TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

Non-Mendelian inheritance patterns and extreme deviation rates of CGG repeats in autism.

As expansions of CGG short tandem repeats (STRs) are established as the genetic etiology of many neurodevelopmental disorders, we aimed to elucidate the inheritance patterns and role of CGG STRs in autism-spectrum disorder (ASD). By genotyping 6063 CGG STR loci in a large cohort of trios and quads with an ASD-affected proband, we determined an unprecedented rate of CGG repeat length deviation across a single generation. Although the concept of repeat length being linked to deviation rate was solidified, we show how shorter STRs display greater degrees of size variation. We observed that CGG STRs did not segregate by Mendelian principles but with a bias against longer repeats, which appeared to magnify as repeat length increased. Through logistic regression, we identified 19 genes that displayed significantly higher rates and degrees of CGG STR expansion within the ASD-affected probands (P < 1 × 10-5). This study not only highlights novel repeat expansions that may play a role in ASD but also reinforces the hypothesis that CGG STRs are specifically linked to human cognition.

Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia.

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared with 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. A total of 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutations or insertions/deletions, compared with 4.1% in other subtypes. CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, recombination-activating gene-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared with 7.7% in non-DS-ALL. Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival, even after adjusting for known clinical risk factors. These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Ependymal cells undergo astrocyte-like reactivity in response to neuroinflammation.

Ependymal cells form a specialized brain-cerebrospinal fluid (CSF) interface and regulate local CSF microcirculation. It is becoming increasingly recognized that ependymal cells assume a reactive state in response to aging and disease, including conditions involving hypoxia, hydrocephalus, neurodegeneration, and neuroinflammation. Yet what transcriptional signatures govern these reactive states and whether this reactivity shares any similarities with classical descriptions of glial reactivity (i.e., in astrocytes) remain largely unexplored. Using single-cell transcriptomics, we interrogated this phenomenon by directly comparing the reactive ependymal cell transcriptome to the reactive astrocyte transcriptome using a well-established model of autoimmune-mediated neuroinflammation (MOG35-55 EAE). In doing so, we unveiled core glial reactivity-associated genes that defined the reactive ependymal cell and astrocyte response to MOG35-55 EAE. Interestingly, known reactive astrocyte genes from other CNS injury/disease contexts were also up-regulated by MOG35-55 EAE ependymal cells, suggesting that this state may be conserved in response to a variety of pathologies. We were also able to recapitulate features of the reactive ependymal cell state acutely using a classic neuroinflammatory cocktail (IFNγ/LPS) both in vitro and in vivo. Taken together, by comparing reactive ependymal cells and astrocytes, we identified a conserved signature underlying glial reactivity that was present in several neuroinflammatory contexts. Future work will explore the mechanisms driving ependymal reactivity and assess downstream functional consequences.

Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.

The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

Biological differences between adult and perinatal human mesenchymal stromal cells and their impact on the manufacturing processes.

The biological properties of human mesenchymal stromal cells (hMSCs) have been explored in over a thousand clinical trials in the last decade. Although hMSCs can be isolated from multiple sources, the degree of biological similarity between cell populations from these sources remains to be determined. A comparative study was performed investigating the growth kinetics and functionality of hMSCs isolated from adipose tissue (AT), bone marrow (BM) and umbilical cord tissue (UCT) expanded in monolayer over five passages. Adult hMSCs (AT, BM) had a slower proliferation ability than the UCT-hMSCs, with no apparent differences in their glucose consumption profile. BM-hMSCs produced higher concentrations of endogenous vascular endothelial growth factor (VEGF) compared to AT- and UCT-hMSCs. This study also revealed that UCT-hMSCs were more efficiently transduced by a lentiviral vector carrying a VEGF gene than their adult counterparts. Following cellular immunophenotypic characterization, no differences across the sources were found in the expression levels of the typical markers used to identify hMSCs. This work established a systematic approach for cell source selection depending on the hMSC's intended clinical application.

Testosterone, gender identity and gender-stereotyped personality attributes.

Sex/gender differences in personality associated with gender stereotyped behavior are widely studied in psychology yet remain a subject of ongoing debate. Exposure to testosterone during developmental periods is considered to be a primary mediator of many sex/gender differences in behavior. Extensions of this research has led to both lay beliefs and initial research about individual differences in basal testosterone in adulthood relating to "masculine" personality. In this study, we explored the relationships between testosterone, gender identity, and gender stereotyped personality attributes in a sample of over 400 university students (65 % female assigned at birth). Participants provided ratings of their self-perceived masculinity and femininity, resulting in a continuous measure of gender identity, and a set of agentic and communal personality attributes. A saliva sample was also provided for assay of basal testosterone. Results showed no compelling evidence that basal testosterone correlates with gender-stereotyped personality attributes or explains the relationship between sex/gender identity and these attributes, across, within, or covarying out sex assigned at birth. Contributing to a more gender diverse approach to assessing sex/gender relationships with personality and testosterone, our continuous measure of self-perceived masculinity and femininity predicted additional variance in personality beyond binary sex and showed some preliminary but weak relationships with testosterone. Results from this study cast doubt on the activational testosterone-masculinity hypothesis for explaining sex differences in gender stereotyped traits and within-sex/gender variation in attributes associated with agency and communality.

Development and Preliminary Evaluation of A Soft Tissue Microtia Simulator.

Surgical simulation has been used extensively for learning microtia reconstruction and has almost exclusively involved framework creation. However, soft tissue reconstruction in microtia is equally challenging and would benefit from a simulation platform. This study aimed to describe the development and preliminary evaluation of a high-fidelity soft tissue microtia simulator. Three-dimensional modeling software, fused deposition 3-dimensional printing, adhesive techniques, silicones, and polyurethane rubbers were utilized to create a right lobular-type microtia simulator that comprises skin, subcutaneous tissue, and cartilage. Two expert microtia surgeons performed a microtia reconstruction on the simulator and evaluated its value and realism using a Likert-type questionnaire. The surgeons utilized a previously developed synthetic framework and successfully performed the critical steps of the soft tissue reconstruction, including marking, incising, dissection, removal of the cartilage remnant, drain insertion, insertion of the framework, closing of the skin, and demonstration of the soft tissue conforming over the framework using suction. A preliminary assessment of the simulator demonstrated that the simulator is anatomically accurate, realistic, and highly valuable as a training tool. A high-fidelity soft tissue microtia simulator was successfully developed and tested. The simulator provides a valuable training platform for learning a critical component of microtia reconstruction.

Bilateral Cleft lip Simulation.

OBJECTIVE: To evaluate the features, anatomic accuracy, and educational value of a high-fidelity bilateral cleft lip simulator. DESIGN: Evaluation of the simulator by expert cleft surgeons after performing a simulated bilateral cleft lip repair. SETTING: The simulator was evaluated by the surgeons during the Latin American Craniofacial Association meeting. PARTICIPANTS: Eleven experienced cleft surgeons evaluated the simulator. The cleft surgeons were selected based on their availability during the meeting. INTERVENTIONS: The participants performed a simulated bilateral cleft lip repair. They were each provided with a questionnaire assessing the simulator's features, realism and value as a training tool. MAIN OUTCOME MEASURE (S): The main outcome measure are the scores obtained from a Likert-type questionnaire assessing the simulators features, realism and value. RESULTS: Overall, the surgeons agreed with the simulator's realism and anatomic accuracy (average score of 3.7 out of 5). Overall, the surgeons strongly agreed with the value of the simulator as a training tool (average score of 4.6 out of 5). CONCLUSIONS: A high-fidelity bilateral cleft lip simulator was developed that is realistic and valuable as a training tool. The simulator provides a comprehensive training platform to gain hands-on experience in bilateral cleft lip repair before operating on real patients.

FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development.

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.

Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis.

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice. Both BKI-1770 and BKI-1841 had efficacy in the C. parvum newborn calf model, reducing diarrhea and oocyst excretion. However, both compounds caused hyperflexion of the limbs seen as dropped pasterns. Toxicity experiments in rats and calves dosed with BKI-1770 showed enlargement of the epiphyseal growth plate at doses only slightly higher than the efficacious dose. Mice were used as a screen to check for bone toxicity, by changes to the tibia epiphyseal growth plate, or neurological causes, by use of a locomotor activity box. These results showed neurological effects from both BKI-1770 and BKI-1841 and bone toxicity in mice from BKI-1770, indicating one or both effects may be contributing to toxicity. However, BKI-1708 remains a viable treatment candidate for further evaluation as it showed no signs of bone toxicity or neurological effects in mice.

Psychological value theory: A computational cognitive model of charitable giving.

Charitable giving involves a complex economic and social decision because the giver expends resources for goods or services they will never receive. Although psychologists have identified numerous factors that influence charitable giving, there currently exists no unifying computational model of charitable choice. Here, we submit one such model, based within the strictures of Psychological Value Theory (PVT). In four experiments, we assess whether charitable giving is driven by the perceived Psychological Value of the recipient. Across all four experiments, we simultaneously predict response choice and response time with high accuracy. In a fifth experiment, we show that PVT predicts charitable giving more accurately than an account based on competence and warmth. PVT accurately predicts which charity a respondent will choose to donate to and separately, whether a respondent will choose to donate at all. PVT models the cognitive processes underlying charitable donations and it provides a computational framework for integrating known influences on charitable giving. For example, we show that in-group preference influences charitable giving by changing the Psychological Values of the options, rather than by bringing about a response bias toward the in-group.

Scalable manufacturing of gene-modified human mesenchymal stromal cells with microcarriers in spinner flasks.

Due to their immunomodulatory properties and in vitro differentiation ability, human mesenchymal stromal cells (hMSCs) have been investigated in more than 1000 clinical trials over the last decade. Multiple studies that have explored the development of gene-modified hMSC-based products are now reaching early stages of clinical trial programmes. From an engineering perspective, the challenge lies in developing manufacturing methods capable of producing sufficient doses of ex vivo gene-modified hMSCs for clinical applications. This work demonstrates, for the first time, a scalable manufacturing process using a microcarrier-bioreactor system for the expansion of gene-modified hMSCs. Upon isolation, umbilical cord tissue mesenchymal stromal cells (UCT-hMSCs) were transduced using a lentiviral vector (LV) with green fluorescent protein (GFP) or vascular endothelial growth factor (VEGF) transgenes. The cells were then seeded in 100 mL spinner flasks using Spherecol microcarriers and expanded for seven days. After six days in culture, both non-transduced and transduced cell populations attained comparable maximum cell concentrations (≈1.8 × 105 cell/mL). Analysis of the culture supernatant identified that glucose was fully depleted after day five across the cell populations. Lactate concentrations observed throughout the culture reached a maximum of 7.5 mM on day seven. Immunophenotype analysis revealed that the transduction followed by an expansion step was not responsible for the downregulation of the cell surface receptors used to identify hMSCs. The levels of CD73, CD90, and CD105 expressing cells were above 90% for the non-transduced and transduced cells. In addition, the expression of negative markers (CD11b, CD19, CD34, CD45, and HLA-DR) was also shown to be below 5%, which is aligned with the criteria established for hMSCs by the International Society for Cell and Gene Therapy (ISCT). This work provides a foundation for the scalable manufacturing of gene-modified hMSCs which will overcome a significant translational and commercial bottleneck. KEY POINTS: • hMSCs were successfully transduced by lentiviral vectors carrying two different transgenes: GFP and VEGF • Transduced hMSCs were successfully expanded on microcarriers using spinner flasks during a period of 7 days • The genetic modification step did not cause any detrimental impact on the hMSC immunophenotype characteristics.

Patient preferences for heart valve disease intervention.

BACKGROUND: This study aimed to determine how patients trade-off the benefits and risks of two different types of procedures used to treat heart valve disease (HVD). It also aimed to determine patients' preferences for HVD treatments (predicted uptake) and the relative importance of each treatment attribute. METHODS: A discrete choice experiment (DCE) was conducted in Australia and Japan with patients who required a heart valve procedure. Patients were stratified into three categories: no prior procedure experience, minimally invasive procedure experience and invasive procedure experience. DCE attributes included risk of mortality; risk of stroke; needing dialysis; needing a new pacemaker; valve durability; independence 1 month after surgery; and out-of-pocket expenses. Participants chose between two hypothetical labelled approaches to therapy ('invasive procedure' and 'minimally invasive procedure'), with a separate opt-out included. A mixed multinomial logit model was used to analyse preferences. RESULTS: The DCE was completed by 143 Australian and 206 Japanese patients. Both populations demonstrated an overall preference for the minimally invasive procedure over the invasive procedure. All attributes tested significantly predicted choice and were important to patient decision-making. However, patients' choices were most influenced by the durability of the valve and the likelihood of independence postprocedure, irrespective of their prior procedure experience. Differences in preference were observed between Australian and Japanese patients; valve durability was the most important attribute among Australian patients, while Japanese patients emphasised regaining independence postsurgery. Risk of mortality was less important relative to other key attributes in Japan; however, it remained significant to the model. CONCLUSIONS: HVD patients prefer a minimally invasive procedure over an invasive procedure, irrespective of prior treatment experience. Key attributes contributing to treatment preferences are valve durability and faster recovery. These results can be used to help inform healthcare decision-makers about what features of heart valve procedures patients value most. PATIENT AND PUBLIC CONTRIBUTION: People with lived experience of HVD were included in multiple stages of the design phase of this research. First, patients and doctors were consulted by taking part in qualitative interviews. The qualitative interviews helped inform which treatment attributes to include in the DCE based on what was important to those with lived experience and those who help make treatment decisions on behalf of patients. Qualitative interview participants also assisted with the framing of questions in the online survey to ensure the terminology was patient-friendly and relevant to those with lived experience. Following qualitative interviews, the DCE attribute list was agreed on in expert consultation with a steering committee, which included patient representatives and treating physicians (interventional cardiologists, cardiothoracic surgeons). The survey was also pilot tested with a small sample of patients and minor adjustments were made to the wording to ensure it was appropriate and meaningful to those with lived experience of HVD.

Age-dependent early complications of hypospadias repair: a single institutional experience.

PURPOSE: To correlate age at hypospadias repair with early post-operative complications and highlight need for adaptation to post-operative care in older children. METHODS: Anecdotal evidence suggests boys with delayed surgery for hypospadias suffer increased rates of early post-operative complication. Hence, a retrospective analysis was conducted of all patients undergoing hypospadias repair between March 2019 and 2022. RESULTS: Ninety eight patients were divided into Group A (< 2years of age at first surgery) or Group B (> 2years). While patients in Group A encountered no early post-operative complications, seven in Group B (11%) suffered a range of complications including dislodged stents (3/7), significant spasmodic pain requiring prolonged hospital stay (2/7) and urinary retention (2/7). More than half of these children required emergency supra-pubic catheter insertion. CONCLUSION: Significantly more children undergoing hypospadias surgery after the age of 2 years suffered complications within the early post-operative period. This resulted in prolonged hospital stays and a number returning to theatre for insertion of a supra-pubic catheter. We recommend a tailored approach to the post-operative care of older children undergoing hypospadias repair, including strict parental education regarding dressing/stent care and medication compliance, as well as efforts to enhance robustness of dressings and stent anchorage in children likely to pull at stents.

Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype.

Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition-a well-known hallmark of fibrotic disease. Transforming growth factor-ß (TGF-ß) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-ß-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-ß-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-ß, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-ß stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-ß-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-ß-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis.

Prior aerobic exercise mitigates the decrease in serum osteoglycin and lipocalin-2 following high-glucose mixed-nutrient meal ingestion in young men.

Osteoglycin (OGN) and lipocalin-2 (LCN2) are hormones that can be secreted by bone and have been linked to glucose homeostasis in rodents. However, the endocrine role of these hormones in humans is contradictory and unclear. We examined the effects of exercise and meal ingestion on circulating serum OGN and LCN2 levels in eight healthy males {age: 28 [25, 30] years [median ± interquartile range (IQR)] and body mass index [BMI]: 24.3 [23.6, 25.5] kg/m2}. In a randomized crossover design, participants ingested a high-glucose (1.1 g glucose/kg body wt) mixed-nutrient meal (45% carbohydrate, 20% protein, and 35% fat) on a rest-control day and 3 and 24 h after aerobic cycling exercise (1 h at 70%-75% V̇o2peak). Acute aerobic exercise increased serum LCN2 levels immediately after exercise (∼61%), which remained elevated 3-h postexercise (∼55%). In contrast, serum OGN remained similar to baseline levels throughout the 3-h postexercise recovery period. The ingestion of a high-glucose mixed-nutrient meal led to a decrease in serum OGN at 90-min (approximately -17%) and 120-min postprandial (approximately -44%), and a decrease in LCN2 at 120-min postprandial (approximately -26%). Compared with the control meal, prior exercise elevated serum OGN and LCN2 levels at 120-min postprandial when the meal was ingested 3-h (OGN: ∼74% and LCN2: ∼68%) and 24-h postexercise (OGN: ∼56% and LCN2: ∼16%). Acute exercise increases serum LCN2 and attenuates the postprandial decrease in OGN and LCN2 following high-glucose mixed-nutrient meal ingestion. The potential endocrine role of circulating OGN and LCN2 in humans warrants further investigation.NEW & NOTEWORTHY We provide novel evidence that OGN and LCN2 decrease 120 min after ingesting a high-glucose mixed-nutrient meal in healthy adults. Acute aerobic exercise increases circulating LCN2 for up to 3-h postexercise, whereas circulating OGN remains similar to baseline. Despite differing postexercise responses, postprandial LCN2 and OGN are elevated when the high-glucose meal is ingested 3-h and 24-h postexercise. Findings support that OGN and LCN2 are dynamically linked to energy homeostasis in humans.

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Sex differences in time to primary percutaneous coronary intervention and outcomes in patients presenting with ST-segment elevation myocardial infarction.

OBJECTIVES: We assessed sex differences in treatment and outcomes in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). BACKGROUND: Historically, delays to timely reperfusion and poorer outcomes have been described in women who suffer STEMI. However, whether these sex discrepancies still exist with contemporary STEMI treatment remains to be evaluated. METHODS: Consecutive STEMI patients treated with primary PCI patients over a 10-year period (January 1, 2010 to December 31, 2019) from a tertiary referral center were assessed. Comparisons were performed between patient's sex. Primary outcomes were 30-day and 1-year mortality. Secondary outcomes were STEMI performance measures. RESULTS: Most patients (n = 950; 76%) were male. Females were on average older (66.8 vs. 61.4 years males; p < 0.001). Prehospital treatment delays did not differ between sexes (54 min [IQR: 44-65] females vs. 52 min [IQR: 43-62] males; p = 0.061). STEMI performance measures (door-to-balloon, first medical contact-to-balloon [FMCTB]) differed significantly with longer median durations in females and fewer females achieving FMCTB < 90 min (28% females vs. 39% males; p < 0.001). Women also experienced greater rates of initial radial arterial access failure (11.3% vs. 3.1%; p < 0.001). However, there were no significant sex differences in crude or adjusted mortality between sexes at 30-days (3.6% male vs. 5.1% female; p = 0.241, adjusted OR: 1.1, 95% CI: 0.5-2.2, p = 0.82) or at 1-year (4.8% male vs. 6.8% female; p = 0.190, adjusted OR: 1.0, (95% CI: 0.5-1.8; p = 0.96). CONCLUSION: Small discrepancies between sexes in measures of timely reperfusion for STEMI still exist. No significant sex differences were observed in either 30-day or 1-year mortality.