Dynamics of respiratory infectious diseases under rapid urbanization and COVID-19 pandemic in the subcenter of Beijing during 2014-2022.

Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014-2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014-2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014-2022, and the incidence rate of NRIDs was higher during 2017-2019 (153/100 000) than during 2014-2016 (930/100 000) and during 2020-2022 (371/100 000), respectively (both P < 0.001). The CIU constantly increased with slight fluctuation in 2016 and 2018, respectively. The incidence rate of NRIDs showed an increase along with the CIU during 2014-2019 (r = 0.95, P = 0.004), while the incidence rate's tendency was interrupted by COVID-19 during 2020 with slight decrease in 2020-2021 and rebounded in 2022. For the patients aged <15 years, the incidence rate of NRIDs revealed a very sharp rise at the urbanization period without COVID-19 pandemic compared with that under pre-urbanization period (RR = 7.93, 95 % CI 7.63-8.24), and dropped off to the similar level as of pre-urbanization period when COVID-19 pandemic spread. Conclusions: Urbanization process may increase the incidence of NRIDs but constrained by COVID-19. Certain measures should be taken to prevent and control the effects by urbanization process, such as good natural environment with less population density, ecological environment with good air quality, promoted hand hygiene, mask wearing, keeping interpersonal distance, vaccination, media publicity for NRIDs' prevention and control.

Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.

Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S)616. Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo, we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes.

Resilient Event-Based Fuzzy Fault Detection for DC Microgrids in Finite-Frequency Domain against DoS Attacks.

This paper addresses the problem of fault detection in DC microgrids in the presence of denial-of-service (DoS) attacks. To deal with the nonlinear term in DC microgrids, a Takagi-Sugeno (T-S) model is employed. In contrast to the conventional approach of utilizing current sampling data in the traditional event-triggered mechanism (ETM), a novel integrated ETM employs historical information from measured data. This innovative strategy mitigates the generation of additional triggering packets resulting from random perturbations, thus reducing redundant transmission data. Under the assumption of faults occurring within a finite-frequency domain, a resilient event-based H-/H∞ fault detection filter (FDF) is designed to withstand DoS attacks. The exponential stability conditions are derived in the form of linear matrix inequalities to ensure the performance of fault detected systems. Finally, the simulation results are presented, demonstrating that the designed FDF effectively detects finite-frequency faults in time even under DoS attacks. Furthermore, the FDF exhibits superior fault detection sensitivity compared to the conventional H∞ method, thus confirming the efficacy of the proposed approach. Additionally, it is observed that a trade-off exists between fault detection performance and the data releasing rate (DRR).

Correlation between CEUS LI-RADS categorization of HCC < 20 mm and clinic-pathological features.

OBJECTIVE: To retrospectively evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) LI-RADS in liver nodules < 20 mm at high risk of hepatocellular carcinoma (HCC) and their correlation with clinic-pathological features. METHODS: A total of 432 pathologically proved liver nodules < 20 mm were included from January 2019 to June 2022. Each nodule was categorized as LI-RADS grade (LR)-1 to LR-5 through LR-M according to CEUS LI-RADS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of CEUS LI-RADS were evaluated using pathological reference standard. Correlations between clinic-pathological features and CEUS LI-RADS categorization, together with major CEUS features, were further explored. RESULTS: With LR-5 to diagnose HCC, the sensitivity, specificity, PPV, NPV, and AUC were 50.3%, 70.0%, 91.2%, 18.5%, and 0.601, respectively. The proportion of LR-5 in primary HCCs was significantly higher than that in recurrent ones (p = 0.014). HCC 10-19 mm showed significantly more frequent arterial phase hyper-enhancement (APHE) and late washout (p < 0.05) and less no-washout (p = 0.003) compared with those in HCC < 10 mm. Well-differentiated HCCs showed more frequent non-APHE and no-washout than moderate- and poor-differentiated HCCs (p < 0.05). Upgrading "APHE without washout" LR-4 nodules 10-19 mm with HCC history and "APHE with late mild washout" LR-4 nodules < 10 mm to LR-5 could improve the diagnostic performance of LR-5. The corresponding sensitivity, specificity, PPV, NPV, and AUC are 60.2%, 70.0%, 92.6%, 22.1%, and 0.651, respectively. CONCLUSIONS: CEUS LI-RADS is valuable in the diagnosis of HCC < 20 mm and performance can be improved with the combination of clinic-pathological features. CRITICAL RELEVANCE STATEMENT: CEUS LI-RADS was valuable in the diagnosis of HCC < 20 mm and its diagnostic performance can be improved by combining clinic-pathological features. Further research is needed to define its value in this set of lesions. KEY POINTS: Contrast-enhanced ultrasound can detect small liver lesions where LI-RADS accuracy is uncertain. Many LI-RADS Grade-4 nodules were upgraded to Grade-5 by combining imaging with clinic-pathological factors. The reclassification of LI-RADS Grade-5 can improve sensitivity without decreasing positive predictive value.

Potential clinical value of fibrinogen-like protein 1 as a serum biomarker for the identification of diabetic cardiomyopathy.

Diabetic individuals with diabetic cardiomyopathy (DbCM) present with abnormal myocardial structure and function. DbCM cannot be accurately diagnosed due to the lack of suitable diagnostic biomarkers. In this study, 171 eligible participants were divided into a healthy control (HC), type 2 diabetes mellitus (T2DM) patients without DbCM (T2DM), or DbCM group. Serum fibrinogen-like protein 1 (FGL-1) and other biochemical parameters were determined for all participants. Serum FGL-1 levels were significantly higher in patients with DbCM compared with those in the T2DM group and HCs. Serum FGL-1 levels were negatively correlated with left ventricular fractional shortening and left ventricular ejection fraction (LVEF) and positively correlated with left ventricular mass index in patients with DbCM after adjusting for age, sex and body mass index. Interaction of serum FGL-1 and triglyceride levels on LVEF was noted in patients with DbCM. A composite marker including serum FGL-1 and triglycerides could differentiate patients with DbCM from those with T2DM and HCs with an area under the curve of 0.773 and 0.789, respectively. Composite marker levels were negatively correlated with N-terminal B-type natriuretic peptide levels in patients with DbCM. Circulating FGL-1 may therefore be a valuable index reflecting cardiac functions in DbCM and to diagnose DbCM.

miR394 modulates brassinosteroid signaling to regulate hypocotyl elongation in Arabidopsis.

The interplay between microRNAs (miRNAs) and phytohormones allows plants to integrate multiple internal and external signals to optimize their survival of different environmental conditions. Here, we report that miR394 and its target gene LEAF CURLING RESPONSIVENESS (LCR), which are transcriptionally responsive to BR, participate in BR signaling to regulate hypocotyl elongation in Arabidopsis thaliana. Phenotypic analysis of various transgenic and mutant lines revealed that miR394 negatively regulates BR signaling during hypocotyl elongation, whereas LCR positively regulates this process. Genetically, miR394 functions upstream of BRASSINOSTEROID INSENSITIVE2 (BIN2), BRASSINAZOLEs RESISTANT1 (BZR1), and BRI1-EMS-SUPPRESSOR1 (BES1), but interacts with BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1 SUPRESSOR PROTEIN (BSU1). RNA-sequencing analysis suggested that miR394 inhibits BR signaling through BIN2, as miR394 regulates a significant number of genes in common with BIN2. Additionally, miR394 increases the accumulation of BIN2 but decreases the accumulation of BZR1 and BES1, which are phosphorylated by BIN2. MiR394 also represses the transcription of PACLOBUTRAZOL RESISTANCE1/5/6 and EXPANSIN8, key genes that regulate hypocotyl elongation and are targets of BZR1/BES1. These findings reveal a new role for a miRNA in BR signaling in Arabidopsis.

Three-Dimensional Printable Magnetic Microfibers: Development and Characterization for Four-Dimensional Printing.

This study proposes a novel and simple fabrication method of magnetic microfibers, employing filament stretching three-dimensional (3D) printing, and demonstrates the capacity of four-dimensional (4D) printing of the proposed magnetic microfibers. A ferromagnetic 3D printing filament is prepared by the mixture of neodymium-iron-boron (NdFeB) and polylactic acid (PLA), and we investigate the characteristics of the ferromagnetic filament by mixing ratio, magnetic properties, mechanical properties, and rheological properties through experiments. By thermal extrusion of the ferromagnetic filament through a 3D printer nozzle, various thicknesses (80-500 µm) and lengths (less than ∼5 cm) of ferromagnetic microfibers are achieved with different printing setups, such as filament extrusion amount and printing speed. The printed ferromagnetic microfibers are magnetized to maintain a permanent magnetic dipole moment, and 4D printing can be achieved by the deformations of the permanently magnetized microfibers under magnetic fields. We observe that the mixing ratio, the thickness, and the length of the magnetized microfibers provide distinct deformation of the microfiber for customization of 4D printings. This study exhibits that the permanently magnetized microfibers have a great potential for smart sensors and actuators. Furthermore, we briefly present an application of our proposed magnetic microfibers for bionic motion actuators with various unique undulating and oscillating motions.

Structure-function coupling and hierarchy-specific antidepressant response in major depressive disorder.

BACKGROUND: Extensive research has explored altered structural and functional networks in major depressive disorder (MDD). However, studies examining the relationships between structure and function yielded heterogeneous and inconclusive results. Recent work has suggested that the structure-function relationship is not uniform throughout the brain but varies across different levels of functional hierarchy. This study aims to investigate changes in structure-function couplings (SFC) and their relevance to antidepressant response in MDD from a functional hierarchical perspective. METHODS: We compared regional SFC between individuals with MDD (n = 258) and healthy controls (HC, n = 99) using resting-state functional magnetic resonance imaging and diffusion tensor imaging. We also compared antidepressant non-responders (n = 55) and responders (n = 68, defined by a reduction in depressive severity of >50%). To evaluate variations in altered and response-associated SFC across the functional hierarchy, we ranked significantly different regions by their principal gradient values and assessed patterns of increase or decrease along the gradient axis. The principal gradient value, calculated from 219 healthy individuals in the Human Connectome Project, represents a region's position along the principal gradient axis. RESULTS: Compared to HC, MDD patients exhibited increased SFC in unimodal regions (lower principal gradient) and decreased SFC in transmodal regions (higher principal gradient) (p < 0.001). Responders primarily had higher SFC in unimodal regions and lower SFC in attentional networks (median principal gradient) (p < 0.001). CONCLUSIONS: Our findings reveal opposing SFC alterations in low-level unimodal and high-level transmodal networks, underscoring spatial variability in MDD pathology. Moreover, hierarchy-specific antidepressant effects provide valuable insights into predicting treatment outcomes.

Sex differences in anhedonia in bipolar depression: a resting-state fMRI study.

Previous studies about anhedonia symptoms in bipolar depression (BD) ignored the unique role of gender on brain function. This study aims to explore the regional brain neuroimaging features of BD with anhedonia and the sex differences in these patients. The resting-fMRI by applying fractional amplitude of low-frequency fluctuation (fALFF) method was estimated in 263 patients with BD (174 high anhedonia [HA], 89 low anhedonia [LA]) and 213 healthy controls. The effects of two different factors in patients with BD were analyzed using a 3 (group: HA, LA, HC) × 2 (sex: male, female) ANOVA. The fALFF values were higher in the HA group than in the LA group in the right medial cingulate gyrus and supplementary motor area. For the sex-by-group interaction, the fALFF values of the right hippocampus, left medial occipital gyrus, right insula, and bilateral medial cingulate gyrus were significantly higher in HA males than in LA males but not females. These results suggested that the pattern of high activation could be a marker of anhedonia symptoms in BD males, and the sex differences should be considered in future studies of BD with anhedonia symptoms.

Mass immunisation to eradicate Japanese encephalitis: Real-world evidence from Guizhou Province in 2005-2021.

Objectives: To explore epidemiological changes of Japanese encephalitis (JE) in a long-time span and evaluate the impact of mass immunisation. Method: Data on JE cases from hospitals and the county Centers for Disease Control and Prevention in Guizhou Province was collected between 2005 and 2021. Epidemiological changes were analyzed according to a series of policy implementations and the coronavirus disease 2019 (COVID-19) pandemic. Results: A total of 5138 JE cases and 152 deaths were reported in Guizhou Province during 2005-2021. The average incidence and case fatality rates were 0.83/100,000 and 2.96%, respectively. The JE prevalence showed a declining trend over the years with the reduced incidence gap between age groups and narrowing of the high-epidemic regions. During the COVID-19 pandemic, the JE activity reached its nadir in 2020. The inclusion in the Expanded Program on Immunization of the JE vaccine and catch-up immunisations showed a significant impact on the JE declining incidence rate. Conclusions: The implementation of JE immunisation programs has played a crucial role in controlling its spread. Continued efforts should be made to maintain high coverage of the JE vaccine and strengthen disease surveillance systems, ensuring JE effective control and eventual elimination.

Comparative genomics on chloroplasts of Rubus (Rosaceae).

Rubus, the largest genus in Rosaceae, contains over 1400 species that distributed in multiple habitats across the world, with high species diversity in the temperate regions of Northern Hemisphere. Multiple Rubus species are cultivated for their valuable fruits. However, the intrageneric classification and phylogenetic relationships are still poorly understood. In this study, we sequenced, assembled, and characterized 17 plastomes of Rubus, and conducted comparative genomics integrating with 47 previously issued plastomes of this genus. The 64 plastomes of Rubus exhibited typical quadripartite structure with sizes ranging from 155,144 to 156,700 bp, and contained 132 genes including 87 protein-coding genes, 37 tRNA genes and eight rRNA genes. All plastomes are conservative in the gene order, the frequency of different types of long repeats and simple sequence repeats (SSRs), the codon usage, and the selection pressure of protein-coding genes. However, there are also some differences in the Rubus plastomes, including slight contraction and expansion of the IRs, a variation in the numbers of SSRs and long repeats, and some genes in certain clades undergoing intensified or relaxed purifying selection. Phylogenetic analysis based on whole plastomes showed that the monophyly of Rubus was strongly supported and resolved it into six clades corresponding to six subgenera. Moreover, we identified 12 highly variable regions that could be potential molecular markers for phylogenetic, population genetic, and barcoding studies. Overall, our study provided insight into plastomic structure and sequence diversification of Rubus, which could be beneficial for future studies on identification, evolution, and phylogeny in this genus.

Thrombosis inhibited by Corydalis decumbens through regulating PI3K-Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis decumbens (Thunb.) Pers. was used as stasis-eliminating medicine traditionally to treat cardiovascular disease potentially attributed to its antithrombotic effect, but lack of pharmacological research on it. AIM OF THE STUDY: To investigate the antithrombotic effect of C. decumbens and its preliminary mechanism. MATERIALS AND METHODS: A carrageenan-induced mouse thrombus model and adenosine diphosphate stimulated platelet aggregation of rabbits were used to confirm the inhibitory effect of C. decumbens extract and compounds on thrombosis in vivo. Then, H2O2-induced human umbilical vein endothelial cells (HUVECs) injury model was further adopted to verify the effects of bioactive compounds in vitro. Moreover, in silico network pharmacology analyses and molecular docking were performed to predict the underlying mechanisms, targets, and pathways, and which were further confirmed through western blotting assay. RESULTS: The administration of total extract (TE), total alkaloids (TA) and tetrahydropalmatine (TET) resulted in a significant reduction in black tail thrombus and congestion, along with a decreasing in platelet aggregation of rabbits. A superior antithrombotic effect indicated the bioactive fraction, and then the isolated bioactive compounds, TET and protopine (PRO) increased cell survival, and decreased reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release in H2O2-induced HUVECs injury model. Moreover, the two alkaloids targeted 33 major proteins and influenced 153 pathways in network pharmacology prediction. Among these, HSP90AA1, COX-2, NF-κB/p65, MMP1 and HIF-1α were the key proteins and PI3K-Akt emerged as the major signaling pathway. Further western blotting results supported that five key proteins were downregulated by the two bioactive compounds in H2O2-stimulated HUVECs model. CONCLUSION: C. decumbens exerted protective effect on thrombosis through inhibiting PI3K-Akt pathway and related key proteins, which supported the traditional use and presented potential antithrombotic alkaloids for further investigation.

Protective effect of PCV13 against all-cause hospitalized pneumonia in children in Beijing, China: real-world evidence.

BACKGROUND: The study evaluated the protective effect of 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against all-cause hospitalized pneumonia in children in Beijing. METHODS: Based on the vaccination record and inpatient medical record database of Beijing, children born in 2017 in Beijing, matched by age, gender, and district of the children with the ratio of 1:4, were selected as the vaccinated and unvaccinated groups according whether if vaccinated with PCV13. The incidence rate and 95 % confidence interval (95 %CI), vaccine effectiveness (VE) and direct medical costs of all-cause hospitalized pneumonia were calculated and compared within the same period of 12 months, 18 months, 24 months and 30 months after the birth of the child. RESULTS: The decreased incidence rates of all-cause hospitalized pneumonia were observed at the four points in the PCV13 vaccinated group compared to the unvaccinated group, which were significant at the points of 12 months (0.42 % vs. 0.72 %, P = 0.001), 18 months (0.90 % vs. 1.26 %, P = 0.002) and 24 months (1.37 % vs. 1.65 %, P = 0.046). The VE of PCV13 against all-cause hospitalized pneumonia within 12 months was the highest as 41.9 % (95 % CI 19.6 %, 58.0 %), followed by 29.3 % (95 % CI 11.4 %, 43.5 %) within 18 months, 17.1 % (95 % CI 0.3 %, 31.1 %) within 24 months and it almost disappeared within 30 months. The VE of 4-dose vaccination within 18 months and 24 months were 39.9 % (95 % CI 20.3 %, 54.7 %) and 27.2 % (95 % CI 8.6 %, 42.0 %), respectively. The median hospitalization cost of the children in the vaccinated group was higher at the four points but without significance. CONCLUSIONS: PCV13 had a certain protective effect on all-cause hospitalized pneumonia, and the booster immunization strategy had the best protective effect with great public health significance to enter the immunization program.

Comparative genomics of macaques and integrated insights into genetic variation and population history.

The crab-eating macaques ( Macaca fascicularis ) and rhesus macaques ( M. mulatta ) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is ∼42% lower, while centromeres are ∼3.7 times longer than those in humans. The characterization of ∼2 Mbp fixed genetic variants and ∼240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1 ). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO ). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2 ). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1 , SEMA3F , and HOXD13 ). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.

Development and validation of a clinical and ultrasound features-based nomogram for preoperative differentiation of renal urothelial carcinoma and central renal cell carcinoma.

PURPOSE: This study aimed to develop and validate an ultrasound (US)-based nomogram for the preoperative differentiation of renal urothelial carcinoma (rUC) from central renal cell carcinoma (c-RCC). METHODS: Clinical data and US images of 655 patients with 655 histologically confirmed malignant renal tumors (521 c-RCCs and 134 rUCs) were collected and divided into training (n = 455) and validation (n = 200) cohorts according to examination dates. Conventional US and contrast-enhanced US (CEUS) tumor features were analyzed to determine those that could discriminate rUC from c-RCC. Least absolute shrinkage and selection operator regression was applied to screen clinical and US features for the differentiation of rUC from c-RCC. Using multivariate logistic regression analysis, a diagnostic model of rUC was constructed and visualized as a nomogram. The diagnostic model's performance was assessed in the training and validation cohorts by calculating the area under the receiver operating characteristic curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness of the US-based nomogram. RESULTS: Seven features of both clinical features and ultrasound imaging were selected to build the diagnostic model. The nomogram achieved favorable discrimination in the training (AUC = 0.996, 95% CI: 0.993-0.999) and validation (AUC = 0.995, 95% CI: 0.974, 1.000) cohorts, and good calibration (Brier scores: 0.019 and 0.016, respectively). DCA demonstrated the clinical usefulness of the US-based nomogram. CONCLUSION: A noninvasive clinical and US-based nomogram combining conventional US and CEUS features possesses good predictive value for differentiating rUC from c-RCC.

Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.

Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated with OL-differentiation inhibition and neurogenesis. Notably, BRG1 depletion decreases H3K27me3 deposition, leading to the upregulation of BMP/WNT signaling and proneurogenic genes, which suppresses OL programs. Thus, our findings reveal a hitherto unexplored spatiotemporal-specific role of BRG1 for OPC differentiation in the developing CNS and underscore a new insight into BRG1/PRC2-mediated epigenetic regulation that promotes and safeguards OL lineage commitment and differentiation.

Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

Miao medicine Gu Yan Xiao tincture inhibits mTOR to stimulate chondrocyte autophagy in a rabbit model of osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: The Gu Yan Xiao tincture, a blend of traditional Chinese herbs, is traditionally used for osteoarthritis and related pain. This study investigated its mechanism of action in order to rationalize and validate its therapeutic use. AIM OF THE STUDY: This study analyzed, in a rabbit model of knee osteoarthritis, whether and how Gu Yan Xiao tincture exerts therapeutic benefits by modulating chondrocyte autophagy. MATERIALS AND METHODS: The active constituents within the GYX tincture were identified using liquid chromatography-mass spectrometry. The rabbit model was established by injecting animals with type II collagenase intra-articularly, and the effects of topically applied tincture were examined on osteoarthritis lesions of the knee using histopathology, micro-computed tomography and x-ray imaging. Effects of the tincture were also evaluated on levels of inflammatory cytokines, matrix metalloproteases, and autophagy in chondrocytes. As a positive control, animals were treated with sodium diclofenac. RESULTS: The tincture mitigated the reduction in joint space, hyperplasia of the synovium and matrix metalloproteases in serum that occurred after injection of type II collagenase in rabbits. These therapeutic effects were associated with inhibition of mTOR and activation of autophagy in articular chondrocytes. Inhibiting mTOR with rapamycin potentiated the therapeutic effects of the tincture, while inhibiting autophagy with 3-methyladenine antagonized them. CONCLUSIONS: Gu Yan Xiao tincture mitigates tissue injury in a rabbit model of osteoarthritis, at least in part by inhibiting mTOR and thereby promoting autophagy in chondrocytes. These results rationalize the use of the tincture not only against osteoarthritis but also potentially other diseases involving inhibition of autophagy in bones and joints.