Structural insights into the cooperative nucleosome recognition and chromatin opening by FOXA1 and GATA4.

Mouse FOXA1 and GATA4 are prototypes of pioneer factors, initiating liver cell development by binding to the N1 nucleosome in the enhancer of the ALB1 gene. Using cryoelectron microscopy (cryo-EM), we determined the structures of the free N1 nucleosome and its complexes with FOXA1 and GATA4, both individually and in combination. We found that the DNA-binding domains of FOXA1 and GATA4 mainly recognize the linker DNA and an internal site in the nucleosome, respectively, whereas their intrinsically disordered regions interact with the acidic patch on histone H2A-H2B. FOXA1 efficiently enhances GATA4 binding by repositioning the N1 nucleosome. In vivo DNA editing and bioinformatics analyses suggest that the co-binding mode of FOXA1 and GATA4 plays important roles in regulating genes involved in liver cell functions. Our results reveal the mechanism whereby FOXA1 and GATA4 cooperatively bind to the nucleosome through nucleosome repositioning, opening chromatin by bending linker DNA and obstructing nucleosome packing.

Exploring machine learning applications in Meningioma Research (2004-2023).

Objective: This study aims to examine the trends in machine learning application to meningiomas between 2004 and 2023. Methods: Publication data were extracted from the Science Citation Index Expanded (SCI-E) within the Web of Science Core Collection (WOSCC). Using CiteSpace 6.2.R6, a comprehensive analysis of publications, authors, cited authors, countries, institutions, cited journals, references, and keywords was conducted on December 1, 2023. Results: The analysis included a total of 342 articles. Prior to 2007, no publications existed in this field, and the number remained modest until 2017. A significant increase occurred in publications from 2018 onwards. The majority of the top 10 authors hailed from Germany and China, with the USA also exerting substantial international influence, particularly in academic institutions. Journals from the IEEE series contributed significantly to the publications. "Deep learning," "brain tumor," and "classification" emerged as the primary keywords of focus among researchers. The developmental pattern in this field primarily involved a combination of interdisciplinary integration and the refinement of major disciplinary branches. Conclusion: Machine learning has demonstrated significant value in predicting early meningiomas and tailoring treatment plans. Key research focuses involve optimizing detection indicators and selecting superior machine learning algorithms. Future efforts should aim to develop high-performance algorithms to drive further innovation in this field.

Differentiating small (< 2 cm) pancreatic ductal adenocarcinoma from neuroendocrine tumors with multiparametric MRI-based radiomic features.

OBJECTIVES: To assess MR-based radiomic analysis in preoperatively discriminating small (< 2 cm) pancreatic ductal adenocarcinomas (PDACs) from neuroendocrine tumors (PNETs). METHODS: A total of 197 patients (146 in the training cohort, 51 in the validation cohort) from two centers were retrospectively collected. A total of 7338 radiomics features were extracted from T2-weighted, diffusion-weighted, T1-weighted, arterial phase, portal venous phase and delayed phase imaging. The optimal features were selected by the Mann-Whitney U test, Spearman's rank correlation test and least absolute shrinkage and selection operator method and used to construct the radiomic score (Rad-score). Conventional radiological and clinical features were also assessed. Multivariable logistic regression was used to construct a radiological model, a radiomic model and a fusion model. RESULTS: Nine optimal features were identified and used to build the Rad-score. The radiomic model based on the Rad-score achieved satisfactory results with AUCs of 0.905 and 0.930, sensitivities of 0.780 and 0.800, specificities of 0.906 and 0.952 and accuracies of 0.836 and 0.863 for the training and validation cohorts, respectively. The fusion model, incorporating CA19-9, tumor margins, pancreatic duct dilatation and the Rad-score, exhibited the best performance with AUCs of 0.977 and 0.941, sensitivities of 0.914 and 0.852, specificities of 0.954 and 0.950, and accuracies of 0.932 and 0.894 for the training and validation cohorts, respectively. CONCLUSIONS: The MR-based Rad-score is a novel image biomarker for discriminating small PDACs from PNETs. A fusion model combining radiomic, radiological and clinical features performed very well in differentially diagnosing these two tumors. CLINICAL RELEVANCE STATEMENT: A fusion model combining MR-based radiomic, radiological, and clinical features could help differentiate between small pancreatic ductal adenocarcinomas and pancreatic neuroendocrine tumors. KEY POINTS: Preoperatively differentiating small pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine tumors (PNETs) is challenging. Multiparametric MRI-based Rad-score can be used for discriminating small PDACs from PNETs. A fusion model incorporating radiomic, radiological, and clinical features differentiated small PDACs from PNETs well.

Multiparameter MRI-based radiomics nomogram for preoperative prediction of brain invasion in atypical meningioma:a multicentre study.

OBJECTIVE: To develop a nomogram based on tumor and peritumoral edema (PE) radiomics features extracted from preoperative multiparameter MRI for predicting brain invasion (BI) in atypical meningioma (AM). METHODS: In this retrospective study, according to the 2021 WHO classification criteria, a total of 469 patients with pathologically confirmed AM from three medical centres were enrolled and divided into training (n = 273), internal validation (n = 117) and external validation (n = 79) cohorts. BI was diagnosed based on the histopathological examination. Preoperative contrast-enhanced T1-weighted MR images (T1C) and T2-weighted MR images (T2) for extracting meningioma features and T2-fluid attenuated inversion recovery (FLAIR) sequences for extracting meningioma and PE features were obtained. The multiple logistic regression was applied to develop separate multiparameter radiomics models for comparison. A nomogram was developed by combining radiomics features and clinical risk factors, and the clinical usefulness of the nomogram was verified using decision curve analysis. RESULTS: Among the clinical factors, PE volume and PE/tumor volume ratio are the risk of BI in AM. The combined nomogram based on multiparameter MRI radiomics features of meningioma and PE and clinical indicators achieved the best performance in predicting BI in AM, with area under the curve values of 0.862 (95% CI, 0.819-0.905) in the training cohort, 0.834 (95% CI, 0.780-0.908) in the internal validation cohort and 0.867 (95% CI, 0.785-0.950) in the external validation cohort, respectively. CONCLUSIONS: The nomogram based on tumor and PE radiomics features extracted from preoperative multiparameter MRI and clinical factors can predict the risk of BI in patients with AM.

The independent and joint associations of vitamin B12 and methylmalonic acid on the risk of mortality in individuals with metabolic dysfunction-associated steatotic liver disease.

PURPOSE: To investigate the independent and joint associations of vitamin B12 and methylmalonic acid (MMA) with all-cause, cardiovascular disease (CVD), and cancer mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We included 6797 individuals with MASLD from the U.S. National Health and Nutrition Examination Survey. Serum MMA was measured using gas/liquid chromatography-mass spectrometry. Serum vitamin B12 was measured using commercial kits. The separate and joint associations of dietary intake and serum vitamin B12 (cutoff: 400 pg/mL) and MMA (cutoff: 250 nmol/L) levels with mortality were assessed by Cox proportional hazards regression. RESULTS: During a median follow-up of 9.3 years, 1604 deaths were documented, including 438 from CVD and 365 from cancer. In MASLD patients, dietary intake and serum vitamin B12 did not associate with mortality, while MMA was associated with a 1.35-fold increased risk of all-cause mortality (P-trend < 0.001). The adjusted hazard ratios for the joint association of vitamin B12 and MMA with all-cause and CVD mortality were 1 in the B12lowMMAlow group (reference), 1.02 (0.87-1.20) and 1.15 (0.90-1.47) in the B12highMMAlow group, 1.55 (1.29-1.86) and 1.84 (1.28-2.65) in the B12lowMMAhigh group, and 1.82 (1.49-2.21) and 2.28 (1.40-3.71) in the B12highMMAhigh group, respectively. The joint association was modified by serum folate (P-interaction = 0.001). CONCLUSIONS: In MASLD patients, MMA rather than dietary and serum vitamin B12 was positively associated with all-cause mortality. The joint effect of high levels of MMA and vitamin B12 showed the strongest associations with all-cause and CVD mortality, with a significant interaction with serum folate.

Effects of DASH diet with or without time-restricted eating in the management of stage 1 primary hypertension: a randomized controlled trial.

BACKGROUND: Time-restricted eating (TRE), a popular form of intermittent fasting, has shown benefits for improving metabolic diseases and cardiometabolic health. However, the effect of TRE in the regulation of blood pressure in primary hypertension remains unclear. METHODS: A 6-week randomized controlled trial was conducted, in which a total of 74 stage 1 primary hypertensive patients without high-risk were randomly assigned to Dietary Approaches to Stop Hypertension (DASH) group (n = 37) or DASH + TRE group (n = 37). Participants in the DASH + TRE group were instructed to consume their food within an 8-h window. Scientific research platform in We Chat application was used to track participants. The primary outcome was blood pressure. The secondary outcomes included body composition, cardiometabolic risk factors, inflammation-related parameters, urinary Na+ excretion, other clinical variables and safety outcomes. RESULTS: The reduction of systolic blood pressure and diastolic blood pressure were 5.595 ± 4.072 and 5.351 ± 5.643 mm Hg in the DASH group and 8.459 ± 4.260 and 9.459 ± 4.375 mm Hg in the DASH + TRE group. DASH + TRE group improved blood pressure diurnal rhythm. Subjects in DASH + TRE group had decreased extracellular water and increased urinary Na+ excretion. Furthermore, the decrease in blood pressure was associated with a reduction of extracellular water or increase in urinary Na+ excretion. In addition, safety outcomes such as nighttime hunger were also reported. CONCLUSION: Our study demonstrated that 8-h TRE + DASH diet caused a greater decrease in blood pressure in stage 1 primary hypertensive patients than DASH diet. This study may provide novel insights into the benefits of lifestyle modification in the treatment of primary hypertension. TRIAL REGISTRATION: https://www.chictr.org.cn/ (ChiCTR2300069393, registered on March 15, 2023).

[Site-specific PCR identification of animal species and formula particles of Scorpio].

Scorpio, a commonly used animal medicine in China, is derived from Buthus martensii as recorded in the Chinese Pharmacopoeia. China harbors rich species of Scorpionida and adulterants exist in the raw medicinal material and deep-processed products of Scorpio. The microscopic characteristics of the deep-processed products may be incomplete or lost during processing, which makes the identification difficult. In this study, the maximum likelihood(ML) tree was constructed based on the morphology and cytochrome C oxidase subunit I(COⅠ) to identify the species of Scorpio products. The results showed that the main adulterant of Scorpio was Lychas mucronatus. According to the specific SNP sites in the COⅠ sequence of B. martensii, the stable primers were designed for the identification of the medicinal material and formula granules of Scorpio. The polymerase chain reaction(PCR) at the annealing temperature of 61 ℃ and 30 cycles produced bright specific bands at about 150 bp for both B. martensii and its formula particles and no band for adulterants. The adaptability of the method was investigated, which showed that the bands at about 150 bp were produced for Scorpio medicinal material, lyophilized powder, and formula granules, and commercially available formula granules. The results showed that the established method could be used to identify the adulterants of Scorpio and its formula granules, which could help to improve the quality control system and ensure the safe clinical application of Scorpio formula granules.

[Intervention effect of Erchen Decoction on methionine and choline deficient diet-induced non-alcoholic steatohepatitis in mice].

This study investigated the effect of Erchen Decoction(ECD) on the prevention of non-alcoholic steatohepatitis(NASH) in mice and explored its possible mechanism, so as to provide scientific data for the clinical application of ECD in the prevention of NASH. C57BL/6 male mice were randomly divided into normal group(methionine and choline supplement, MCS), model group(methionine and choline deficient, MCD), low-dose ECD group(ECD＿L, 6 g·kg~(-1)), medium-dose ECD group(ECD＿M, 12 g·kg~(-1)), and high-dose ECD group(ECD＿H, 24 g·kg~(-1)), with eight mice in each group. The MCS group was fed with an MCS diet, and the other groups were fed with an MCD diet. The mice in each group were given corresponding diets, but the drug intervention group was given low-, medium-, and high-dose ECD(10 mL·kg~(-1)·d~(-1)) by intragastric administration for six weeks on the basis of MCD diet feeding, and the mice could eat and drink freely during the whole experiment. At the end of the experiment, mice were fasted overnight(12 h) and were anesthetized with 20% urethane. Thereafter, the blood and liver tissue were collected. The serum was used to detect the levels of alanine aminotransferase(ALT), aspartate aminotransaminase(AST), interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Liver tissue was processed by hematoxylin-eosin(HE) staining and used for hepatic histological analysis and detection of the expression levels of genes and proteins related to nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(Nrf2/GPX4) pathway by real-time quantitative reverse transcriptase-polymerase chain reaction(RT-qPCR) and Western blot analysis, respectively. The results showed that compared with the MCS group, the MCD group showed higher serum ALT and AST levels; the HE staining exhibited fat vacuoles and obvious inflammatory cell infiltration in liver tissue; serum IL-1ß, IL-6, and TNF-α levels were significantly increased, and the serum IL-10 level was significantly decreased. The mRNA expressions of fatty acid synthase(FASN), monocyte chemoattractant protein-1(MCP-1), and IL-1ß in liver tissue were significantly up-regulated, while those of GPX4, Nrf2, and NAD(P)H:quinine oxidoreductase(NQO1) were significantly down-regulated. Compared with the MCD group, the serum ALT and AST levels of ECD＿M and ECD＿H groups were significantly decreased, and the AST level in the ECD＿L group was significantly decreased. The number of fat vacuoles and the degree of inflammatory cell infiltration in liver tissue were improved; serum IL-1ß, IL-6, and TNF-α levels were significantly decreased, but the serum IL-10 level was significantly increased only in the ECD＿H group. The mRNA expressions of FASN, MCP-1, and IL-1ß in liver tissue were significantly down-regulated, and those of GPX4 and NQO1 were significantly up-regulated. The mRNA expressions of Nrf2 in ECD＿M and ECD＿H groups were significantly up-regulated. Western blot results showed that compared with the MCD group, the protein expression levels of Nrf2 and GPX4 in each group were significantly increased after ECD administration, and the protein expression level of FASN was significantly decreased; the protein expression of NQO1 was increased in ECD＿M and ECD＿H groups. In summary, ECD can reduce hepatic lipid accumulation, oxidative stress, liver inflammation, and liver injury in NASH mice, which may be related to the activation of the Nrf2/GPX4 pathway.

The Effects of Traditional Chinese Herbal Dietary Formula on the Ability of Daily Life and Physical Function in Elderly Patients with Mild Cognitive Impairment.

We aimed to examine the association of traditional Chinese herbal dietary formulas with ability of daily life and physical function in elderly patients with mild cognitive impairment. The current study included 60 cases of elderly patients with mild cognitive impairment from Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai University of Traditional Chinese Medicine and Hongkou District, Shanghai. The participants were randomly divided into two groups: group A (herbal dietary formula group, consisting of Alpiniae Oxyphyllae Fructus, Nelumbinis plumula, Chinese Yam, Poria cocos, and Jineijin), 30 cases, and group B (vitamin E), 30 cases, treatment for 3 months. Cognitive function was measured using the Montreal Cognitive Assessment (MOCA) and Mini-Mental State Examination (MMSE); body function was measured using the Chinese Simplified Physical Performance Test (CMPPT), including stand static balance, sitting-up timing, squat timing, and six-meter walk timing. Daily life based on ability was measured by grip strength and the Activity of Daily Living Scale (ADL). The lower the scores of the above items, the poorer the disease degree, except for ADL: the lower the score, the higher the self-care ability. After 3 months of treatment, the two-handed grip strength of both the herbal dietary formula group and vitamin E group increased; the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased after medication, being statistically significantly different (p < 0.05). The two-handed grip strength of group A increased significantly, and the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased distinctly compared with the vitamin E group. There was a statistically significant difference (p < 0.05). The scores of MMSE, MOCA, total CMPPT, and standing static balance of the herbal dietary formula group increased after medication. The difference was statistically significant (p < 0.05). The vitamin E group's MMSE and MOCA scores, CMPPT total scores, and standing resting balance scores did not change significantly after medication (p > 0.05). In summary, a traditional Chinese herbal dietary formula can improve body and cognitive function in patients with MCI, and the curative effect is better than that of vitamin E. Traditional Chinese herbal dietary formulas can improve the daily life quality of MCI patients, which has clinical application value.

Controllable Skeletal and Peripheral Editing of Pyrroles with Vinylcarbenes.

The skeletal editing of azaarenes through insertion, deletion, or swapping of single atoms has recently gained considerable momentum in chemical synthesis. Here, we describe a practical skeletal editing strategy using vinylcarbenes in situ generated from trifluoromethyl vinyl N-triftosylhydrazones, leading to the first dearomative skeletal editing of pyrroles through carbon-atom insertion. Furthermore, depending on the used catalyst and substrate, three types of peripheral editing reactions of pyrroles are also disclosed: α- or γ-selective C-H insertion, and [3+2] cycloaddition. These controllable molecular editing reactions provide a powerful platform for accessing medicinally relevant CF3-containing N-heterocyclic frameworks, such as 2,5-dihydropyridines, piperidines, azabicyclo[3.3.0]octadienes, and allylated pyrroles from readily available pyrroles. Mechanistic insights from experiments and density functional theory (DFT) calculations shed light on the origin of substrate- or catalyst-controlled chemo- and regioselectivity as well as the reaction mechanism.

Biosafe cerium oxide nanozymes protect human pluripotent stem cells and cardiomyocytes from oxidative stress.

BACKGROUND: Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). RESULTS: CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. CONCLUSIONS: CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine.

Acanthopanax senticosus improves cognitive impairment in Alzheimer's disease by promoting the phosphorylation of the MAPK signaling pathway.

Background: Acanthopanax senticosus (AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer's disease (AD). The therapeutic effect and mechanism need to be further investigated. Methods: To confirm the AS play efficacy in alleviating memory impairment in mice, 5×FAD transgenic mice were subjected to an open-field experiment and a novelty recognition experiment. Network pharmacology technique was used to analyze the information of key compounds and potential key targets of AS for the treatment of AD, molecular docking technique was applied to predict the binding ability of targets and compounds, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed on the targets to derive the possible metabolic processes and pathway mechanisms of AS in treating AD. Quantitative real-time PCR (qRT-PCR) and western blot technique were carried out to validate the candidate genes and pathways. Results: In the open-field experiment, compared with the wild-type (WT) group, the number of times the mice in the AD group crossed the central zone was significantly reduced (P< 0.01). Compared with the AD group, the number of times the mice in the AS group crossed the central zone was significantly increased (P< 0.001). In the new object recognition experiment, compared with the WT group, the percentage of times the AD group explored new objects was significantly reduced (P< 0.05). Compared with the AD group, the AS group had an increase in the percentage of time spent exploring new things and the number of times it was explored (P< 0.05). At the same time, the donepezil group had a significantly higher percentage of times exploring new things (P< 0.01). By using network pharmacology technology, 395 common targets of AS and AD were retrieved. The Cytoscape software was used to construct the protein-protein interaction (PPI) network of common targets. Using the algorithm, nine key targets were retrieved: APP, NTRK1, ESR1, CFTR, CSNK2A1, EGFR, ESR2, GSK3B, and PAK1. The results of molecular docking indicate that 11 pairs of compounds and their corresponding targets have a significant binding ability, as the molecular binding energies were less than -7.0. In comparison to the AD group, the mRNA expression of the key target genes was significantly decreased in the AS treatment group (P< 0.001). The KEGG analysis showed that the MAPK signaling pathway was significantly enriched, and Western blot confirmed that the TRAF6 protein decreased significantly (P< 0.0001). Meanwhile, the levels of MAP3K7 and P38 phosphorylation increased, and there was also an increase in the expression of HSP27 proteins. Conclusion: Our study indicates that the multi-component and multi-target properties of AS play an important role in the alleviation of anxiety and memory impairment caused by AD, and the mechanism is involved in the phosphorylation and activation of the MAPK signaling pathway. The results of this study could provide a novel perspective for the clinical treatment of AD.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. AIM: To investigate the impact of JOSD2 on the progression of ESCC. METHODS: Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. RESULTS: Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. CONCLUSION: JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Coordination of pinna, petiole, and root anatomical traits in 24 tropical-subtropical fern species.

Ferns are primitive vascular plants with diverse morphologies and structures. Plant anatomical traits and their linkages can reflect adaptation to the environment; however, these remain are still poorly understood in ferns. The main objective of this study was to explore whether there was structural coordination among and within organs in fern species. We measured 16 hydraulically related anatomical traits of pinnae, petioles, and roots of 24 representative fern species from the tropical and subtropical forest understory and analyzed trait correlation networks. In addition, we examined phylogenetic signals for the anatomical traits and analyzed co-evolutionary relationships. These results indicated that stomatal density and all petiole anatomical traits exhibited significant phylogenetic signals. Evolutionary correlations were observed between the tracheid diameter and wall thickness of the petiole and between the water transport capacity of the petiole and stomatal density. Conversely, anatomical traits of roots (e.g., root diameter) showed no phylogenetic signals and were not significantly correlated with those of the pinnae and petioles, indicating a lack of structural coordination between the below- and above-ground organs. Unlike angiosperms, vein density is unrelated to stomatal density or pinna thickness in ferns. As root diameter decreased, the cortex-to-stele diameter ratio decreased significantly (enhanced water absorption) in angiosperms but remained unchanged in ferns. These differences lead to different responses of ferns to climate change and improve our knowledge of the water adaptation strategies of ferns.

Night eating in timing, frequency, and food quality and risks of all-cause, cancer, and diabetes mortality: findings from national health and nutrition examination survey.

OBJECTIVE: To investigate the association of timing, frequency, and food quality of night eating with all-cause, cancer, and diabetes mortality. METHODS: This study included 41,744 participants from the US National Health and Nutrition Examination Survey (2002-2018). Night eating information was collected by 24-h dietary recall and the exposures were timing, frequency, and food quality of night eating. Food quality was assessed by latent class analysis. The outcomes were all-cause, cancer, and diabetes mortality, which were identified by the National Death Index and the International Classification of Diseases 10th Revision. Adjusted hazard ratios [aHR] with 95% confidence intervals [CI] were computed by Cox regression. RESULTS: During a median follow-up of 8.7 years, 6066 deaths were documented, including 1381 from cancer and 206 from diabetes. Compared with no night eating (eating before 22:00), the later timing of night eating was associated with higher risk of all-cause and diabetes mortality (each P-trend <0.05) rather than cancer mortality, with the highest risk of eating being 00:00-1:00 (aHR 1.38, 95% CI 1.02-1.88) and being 23:00-00:00 (aHR 2.31, 95% CI 1.21-4.40), respectively. However, the increased risks were not observed for 22:00-23:00. Likewise, one time or over frequency of night eating was associated with higher all-cause and diabetes mortality (each P < 0.05). That risks were further observed in high-dietary-energy-density group of night eating (all-cause mortality: aHR 1.21 [95% CI 1.06-1.38]; diabetes mortality: aHR 1.97 [95% CI 1.13-3.45]), but not in low-dietary-energy-density group. Finally, correlation analysis found positive associations of night eating with glycohemoglobin, fasting glucose, and OGTT. CONCLUSIONS: Night eating was associated with increased all-cause, cancer and diabetes mortality; however, reduction of excess mortality risk was observed when eating before 23:00 or low-dietary-energy-density foods.

HAND factors regulate cardiac lineage commitment and differentiation from human pluripotent stem cells.

BACKGROUND: Transcription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1/2 result in severe cardiac defects. However, the function and mechanism of HAND1/2 in regulating human early cardiac lineage commitment and differentiation are still unclear. METHODS: With NKX2.5eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2, respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP+ cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data. RESULTS: Either HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1/2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1/2-deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1/2-deficient hESCs. CONCLUSIONS: HAND1/2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1/2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.

Synthesis, Characterization, and Properties of Sila-Annulated Phenanthrene Imides.

A series of sila-annulated phenanthrene imides were synthesized through a three-step synthetic route, which represent a hybrid class of biphenyl-based π-conjugated molecules incorporating an imide unit and silole. A comprehensive investigation of their structural, photophysical, and electronic properties was studied by experiment and theoretical calculations. Notably, sila-annulated phenanthrene imides with significant aggregation-induced emission (AIE) properties were observed.

Machine learning unveils RNA polymerase II binding as a predictor for SMAD2-dependent transcription dynamics in response to Actvin signalling.

The transforming growth factor-ß (TGF-ß) superfamily, including Nodal and Activin, plays a critical role in various cellular processes. Understanding the intricate regulation and gene expression dynamics of TGF-ß signalling is of interest due to its diverse biological roles. A machine learning approach is used to predict gene expression patterns induced by Activin using features, such as histone modifications, RNA polymerase II binding, SMAD2-binding, and mRNA half-life. RNA sequencing and ChIP sequencing datasets were analysed and differentially expressed SMAD2-binding genes were identified. These genes were classified into activated and repressed categories based on their expression patterns. The predictive power of different features and combinations was evaluated using logistic regression models and their performances were assessed. Results showed that RNA polymerase II binding was the most informative feature for predicting the expression patterns of SMAD2-binding genes. The authors provide insights into the interplay between transcriptional regulation and Activin signalling and offers a computational framework for predicting gene expression patterns in response to cell signalling.

Water storage capacity is inversely associated with xylem embolism resistance in tropical karst tree species.

Tropical karst habitats are characterized by limited and patchy soil, large rocky outcrops and porous substrates, resulting in high habitat heterogeneity and soil moisture fluctuations. Xylem hydraulic efficiency and safety can determine the drought adaptation and spatial distribution of woody plants growing in karst environments. In this study, we measured sapwood-specific hydraulic conductivity (Ks), vulnerability to embolism, wood density, saturated water content, and vessel and pit anatomical characteristics in the branch stems of 12 evergreen tree species in a tropical karst seasonal rainforest in southwestern China. We aimed to characterize the effects of structural characteristics on hydraulic efficiency and safety. Our results showed that there was no significant correlation between Ks and hydraulic safety across the tropical karst woody species. Ks was correlated with hydraulic vessel diameter (r = 0.80, P < 0.05) and vessel density (r = -0.60, P < 0.05), while the stem water potential at 50 and 88% loss of hydraulic conductivity (P50 and P88) were both significantly correlated with wood density (P < 0.05) and saturated water content (P = 0.052 and P < 0.05, respectively). High stem water storage capacity was associated with low cavitation resistance possibly because of its buffering the moisture fluctuations in karst environments. However, both Ks and P50/P88 were decoupled from the anatomical traits of pit and pit membranes. This may explain the lack of tradeoff between hydraulic safety and efficiency in tropical karst evergreen tree species. Our results suggest that diverse hydraulic trait combination may facilitate species coexistence in karst environments with high spatial heterogeneity.