Nonagenarians were more likely to be female (86% vs 58%; p<0.01); there were no other differences between groups in terms of demographics, medical comorbidities, or treatment characteristics. Successful revascularization (TICI 2b–3) was achieved in 79% in both cohorts. Median mRS at 90 days was 5 in octogenarians and 6 in nonagenarians (p=0.09). Functional independence (mRS ≤2) at 90 days was achieved in 12.5% and 19.7% of nonagenarians and octogenarians, respectively (p=0.54). Symptomatic ICH occurred in 21.4% and 6.4% (p=0.03), and 90-day mortality rate was 63% and 40.9% (p=0.07) in nonagenarians and octogenarians, respectively. Conclusions Nonagenarians may be at higher risk of symptomatic ICH than octogenarians, despite similar stroke- and treatment-related factors. While there was a trend towards higher mortality and worse functional outcomes in nonagenarians, the difference was not statistically significant in this relatively small retrospective study.
Differentially methylated regions in bipolar disorder and suicide

The addition of a methyl group to, typically, a cytosine‐guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the SureSelectXT system, Methyl‐Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD‐NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS‐NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS‐BDNS). One DMR from the BDS‐NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (PBootstrapped = 9.0 × 10−3), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, β‐adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences.
Acute Functional Adaptations in Isolated Presynaptic Terminals Unveil Synaptosomal Learning and Memory

Synaptosomes are used to decipher the mechanisms involved in chemical transmission, since they permit highlighting the mechanisms of transmitter release and confirming whether the activation of presynaptic receptors/enzymes can modulate this event. In the last two decades, important progress in the field came from the observations that synaptosomes retain changes elicited by both “in vivo” and “in vitro” acute chemical stimulation. The novelty of these studies is the finding that these adaptations persist beyond the washout of the triggering drug, emerging subsequently as functional modifications of synaptosomal performances, including release efficiency. These findings support the conclusion that synaptosomes are plastic entities that respond dynamically to ambient stimulation, but also that they “learn and memorize” the functional adaptation triggered by acute exposure to chemical agents. This work aims at reviewing the results so far available concerning this form of synaptosomal learning, also highlighting the role of these acute chemical adaptations in pathological conditions.
Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity

Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive AD pathogenesis. One of these forms, iso-Aβ (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-Aβ are α7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-Aβ is a more potent inhibitor of the α7nAChR-mediated calcium current than unmodified Aβ. However, Asp7 isomerization eliminated the ability of Aβ to decrease the α7nAChR levels. These data indicate differences in the interaction of the peptides with the α7nAChR, which we demonstrated using computer modeling. Neither Aβ nor iso-Aβ competed with 125I-α-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-Aβ was mediated by the α7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of Aβ on the functional activity of the α7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.
2,4-Dinitrotoluene (DNT) Perturbs Yolk Absorption, Liver Development and Lipid Metabolism/Oxygen Transport Gene Expression in Zebrafish Embryos and Larvae

2,4-dinitrotoluene (2,4-DNT) is a common environmental pollutant, and was classified as a group 2B human carcinogenic compound by the International Agency for Research on Cancer. This study determined the toxic effects of 2,4-DNT exposure on zebrafish at the embryo-larvae stage, in terms of organ morphogenesis and the expression pattern of selected target genes related to lipid metabolism and oxygen transportation. The results showed that the 120-h post-fertilization LC50 of 2,4-DNT was 9.59 mg/L with a 95% confidence interval of 8.89–10.44 mg/L. The larvae treated with 2,4-DNT showed toxic symptoms including smaller body, less skin pigment production, yolk malabsorption, and disordered liver development. Further studies on the expression of genes related to lipid transport and metabolism, and respiration indicated that they were significantly affected by 2,4-DNT. It is concluded that 2,4-DNT exposure perturbed liver development and yolk absorption in early-life zebrafish, and disturbed the lipid metabolism /oxygen transport gene expression.
Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ITD AML

Fms‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3‐ITD+ AML. Using RNA sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3‐ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0–3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3‐ITD+ AML and could help stratify future targeted treatment strategies.
Ontogeny of effective mechanical advantage in eastern cottontail rabbits (Sylvilagus floridanus)

ABSTRACT Juvenile animals must survive in the same environment as adults despite smaller sizes, immature musculoskeletal tissues, general ecological naïveté and other limits of performance. Developmental changes in muscle leverage could constitute one mechanism to promote increased performance in juveniles despite ontogenetic limitations. We tested this hypothesis using a holistic dataset on growth and locomotor development in wild eastern cottontail rabbits (Sylvilagus floridanus) to examine ontogenetic changes in hindlimb muscle effective mechanical advantage (EMA). EMA is a dimensionless index of muscle leverage, equal to the quotient of average muscle lever length and the load arm length of the ground reaction force (GRF), effectively representing the magnitude of output force arising from a given muscle force. We found that EMA at the hip and ankle joints, as well as overall hindlimb EMA, significantly declined across ontogeny in S. floridanus, whereas EMA at the knee joint remained unchanged. Ontogenetic decreases in EMA were due to isometric scaling of muscle lever arm lengths alongside positive ontogenetic allometry of GRF load arm lengths – which in turn was primarily related to positive allometry of hindlimb segment lengths. Greater EMA limits the estimated volume of hindlimb extensor muscle that has to be activated in young rabbits, likely mitigating the energetic cost of locomotion and saving metabolic resources for other physiological functions, such as growth and tissue differentiation. An additional examination of limb growth allometry across a diverse sample of mammalian taxa suggests that ontogenetic decreases in limb joint EMA may be a common mammalian trend. Editors' Choice: Hindlimb muscle leverage declines during growth in cottontail rabbits, likely promoting increased locomotor performance during the precarious juvenile period of life history.
Development and Validation of a Nomogram for Predicting Survival in Patients with Thyroid Cancer

Background The AJCC staging system is inadequate for use in patients with thyroid carcinomas. Here, we aimed to establish a nomogram for thyroid cancer, and we compare its prognostic value with the AJCC staging system in adults diagnosed with thyroid carcinoma. Material/Methods Patient records were obtained from the Surveillance, Epidemiology, and End Result database. The 8491 included patients were divided into a modeling cohort (n=5943) and a validation cohort (n=2548). The variables included in the modeling cohort were selected using a backward stepwise selection method with Cox regression, and the prognosis nomogram was constructed. In the validation cohort, we compared our survival model with the AJCC prognosis model using the concordance index, the area under the time-dependent receiver operating characteristic curve, the net reclassification improvement, the integrated discrimination improvement, calibration plotting, and decision curve analysis. Results Twelve independent prognostic factors were identified and used to establish the nomogram. In particular, marital status was included in a survival prediction model of thyroid cancer for the first time. The concordance index, area under the time-dependent receiver operating characteristic curve, net reclassification improvement, integrated discrimination improvement, calibration plotting, and decision curve analysis for the nomogram showed better performance compared to the AJCC staging system. Conclusions We have developed and validated a highly accurate thyroid cancer prognosis nomogram. The prognostic value of the nomogram is better than that of the AJCC staging system alone.
The first‐generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well‐being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment.
Exploring customer brand engagement: definition and themes

Organizations are increasingly seeking customer participation and engagement with their brands. Despite significant practitioner interest, scholarly inquiry into the ‘customer brand engagement’ (CBE) concept has transpired in the literature only relatively recently, resulting in a limited understanding of the concept to-date. This paper addresses this research gap by providing a literature review in this area, and developing a CBE conceptualization based on an integrative deductive (literature-based)/inductive (data-based) approach. Data were sourced from exploratory, qualitative depth-interviews and a focus group employing a total of 14 informants. Extending previous research, CBE is viewed from relationship marketing (RM) and service-dominant (S-D) logic perspectives, whilst an integrative linkage to social exchange theory (SET) is also drawn. Based on the analysis, CBE is defined as ‘the level of a customer's cognitive, emotional and behavioral investment in specific brand interactions’. Further, three key CBE themes are identified, including ‘immersion’, ‘passion’ and ‘activation’. The paper concludes with an overview of key research limitations and implications.
Function of Green Tea Catechins in the Brain: Epigallocatechin Gallate and its Metabolites

Over the last three decades, green tea has been studied for its beneficial effects, including anti-cancer, anti-obesity, anti-diabetes, anti-inflammatory, and neuroprotective effects. At present, a number of studies that have employed animal, human and cell cultures support the potential neuroprotective effects of green tea catechins against neurological disorders. However, the concentration of (−)-epigallocatechin gallate (EGCG) in systemic circulation is very low and EGCG disappears within several hours. EGCG undergoes microbial degradation in the small intestine and later in the large intestine, resulting in the formation of various microbial ring-fission metabolites which are detectable in the plasma and urine as free and conjugated forms. Recently, in vitro experiments suggested that EGCG and its metabolites could reach the brain parenchyma through the blood–brain barrier and induce neuritogenesis. These results suggest that metabolites of EGCG may play an important role, alongside the beneficial activities of EGCG, in reducing neurodegenerative diseases. In this review, we discuss the function of EGCG and its microbial ring-fission metabolites in the brain in suppressing brain dysfunction. Other possible actions of EGCG metabolites will also be discussed.