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Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice
Full text linkParkinson’s disease (PD) is a neurodegenerative disorder affecting nearly 10 mil- lion people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural pheno- types have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with H2O2 to study susceptibility towards oxidative stress in vitro. KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dys- regulated in KI mice brains: Dopamine transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD
Deciphering the Role of Kruppel-like Factor 9 in Sepsis and Immunity: Perspectives from Joint Collective Omics Data and a Literature Review
No full textPublicly available transcriptome profiling data show that the abundance of Kruppel-like factor 9 (KLF9) transcripts is elevated in neutrophils exposed to the plasma of septic patients. KLF9 is a transcription factor involved in regulating cancer cell proliferation, neurological development and reproduction, but its possible role in sepsis has not been reported in the literature. In the context of this review, further exploration of the public literature and transcriptional profiling records revealed the following: 1) KLF9 transcript abundance is also increased in vivo in patients with sepsis across multiple datasets. 2) KLF9 is one of the few members of the KLF family that can be induced by treatment with the broad-spectrum immune activator PMA/ionomycin. 3) Among other known roles, KLF9 contributes to increased oxidative stress and tissue injury via the repression of the levels of antioxidants such as thioredoxin reductase 2. A similar role can be inferred in neutrophils in the context of sepsis. Taken together, this gene-centric review of omics and bibliographic records identified potential gaps in biomedical knowledge about the role of KLF9 in sepsis and immunity and identified potential avenues for downstream investigation
Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP).
Full text linkAccumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy
Machine Learning to Detect Cervical Spine Fractures Missed by Radiologists on CT: Analysis Using Seven Award-Winning Models from the RSNA 2022 Cervical Spine Fracture AI Challenge.
No full textBACKGROUND. Available data on radiologists’ missed cervical spine fractures arebased primarily on studies using human reviewers to identify errors on reevaluation;such studies do not capture the full extent of missed fractures.OBJECTIVE. The purpose of this study was to use machine learning (ML) models toidentify cervical spine fractures on CT missed by interpreting radiologists, characterizethe nature of these fractures, and assess their clinical significance.METHODS. This retrospective study included all cervical spine CT examinationsperformed in adult patients in the emergency department between January 1, 2018,and December 31, 2022. Examinations reported as negative for cervical spine fracturewere processed by seven award-winning ML models from the 2022 Radiological Soci-ety of North America Cervical Spine Fracture AI Challenge; examinations classified aspositive by at least four of the seven models were considered to have ML-detected frac-tures. Two neuroradiologists independently reviewed examinations with ML-detectedfractures using ML-derived heat maps to identify those representing true missed frac-tures. The neuroradiologists further assessed the fractures’ extent. Two spine surgeonsindependently assessed whether missed fractures were clinically significant (i.e., war-ranting at least one of surgical consultation, MRI, CTA, or collar immobilization).RESULTS. The study included 6671 patients (2414 women, 4257 men; mean age,54.6 ± 22.1 [SD] years) who underwent a total of 6979 cervical spine CT examina-tions. Interpreting radiologists reported 6378 examinations as negative for fracture.Of these, 356 had ML-detected fractures (i.e., positive by at least four of seven mod-els). The neuroradiologists classified 40 of these examinations, in 39 unique patients,as having true fractures. ML-detected missed true fractures involved 51 unique sites,most commonly the C7 transverse process (n = 12), C5 spinous process (n = 12), and C6spinous process (n = 8). The surgeons considered missed fractures clinically significantin 15 of 40 examinations (MRI and collar immobilization [n = 7], MRI and surgical eval-uation [n = 1], CTA [n = 9]). Interobserver agreement, expressed as kappa, was 0.88 be-tween neuroradiologists for true fracture classification and 0.94 between surgeons forclinical significance classification.CONCLUSION. ML models identified cervical spine fractures missed by radiolo-gists. These fractures were further characterized to systematically highlight radiolo-gists’ common misses.CLINICAL IMPACT. This ML-based framework can be applied in quality improve-ment efforts, to help refine radiologists’ search patterns based on prone-to-miss findings
HAND1, partially mediated through ape-specific LTR binding, is essential for human extra-embryonic mesenchyme derivation from iPSCs.
Full text linkThe specification of extra-embryonic mesenchyme (ExMC) is a prime example of developmental divergence between mouse and human. Derived from definitive mesoderm during mouse gastrulation, the human ExMC first appears at peri-implantation prior to gastrulation and therefore its human cellular origin, still unknown, must differ. In a human pluripotent stem cell model, we report that ExMC shares progenitor cells with trophoblast, suggesting a trophectoderm origin. This ability to form ExMC appears to extend to human trophoblast stem cell lines. We define HAND1 as an essential regulator of ExMC specification, with null cells remaining in the trophoblast lineage. Bound by HAND1, ape-specific, endogenous retrovirus-derived LTR2B contributes to unique features of ExMC. Additionally, ExMC supports the maintenance of pluripotent stem cells, possibly reflecting a role in maintaining epiblast pluripotency through peri-implantation development. Our data emphasize the nascent evolutionary innovation in human early development and provide a cellular system to study this
Polyploid superficial uroepithelial bladder barrier cells express features of cellular senescence across the lifespan and are insensitive to senolytics.
Full text linkLower urinary tract dysfunction (LUTD) increases with aging. Ensuing symptoms including incontinence greatly impact quality of life, isolation, depression, and nursing home admission. The aging bladder is hypothesized to be central to this decline, however, it remains difficult to pinpoint a singular strong driver of aging-related bladder dysfunction. Many molecular and cellular changes occur with aging, contributing to decreased resilience to internal and external stressors, affecting urinary control and exacerbating LUTD. In this study, we examined whether cellular senescence, a cell fate involved in the etiology of most aging diseases, contributes to LUTD. We found that umbrella cells (UCs), luminal barrier uroepithelial cells in the bladder, show senescence features over the mouse lifespan. These polyploid UCs exhibit high cyclin D1 staining, previously reported to mediate tetraploidy-induced senescence in vitro. These senescent UCs were not eliminated by the senolytic combination of Dasatinib and Quercetin. We also tested the effect of a high-fat diet (HFD) and senescent cell transplantation on bladder function and showed that both models induce cystometric changes similar to natural aging in mice, with no effect of senolytics on HFD-induced changes. These findings illustrate the heterogeneity of cellular senescence in varied tissues, while also providing potential insights into the origin of urothelial cancer. We conclude that senescence of bladder uroepithelial cells plays a role in normal physiology, namely in their role as barrier cells, helping promote uroepithelial integrity and impermeability and maintaining the urine-blood barrier
System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans.
No full textWe performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell-cell interactions, along with survival factors APRIL and the MIF-CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability
Nanomedicine targeting PPAR in adipose tissue macrophages improves lipid metabolism and obesity-induced metabolic dysfunction.
No full textExcess body fat leads to an overabundance of adipose tissue macrophages (AT MΦs) with altered phenotypes that play pathogenic roles in obesity comorbidities including diabetes and cancer. Peroxisome proliferator-activated receptors (PPARs) are leading targets to modulate AT MΦ phenotype. Here, we developed a dextran-based nanomedicine that delivers PPARα/γ agonists to AT MΦs and improves obesity and diabetic phenotypes in vivo. Within 1 week of treatment, AT MΦs decreased and became lipid laden, while extracellular vesicles secreted from AT decreased and reduced in lipid content. Within 2 weeks, glucose tolerance returned to levels of lean controls, followed by weight loss and reduced food intake. After 4 weeks, AT browning and amelioration of hepatic steatosis were evident. The physiological shifts were reproducible in three rodent models of obesity, spanning sexes and gonadal status. Effects were enhanced for the targeted nanomedicine compared with free drugs at equivalent doses, supporting the hypothesis that targeted PPAR activation in AT MΦs benefits systemic metabolism
