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Tree growth and longevity trade-offs fundamentally shape the terrestrial carbon balance. Yet, we lack a unified understanding of how such trade-offs vary across the world's forests. By mapping life history traits for a wide range of species across the Americas, we reveal considerable variation in life expectancies from 10 centimeters in diameter (ranging from 1.3 to 3195 years) and show that the pace of life for trees can be accurately classified into four demographic functional types. We found emergent patterns in the strength of trade-offs between growth and longevity across a temperature gradient. Furthermore, we show that the diversity of life history traits varies predictably across forest biomes, giving rise to a positive relationship between trait diversity and productivity. Our pan-latitudinal assessment provides new insights into the demographic mechanisms that govern the carbon turnover rate across forest biomes.
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Ciclo do Carbono , Florestas , Características de História de Vida , Árvores , Carbono/metabolismo , Longevidade , Temperatura , Árvores/crescimento & desenvolvimentoRESUMO
Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model. Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice assessed with a multiplex assay, and tumor molecular biology and histology characterized with Western blotting and H&E histological staining. Results: WT tumor-bearing mice had increased levels of plasma SAA compared to wild-type control mice, while SAADKO control and tumor-bearing mice presented with lower levels of SAA in their plasma. SAADKO tumor-bearing mice also displayed significantly lower concentrations of systemic inflammatory markers. Tumors from SAADKO mice overall had lower levels of SAA compared to tumors from wild-type mice, decreased apoptosis and inflammasome signaling, and little to no tumor necrosis. Conclusions: We demonstrated that systemic SAA1/2 stimulates the activation of the NLRP3 inflammasome in breast tumors, leading to the production of pro-inflammatory cytokines. This, in turn, promoted apoptosis and tumor necrosis but did not significantly impact tumor growth or histological grading.
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The nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS, and highlight exciting new discoveries about their contributions to CNS development, maintenance, and plasticity.
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The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFß) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.
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Endometriose , Endométrio , Análise de Célula Única , Humanos , Feminino , Endométrio/metabolismo , Endométrio/citologia , Análise de Célula Única/métodos , Endometriose/genética , Endometriose/patologia , Endometriose/metabolismo , Transcriptoma , Células Estromais/metabolismo , Células Epiteliais/metabolismo , Estudo de Associação Genômica Ampla , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Perfilação da Expressão Gênica/métodos , Transdução de Sinais/genética , Fibroblastos/metabolismoRESUMO
BACKGROUND: Concern about clozapine-associated neutropenia contributes to clozapine's underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking. METHODS: Patients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC's < 2000 cells/µL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored. RESULTS: 974 received clozapine and had ANC's available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]). DISCUSSION: To our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.
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Antipsicóticos , Clozapina , Neutropenia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antipsicóticos/efeitos adversos , Negro ou Afro-Americano , Clozapina/efeitos adversos , Sistema do Grupo Sanguíneo Duffy/genética , Contagem de Leucócitos , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Esquizofrenia/tratamento farmacológico , Fatores de Tempo , Estados Unidos , BrancosRESUMO
Non-surgical (reversible) male contraception methods, when approved for general clinical application, should be made available to all interested men aged 18 50 years in good general health regardless of their semen parameters. In the preliminary workup, a complete personal and family history aimed at identifying specific conditions that may potentially increase the risks for adverse effects (associated with testosterone replacement) is advisable but a general or andrological examination is not required, unless indicated by the history. Baseline body weight, blood pressure and haemoglobin should be recorded for the purpose of future monitoring. While risks and benefits of vasectomy have been well established, appropriately nuanced patient counselling and assessment are essential for ensuring a satisfactory outcome of vasectomy.
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Vasectomia , Humanos , Masculino , Vasectomia/efeitos adversos , Pessoa de Meia-Idade , Anticoncepção/métodos , Anticoncepção/efeitos adversos , Adulto , Testosterona/uso terapêutico , Testosterona/efeitos adversos , Testosterona/sangue , Anticoncepcionais Masculinos/uso terapêutico , Anticoncepcionais Masculinos/efeitos adversos , AdolescenteRESUMO
Transformers have achieved remarkable performance in multivariate time series(MTS) forecasting due to their capability to capture long-term dependencies. However, the canonical attention mechanism has two key limitations: (1) its quadratic time complexity limits the sequence length, and (2) it generates future values from the entire historical sequence. To address this, we propose a Dozer Attention mechanism consisting of three sparse components: (1) Local, each query exclusively attends to keys within a localized window of neighboring time steps. (2) Stride, enables each query to attend to keys at predefined intervals. (3) Vary, allows queries to selectively attend to keys from a subset of the historical sequence. Notably, the size of this subset dynamically expands as forecasting horizons extend. Those three components are designed to capture essential attributes of MTS data, including locality, seasonality, and global temporal dependencies. Additionally, we present the Dozerformer Framework, incorporating the Dozer Attention mechanism for the MTS forecasting task. We evaluated the proposed Dozerformer framework with recent state-of-the-art methods on nine benchmark datasets and confirmed its superior performance. The experimental results indicate that excluding a subset of historical time steps from the time series forecasting process does not compromise accuracy while significantly improving efficiency. Code is available at https://github.com/GRYGY1215/Dozerformer.
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ABSTRACT: Ensuring students are prepared for the Physician Assistant National Certification Exam (PANCE) is an institutional priority for all physician assistant programs. While many factors predicting PANCE performance have been investigated, exploration and discussions of interventions to improve PANCE performance are limited. Repeated exposure to board-style questions has been shown to improve board scores in similar populations. Currently, existing question banks cannot be used to generate secure summative examinations, and commercial question banks may perpetuate inequitable access among physician assistant (PA) students. To address this issue, the University of Oklahoma Physician Assistant program used a community of practice model to create a mock board exam writing group. The group was created to facilitate the development of 9 PANCE-style exams to bolster students' clinical preparedness and PANCE performance. These writing groups also provided a platform for junior faculty to receive feedback and guidance from senior colleagues, thus facilitating and promoting mentorship. This article highlights the potential benefits of mock board exam writing groups in PA education and provides insight into their development and implementation.
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Currículo , Avaliação Educacional , Assistentes Médicos , Redação , Assistentes Médicos/educação , Humanos , Redação/normas , Avaliação Educacional/métodos , Mentores , Certificação/normas , Docentes/normasRESUMO
AIM: To explore the use of histogram features on noninvasive arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in differentiating isocitrate dehydrogenase mutant-type (IDH-mut) from isocitrate dehydrogenase wild-type (IDH-wt) gliomas, and lower-grade gliomas (LGGs) from glioblastomas. MATERIAL AND METHODS: This retrospective study included 131 patients who underwent ASL MRI and anatomic MRI. Cerebral blood flow (CBF) maps were calculated, from which 10 histogram features describing the CBF distribution were extracted within the tumor region. Correlation analysis was performed to determine the correlations between histogram features as well as tumor grades and IDH genotypes. The independent t-test and Fisher's exact test were used to determine differences in the extracted histogram features, age at diagnosis, and sex in different glioma subtypes. Multivariate binary logistic regression analysis was performed, and diagnostic performances were evaluated with the receiver operating characteristic curves. RESULTS: CBF histogram features were significantly correlated with tumor grades and IDH genotypes. These features can effectively differentiate LGGs from glioblastomas, and IDH-mut from IDH-wt gliomas. The area under the receiving operating characteristic curve of the model calculated using combined CBF 30th percentile and age at diagnosis in differentiating LGGs from glioblastomas was 0.73. Integrating age at diagnosis and CBF 10th percentile could be more effective in differentiating IDH-mut from IDH-wt gliomas. Furthermore, the combined model had a better area under the receiving operating characteristic curve at 0.856 (sensitivity: 84.4%, specificity: 82.9%). CONCLUSION: The histogram features on ASL were significantly correlated with tumor grade and IDH genotypes. Moreover, the use of these features could effectively differentiate glioma subtypes. The combined application of age at diagnosis and perfusion histogram features resulted in a more comprehensive identification of tumor subtypes. Therefore, ASL can be a noninvasive tool for the pre-surgical evaluation of gliomas.
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Neoplasias Encefálicas , Genótipo , Glioma , Isocitrato Desidrogenase , Marcadores de Spin , Humanos , Isocitrato Desidrogenase/genética , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Feminino , Masculino , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Circulação Cerebrovascular , Imageamento por Ressonância Magnética/métodos , Adulto Jovem , Mutação , Gradação de Tumores , Angiografia por Ressonância Magnética/métodosRESUMO
Empirical evidence for a low normal or reference interval for serum prolactin (PRL) is lacking for men, while the implications of very low PRL levels for human health have never been studied. A clinical state of "PRL deficiency" has not been defined except in relation to lactation. Using data from the European Male Ageing Study (EMAS), we analyzed the distribution of PRL in 3,369 community-dwelling European men, aged 40-80 years at phase-1 and free from acute illnesses. In total, 2,948 and 2,644 PRL samples were collected during phase-1 and phase-2 (3 to 5.7 years later). All samples were analysed in the same centre with the same assay. After excluding individuals with known pituitary diseases, PRL ≥ 35 ng/ml, and PRL-altering drugs including antipsychotic agents, selective serotonin reuptake inhibitors, or dopamine agonists, 5,086 data points (2,845 in phase-1 and 2,241 in phase-2) were available for analysis. The results showed that PRL declined minimally with age (slope = -0.02) and did not correlate with BMI. The positively skewed PRL distribution was log-transformed to a symmetrical distribution (skewness reduced from 13.3 to 0.015). Using two-sigma empirical rule (2[]SD about the mean), a threshold at 2.5% of the lower end of the distribution was shown to correspond to a PRL value of 2.98ng/ml. With reference to individuals with PRL levels of 5-34.9 ng/ml (event rate = 6.3%), the adjusted risk of developing type 2 diabetes increased progressively in those with PRL levels of 3-4.9 ng/ml: event rate = 9.3%, OR (95% CI) 1.59 (0.93-2.71), and more so with PRL levels of 0.3-2.9 ng/ml: event rate = 22.7%, OR 5.45 (1.78-16.62). There was also an increasing trend in prediabetes and diabetes based on fasting blood glucose levels was observed with lower categories of PRL. However, PRL levels were not associated with cancer, cardiovascular diseases, depressive symptoms or mortality. Our findings suggest that a PRL level below 3 ng/ml (64 mlU/l) significantly identifies European men with a clinically-important outcome (of type 2 diabetes), offering a lower reference-value for research and clinical practice.
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Purpose: To test the hypothesis that (C-C motif) ligand 2 (CCL2) and CCL3 impact retinal function decline and inflammation during Staphylococcus aureus endophthalmitis. Methods: Experimental endophthalmitis was initiated by intravitreal injection of 5000 colony-forming units of S. aureus into the eyes of C57BL/6J, CCL2-/-, or CCL3-/- mice. At 12 and 24 hours post-infection, retinal function, bacterial load, and myeloperoxidase levels were quantified. Results: During S. aureus endophthalmitis, we observed a significant improvement in retinal function in CCL2-/- mice relative to C57BL/6J mice at 12 hours but not at 24 hours. In CCL3-/- mice, retinal function was significantly improved relative to C57BL/6J mice at 12 and 24 hours. The absence of CCL2 did not alter intraocular S. aureus intraocular concentrations. However, CCL3-/- mice had significantly lower intraocular S. aureus at 12 hours but not at 24 hours. No difference in myeloperoxidase levels was observed between C57BL/6J and CCL2-/- mice at 12 hours. CCL3-/- mice had almost no myeloperoxidase at 12 hours. At 24 hours, increased myeloperoxidase was observed in CCL2-/- and CCL3-/- mice relative to C57BL/6J mice. Conclusions: Although the absence of CCL2 resulted in improved retinal function retention at 12 hours, CCL3 deficiency resulted in improved retinal function at 12 and 24 hours. CCL3 deficiency, but not CCL2 deficiency, resulted in almost no inflammation at 12 hours. However, at 24 hours, the absence of CCL2 or CCL3 resulted in significantly increased inflammation. These results suggest that, although both CCL2 and CCL3 impact intraocular infection outcomes, CCL3 may have a more significant impact in S. aureus endophthalmitis.
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Quimiocina CCL2 , Quimiocina CCL3 , Modelos Animais de Doenças , Endoftalmite , Infecções Oculares Bacterianas , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas , Staphylococcus aureus , Animais , Endoftalmite/microbiologia , Endoftalmite/metabolismo , Camundongos , Infecções Estafilocócicas/microbiologia , Infecções Oculares Bacterianas/microbiologia , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Camundongos Knockout , Peroxidase/metabolismo , Retina/metabolismo , Retina/microbiologia , EletrorretinografiaRESUMO
BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
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Doenças Cardiovasculares , Causas de Morte , Di-Hidrotestosterona , Estradiol , Hormônio Luteinizante , Globulina de Ligação a Hormônio Sexual , Testosterona , Humanos , Masculino , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Testosterona/sangue , Globulina de Ligação a Hormônio Sexual/análise , Globulina de Ligação a Hormônio Sexual/metabolismo , Estradiol/sangue , Hormônio Luteinizante/sangue , Di-Hidrotestosterona/sangue , Incidência , Fatores de Risco , Idoso , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND AIMS: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of Serum Amyloid A (SAA) significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice. METHODS: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end of the study. Mice with at least a 25% increase in the luminal diameter of the abdominal aorta after 4 weeks of AngII infusion were stratified into 2 groups. The first group received a control antisense oligonucleotide (Ctr ASO), and the second group received ASO that suppresses SAA (SAA-ASO) until the end of the study. RESULTS: Plasma SAA levels were significantly reduced by the SAA ASO treatment. While mice that received the control ASO had continued aortic dilation throughout the AngII infusion periods, the mice that received SAA-ASO had a significant reduction in the progression of aortic dilation, which was associated with significant reductions in matrix metalloprotease activities, decreased macrophage infiltration and decreased elastin breaks in the abdominal aortas. CONCLUSIONS: We demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from the progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.
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Angiotensina II , Aneurisma da Aorta Abdominal , Humanos , Masculino , Animais , Camundongos , Angiotensina II/farmacologia , Proteína Amiloide A Sérica/genética , Oligonucleotídeos Antissenso/uso terapêutico , Camundongos Endogâmicos C57BL , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/prevenção & controle , Aorta Abdominal , Obesidade , Modelos Animais de Doenças , Camundongos Knockout , Apolipoproteínas ERESUMO
Proton exchange underpins essential mechanisms in diverse MR imaging contrasts. Omega plots have proven effective in mapping proton exchange rates (kex) in live human brains, enabling the differentiation of MS lesion activities and characterization of ischemic stroke. However, Omega plots require extended saturation durations (typically 5 to 10 s), resulting in high specific absorption rates (SAR) that can hinder clinical feasibility. In this study, we introduce a novel kex mapping approach, named induced Saturation Transfer Recovery Steady-States (iSTRESS). iSTRESS integrates an excitation flip angle pulse prior to chemical exchange saturation transfer (CEST) saturation, effectively aligning the magnetization with its steady-state value. This innovation reduces saturation times and mitigates SAR concerns. The formula for iSTRESS-based kex quantification was derived theoretically, involving two measurements with distinct excitation flip angles and saturation B1 values. Bloch-McConnell simulations confirmed that iSTRESS-based kex values closely matched input values (R2 > 0.99). An iSTRESS MRI sequence was implemented on a 9.4 T preclinical MRI, imaging protein phantoms with pH values ranging from 6.2 to 7.4 (n = 4). Z-spectra were acquired using excitation flip angles of 30° and 60°, followed by CEST saturation at powers of 30 and 120 Hz respectively, with a total saturation time of <1 s, resulting in two iSTRESS states for kex mapping. kex maps derived from the phantom study exhibited a linear correlation (R2 > 0.99) with Omega plot results. The developed iSTRESS method allows for kex quantification with significantly reduced saturation times, effectively minimizing SAR concerns.
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Imageamento por Ressonância Magnética , Prótons , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Concentração de Íons de Hidrogênio , Meios de Contraste , Imagens de FantasmasAssuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Carcinoma Basocelular/cirurgia , Carcinoma Basocelular/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Feminino , Masculino , Fatores Sexuais , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Cirurgia de Mohs , Idoso de 80 Anos ou maisRESUMO
Human primordial germ cells (hPGCs), the precursors of eggs and sperm, start their complex development shortly after specification and during their migration to the primitive gonads. Here, we describe protocols for specifying hPGC-like cells (hPGCLCs) from resetting precursors and progressing them with the support of human hindgut organoids. Resetting hPGCLCs (rhPGCLCs) are specified from human embryonic stem cells (hESCs) transitioning from the primed into the naive state of pluripotency. Hindgut organoids are also derived from hESCs after a sequential differentiation into a posterior endoderm/hindgut fate. Both rhPGCLCs and hindgut organoids are combined and co-cultured for 25 d. The entire procedure takes ~1.5 months and can be successfully implemented by a doctoral or graduate student with basic skills and experience in hESC cultures. The co-culture system supports the progression of rhPGCLCs at a developmental timing analogous to that observed in vivo. Compared with previously developed hPGCLC progression protocols, which depend on co-cultures with mouse embryonic gonadal tissue, our co-culture system represents a developmentally relevant model closer to the environment that hPGCs first encounter after specification. Together with the potential for investigations of events during hPGC specification and early development, these protocols provide a practical approach to designing efficient models for in vitro gametogenesis. Notably, the rhPGCLC-hindgut co-culture system can also be adapted to study failings in hPGC migration, which are associated with the etiology of some forms of infertility and germ cell tumors.
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Endoderma , Sêmen , Humanos , Masculino , Animais , Camundongos , Células Germinativas , Diferenciação Celular , OrganoidesRESUMO
The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural tube, the embryonic precursor to the human nervous system. Historically, studies of neural tube patterning have relied on animal models to uncover underlying principles. Recently, models of neurodevelopment based on human pluripotent stem cells, including neural organoids1-5 and bioengineered neural tube development models6-10, have emerged. However, such models fail to recapitulate neural patterning along both rostral-caudal and dorsal-ventral axes in a three-dimensional tubular geometry, a hallmark of neural tube development. Here we report a human pluripotent stem cell-based, microfluidic neural tube-like structure, the development of which recapitulates several crucial aspects of neural patterning in brain and spinal cord regions and along rostral-caudal and dorsal-ventral axes. This structure was utilized for studying neuronal lineage development, which revealed pre-patterning of axial identities of neural crest progenitors and functional roles of neuromesodermal progenitors and the caudal gene CDX2 in spinal cord and trunk neural crest development. We further developed dorsal-ventral patterned microfluidic forebrain-like structures with spatially segregated dorsal and ventral regions and layered apicobasal cellular organizations that mimic development of the human forebrain pallium and subpallium, respectively. Together, these microfluidics-based neurodevelopment models provide three-dimensional lumenal tissue architectures with in vivo-like spatiotemporal cell differentiation and organization, which will facilitate the study of human neurodevelopment and disease.
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Padronização Corporal , Microfluídica , Tubo Neural , Humanos , Técnicas de Cultura de Células em Três Dimensões , Diferenciação Celular , Crista Neural/citologia , Crista Neural/embriologia , Tubo Neural/citologia , Tubo Neural/embriologia , Células-Tronco Pluripotentes/citologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Medula Espinal/citologia , Medula Espinal/embriologiaRESUMO
Multivariate time series forecasting is a critical problem in many real-world scenarios. Recent advances in deep learning have significantly enhanced the ability to tackle such problems. However, a primary challenge in time series forecasting comes from the imbalanced time series data that include extreme events. Despite being a small fraction of the data instances, extreme events can have a negative impact on forecasting as they deviate from the majority. However, many recent time series forecasting methods neglect this issue, leading to suboptimal performance. To address these challenges, we introduce a novel model, the Extreme Event Adaptive Gated Recurrent Unit (eGRU), tailored explicitly for forecasting tasks. The eGRU is designed to effectively learn both normal and extreme event patterns within time series data. Furthermore, we introduce a time series data segmentation technique that divides the input sequence into segments, each comprising multiple time steps. This segmentation empowers the eGRU to capture data patterns at different time step resolutions while simultaneously reducing the overall input length. We conducted comprehensive experiments on four real-world benchmark datasets to evaluate the eGRU's performance. Our results showcase its superiority over vanilla RNNs, LSTMs, GRUs, and other state-of-the-art RNN variants in multivariate time series forecasting. Additionally, we conducted ablation studies to demonstrate the consistently superior performance of eGRU in generating accurate forecasts while incorporating a diverse range of labeling results.
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This study has explored the DSC, UV-Vis absorption spectroscopy, gamma ray and neutron shielding properties of Bi2O3-B2O3-MnO2: ZrO2 glasses. It demonstrates a unique approach to photon shielding analysis using JENDL/PD-2016 photonuclear data and employs a validated spherical neutron model for neutron shielding. Five transparent glasses were prepared with the chemical composition (in mol%) of 29Bi2O3-70B2O3-(1-x)MnO2: xZrO2, and labeled as MZ0.00 (for x = 0), MZ0.25 (for x = 0.25), MZ0.50 (for x = 0.5), MZ0.75 (for x = 0.75) and MZ1.00 (for x = 1). The glass ceramic nature of the samples has been characterized by DTA thermograms. The glass forming ability parameters (Kgl, S & H) were found to be highest for the sample MZ1.00. The UV-Visible optical absorption spectra have been interpreted, and hence the cut-off wavelength (λcut-off) and optical band gap (Eo) were evaluated. The absorption spectra have revealed the co-existence of manganese ions in three stable valence states Mn4+, Mn3+ and Mn2+ in the samples. When ZrO2 nanoparticles were added in the composition up to x = 0.50 mol%, the red shift in the cut-off wavelength (λcut-off) with gradual shrinkage in optical band gap (Eo) has been observed. Also, the linear and non-linear optical parameters viz., refractive index (no), non-linear refractive index (n2), linear optical susceptibility (χ(1)) and non-linear optical susceptibility (χ(3)) have been evaluated. These parameters showcased that B-O, Bi-O, Mn-O, Zr-O, etc. bonds could be strengthened by subsequent reduction of polarization of the trivalent ions (B3+ ions, Bi3+ ions and Mn3+ ions) in the glass system at higher concentrations of ZrO2. Photoatomic and photonuclear attenuation studies portrayed that the sample MZ0.50 has the lowest photon shielding capability. The fast neutron effective removal cross section (ΣR) was observed to be the highest for the sample MZ1.00. Thus, these glasses can be used to design the thermally stable transparent glasses, tunable optical elements, and radiation shielding materials.
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Dominance of neotropical tree communities by a few species is widely documented, but dominant trees show a variety of distributional patterns still poorly understood. Here, we used 503 forest inventory plots (93,719 individuals ≥2.5 cm diameter, 2609 species) to explore the relationships between local abundance, regional frequency and spatial aggregation of dominant species in four main habitat types in western Amazonia. Although the abundance-occupancy relationship is positive for the full dataset, we found that among dominant Amazonian tree species, there is a strong negative relationship between local abundance and regional frequency and/or spatial aggregation across habitat types. Our findings suggest an ecological trade-off whereby dominant species can be locally abundant (local dominants) or regionally widespread (widespread dominants), but rarely both (oligarchs). Given the importance of dominant species as drivers of diversity and ecosystem functioning, unravelling different dominance patterns is a research priority to direct conservation efforts in Amazonian forests.