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1.
bioRxiv ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39005353

RESUMO

The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

2.
Science ; 385(6704): 53-56, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38843354

RESUMO

The persistence of voltage-switchable collective electronic phenomena down to the atomic scale has extensive implications for area- and energy-efficient electronics, especially in emerging nonvolatile memory technology. We investigate the performance of a ferroelectric field-effect transistor (FeFET) based on sliding ferroelectricity in bilayer boron nitride at room temperature. Sliding ferroelectricity represents a different form of atomically thin two-dimensional (2D) ferroelectrics, characterized by the switching of out-of-plane polarization through interlayer sliding motion. We examined the FeFET device employing monolayer graphene as the channel layer, which demonstrated ultrafast switching speeds on the nanosecond scale and high endurance exceeding 1011 switching cycles, comparable to state-of-the-art FeFET devices. These characteristics highlight the potential of 2D sliding ferroelectrics for inspiring next-generation nonvolatile memory technology.

3.
bioRxiv ; 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38854134

RESUMO

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

5.
Cell Rep Med ; 5(4): 101490, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38574736

RESUMO

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.


Assuntos
Esclerose Múltipla , Animais , Humanos , Esclerose Múltipla/patologia , Retina/patologia , Neurônios/patologia , Modelos Animais , Atrofia/patologia
6.
Phys Rev Lett ; 132(11): 116601, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38563950

RESUMO

Ultrathin bismuth exhibits rich physics including strong spin-orbit coupling, ferroelectricity, nontrivial topology, and light-induced structural dynamics. We use ab initio calculations to show that light can induce structural transitions to four transient phases in bismuth monolayers. These light-induced phases exhibit nontrivial topological character, which we illustrate using the recently introduced concept of spin bands and spin-resolved Wilson loops. Specifically, we find that the topology changes via the closing of the electron and spin band gaps during photoinduced structural phase transitions, leading to distinct edge states. Our study provides strategies to tailor electronic and spin topology via ultrafast control of photoexcited carriers and associated structural dynamics.

7.
J Immunother ; 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38664936

RESUMO

SUMMARY: Standard of care treatment for metastatic cutaneous adnexal carcinomas is not well established. In this case report, we highlight the successful use of anti-programmed cell death protein 1 (anti-PD-1) therapy in treating a patient with low tumor mutation burden, microsatellite stable, high programmed death-ligand 1 (PD-L1) gene expression, metastatic primary cutaneous adnexal carcinoma with significant radiographic, and circulating tumor DNA response with durable benefit. Immune checkpoint inhibitors hold promise as a future treatment option in rare instances of metastatic disease from primary skin adnexal carcinoma. Further studies are needed to identify better immune checkpoint inhibitor predictive biomarkers for rare, advanced-stage non-melanoma skin cancers.

8.
Work ; 77(4): 1285-1294, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38489209

RESUMO

BACKGROUND: During periods of high-volume vigorous exercise, United States Marine Corps recruits often experience musculoskeletal injuries. While the program of instruction (POI) for basic training is a defined training volume, the total workload of boot camp, including movements around the base, is unknown. OBJECTIVE: The present study aimed to quantify the daily total workload, energy expenditure, and sleep during basic recruit training at Marine Corps Recruit Depot (MCRD) San Diego. METHODS: Eighty-four male recruits from MCRD San Diego wore wrist wearable physiological monitors to capture their complete workload (mileage from steps), energy expenditure, and sleep throughout the 10-week boot camp. RESULTS: Marine recruits traveled an average of 11.5±3.4 miles per day (M±SD), expended 4105±823 kcal per day, and slept an average of 5 : 48±1 : 06 hours and minutes per night. While the POI designates a total of 46.3 miles of running and hiking, the actual daily average miles yielded approximately 657.6±107.2 miles over the 10-week boot camp. CONCLUSION: Recruit training requires high physical demand and time under tension due to the cumulative volume of movements around base in addition to the POI planned physical training.


Assuntos
Militares , Carga de Trabalho , Humanos , Masculino , Estados Unidos , Exercício Físico , Metabolismo Energético
10.
J Sleep Res ; : e14161, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38308529

RESUMO

The detrimental effects of sleep loss on overall decision-making have been well described. Due to the complex nature of decisions, there remains a need for studies to identify specific mechanisms of decision-making vulnerable to sleep loss. Bayesian perspectives of decision-making posit judgement formation during decision-making occurs via a process of integrating knowledge gleaned from past experiences (priors) with new information from current observations (likelihoods). We investigated the effects of sleep loss on the ability to integrate multiple sources of information during decision-making by reporting results from two experiments: the first implementing both sleep restriction (SR) and total sleep deprivation (TSD) protocols, and the second implementing an SR protocol. In both experiments, participants were administered the Bayes Decisions Task on which optimal performance requires the integration of Bayesian prior and likelihood information. Participants in Experiment 1 showed reduced reliance on both information sources after SR, while no significant change was observed after TSD. Participants in Experiment 2 showed reduced reliance on likelihood after SR, especially during morning testing sessions. No accuracy-related impairments resulting from SR and TSD were observed in both experiments. Our findings show SR affects decision-making through altering the way individuals integrate available sources of information. Additionally, the ability to integrate information during SR may be influenced by time of day. Broadly, our findings carry implications for working professionals who are required to make high-stakes decisions on the job, yet consistently receive insufficient sleep due to work schedule demands.

11.
Emotion ; 24(3): 894-911, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37956091

RESUMO

The valence of an individual's emotional response to an event is often thought to depend on their prior expectations for the event: better-than-expected outcomes produce positive affect and worse-than-expected outcomes produce negative affect. In recent years, this hypothesis has been instantiated within influential computational models of subjective affect that assume the valence of affect is driven by reward prediction errors. However, there remain a number of open questions regarding this association. In this project, we investigated the moderating effects of outcome valence and decision context (Experiment 1: free vs. forced choices; Experiment 2: trials with vs. trials without counterfactual feedback) on the effects of reward prediction errors on subjective affect. We conducted two online experiments (N = 300 in total) of general-population samples recruited via Prolific to complete a risky decision-making task with an embedded high-resolution sampling of subjective affect. Hierarchical Bayesian computational modeling revealed that both outcome amount and reward prediction errors influenced subjective affect, but that the effects of reward prediction errors were moderated by both outcome valence and decision context. Specifically, we found evidence that only negative reward prediction errors (worse-than-expected outcomes) influenced subjective affect, with no significant effect of positive reward prediction errors (better-than-expected outcomes). Moreover, these effects were only apparent on trials in which participants made a choice freely (but not on forced-choice trials) and when counterfactual feedback was absent (but not when counterfactual feedback was present). These results deepen our understanding of the effects of reward prediction errors on subjective affect. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Tomada de Decisões , Recompensa , Humanos , Tomada de Decisões/fisiologia , Teorema de Bayes , Retroalimentação
13.
Brain Behav Immun ; 116: 349-361, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38142918

RESUMO

Maternal immune activation (MIA) during pregnancy increases the risk for the unborn foetus to develop neurodevelopmental conditions such as autism spectrum disorder and schizophrenia later in life. MIA mouse models recapitulate behavioural and biological phenotypes relevant to both conditions, and are valuable models to test novel treatment approaches. Selenium (Se) has potent anti-inflammatory properties suggesting it may be an effective prophylactic treatment against MIA. The aim of this study was to determine if Se supplementation during pregnancy can prevent adverse effects of MIA on offspring brain and behaviour in a mouse model. Selenium was administered via drinking water (1.5 ppm) to pregnant dams from gestational day (GD) 9 to birth, and MIA was induced at GD17 using polyinosinic:polycytidylic acid (poly-I:C, 20 mg/kg via intraperitoneal injection). Foetal placenta and brain cytokine levels were assessed using a Luminex assay and brain elemental nutrients assessed using inductively coupled plasma- mass spectrometry. Adult offspring were behaviourally assessed using a reinforcement learning paradigm, the three-chamber sociability test and the open field test. MIA elevated placental IL-1ß and IL-17, and Se supplementation successfully prevented this elevation. MIA caused an increase in foetal brain calcium, which was prevented by Se supplement. MIA caused in offspring a female-specific reduction in sociability, which was recovered by Se, and a male-specific reduction in social memory, which was not recovered by Se. Exposure to poly-I:C or selenium, but not both, reduced performance in the reinforcement learning task. Computational modelling indicated that this was predominantly due to increased exploratory behaviour, rather than reduced rate of learning the location of the food reward. This study demonstrates that while Se may be beneficial in ameliorating sociability deficits caused by MIA, it may have negative effects in other behavioural domains. Caution in the use of Se supplementation during pregnancy is therefore warranted.


Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Selênio , Camundongos , Animais , Feminino , Gravidez , Masculino , Humanos , Comportamento Animal/fisiologia , Selênio/farmacologia , Placenta , Modelos Animais de Doenças , Poli I-C/farmacologia , Suplementos Nutricionais
14.
J Sports Sci Med ; 22(4): 658-666, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38045749

RESUMO

Wearables are lightweight, portable technology devices that are traditionally used to monitor physical activity and workload as well as basic physiological parameters such as heart rate. However recent advances in monitors have enabled better algorithms for estimation of caloric expenditure from heart rate for use in weight loss as well as sport performance. can be used for estimating energy expenditure and nutritional demand. Recently, the military has adopted the use of personal wearables for utilization in field studies for ecological validity of training. With popularity of use, the need for validation of these devices for caloric estimates is needed to assist in work-rest cycles. Thus the purpose of this effort was to evaluate the Polar Grit X for energy expenditure (EE) for use in military training exercises. Polar Grit X Pro watches were worn by active-duty elite male operators (N = 16; age: 31.7 ± 5.0 years, height: 180.1 ± 6.2 cm, weight: 91.7 ± 9.4 kg). Metrics were measured against indirect calorimetry of a metabolic cart and heart rate via a Polar heart rate monitor chest strap while exercising on a treadmill. Participants each performed five 10-minute bouts of running at a self-selected speed and incline to maintain a heart rate within one of five heart rate zones, as ordered and defined by Polar. Polar Grit X Pro watch had a good to excellent interrater reliability to indirect calorimetry at estimating energy expenditure (ICC = 0.8, 95% CI = 0.61-0.89, F (74,17.3) = 11.76, p < 0.0001) and a fair to good interrater reliability in estimating macronutrient partitioning (ICC = 0.49, 95% CI = 0.3-0.65, F (74,74.54) = 2.98, p < 0.0001). There is a strong relationship between energy expenditure as estimated from the Polar Grit X Pro and measured through indirect calorimetry. The Polar Grit X Pro watch is a suitable tool for estimating energy expenditure in free-living participants in a field setting and at a range of exercise intensities.


Assuntos
Militares , Humanos , Masculino , Adulto , Projetos Piloto , Reprodutibilidade dos Testes , Exercício Físico/fisiologia , Metabolismo Energético/fisiologia
15.
PLoS Comput Biol ; 19(12): e1011707, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38127874

RESUMO

Positive and negative affective states are respectively associated with optimistic and pessimistic expectations regarding future reward. One mechanism that might underlie these affect-related expectation biases is attention to positive- versus negative-valence features (e.g., attending to the positive reviews of a restaurant versus its expensive price). Here we tested the effects of experimentally induced positive and negative affect on feature-based attention in 120 participants completing a compound-generalization task with eye-tracking. We found that participants' reward expectations for novel compound stimuli were modulated in an affect-congruent way: positive affect induction increased reward expectations for compounds, whereas negative affect induction decreased reward expectations. Computational modelling and eye-tracking analyses each revealed that these effects were driven by affect-congruent changes in participants' allocation of attention to high- versus low-value features of compounds. These results provide mechanistic insight into a process by which affect produces biases in generalized reward expectations.


Assuntos
Motivação , Pessimismo , Humanos , Emoções , Generalização Psicológica , Recompensa
16.
Ther Adv Urol ; 15: 17562872231206239, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37868369

RESUMO

Background: The ideal surgical approach for the management of varicocele in children and adolescents remains controversial. Several techniques are available including artery- or lymphatic-sparing with optical magnification (via open inguinal or sub-inguinal approach), laparoscopic, antegrade and retrograde embolization/sclerotherapy. Objectives: We aimed to appraise the clinical outcomes of these techniques in children and adolescents. Data Sources and Methods: A systematic review was conducted (1997-2023). Meta-analysis or proportional meta-analysis for non-comparative studies (Freeman-Tukey transformation) using the random effects model was conducted. Results are expressed as overall proportion % and 95% confidence interval (CI). Results: We identified 1910 studies; 632 duplicates were removed, 1278 were screened, 203 were reviewed and 56 were included, with 12 reporting on 2 different techniques (total of 68 data sets). Optical magnification via inguinal approach (498 cases): recurrence 2.5% (0.6-5.6), hydrocele 1.6% (0.47-3.4), testicular atrophy 1% (0.3-2.0), complications 1.1% (0.2-2.6); optical magnification via sub-inguinal approach (592 cases): recurrence 2.1% (0.7-4.4), hydrocele 1.26% (0.5-2.3), testicular atrophy 0.5% (0.1-1.3), complications 4% (1.0-8.8). Laparoscopic with mass-ligation/division (1943 cases): recurrence 2.9% (1.5-4.6), hydrocele 11.4% (8.3-14.9); complications 1.5% (0.6-2.9); laparoscopic with lymphatic-sparing (974 cases): recurrence 2.4% (1.5-3.5), hydrocele 1.2% (0.45-3.36), complications 1.2% (0.05-3.9); laparoscopic with artery-sparing (228 cases): recurrence 6.6% (2.3-12.9), hydrocele 6.5% (2.6-12.0). Antegrade embolization/sclerotherapy (403 cases): recurrence 7.6% (5.2-10.4), hydrocele 0.8% (0.17-1.9), technical failure 0.6% (0.1-1.6), complications 4.0% (2.3-6.1); retrograde embolization/sclerotherapy (509 cases): recurrence 6.9% (4.6-9.5), hydrocele 0.8% (0.05-2.5), technical failure 10.2% (4.6-17.6), and complications 4.8% (1.0-11.2). Conclusion: The recurrence rate varies between 2.1% and 7.6% and is higher with the embolization/sclerotherapy techniques. Post-operative hydrocele rate varies between 0.8% and 11.4% and is higher with the laparoscopic mass-ligation/division technique. Testicular atrophy has not been reported with the laparoscopic and embolization/sclerotherapy techniques. The retrograde embolization technique is associated with 10% technical failure (inability to complete the procedure). The laparoscopic lymphatic-sparing technique is characterized by the lowest recurrence rate, incidence of hydrocele and other complications, and no reports of testicular atrophy.

17.
Case Rep Pathol ; 2023: 2960965, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37822715

RESUMO

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) is the most common lymphoid malignancy in the Western world and classically presents as a rapidly enlarging nodal or extranodal mass. Cutaneous involvement by systemic DLBCL NOS is an infrequent clinical presentation, encountered in only 1.5-3.5% of cases, while disseminated cutaneous disease with multiple subcutaneous nodules at the time of diagnosis is unusual and can present a diagnostic challenge. The differential diagnosis when encountering a high-grade B-cell malignancy at a cutaneous site is broad and includes primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2), and other potential entities which must all be carefully considered before rendering a final diagnosis. In this report, we describe the case of a 69-year-old man who was seen at our hospital due to generalized weakness and was found to have multiple subcutaneous nodules representing disseminated DLBCL NOS. The case was complicated by concurrent monoclonal B-cell lymphocytosis involving the bone marrow.

18.
Artigo em Inglês | MEDLINE | ID: mdl-37754657

RESUMO

The In Conversation: Boundary, Spanners, Thinkers and Policy Actors Round Table Series provides a platform for researchers, policy actors, and implementation experts to elevate discussion on emerging issues, present new and upcoming research, and facilitate conversations around impacts and possible solutions. This brief report, on trees, climate change, and health, reflects a conversation between the authors of this paper, along with supporting literature. It explores the potential of green spaces and trees as a viable strategy to address climate change challenges and simultaneously improve population health, well-being, and health equity. In particular, it highlights the public health benefits of trees and green space, the challenges faced in urban areas, and opportunities for the protection, maintenance and regeneration of urban green space.


Assuntos
Planejamento de Cidades , Árvores , Humanos , Mudança Climática , Comunicação
19.
J Cutan Pathol ; 50(11): 963-970, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37649312

RESUMO

Pilomatricomas (PMs) are common benign adnexal tumors that show a predilection for the head and neck region and are characterized at the molecular level by activating mutations in the beta-catenin (CTNNB1) gene. Giant PMs are a rare histopathological variant, according to the World Health Organization, which are defined by a size greater than 4 cm and are reported to show upregulation of yes-associated protein compared to PMs of typical 1-3 cm size. We describe the case of a 67-year-old man with an 8 cm giant PM involving his temporal scalp, whose PM we characterized by 10X spatial gene expression analysis. This revealed five total transcriptomic clusters, including four distinct clusters within the giant PM, each with a unique transcriptional pattern of hair follicle-related factors, keratin gene expression, and beta-catenin pathway activity.


Assuntos
Doenças do Cabelo , Pilomatrixoma , Neoplasias Cutâneas , Masculino , Humanos , Idoso , Pilomatrixoma/patologia , beta Catenina/genética , beta Catenina/metabolismo , Transcriptoma , Doenças do Cabelo/patologia , Neoplasias Cutâneas/patologia , Perfilação da Expressão Gênica
20.
Nat Hum Behav ; 7(10): 1667-1681, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37414886

RESUMO

Although online samples have many advantages for psychiatric research, some potential pitfalls of this approach are not widely understood. Here we detail circumstances in which spurious correlations may arise between task behaviour and symptom scores. The problem arises because many psychiatric symptom surveys have asymmetric score distributions in the general population, meaning that careless responders on these surveys will show apparently elevated symptom levels. If these participants are similarly careless in their task performance, this may result in a spurious association between symptom scores and task behaviour. We demonstrate this pattern of results in two samples of participants recruited online (total N = 779) who performed one of two common cognitive tasks. False-positive rates for these spurious correlations increase with sample size, contrary to common assumptions. Excluding participants flagged for careless responding on surveys abolished the spurious correlations, but exclusion based on task performance alone was less effective.

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