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As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of - 5.5 (- 6.5, - 3.5) points from baseline to 3-months follow-up (Z = - 2.6, p = 0.009, r = - 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care.
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Infecções por HIV , Psilocibina , Vergonha , Humanos , Psilocibina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Projetos Piloto , Estigma SocialRESUMO
BACKGROUND: Therapeutic hypothermia has shown potential in cardiac intervention for years; however, its adoption into the neurovascular space has been limited. Studies have pointed to slow cooling and limited depth of hypothermia yielding negative outcomes. Here we present an insulated catheter that allows for consistent infusion of chilled saline directly to the brain. Direct delivery of cold saline allows a faster depth of hypothermia, which could have a benefit to the growth of ischemic lesions. METHODS: Ten canines were randomized to either receive selective brain cooling or no additional therapy. Eight animals were successfully enrolled (n = 4 per group). Each animal underwent a temporary middle cerebral artery occlusion (MCAO) for a total of 45â min. Five minutes prior to flow restoration, chilled saline was injected through the ipsilateral internal carotid artery using an insulated catheter to ensure delivery temperature. The treatment continued for 20â min, after which the animal was transferred to an MRI scanner for imaging. RESULTS: Of the 8 animals that were successfully enrolled in the study, 3 were able to survive to the 30-day endpoint with no differences between the cooled and control animals. There was no difference in the initial mean infarct size between the groups; however, animals that did not receive cooling had infarcts continuing to progress more rapidly after the MCAO was removed (13.8% vs 161.3%, p = 0.016, cooled vs control). CONCLUSIONS: Selective hypothermia was able to reduce the post-MCAO infarct progression in a canine model of temporary MCAO.
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OBJECTIVES: The Centers for Disease Control and Prevention (CDC) needs leaders at all levels who can address technical and adaptive challenges in a changing public health landscape. We assessed the feasibility of implementing an enterprise-wide leadership development model. METHODS: In June 2023, we launched a pilot program, Learn and Lead, for nonsupervisory staff in early and mid-career levels. One hundred sixty-nine participants registered, and 149 completed at least 6 weeks of the 8-week program. We gathered quantitative and qualitative data through weekly electronic surveys and in-depth interviews. We calculated frequencies for closed-ended Likert-scale items and performed content analysis of open-ended items to assess most frequently mentioned themes. We based the pilot's design on CDC's leadership development framework to assess application of the framework and alignment of curriculum to the framework. RESULTS: Three themes emerged: logistics and facilitation, leadership development curriculum, and making connections with self and others. Findings for logistics and facilitation highlighted preferences for course length, small breakout groups, mixed weeks, and value of staff support. Findings for the leadership development curriculum underscored the relevance of the US Office of Personnel Management's fundamental competencies to leadership development. Findings for making connections with self and others supported the cohort model and the importance of networking. CONCLUSIONS: The pilot curriculum aligned well with the CDC leadership development framework. Feedback provided by pilot participants is being used to help shape CDC's ongoing leadership development efforts.
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Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.
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This study examined the development of empathic care across three generations in a sample of 184 adolescents in the United States (99 female, 85 male; 58% White, 29% African American, 8% mixed race/ethnicity, 5% other groups), followed from their family of origin at age 13 into their parenting years (through their mid-30s). Mothers' empathic support toward adolescents at age 13 predicted teens' empathy for close friends across adolescence (13-19 years). Participants' empathic support for friends in late adolescence predicted more supportive parenting behavior in adulthood, which in turn was associated with their children's empathy at age 3-8 years. Results suggest that individuals "pay forward" the empathic care they receive from parents, and that skills developed in adolescent friendships may inform later parenting.
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Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome-proliferator-activated receptor γ coactivator 1α, a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron-free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle-derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules.
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Fator Neurotrófico Derivado do Encéfalo , Exossomos , Músculo Esquelético , Exossomos/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/inervação , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos , Fibronectinas/metabolismo , Neurônios Motores/metabolismo , Interleucina-6/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Neurônios/metabolismo , Fatores de Crescimento Neural/metabolismo , MiocinasRESUMO
Background: Many clinical trials fail because of poor recruitment and enrollment which can directly impact the success of biomedical and clinical research outcomes. Options to leverage digital technology for improving clinical trial management are expansive, with potential benefits for improving access to clinical trials, encouraging trial diversity and inclusion, and potential cost-savings through enhanced efficiency. Objectives: This systematic review has two key aims: (1) identify and describe the digital technologies applied in clinical trial recruitment and enrollment and (2) evaluate evidence of these technologies addressing the recruitment and enrollment of racial and ethnic minority groups. Methods: We conducted a cross-disciplinary review of articles from PubMed, IEEE Xplore, and ACM Digital Library, published in English between January 2012 and July 2022, using MeSH terms and keywords for digital health, clinical trials, and recruitment and enrollment. Articles unrelated to technology in the recruitment/enrollment process or those discussing recruitment/enrollment without technology aspects were excluded. Results: The review returned 614 results, with 21 articles (four reviews and 17 original research articles) deemed suitable for inclusion after screening and full-text review. To address the first objective, various digital technologies were identified and characterized, which included articles with more than one technology subcategory including (a) multimedia presentations (19%, n = 4); (b) mobile applications (14%, n = 3); (c) social media platforms (29%, n = 6); (d) machine learning and computer algorithms (19%, n = 4); (e) e-consenting (24%, n = 5); (f) blockchain (5%, n = 1); (g) web-based programs (24%, n = 5); and (h) virtual messaging (24%, n = 5). Additionally, subthemes, including specific diseases or conditions addressed, privacy and regulatory concerns, cost/benefit analyses, and ethnic and minority recruitment considerations, were identified and discussed. Limited research was found to support a particular technology's effectiveness in racial and ethnic minority recruitment and enrollment. Conclusion: Results from this review illustrate that several types of technology are currently being explored and utilized in clinical trial recruitment and enrollment stages. However, evidence supporting the use of digital technologies is varied and requires further research and evaluation to identify the most valuable opportunities for encouraging diversity in clinical trial recruitment and enrollment practices.
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MOTIVATION: Supervised deep learning is used to model the complex relationship between genomic sequence and regulatory function. Understanding how these models make predictions can provide biological insight into regulatory functions. Given the complexity of the sequence to regulatory function mapping (the cis-regulatory code), it has been suggested that the genome contains insufficient sequence variation to train models with suitable complexity. Data augmentation is a widely used approach to increase the data variation available for model training, however current data augmentation methods for genomic sequence data are limited. RESULTS: Inspired by the success of comparative genomics, we show that augmenting genomic sequences with evolutionarily related sequences from other species, which we term phylogenetic augmentation, improves the performance of deep learning models trained on regulatory genomic sequences to predict high-throughput functional assay measurements. Additionally, we show that phylogenetic augmentation can rescue model performance when the training set is down-sampled and permits deep learning on a real-world small dataset, demonstrating that this approach improves data efficiency. Overall, this data augmentation method represents a solution for improving model performance that is applicable to many supervised deep-learning problems in genomics. AVAILABILITY AND IMPLEMENTATION: The open-source GitHub repository agduncan94/phylogenetic_augmentation_paper includes the code for rerunning the analyses here and recreating the figures.
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Aprendizado Profundo , Genômica , Filogenia , Genômica/métodos , Aprendizado de Máquina Supervisionado , HumanosRESUMO
The uterine muscular layer, or myometrium, undergoes profound changes in global gene expression during its progression from a quiescent state during pregnancy to a contractile state at the onset of labor. In this study, we investigate the role of SOX family transcription factors in myometrial cells and provide evidence for the role of SOX4 in regulating labor-associated genes. We show that Sox4 has elevated expression in the murine myometrium during a term laboring process and in two mouse models of preterm labor. Additionally, SOX4 differentially affects labor-associated gene promoter activity in cooperation with activator protein 1 (AP-1) dimers. SOX4 exerted no effect on the Gja1 promoter; a JUND-specific activation effect at the Fos promoter; a positive activation effect on the Mmp11 promoter with the AP-1 dimers; and surprisingly, we noted that the reporter expression of the Ptgs2 promoter in the presence of JUND and FOSL2 was repressed by the addition of SOX4. Our data indicate SOX4 may play a diverse role in regulating gene expression in the laboring myometrium in cooperation with AP-1 factors. This study enhances our current understanding of the regulatory network that governs the transcriptional changes associated with the onset of labor and highlights a new molecular player that may contribute to the labor transcriptional program.
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Trabalho de Parto , Miométrio , Animais , Feminino , Camundongos , Gravidez , Trabalho de Parto/genética , Trabalho de Parto/metabolismo , Miométrio/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Útero/metabolismoRESUMO
ABSTRACT: Pain anticipation during conditions of uncertainty can unveil intrinsic biases, and understanding these biases can guide pain treatment interventions. This study used machine learning and functional magnetic resonance imaging to predict anticipatory responses in a pain anticipation experiment. One hundred forty-seven participants that included healthy controls (n = 57) and individuals with current and/or past mental health diagnosis (n = 90) received cues indicating upcoming pain stimuli: 2 cues predicted high and low temperatures, while a third cue introduced uncertainty. Accurate differentiation of neural patterns associated with specific anticipatory conditions was observed, involving activation in the anterior short gyrus of the insula and the nucleus accumbens. Three distinct response profiles emerged: subjects with a negative bias towards high pain anticipation, those with a positive bias towards low pain anticipation, and individuals whose predictions during uncertainty were unbiased. These profiles remained stable over one year, were consistent across diagnosed psychopathologies, and correlated with cognitive coping styles and underlying insula anatomy. The findings suggest that individualized and stable pain anticipation occurs in uncertain conditions.
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Antecipação Psicológica , Imageamento por Ressonância Magnética , Dor , Humanos , Incerteza , Masculino , Feminino , Adulto , Antecipação Psicológica/fisiologia , Dor/psicologia , Dor/fisiopatologia , Dor/diagnóstico por imagem , Adulto Jovem , Pessoa de Meia-Idade , Aprendizado de Máquina , Mapeamento Encefálico , Sinais (Psicologia) , Medição da Dor/métodosRESUMO
Optimal imaging strategies remain underdeveloped to maximize information for fluorescence microscopy while minimizing the harm to fragile living systems. Taking hint from the supercontinuum generation in ultrafast laser physics, we generated supercontinuum fluorescence from untreated unlabeled live samples before nonlinear photodamage onset. Our imaging achieved high-content cell phenotyping and tissue histology, identified bovine embryo polarization, quantified aging-related stress across cell types and species, demystified embryogenesis before and after implantation, sensed drug cytotoxicity in real-time, scanned brain area for targeted patching, optimized machine learning to track small moving organisms, induced two-photon phototropism of leaf chloroplasts under two-photon photosynthesis, unraveled microscopic origin of autumn colors, and interrogated intestinal microbiome. The results enable a facility-type microscope to freely explore vital molecular biology across life sciences.
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Hypoxia is a significant source of metabolic stress that activates many cellular pathways involved in cellular differentiation, proliferation, and cell death. Hypoxia is also a major component in many human diseases and a known driver of many cancers. Despite the challenges posed by hypoxia, there are animals that display impressive capacity to withstand lethal levels of hypoxia for prolonged periods of time and thus offer a gateway to a more comprehensive understanding of the hypoxic response in vertebrates. The weakly electric fish genus Brachyhypopomus inhabits some of the most challenging aquatic ecosystems in the world, with some species experiencing seasonal anoxia, thus providing a unique system to study the cellular and molecular mechanisms of hypoxia tolerance. In this study, we use closely related species of Brachyhypopomus that display a range of hypoxia tolerances to probe for the underlying molecular mechanisms via hypoxia inducible factors (HIFs)-transcription factors known to coordinate the cellular response to hypoxia in vertebrates. We find that HIF1⺠from hypoxia tolerant Brachyhypopomus species displays higher transactivation in response to hypoxia than that of intolerant species, when overexpressed in live cells. Moreover, we identified two SUMO-interacting motifs near the oxygen-dependent degradation and transactivation domains of the HIF1⺠protein that appear to boost transactivation of HIF1, regardless of the genetic background. Together with computational analyses of selection, this shows that evolution of HIF1⺠are likely to underlie adaptations to hypoxia tolerance in Brachyhypopomus electric fishes, with changes in two SUMO-interacting motifs facilitating the mechanism of this tolerance.
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Peixe Elétrico , Subunidade alfa do Fator 1 Induzível por Hipóxia , Oxigênio , Animais , Ecossistema , Peixe Elétrico/genética , Peixe Elétrico/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Anaerobiose , Oxigênio/metabolismoRESUMO
This Viewpoint discusses the use of psychedelics in treatment for substance use disorders.
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To address high rates of mental health and developmental concerns facing young children ages 0-6 in the United States and internationally, providers across professional sectors need Infant and early childhood mental health (IECMH) training and support. The training and teleconsultation program (TTP) is a state-funded program developed in one Mountain West state in the United States to provide free IECMH training and teleconsultation to any provider working with young children. The TTP included access to webinars and individual or group consultation with licensed mental health providers. Webinars focused on increasing awareness and knowledge related to attachment and child development, supporting parents and caregivers, trauma-informed practice, supporting emotional health of staff and providers, and culturally responsive practices with infants, young children, and caregivers. Teleconsultation included case consultation, reflective individual and group supervision, and collaboration supports/referrals. During the 18-month evaluation period, 1568 unique providers engaged in either training or teleconsultation services, an average of 9% growth in new providers each month, with representation from all professional sectors and all state counties. This program demonstrates the feasibility and need for statewide training and teleconsultation programs to help meet the needs of providers who interact with and support young children and caregivers.
Para lidiar con las altas tasas de salud mental y preocupaciones sobre el desarrollo a las que se enfrentan los pequeños niños de edad 0-6 en los Estados Unidos e internacionalmente, quienes proveen el servicio dentro de la gama de todos los sectores profesionales necesitan entrenamiento y apoyo en el campo de la salud mental infantil y la temprana niñez (IECMH). El programa de entrenamiento y teleconsulta (TTP) es un programa con fondos estatales desarrollado en un estado del oeste montañoso en los Estados Unidos para ofrecer entrenamiento y teleconsulta gratis en IECMH a cualquier profesional que trabaja con niños pequeños. El TTP incluye acceso a seminarios web y consulta individual o en grupo con profesionales licenciados de la salud mental. Los seminarios web se enfocaron en incrementar la conciencia y el conocimiento relacionado con la afectividad y el desarrollo del niño, apoyar a progenitores y cuidadores, la práctica con atención informada sobre trauma, apoyar la salud emocional del personal y los proveedores, así como las prácticas culturalmente sensibles con los infantes, niños pequeños y quienes les cuidan. La teleconsulta incluyó consulta de casos, supervisión con reflexión tanto individual como de grupo, así como los apoyos/referencias colaborativas. Durante el período de evaluación de 18 meses, 1,568 proveedores con características particulares recibieron los servicios del entrenamiento o de la teleconsulta, un promedio de 9% de aumento de nuevos proveedores cada mes, con representación de todos los sectores profesionales y todos los condados del estado. Este programa demuestra la posibilidad y necesidad de programas de entrenamiento y teleconsulta a través de todo el estado para ayudar a satisfacer las necesidades de los proveedores que interactúan con y apoyan a los niños pequeños y quienes les cuidan.
Pour faire face aux taux élevés d'inquiétudes en matière de santé mentale et de comportement dont sont témoins les jeunes enfants âgés de 0-6 ans aux Etats-Unis et internationalement, les prestataires au travers des secteurs professionnels ont besoin de formation et de soutien en santé mentale du nourrisson et de la petite enfance (IECMH). Le programme de téléconsultation et de formation (TTP en anglais) est un programme financé au niveau de l'état développé dans un état des montagnes rocheuses aux Etats-Unis afin d'offrir une formation et une téléconsultation IECMH gratuite à tout prestataire travaillant avec de jeunes enfants. Le TTP a incorporé un accès à des webinaires et à une consultation individuelle ou de groupe avec des prestataires de santé mentale agréés. Les webinaires ont porté sur l'accroissement de la sensibilisation et des connaissances liées à l'attachement et au développement de l'enfant, au soutien des parents et des personnes prenant soin des enfants, à une pratique consciente des traumas, et au soutien de la santé émotionnelle des employés et des prestataires, et à des pratiques culturellement adaptées avec les nourrissons, les jeunes enfants et les personnes prenant soin d'eux. La téléconsultation a inclus une consultation de cas, une supervision de réflexion individuelle et de groupe, et des soutiens/références de collaboration. Durant la période d'évaluation de 18 mois, 1568 prestataires uniques se sont engagés soit dans une formation ou des services de téléconsultation, avec une moyenne de 9% de croissance chez les nouveaux prestataires chaque mois, avec une représentation de tous les secteurs professionnels et les comtés de l'état. Ce programme démontre la fiabilité et le besoin de programmes de formation et de téléconsultations au niveau de l'état afin d'aider à remplir les besoins des prestataires qui travaillent et soutiennent les jeunes enfants et les personnes prenant soin d'eux.
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Consulta Remota , Lactente , Criança , Humanos , Pré-Escolar , Estados Unidos , Desenvolvimento de Programas , Estudos de Viabilidade , Saúde Mental , Pais/psicologiaRESUMO
The clinical investigation of psychedelic medicines has blossomed over the last 5 years. Data from a Phase 3 industry trial and a multicenter Phase 2 industry trial, in addition to multiple early phase investigator-initiated and industry trials, have now been published in peer-reviewed journals. This narrative review summarizes both the recent data and the current clinical trials that are being conducted with various classes of "psyche-manifesting" substances, which may prove beneficial in the treatment of a broad range of conditions. Methodological considerations, unique challenges, and next steps for research are discussed in keeping with the uniquely "experiential" nature of these therapies.
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Alucinógenos , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Estudos Multicêntricos como AssuntoRESUMO
Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where combinations of modifications specify unique downstream functions, is widely accepted and can be demonstrated in vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognize trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me2/3 during mitosis. We find that H3T3ph anti-correlates with adjacent H3K4me2/3 in cells, and that the PHD domain of TAF3 can bind H3K4me2/3 in isolated mitotic chromatin despite the presence of H3T3ph. Unlike in vitro, H3K4 readers are still displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.
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Histonas , Fatores de Transcrição , Histonas/metabolismo , Fosforilação , Fatores de Transcrição/metabolismo , Leitura , Cromossomos/genética , Cromossomos/metabolismo , Mitose/genéticaRESUMO
P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human-mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were defined on aligned reference CT and serial SPECT images. Organs with the highest estimated dose values (mSv/MBq) for FF-21101(111In) were the lungs (0.840), spleen (0.816), liver (0.751), kidneys (0.629), and heart wall (0.451); and for FF-21101(90Y) dose values were: lungs (10.49), spleen (8.21), kidneys (5.92), liver (5.46), and heart wall (2.61). FF-21101(111In) exhibits favorable biodistribution in cynomolgus macaques and estimated human dosimetric characteristics. Data obtained in this study were used to support the filing of an investigational new drug application with the FDA for a Phase I clinical trial.
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The neurovascular system forms the interface between the tissue of the central nervous system (CNS) and circulating blood. It plays a critical role in regulating movement of ions, small molecules, and cellular regulators into and out of brain tissue and in sustaining brain health. The neurovascular unit (NVU), the cells that form the structural and functional link between cells of the brain and the vasculature, maintains the blood-brain interface (BBI), controls cerebral blood flow, and surveils for injury. The neurovascular system is dynamic; it undergoes tight regulation of biochemical and cellular interactions to balance and support brain function. Development of an intrinsic circadian clock enables the NVU to anticipate rhythmic changes in brain activity and body physiology that occur over the day-night cycle. The development of circadian neurovascular function involves multiple cell types. We address the functional aspects of the circadian clock in the components of the NVU and their effects in regulating neurovascular physiology, including BBI permeability, cerebral blood flow, and inflammation. Disrupting the circadian clock impairs a number of physiological processes associated with the NVU, many of which are correlated with an increased risk of dysfunction and disease. Consequently, understanding the cell biology and physiology of the NVU is critical to diminishing consequences of impaired neurovascular function, including cerebral bleeding and neurodegeneration.
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This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .
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N-Metil-3,4-Metilenodioxianfetamina , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Resultado do Tratamento , Terapia Combinada , Método Duplo-CegoRESUMO
IMPORTANCE: CD34+ hematopoietic progenitor cells (HPCs) are an important cellular reservoir for latent human cytomegalovirus (HCMV). Several HCMV genes are expressed during latency that are involved with the maintenance of the viral genome in CD34+ HPC. However, little is known about the process of viral reactivation in these cells. Here, we describe a viral protein, pUL8, and its interaction and stabilization with members of the Wnt/ß-catenin pathway as an important component of viral reactivation. We further define that pUL8 and ß-catenin interact with DVL2 via a PDZ-binding domain, and loss of UL8 interaction with ß-catenin-DVL2 restricts viral reactivation. Our findings will be instrumental in understanding the molecular processes involved in HCMV reactivation in order to design new antiviral therapeutics.