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Physical inactivity contributes to over 800,000 deaths annually. Numerous non-pharmacological interventions provide a route to address this behavioural risk factor linked to the growth of non-communicable diseases. Here, we consider a nature-based intervention, specifically group outdoor health walks (GOHW), as a non-pharmacological intervention to increase physical activity and contribute to health and quality of life amongst older adults. We used the theoretically grounded Capability, Opportunity, Motivation, and Behaviour (COM-B) model as a lens to examine interviews with participants in a GOHW with an activity tracker and signposted by health clinics in Scotland, UK. Analysis identified capabilities, opportunities, and motivations, their impact on behaviour, and perceived physical and mental health. The application of the COM-B model to intervention evaluation allowed us to examine two separate behaviours, that of (i) engaging with the intervention itself, and (ii) incorporating the behaviour into one's life that the intervention targets. Analysis identified emerging capabilities, opportunities, and motivations that supported additional health-promoting behaviours, including increased time outdoors in nature and leadership to self-organise continued group walks. We offer insight into the design of nature-based interventions to effectively engage older adults with chronic health conditions and foster personal behaviour change for health and well-being.
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Exercício Físico , Promoção da Saúde , Motivação , Humanos , Idoso , Promoção da Saúde/métodos , Feminino , Masculino , Escócia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Pesquisa Qualitativa , Caminhada/psicologia , Comportamentos Relacionados com a Saúde , Qualidade de VidaRESUMO
BACKGROUND: Beneficial effects of breathing at FIO2 < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with FIO2 as low as 0.11 in 5 healthy volunteers. METHODS: All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from FIO2 of 0.16 on the first day to FIO2 of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' SpO2 , heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments. RESULTS: Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased SpO2 and increased heart rate. At FIO2 of 0.14, the mean SpO2 was 92%; at FIO2 of 0.13, the mean SpO2 was 93%; at FIO2 of 0.12, the mean SpO2 was 88%; at FIO2 of 0.11, the mean SpO2 was 85%; and, finally, at an FIO2 of 0.21, the mean SpO2 was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension. CONCLUSIONS: Results of the current physiologic study suggests that, within a hospital setting, delivering FIO2 as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested.
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INTRODUCTION: In the Medscape 2020 Compensation Report, family physicians ranked low for feeling fairly compensated, choosing their specialty again and choosing medicine again. However, the Medscape data may not represent military family physicians. METHODS: A large survey was emailed to 2,562 military family physicians via a military professional organization list-serve from February to April 2021. The inquiry included 6 statements pertaining to professional satisfaction. The main outcome measures were proportions of "agree" and "strongly agree." The proportions were compared to the Medscape Compensation Report 2020 and 2022. Statistical analysis was completed with a two-tailed Z-score for 2 populations. RESULTS: Sixty-one percent of military family physicians feel fairly compensated compared to 54% of civilian family physicians in 2020 and 55% in 2022 (P = .065, .119). Eighty-six percent of military family physicians would reselect medicine compared to 74% of civilian family physicians in 2020 and 73% in 2022 (P < .001 for both). Eighty percent of military family physicians would reselect their specialty again compared to 70% of civilians in 2020 and 68% in 2022 (P = .004, P = .001, respectively). CONCLUSIONS: Military family physicians were more likely to choose medicine generally and family medicine specifically again. Military family physicians and civilian family physicians do not statistically differ in feeling fairly compensated. A strong majority of military family physicians are satisfied with their military-sponsored medical education.
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Satisfação no Emprego , Militares , Médicos de Família , Humanos , Médicos de Família/estatística & dados numéricos , Médicos de Família/psicologia , Médicos de Família/tendências , Inquéritos e Questionários , Masculino , Feminino , Militares/estatística & dados numéricos , Militares/psicologia , Adulto , Pessoa de Meia-Idade , Satisfação Pessoal , Estados Unidos , Medicina Militar/estatística & dados numéricos , Medicina Militar/métodos , Medicina Militar/normas , Medicina Militar/tendênciasRESUMO
Introduction: Climate change is the single biggest health threat facing humanity, with direct and indirect impacts on mental health, yet health impacts of climate change remain notably absent from most medical school curricula. We describe a timely interactive educational session on climate change and mental health that was implemented and studied on a medical student clinical psychiatry rotation. Methods: We developed a 1-hour introductory session on the mental health impacts of climate change and potential solutions. The session was delivered to third-year medical students on their 4-week clinical psychiatry rotation and included pre- and postsession survey questions assessing their knowledge, comfort, and readiness regarding the topic. Results: Seventy students participated in the session, with 49 students completing the pre- and postsession surveys, giving a response rate of 70%. The average score for the four Likert-scale questions on the survey increased from 2.7 presession to 3.9 postsession on a 5-point scale (1 = strongly disagree, 5 = strongly agree). All questions displayed statistically significant improvement. Qualitative analysis identified knowledge gained about the mental health impacts of climate change as the most important aspect of the session to students. Discussion: The introductory session effectively filled an urgent need in medical education curricula regarding climate change's effects on human health. Overall, distribution of and improvement upon this timely teaching content can serve a valuable role in medical student education as the effects of climate change, particularly on mental health, continue to progress throughout the century.
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Mudança Climática , Currículo , Educação de Graduação em Medicina , Saúde Mental , Estudantes de Medicina , Humanos , Inquéritos e Questionários , Educação de Graduação em Medicina/métodos , Estudantes de Medicina/psicologia , Estudantes de Medicina/estatística & dados numéricos , Psiquiatria/educaçãoRESUMO
Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.
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Doença de Alzheimer , Apatia , Transtornos Psicóticos , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Sintomas ComportamentaisRESUMO
ABSTRACT: Hyperactivation of the NF-κB cascade propagates oncogenic signaling and proinflammation, which together augments disease burden in myeloproliferative neoplasms (MPNs). Here, we systematically ablate NF-κB signaling effectors to identify core dependencies using a series of primary samples and syngeneic and patient-derived xenograft (PDX) mouse models. Conditional knockout of Rela attenuated Jak2V617F- and MPLW515L-driven onset of polycythemia vera and myelofibrosis disease hallmarks, respectively. In PDXs, RELA knockout diminished leukemic engraftment and bone marrow fibrosis while extending survival. Knockout of upstream effector Myd88 also alleviated disease burden; conversely, perturbation of negative regulator miR-146a microRNA induced earlier lethality and exacerbated disease. Perturbation of NF-κB effectors further skewed the abundance and distribution of hematopoietic multipotent progenitors. Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in nondiseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.
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Transtornos Mieloproliferativos , NF-kappa B , Transdução de Sinais , Animais , Camundongos , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/metabolismo , NF-kappa B/metabolismo , Camundongos Knockout , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genéticaRESUMO
Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.
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Myeloproliferative neoplasms (MPNs) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induced a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to an erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated the MPN disease burden, including leukemic engraftment and splenomegaly, in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only for primary MPN samples harboring ASXL1 mutations. Last, treatment of CD34+ hematopoietic/stem progenitor cells with the PRMT6 inhibitor EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.
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Transtornos Mieloproliferativos , Neoplasias , Humanos , Eritropoese/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Transdução de Sinais , Mutação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Nucleares/genética , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismoRESUMO
Woolly mammoths in mainland Alaska overlapped with the region's first people for at least a millennium. However, it is unclear how mammoths used the space shared with people. Here, we use detailed isotopic analyses of a female mammoth tusk found in a 14,000-year-old archaeological site to show that she moved ~1000 kilometers from northwestern Canada to inhabit an area with the highest density of early archaeological sites in interior Alaska until her death. DNA from the tusk and other local contemporaneous archaeological mammoth remains revealed that multiple mammoth herds congregated in this region. Early Alaskans seem to have structured their settlements partly based on mammoth prevalence and made use of mammoths for raw materials and likely food.
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Mamutes , Humanos , Animais , Feminino , Recém-Nascido , Mamutes/genética , DNA , Canadá , Alaska , FósseisRESUMO
Depression is a common and devastating neuropsychiatric symptom in the elderly and in patients with dementia. In particular, nearly 80% of patients with Alzheimer's Disease dementia experience depression during disease development and progression. However, it is unknown whether the depression in patients with dementia shares the same molecular mechanisms as depression presenting as primary psychiatric disease or occurs and persists through alternative mechanisms. In this review, we discuss how the clinical presentation and treatment differ between depression in dementia and as a primary psychiatric disease, with a focus on major depressive disorder. Then, we hypothesize several molecular mechanisms that may be unique to depression in dementia such as neuropathological changes, inflammation, and vascular events. Finally, we discuss existing issues and future directions for investigation and treatment of depression in dementia.
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Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F-knockin mice with α-KG supplementation significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte, and platelet counts. Finally, α-KG treatment significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling that contributes to platelet hyperreactivity in MPN patients.
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Transtornos Mieloproliferativos , Neoplasias , Trombocitemia Essencial , Humanos , Camundongos , Animais , Multiômica , Fosfatidilinositol 3-Quinases/genética , Proteômica , Proteínas Proto-Oncogênicas c-akt/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Trombocitemia Essencial/genética , Inflamação , Serina-Treonina Quinases TOR/genética , Trifosfato de Adenosina , Janus Quinase 2/genética , MutaçãoRESUMO
Mutations in the degradative ubiquitin ligase anaphase-promoting complex (APC) alter neurodevelopment by impairing proteasomal protein clearance, but our understanding of their molecular and cellular pathogenesis remains limited. Here, we employ the proteomic-based discovery of APC substrates in APC mutant mouse brain and human cell lines and identify the chromosome-passenger complex (CPC), topoisomerase 2a (Top2a), and Ki-67 as major chromatin factors targeted by the APC during neuronal differentiation. These substrates accumulate in phosphorylated form, suggesting that they fail to be eliminated after mitosis during terminal differentiation. The accumulation of the CPC kinase Aurora B within constitutive heterochromatin and hyperphosphorylation of its target histone 3 are corrected in the mutant brain by pharmacologic Aurora B inhibition. Surprisingly, the reduction of Ki-67, but not H3S10ph, rescued the function of constitutive heterochromatin in APC mutant neurons. These results expand our understanding of how ubiquitin signaling regulates chromatin during neurodevelopment and identify potential therapeutic targets in APC-related disorders.
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Anáfase , Cromatina , Camundongos , Animais , Humanos , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Heterocromatina , Fosfoproteínas/metabolismo , Antígeno Ki-67/metabolismo , Proteômica , Ubiquitinação , Mitose , Ubiquitina/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
Cell cycle transitions result from global changes in protein phosphorylation states triggered by cyclin-dependent kinases (CDKs). To understand how this complexity produces an ordered and rapid cellular reorganisation, we generated a high-resolution map of changing phosphosites throughout unperturbed early cell cycles in single Xenopus embryos, derived the emergent principles through systems biology analysis, and tested them by biophysical modelling and biochemical experiments. We found that most dynamic phosphosites share two key characteristics: they occur on highly disordered proteins that localise to membraneless organelles, and are CDK targets. Furthermore, CDK-mediated multisite phosphorylation can switch homotypic interactions of such proteins between favourable and inhibitory modes for biomolecular condensate formation. These results provide insight into the molecular mechanisms and kinetics of mitotic cellular reorganisation.
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Proteínas de Ciclo Celular , Quinases Ciclina-Dependentes , Quinases Ciclina-Dependentes/metabolismo , Fosforilação , Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Quinase 2 Dependente de Ciclina/metabolismoRESUMO
Histone post-translational modifications promote a chromatin environment that controls transcription, DNA replication and repair, but surprisingly few phosphorylations have been documented. We report the discovery of histone H3 serine-57 phosphorylation (H3S57ph) and show that it is implicated in different DNA repair pathways from fungi to vertebrates. We identified CHK1 as a major human H3S57 kinase, and disrupting or constitutively mimicking H3S57ph had opposing effects on rate of recovery from replication stress, 53BP1 chromatin binding, and dependency on RAD52. In fission yeast, mutation of all H3 alleles to S57A abrogated DNA repair by both non-homologous end-joining and homologous recombination, while cells with phospho-mimicking S57D alleles were partly compromised for both repair pathways, presented aberrant Rad52 foci and were strongly sensitised to replication stress. Mechanistically, H3S57ph loosens DNA-histone contacts, increasing nucleosome mobility, and interacts with H3K56. Our results suggest that dynamic phosphorylation of H3S57 is required for DNA repair and recovery from replication stress, opening avenues for investigating the role of this modification in other DNA-related processes.
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Histonas , Vírus da Influenza A , Humanos , Animais , Fosforilação , Processamento de Proteína Pós-Traducional , Reparo do DNA , CromatinaRESUMO
Hyperactivation of JAK2 kinase is a unifying feature of human Ph- myeloproliferative neoplasms (MPNs), most commonly due to the JAK2 V617F mutation. Mice harboring a homologous mutation in the Jak2 locus exhibit a phenotype resembling polycythemia vera. NFκB pathway hyperactivation is present in myeloid neoplasms, including MPNs, despite scarcity of mutations in NFκB pathway genes. To determine the impact of NFκB pathway hyperactivation in conjunction with Jak2 V617F, we utilized Ikk2 (Ikk2-CA) mice. Pan-hematopoietic Ikk2-CA alone produced depletion of hematopoietic stem cells and B cells. When combined with the Jak2 V617F mutation, Ikk2-CA rescued the polycythemia vera phenotype of Jak2 V617F. Likewise, Jak2 V617F ameliorated defects in hematopoiesis produced by Ikk2-CA. Single-cell RNA sequencing of hematopoietic stem and progenitor cells revealed multiple genes antagonistically regulated by Jak2 and Ikk2, including subsets whose expression was altered by Jak2 V617F and/or Ikk2-CA but partly or fully rectified in the double mutant. We hypothesize that Jak2 promotes hematopoietic stem cell population self-renewal, whereas Ikk2 promotes myeloid lineage differentiation, and biases cell fates at several branch points in hematopoiesis. Jak2 and Ikk2 both regulate multiple genes affecting myeloid maturation and cell death. Therefore, the presence of dual Jak2 and NFκB hyperactivation may present neomorphic therapeutic vulnerabilities in myeloid neoplasms.
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Transtornos Mieloproliferativos , Policitemia Vera , Camundongos , Humanos , Animais , Policitemia Vera/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Mutação , Células-Tronco Hematopoéticas/metabolismo , Hematopoese/genética , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Bacterial species often undergo rampant recombination yet maintain cohesive genomic identity. Ecological differences can generate recombination barriers between species and sustain genomic clusters in the short term. But can these forces prevent genomic mixing during long-term coevolution? Cyanobacteria in Yellowstone hot springs comprise several diverse species that have coevolved for hundreds of thousands of years, providing a rare natural experiment. By analyzing more than 300 single-cell genomes, we show that despite each species forming a distinct genomic cluster, much of the diversity within species is the result of hybridization driven by selection, which has mixed their ancestral genotypes. This widespread mixing is contrary to the prevailing view that ecological barriers can maintain cohesive bacterial species and highlights the importance of hybridization as a source of genomic diversity.
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Hormones in biological media reveal endocrine activity related to development, reproduction, disease and stress on different timescales1. Serum provides immediate circulating concentrations2, whereas various tissues record steroid hormones accumulated over time3,4. Hormones have been studied in keratin, bones and teeth in modern5-8 and ancient contexts9-12; however, the biological significance of such records is subject to ongoing debate10,13-16, and the utility of tooth-associated hormones has not previously been demonstrated. Here we use liquid chromatography with tandem mass spectrometry paired with fine-scale serial sampling to measure steroid hormone concentrations in modern and fossil tusk dentin. An adult male African elephant (Loxodonta africana) tusk shows periodic increases in testosterone that reveal episodes of musth17-19, an annually recurring period of behavioural and physiological changes that enhance mating success20-23. Parallel assessments of a male woolly mammoth (Mammuthus primigenius) tusk show that mammoths also experienced musth. These results set the stage for wide-ranging studies using steroids preserved in dentin to investigate development, reproduction and stress in modern and extinct mammals. Because dentin grows by apposition, resists degradation, and often contains growth lines, teeth have advantages over other tissues that are used as records of endocrine data. Given the low mass of dentin powder required for analytical precision, we anticipate dentin-hormone studies to extend to smaller animals. Thus, in addition to broad applications in zoology and palaeontology, tooth hormone records could support medical, forensic, veterinary and archaeological studies.
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Elefantes , Fósseis , Mamutes , Testosterona , Dente , Animais , Masculino , Elefantes/anatomia & histologia , Elefantes/metabolismo , Mamutes/anatomia & histologia , Mamutes/metabolismo , Esteroides/análise , Esteroides/metabolismo , Testosterona/análise , Testosterona/metabolismo , Dente/química , Dente/metabolismo , Dentina/química , Dentina/metabolismoRESUMO
Background: Pathological amyloid-ß and α-synuclein are associated with a spectrum of related dementias, ranging from Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) to Parkinson disease dementia (PDD). While these diseases share clinical and pathological features, they also have unique patterns of pathology. However, epigenetic factors that contribute to these pathological differences remain unknown. Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. Methods: We employed an Illumina Infinium 850k array and RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. Results: We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Conclusion: Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias.
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Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first-line therapeutic agents. However, despite all having potent capacity to suppress JAK-STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA-approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2-mutant in vitro models, all four inhibitors demonstrated similar anti-proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient-derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA-sequencing and gene set enrichment analyses, differential suppressive degrees of JAK-STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.