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Background: Retrograde intrarenal surgery (RIRS) is the main treatments for upper urinary tract stones. The Ureteral Access Sheath (UAS) serves as a supplementary tool, facilitating direct kidney access during RIRS. High quality of evidence comparing tip bendable suction ureteral access sheath (S-UAS) with traditional UAS in RIRS for the treatment of renal and ureteral stones is lacking. The purpose of the study is to compare the efficacy and safety of S-UAS with traditional UAS in RIRS for the treatment of renal or ureteral stones ≤30 mm. Methods: An international, multicenter, and superiority randomized controlled trial included 320 intention-to-treat patients across 8 medical centers in China, the Philippines, Malaysia and Turkey from August 2023 to February 2024. The inclusion criteria were patients ≥18 years old with renal or ureteral stones ≤30 mm. RIRS was performed using either S-UAS or traditional UAS. The primary outcome was the immediately stone-free rate (SFR). Secondary outcomes included SFR 3 months after operation, operating time, hospital stay, auxiliary procedures, complications (using the Clavien-Dindo grading system), and improvement in the Quality of Life (QoL) score. Differences between proportions [risk difference (RD)]/means [mean difference (MD)] and 95% confidence intervals (CI) were presented. This study is registered at ClinicalTrials.gov: NCT05952635. Findings: The S-UAS group demonstrated a significantly higher immediately SFR (81.3% versus 49.4%; RD 31.9%; 95% CI 22.5%-41.7%; p = 0.004) compared to the traditional UAS group, as determined by the one-side superiority test. Additionally, the S-UAS group exhibited a higher SFR at 3 months post-operation (87.5% versus 70.0%; RD 17.5%; 95% CI 8.7%-26.3%; p < 0.001), lower postoperative fever rate (RD -11.9%; 95% CI -18.7% to -4.9%; p < 0.001), reduced use of stone baskets (RD -70.6%; 95% CI -77.8% to -63.5%; p < 0.001), and better QoL improvement (MD 7.25; 95% CI 2.21-12.29; p = 0.005). No statistically significant differences were observed in operation time, hospital stay, or the need for second-stage RIRS. Interpretation: In RIRS for upper urinary tract stones ≤30 mm, S-UAS exhibited superior performance compared to traditional UAS, demonstrating higher SFR, reduced postoperative fever rate, and improved QoL outcomes. S-UAS emerges as a prudent and advantageous alternative to traditional UAS for RIRS. Funding: National Natural Science Foundation of China and Guangdong Province, and Zhejiang Medicine and Health Program.
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Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder, where renal cell carcinoma (RCC) serves as a significant cause of mortality. We collected peripheral blood from 61 VHL-RCC patients and 31 healthy individuals, along with 19 paired RCC tumor and adjacent non-malignant samples. Using liquid chromatography-mass spectrometry, we identified 238 plasma and 241 tissue differentially abundant metabolites (DAMs), highlighting key pathways such as arginine and proline metabolism. The top 10 of the 23 DAMs, common to both plasma and tissue, were instrumental in constructing a high-performance diagnostic model. These DAMs demonstrated significant correlations with VHL gene mutation types. Cox regression analysis revealed that plasma levels of N2,N2-dimethylguanosine were associated with the timing of RCC onset in VHL patients, acting as an independent predictive factor. This study enhances diagnostic accuracy for this rare condition and opens new avenues for exploring metabolic mechanisms of the disease and potential therapeutic directions.
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Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
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Stomata play a crucial role in plants by controlling water status and responding to drought stress. However, simultaneously improving stomatal opening and drought tolerance has proven to be a significant challenge. To address this issue, we employed the OnGuard quantitative model, which accurately represents the mechanics and coordination of ion transporters in guard cells. With the guidance of OnGuard, we successfully engineered plants that overexpressed the main tonoplast Ca2+-ATPase gene, ACA11, which promotes stomatal opening and enhances plant growth. Surprisingly, these transgenic plants also exhibited improved drought tolerance due to reduced water loss through their stomata. Again, OnGuard assisted us in understanding the mechanism behind the unexpected stomatal behaviors observed in the ACA11 overexpressing plants. Our study revealed that the overexpression of ACA11 facilitated the accumulation of Ca2+ in the vacuole, thereby influencing Ca2+ storage and leading to an enhanced Ca2+ elevation in response to abscisic acid. This regulatory cascade finely tunes stomatal responses, ultimately leading to enhanced drought tolerance. Our findings underscore the importance of tonoplast Ca2+-ATPase in manipulating stomatal behavior and improving drought tolerance. Furthermore, these results highlight the diverse functions of tonoplast-localized ACA11 in response to different conditions, emphasizing its potential for future applications in plant enhancement.
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GPT-4, as the most advanced version of OpenAI's large language models, has attracted widespread attention, rapidly becoming an indispensable AI tool across various areas. This includes its exploration by scientists for diverse applications. Our study focused on assessing GPT-4's capabilities in generating text, tables, and diagrams for biomedical review papers. We also assessed the consistency in text generation by GPT-4, along with potential plagiarism issues when employing this model for the composition of scientific review papers. Based on the results, we suggest the development of enhanced functionalities in ChatGPT, aiming to meet the needs of the scientific community more effectively. This includes enhancements in uploaded document processing for reference materials, a deeper grasp of intricate biomedical concepts, more precise and efficient information distillation for table generation, and a further refined model specifically tailored for scientific diagram creation.
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A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
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In advanced batteries, interphases serve as the key component in stabilizing the electrolyte with reactive electrode materials far beyond thermodynamic equilibria. While an active interphase facilitates the transport of working ions, an inactive interphase obstructs ion flow, constituting the primary barrier to the realization of battery chemistries. Here, a successful transformation of a traditionally inactive passivating layer on Mg-metal anode, characteristic of Mg-metal batteries with typical carbonate electrolytes, into an active and robust interphase in the Li-metal scenario is presented. By further strategically designing magnesiated Li+ electrolytes, the in situ development of this resilient interphase on Li-metal anodes, imparting enduring stability to Li-metal batteries with nickel-rich cathodes is induced. It is identified that the strong affinity between Mg2+ and anions in magnesiated Li+ electrolytes assembles ionic clusters with a bias for reducibility, thereby catalyzing the creation of anion-derived interphases rich in inorganic constituents. The prevalence of ionic clusters induced by magnesiation of electrolytes has brought properties only available in high-concentration electrolytes, suggesting a fresh paradigm of tailing electrolytes for highly reversible LMBs.
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Porous copper (Cu) current collectors show promise in stabilizing Li metal anodes (LMAs). However, insufficient lithiophilicity of pure Cu and limited porosity in three-dimensional (3D) porous Cu structures led to an inefficient Li-Cu composite preparation and poor electrochemical performance of Li-Cu composite anodes. Herein, we propose a porous Cu-CuZn (DG-CCZ) host for Li composite anodes to tackle these issues. This architecture features a pore size distribution and lithiophilic-lithiophobic characteristics designed in a gradient distribution from the inside to the outside of the anode structure. This dual-gradient porous Cu-CuZn exhibits exceptional capillary wettability to molten Li and provides a high porosity of up to 66.05%. This design promotes preferential Li deposition in the interior of the porous structure during battery operation, effectively inhibiting Li dendrite formation. Consequently, all cell systems achieve significantly improved cycling stability, including Li half-cells, Li-Li symmetric cells, and Li-LFP full cells. When paired synergistically with the double-coated LiFePO4 cathode, the pouch cell configured with multiple electrodes demonstrates an impressive discharge capacity of 159.3 mAh g-1 at 1C. We believe this study can inspire the design of future 3D Li anodes with enhanced Li utilization efficiency and facilitate the development of future high-energy Li metal batteries.
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Ceria nanoparticles (CeO2 NPs) have become popular materials in biomedical and industrial fields due to their potential applications in anti-oxidation, cancer therapy, photocatalytic degradation of pollutants, sensors, etc. Many methods, including gas phase, solid phase, liquid phase, and the newly proposed green synthesis method, have been reported for the synthesis of CeO2 NPs. Due to the wide application of CeO2 NPs, concerns about their adverse impacts on human health have been raised. This review covers recent studies on the biomedical applications of CeO2 NPs, including their use in the treatment of various diseases (e.|g., Alzheimer's disease, ischemic stroke, retinal damage, chronic inflammation, and cancer). CeO2 NP toxicity is discussed in terms of the different systems of the human body (e.|g., cytotoxicity, genotoxicity, respiratory toxicity, neurotoxicity, and hepatotoxicity). This comprehensive review covers both fundamental discoveries and exploratory progress in CeO2 NP research that may lead to practical developments in the future.
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Cerio , Cerio/química , Cerio/toxicidad , Humanos , Animales , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/química , Neoplasias/tratamiento farmacológico , Enfermedad de Alzheimer , Nanopartículas/toxicidadRESUMEN
Climate change-induced drought is a major threat to agriculture. C4 crops have a higher water use efficiency (WUE) and better adaptability to drought than C3 crops due to their smaller stomatal morphology and faster response. However, our understanding of stomatal behaviours in both C3 and C4 Poaceae crops is limited by knowledge gaps in physical traits of guard cell (GC) and subsidiary cell (SC). We employed infrared gas exchange analysis and a stomatal assay to explore the relationship between GC/SC sizes and stomatal kinetics across diverse drought conditions in two C3 (wheat and barley) and three C4 (maize, sorghum and foxtail millet) upland Poaceae crops. Through statistical analyses, we proposed a GCSC-τ model to demonstrate how morphological differences affect stomatal kinetics in C4 Poaceae crops. Our findings reveal that morphological variations specifically correlate with stomatal kinetics in C4 Poaceae crops, but not in C3 ones. Subsequent modelling and experimental validation provide further evidence that GC/SC sizes significantly impact stomatal kinetics, which affects stomatal responses to different drought conditions and thereby WUE in C4 Poaceae crops. These findings emphasize the crucial advantage of GC/SC morphological characteristics and stomatal kinetics for the drought adaptability of C4 Poaceae crops, highlighting their potential as future climate-resilient crops.
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Adaptación Fisiológica , Tamaño de la Célula , Productos Agrícolas , Sequías , Grano Comestible , Estomas de Plantas , Estomas de Plantas/fisiología , Grano Comestible/fisiología , Cinética , Productos Agrícolas/fisiología , Modelos Biológicos , Agua/metabolismo , Agua/fisiologíaRESUMEN
Tetrahedral DNA nanostructure (TDN) is highly promising in developing electrochemical aptamer-based (E-AB) sensors for biomolecular detection, owing to its inherit programmability, spatial orientation and structural robustness. However, current interrogation strategies applied for TDN-based E-AB sensors, including enzyme-based amperometry, voltammetry, and electrochemical impedance spectroscopy, either require complicated probe design or suffer from limited applicability or selectivity. In this study, a TDN pendulum-empowered E-AB sensor interrogated by chronoamperometry for reagent-free and continuous monitoring of a blood clotting enzyme, thrombin, was developed. TDN pendulums with extended aptamer sequences at three vertices were immobilized on a gold electrode via a thiolated double-stranded DNA (dsDNA) at the fourth vertex, and their motion is modulated by the bonding of target thrombin to aptamers. We observed a significantly amplified signalling output on our sensor based on the TDN pendulum compared to E-AB sensors modified with linear pendulums. Moreover, our sensor achieved highly selective and rapidly responsive measurement of thrombin in both PBS and artificial urine, with a wide dynamic range from 1 pM to 10 nM. This study shows chronoamperometry-enabled continuous biomarker monitoring on a sub-second timescale with a drift-free baseline, demonstrating a novel approach to accurately detect molecular dynamics in real time.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , ADN , Técnicas Electroquímicas , Nanoestructuras , Trombina , Aptámeros de Nucleótidos/química , Técnicas Electroquímicas/métodos , Nanoestructuras/química , Trombina/análisis , Técnicas Biosensibles/métodos , ADN/química , Biomarcadores/orina , Biomarcadores/análisis , Biomarcadores/sangre , Humanos , Oro/química , Electrodos , Límite de DetecciónRESUMEN
INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.
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Secuenciación de Nucleótidos de Alto Rendimiento , Placenta , Caracteres Sexuales , Humanos , Femenino , Embarazo , Masculino , Placenta/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Adulto , Transcriptoma , Tercer Trimestre del Embarazo/genética , Análisis de Secuencia de ARN , Primer Trimestre del Embarazo/genética , Primer Trimestre del Embarazo/metabolismoRESUMEN
This investigation delves into the pervasive yet insufficiently examined phenomenon of "cyberloafing", characterized by employees engaging in non-work-related internet activities during office hours. Despite its frequent occurrence in contemporary work environments, the fundamental mechanisms underpinning cyberloafing remain largely uncharted. This study uses the conservation of resources theory and the cognitive-affective personality system framework to demystify the relationship between role stress and cyberloafing. We developed a dual-path model to assess the mediating roles of perceived insider status and emotional exhaustion. Employing SPSS and Smart PLS for data analysis, our research sampled 210 corporate employees. The findings reveal that role stress predicts perceived insider status and emotional exhaustion significantly. Notably, while perceived insider status negatively correlates with cyberloafing, emotional exhaustion shows a positive correlation. These factors mediate the relationship between role stress and cyberloafing, underscoring a multifaceted dynamic. Our results provide new theoretical insights into the mechanisms of employee counterproductive behavior, specifically in the context of cyberloafing, and broaden our understanding of its determinants. This study illuminates theoretical nuances and offers practical implications for managerial strategies and future scholarly inquiries into organizational behavior.
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Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.
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Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Humanos , Feocromocitoma/genética , Microambiente Tumoral , Neoplasias de las Glándulas Suprarrenales/genética , Presentación de Antígeno , Linfocitos T CD8-positivosRESUMEN
Transforming growth factor ß1 (TGFB1) refers to a pleiotropic cytokine exerting contrasting roles in hematopoietic stem cells (HSCs) functions in vitro and in vivo. However, the understanding of hematopoiesis in vivo, when TGFB1 is constantly deactivated, is still unclear, mainly due to significant embryonic lethality and the emergence of a fatal inflammatory condition, which makes doing these investigations challenging. Our study aims to find the specific role of TGFB1 in regulating hematopoiesis in vivo. We engineered mice strains (Vav1 or Mx1 promoter-driven TGFB1 knockout) with conditional knockout of TGFB1 to study its role in hematopoiesis in vivo. In fetal and adult hematopoiesis, TGFB1 KO mice displayed deficiency and decreased self-renewal capacity of HSCs with myeloid-biased differentiation. The results were different from the regulating role of TGFB1 in vitro. Additionally, our results showed that TGFB1 deficiency from fetal hematopoiesis stage caused more severe defect of HSCs than in the adult stage. Mechanistically, our findings identified TGFB1-SOX9-FOS/JUNB/TWIST1 signal axis as an essential regulating pathway in HSCs homeostasis. Our study may provide a scientific basis for clinical HSC transplantation and expansion.
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Hematopoyesis , Células Madre Hematopoyéticas , Factor de Crecimiento Transformador beta1 , Animales , Ratones , Diferenciación Celular , Citocinas/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.
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The placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal-fetal health. The normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes (SEGs) not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background. Placenta expresses 14,979 polyadenylated genes above sequencing noise (transcripts per million > 0.66), with 10.7% SEGs across gestation. Differentially expressed genes (DEGs) account for 86.7% of genes in the full cohort [false discovery rate (FDR) < 0.05]. Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR < 0.001, fold change > 1.5), there remains 50.1% DEGs (3353 upregulated in first and 4155 upregulated in third trimester). This is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and SEGs may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers for maternal-fetal health.
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Placenta , Primer Trimestre del Embarazo , Tercer Trimestre del Embarazo , ARN Mensajero , Transcriptoma , Humanos , Femenino , Embarazo , Tercer Trimestre del Embarazo/genética , Placenta/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Primer Trimestre del Embarazo/genética , Adulto , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
The differentiation of embryonic stem cells (ESCs) begins with the transition from the naive to the primed state. The formative state was recently established as a critical intermediate between the two states. Here, we demonstrate the role of the histone chaperone FACT in regulating the naive-to-formative transition. We found that the Q265K mutation in the FACT subunit SSRP1 increased the binding of FACT to histone H3-H4, impaired nucleosome disassembly in vitro, and reduced the turnover of FACT on chromatin in vivo. Strikingly, mouse ESCs harboring this mutation showed elevated naive-to-formative transition. Mechanistically, the SSRP1-Q265K mutation enriched FACT at the enhancers of formative-specific genes to increase targeted gene expression. Together, these findings suggest that the turnover of FACT on chromatin is crucial for regulating the enhancers of formative-specific genes, thereby mediating the naive-to-formative transition. This study highlights the significance of FACT in fine-tuning cell fate transition during early development.
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Human motion generation aims to generate natural human pose sequences and shows immense potential for real-world applications. Substantial progress has been made recently in motion data collection technologies and generation methods, laying the foundation for increasing interest in human motion generation. Most research within this field focuses on generating human motions based on conditional signals, such as text, audio, and scene contexts. While significant advancements have been made in recent years, the task continues to pose challenges due to the intricate nature of human motion and its implicit relationship with conditional signals. In this survey, we present a comprehensive literature review of human motion generation, which, to the best of our knowledge, is the first of its kind in this field. We begin by introducing the background of human motion and generative models, followed by an examination of representative methods for three mainstream sub-tasks: text-conditioned, audio-conditioned, and scene-conditioned human motion generation. Additionally, we provide an overview of common datasets and evaluation metrics. Lastly, we discuss open problems and outline potential future research directions. We hope that this survey could provide the community with a comprehensive glimpse of this rapidly evolving field and inspire novel ideas that address the outstanding challenges.
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Algoritmos , Benchmarking , Humanos , Movimiento (Física)RESUMEN
OBJECTIVE: We aimed to investigate the hypothesis that interferon (IFN)-stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression. METHODS: Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK-J4). GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE. RESULTS: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control monocytes, as well as increased levels of isocitrate dehydrogenase and its product, α-ketoglutarate (α-KG). Because α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving "trained immune" responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly, decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression, and kidney pathology in R848-treated BALB/c mice. CONCLUSION: Our study suggests long-term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone-modifying enzymes, such as KDM6A/B, may reduce IFN responses in SLE.