Chemical Proteomics Reveals Nε-Fatty-Acylation of Septins by Rho Inactivation Domain (RID) of the Vibrio MARTX Toxin to Alter Septin Localization and Organization.

Vibrio species, the Gram-negative bacterial pathogens causing cholera and sepsis, produce multiple secreted virulence factors for infection and pathogenesis. Among these is the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin that releases several critical effector domains with distinct functions inside eukaryotic host cells. One such effector domain, the Rho inactivation domain (RID), has been discovered to catalyze long-chain Nε-fatty-acylation on lysine residues of Rho GTPases, causing inactivation of Rho GTPases and disruption of the host actin cytoskeleton. However, whether RID modifies other host proteins to exert additional functions remains to be determined. Herein, we describe the integration of bioorthogonal chemical labeling and quantitative proteomics to globally profile the target proteins modified by RID in living cells. More than 246 proteins are identified as new RID substrates, including many involved in GTPase regulation, cytoskeletal organization, and cell division. We demonstrate that RID extensively Nε-fatty-acylates septin proteins, the fourth cytoskeletal component of mammalian cells with important roles in diverse cellular processes. While affinity purification and mass spectrometry analysis show that RID-mediated Nε-fatty-acylation does not affect septin-septin interactions, this modification increases the membrane association of septins and confers localization to detergent-resistant membrane rafts. As a result, the filamentous assembly and organization of septins are disrupted by RID-mediated Nε-fatty-acylation, further contributing to cytoskeletal and mitotic defects that phenocopy the effects of septin depletion. Overall, our work greatly expands the substrate scope and function of RID and demonstrates the role of RID-mediated Nε-fatty-acylation in manipulating septin localization and organization.

miR-486-5p diagnosed atrial fibrillation, predicted the risk of left atrial fibrosis, and regulated angiotensin II-induced cardiac fibrosis via modulating PI3K/Akt signaling through targeting FOXO1.

This study focused on miR-486-5p in atrial fibrillation (AF) evaluating its clinical significance and revealing its regulatory mechanism in cardiac fibroblasts, aiming to explore a novel biomarker for AF. The study enrolled 131 AF patients and 77 non-AF individuals. With the help of polymerase chain reaction (PCR), the expression of miR-486-5p was evaluated. The significance of miR-486-5p in the diagnosis of AF and the occurrence of left atrial fibrosis (LAF) was assessed by receiver operating curve (ROC) and logistic analyses. The regulatory effect and mechanism of miR-486-5p on cardiac fibrosis were investigated in human cardiac fibroblasts treated with angiotensin II. miR-486-5p was significantly upregulated in AF patients and discriminated AF patients from non-AF individuals. Increasing miR-486-5p showed a significant association with decreasing left ventricular ejection fraction (LVEF), increasing left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVEDd), and the high incidence of LAF in AF patients. Moreover, miR-486-5p was identified as a risk factor for LAF and could distinguish AF patients with LAF and without LAF. In cardiac fibroblasts, angiotensin II induced the upregulation of miR-486-5p and promoted cell proliferation, migration, and collagen synthesis. miR-486-5p negatively regulated forkhead box O1 (FOXO1) and its knockdown could reverse the promoted effect of angiotensin II. FOXO1 alleviated the effect of miR-486-5p, and the miR-486-5p/FOXO1 could activate PI3K/Akt signaling. The activation of PI3K/Akt signaling alleviated the enhanced proliferation, migration, and collagen synthesis of cardiac fibroblasts induced by angiotensin II, and its inhibition showed opposite effects. Increased miR-486-5p served as a biomarker for the diagnosis and development prediction of AF. miR-486-5p regulated cardiac fibroblast viability and collagen synthesis via modulating the PI3K/Akt signaling through targeting FOXO1.

Spatial and Temporal Patterns of Disease Burden attributable to High Body Mass Index in Belt and Road Initiative Countries, 1990-2019.

OBJECTIVE: This study aimed to analyze the spatial and temporal patterns of disease burden attributed to high body mass index (DB-hBMI) from 1990 to 2019 in Belt and Road Initiative (BRI) countries, in light of increasing hBMI prevalence worldwide. DESIGN: The study was a secondary analysis of global burden of disease 2019 (GBD 2019) that analyzed (using Joinpoint regression analysis) numbers and the age-standardized rate of mortality and disability-adjusted life years (DALYs) of hBMI-induced diseases and their trends from 1990 to 2019 and in the final decade. SETTING: GBD 2019 study data for BRI countries were categorized by country, age, gender, and disease. PARTICIPANTS: GBD 2019 data were used to analyze DB-hBMI in BRI countries. RESULTS: In 2019, China, India, and Russia reported the highest mortality and DALYs among BRI countries. From 1990 to 2019, the age-standardized DALYs increased in Southeast Asia and South Asia, whereas many European countries saw declines. Notably, Bangladesh, Nepal, and Vietnam showed the steepest increases, with AAPC values of 4.42%, 4.19%, and 4.28%, respectively (all P<0.05). In contrast, Israel, Slovenia, and Poland experienced significant reductions, with APCC values of -1.70%, -1.63%, and -1.58%, respectively (all P<0.05). The most rapid increases among males were seen in Vietnam, Nepal, and Bangladesh, while Jordan, Poland, and Slovenia recorded the fastest declines among females. Across most BRI countries, the burden of diabetes and kidney diseases related to hBMI showed a significant uptrend. CONCLUSION: DB-hBMI varies significantly by region, age, gender, and disease type across BRI countries. It can pose a substantial threat to public health.

Estrogen downregulates CD73/adenosine axis hyperactivity via adaptive modulation PI3K/Akt signaling to prevent myocarditis and arrhythmias during chronic catecholamines stress.

BACKGROUND: During myocardial damage, the sex hormone estrogen and CD73, the main enzyme that converts AMP into adenosine, are cardioprotective molecules. However, it is unclear how these two molecules work together to provide cardioprotection. The current study aimed to elucidate the interaction between estrogen and CD73 under chronic stress. METHODS: Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. Two weeks after the operation, the mice were treated with daily isoproterenol (10 mg/kg/day) injections for 14 days. The effect of E2 on relevant cardiac injury biomarkers (BNP, ANP), myocardial morphology (cardiomyocyte surface area), electrocardiography, CD73 protein expression and activity, and macrophage (CD86 + and CD206 +) infiltrations were assessed. In vitro, H9C2 cells were treated with 1 nM of estrogen and 10 mM APCP (CD73 inhibitor α, ß-methylene adenosine-5'-diphosphate), 10 µM isoproterenol and 20 µm LY294002 (PI3K inhibitor) for 24 h and western blot was done to elucidate the mechanism behind the effect of estrogen on the CD73/adenosine axis. RESULTS: Estrogen deficiency during chronic catecholamine stress caused myocardial injury, thereby triggering the hyperactivity of the CD73/adenosine axis, which aggravated myocarditis, adverse remodeling, and arrhythmias. However, estrogen normalizes CD73/Adenosine axis via the upregulation of PI3K/Akt pathways to prevent adverse outcomes during stress. In vivo results showed that the inhibition of PI3K significantly decreased PI3K/Akt pathways while upregulating the CD73/adenosine axis and apoptosis. CONCLUSION: Estrogen's pleiotropy cardioprotection mechanism during stress includes its normalization of the CD73/Adenosine axis via the PI3K/Akt pathway. Video Abstract.

Nonequilibrium interactions between multi-scale colloids regulate the suspension microstructure and rheology.

Understanding nonequilibrium interactions of multi-component colloidal suspensions is critical for many dynamical settings such as self-assembly and material processing. A key question is how the nonequilibrium distributions of individual components influence the effective interparticle interactions and flow behavior. In this work, we develop a first-principle framework to study a bidisperse suspension of colloids and depletants using a Smoluchowski equation and corroborated by Brownian dynamics (BD) simulations. Using nonlinear microrheology as a case study, we demonstrate that effective depletion interactions between driven colloids are sensitive to particle timescales out of equilibrium and cannot be predicted by equilibrium-based pair potentials like Asakura-Oosawa. Furthermore, we show that the interplay between Brownian relaxation timescales of different species plays a critical role in governing the viscosity of multi-component suspensions. Our model highlights the limitations of using equilibrium pair potentials to approximate interparticle interactions in nonequilibrium processes such as hydrodynamic flows and presents a useful framework for studying the transport of driven, interacting suspensions.

Dynamic interfaces for contact-time control of colloidal interactions.

Understanding pairwise interactions between colloidal particles out of equilibrium has a profound impact on dynamical processes such as colloidal self assembly. However, traditional colloidal interactions are effectively quasi-static on colloidal timescales and cannot be modulated out of equilibrium. A mechanism to dynamically tune the interactions during colloidal contacts can provide new avenues for self assembly and material design. In this work, we develop a framework based on polymer-coated colloids and demonstrate that in-plane surface mobility and mechanical relaxation of polymers at colloidal contact interfaces enable an effective, dynamic interaction. Combining analytical theory, simulations, and optical tweezer experiments, we demonstrate precise control of dynamic pair interactions over a range of pico-Newton forces and seconds timescales. Our model helps further the general understanding of out-of-equilibrium colloidal assemblies while providing extensive design freedom via interface modulation and nonequilibrium processing.

CHD-related/specific mortality of 3.17 million people in a transitioning region: trends, risk factors, and prevention.

BACKGROUND: Demographic shifts cause uncertain changes in the burden of coronary heart disease (CHD) in transitioning regions. We aimed to analyze the trends of CHD burden and its risk factors in Pudong, Shanghai, and explore prevention strategies for transitioning regions. METHODS: We analyzed CHD-related and CHD-specific deaths in Pudong from 2005 to 2020, including the crude mortality rate (CMR), age-standardized mortality rate worldwide (ASMRW), years of life lost (YLL), and age-specific proportions. We also examined the impact of population aging on the burden of CHD. The Joinpoint Regression Program was used to analyze trends, and the decomposition method was used to evaluate the impact of demographics on the mortality rate. RESULTS: Of the 86,171 CHD-related deaths, 52,152 (60.52%) were CHD-specific deaths. For both CHD-related and CHD-specific deaths, there was a significant increase in the CMR, ASMRW, and YLL rate, except in the 70-79-year age group, which exhibited a distinctive and statistically significant decline in these rates (all P < 0.05). There were steadily increasing trends in the rates caused by aging from 2005 to 2020, with average annual percent changes (AAPCs) of 42.59% and 41.43%, respectively (all P < 0.05). CONCLUSIONS: Our results indicate that the CHD burden in Pudong has been persistently increasing, but in the age group of 70-79 years, substantial declines were observed. The quality of primary healthcare services may be a critical point in addressing the overwhelming CHD burden.

Effects of mutual intercropping on cadmium accumulation of Solanum photeinocarpum Nakamura et Odashima and its post-grafting generations.

The cadmium (Cd) contaminated agricultural soil has become serious in recent years, but it will take long time for Cd-hyperaccumulator to remedy. To speed up the remediation of agricultural soil and achieve the safe agricultural production as soon as possible, the potential Cd-hyperaccumulator Solanum photeinocarpum Nakamura et Odashima was intercropped with its post-grafting generations in Cd-contaminated soil. Intercropping increased the biomass, Cd contents and Cd extractions of S. photeinocarpum and its post-grafting generations in the pot and field experiments. Both the whole plant or shoot biomass and the Cd extraction by whole plant or shoot in intercroppings had a linear regression relationship with that in monocultures. In the field experiment, intercropping increased the shoot Cd extraction of S. photeinocarpum by 9.86%-40.06% compared with the monoculture. Intercropping increased the content of chlorophyll, activity of superoxide dismutase, activity of catalase, and soluble protein content of S. photeinocarpum and its post-grafting generations but reduced their peroxidase activities in the pot experiment. Therefore, intercropping S. photeinocarpum with its post-grafting generations can improve their phytoremediation ability, and the best choice is S. photeinocarpum intercropped with its post-grafting generation of wild potato rootstock. Novelty statementIntercropping Solanum photeinocarpum Nakamura et Odashima with its post-grafting generations could mutually promote the Cd accumulation in the two types of plant species, and improve their phytoremediation ability for remedying the Cd-contaminated soil.

Transcriptome Profiles Reveal the Promoting Effects of Exogenous Melatonin on Fruit Softening of Chinese Plum.

In this study, we investigated the effect of exogenous melatonin (MT) on cell wall metabolism leading to Chinese plum (Prunus salicina Lindl.) fruit softening. Exogenous MT treatment increased the endogenous MT content in plum fruits before fruit ripening. However, in mature plum fruits, exogenous MT treatment decreased the fruit hardness, pulp hardness, fruit elasticity, contents of ion-bound pectin, covalently-bound pectin, hemicellulose, and cellulose, and activities of xyloglucan endotransglycosylase/hydrolase and endo-ß-1,4-glucanase, and increased the water-soluble pectin content, and activities of pectin methyl esterase, pectin lyase, polygalacturonase, ß-galactopyranosidase, and α-L-arabinofuranosidase. Transcriptome analysis revealed that the differentially expressed genes (DEGs) associated with cell wall metabolism in the exogenous MT-treated plum fruits were mainly enriched in the pentose and glucuronate interconversions, phenylpropanoid biosynthesis, cyanoamino acid metabolism, and galactose metabolism pathways. Analysis of these DEGs revealed that exogenous MT treatment affected the expression of genes regulating the cell wall metabolism. Overall, exogenous MT treatment promotes the fruit softening of Chinese plum.

Melatonin Promotes Iron Reactivation and Reutilization in Peach Plants under Iron Deficiency.

The yellowing of leaves due to iron deficiency is a prevalent issue in peach production. Although the capacity of exogenous melatonin (MT) to promote iron uptake in peach plants has been demonstrated, its underlying mechanism remains ambiguous. This investigation was carried out to further study the effects of exogenous MT on the iron absorption and transport mechanisms of peach (Prunus persica) plants under iron-deficient conditions through transcriptome sequencing. Under both iron-deficient and iron-supplied conditions, MT increased the content of photosynthetic pigments in peach leaves and decreased the concentrations of pectin, hemicellulose, cell wall iron, pectin iron, and hemicellulose iron in peach plants to a certain extent. These effects stemmed from the inhibitory effect of MT on the polygalacturonase (PG), cellulase (Cx), phenylalanine ammonia-lyase (PAL), and cinnamoyl-coenzyme A reductase (CCR) activities, as well as the promotional effect of MT on the cinnamic acid-4-hydroxylase (C4H) activity, facilitating the reactivation of cell wall component iron. Additionally, MT increased the ferric-chelate reductase (FCR) activity and the contents of total and active iron in various organs of peach plants under iron-deficient and iron-supplied conditions. Transcriptome analysis revealed that the differentially expressed genes (DEGs) linked to iron metabolism in MT-treated peach plants were primarily enriched in the aminoacyl-tRNA biosynthesis pathway under iron-deficient conditions. Furthermore, MT influenced the expression levels of these DEGs, regulating cell wall metabolism, lignin metabolism, and iron translocation within peach plants. Overall, the application of exogenous MT promotes the reactivation and reutilization of iron in peach plants.

Revisiting Supersaturation of a Biopharmaceutical Classification System IIB Drug: Evaluation via a Multi-Cup Dissolution Approach and Molecular Dynamic Simulation.

As a subclass of the biopharmaceutical classification system (BCS) class II, basic drugs (BCS IIB) exhibit pH-dependent solubility and tend to generate supersaturation in the gastrointestinal tract, leading to less qualified in vitro-in vivo correlation (IVIVC). This study aims to develop a physiologically based multi-cup dissolution approach to improve the evaluation of the supersaturation for a higher quality of IVIVC and preliminarily explores the molecular mechanism of supersaturation and precipitation of ketoconazole affected by Polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methyl-cellulose (HPMC). The concentration of ketoconazole in each cup of the dynamic gastrointestinal model (DGIM) was measured using fiber optical probes. Molecular interactions between ketoconazole and PVPVA or HPMC were simulated by Materials Studio. The results demonstrated that PVPVA and HPMC improved and maintained the supersaturation of ketoconazole. PVPVA exhibited superior precipitation inhibitory effect on ketoconazole molecule aggregation due to slightly stronger van der Waals forces as well as unique electrostatic forces, thereby further enhancing in vitro drug absorption, which correlated well with in vivo drug absorption. Compared with a conventional dissolution apparatus paddle method, the DGIM improved the mean prediction error through the IVIVC from 19.30% to 9.96%, reaching the qualification criteria. In conclusion, the physiologically based multi-cup dissolution approach enables improved evaluation of supersaturation in gastrointestinal transportation of BCS IIB drug ketoconazole, enabling screening screen precipitation inhibitors and achieving qualified IVIVC for drug formulation studies.

Self-Cascade Nanoenzyme of Cupric Oxide Nanoparticles (CuO NPs) Induced in Situ Catalysis Formation of Polyelectrolyte as Template for the Synthesis of Near-Infrared Fluorescent Silver Nanoclusters and the Application in Glutathione Detection and Bioimaging.

In this work, near-infrared fluorescent silver nanoclusters (Ag NCs) were prepared based on the in situ formed poly methacrylic acid (PMAA) as the template and stabilizer, which is synthesized by methacrylic acid (MAA) and hydroxyl radical (·OH) that is generated by the cascade nanoenzyme reaction of cupric oxide nanoparticles (CuO NPs). CuO NPs possess the intrinsic glutathione-like (GPx-like) and peroxidase-like (POD-like) activities, which can catalyze glutathione (GSH) and O2 to produce hydrogen peroxide (H2O2), and then transform into ·OH. The fluorescence intensity of Ag NCs decreases with the addition of GSH, because the -SH can easily anchor on the surface, resulting in the PMAA leaving the Ag NCs, and the coeffect of GSH and PMAA results in the aggregation to form larger Ag NPs. A good linear relationship between the fluorescence quenching rate and the GSH concentration was found in the range 0.01-40 µM with the detection limit 8.0 nM. The Ag NCs can be applied in the detection of GSH in the serum, as well as bioimaging of endogenous and exogenous GSH in cells with high sensitivity. Moreover, the normal and cancer cells can be distinguished through bioimaging because of the different GSH levels. The new method for the preparation of biocompatible nanoprobe based on the nanozyme tandem catalysis and the in situ formed template can avoid the direct usage of polymers or protein templates that hinder preparation and separation, providing a reliable approach for the synthesis, biosensing, and bioimaging of nanoclusters.

Fatty Acyl Sulfonyl Fluoride as an Activity-Based Probe for Profiling Fatty Acid-Associated Proteins in Living Cells.

Fatty acids play fundamental structural, metabolic, functional, and signaling roles in all biological systems. Altered fatty acid levels and metabolism have been associated with many pathological conditions. Chemical probes have greatly facilitated biological studies on fatty acids. Herein, we report the development and characterization of an alkynyl-functionalized long-chain fatty acid-based sulfonyl fluoride probe for covalent labelling, enrichment, and identification of fatty acid-associated proteins in living cells. Our quantitative chemical proteomics show that this sulfonyl fluoride probe targets diverse classes of fatty acid-associated proteins including many metabolic serine hydrolases that are known to be involved in fatty acid metabolism and modification. We further validate that the probe covalently modifies the catalytically or functionally essential serine or tyrosine residues of its target proteins and enables evaluation of their inhibitors. The sulfonyl fluoride-based chemical probe thus represents a new tool for profiling the expression and activity of fatty acid-associated proteins in living cells.

A fluorescence nanoplatform for the determination of hydrogen peroxide and adenosine triphosphate via tuning of the peroxidase-like activity of CuO nanoparticle decorated UiO-66.

A novel nanocomposite of CuO nanoparticle-modified Zr-MOF (CuO/UiO-66) was synthesized and developed as a fluorescence nanoplatform for H2O2 and adenosine triphosphate (ATP) via the "turn-on-off" mode in the presence of terephthalic acid (TA). The structure of CuO/UiO-66 was thoroughly characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and other techniques. The CuO/UiO-66 with enhanced peroxidase-like (POD) activity obtained due to the Zr4+ in UiO-66 is beneficial to the aggregation of CuO NPs on its surface. As a result, the strengthened fluorescence at 425 nm with the excitation of 300 nm was found due to the highly fluorescent species of TAOH. This is produced by the oxidation of TA by ·OH that came from the catalysis of H2O2 via the peroxidase mimic of CuO/UiO-66. Hence the modification of CuO NPs on porous UiO-66 can provide a friendly and sensitive physiological condition for H2O2 detection. However, upon addition of ATP, the fluorescence intensity of TAOH at 425 nm effectively declined owing to the formation of complexation of Zr4+-ATP and the interaction of CuO to ATP which hampers the catalytic reaction of CuO/UiO-66 to H2O2. The specific interaction induced "inhibition of the peroxide-like activity" endows the sensitive and selective recognition of ATP. The detection limits were 16.87 ± 0.2 nM and 0.82 ± 0.1 nM, and linear analytical ranges were 0.02-100 µM and 0.002-30 µM for H2O2 and ATP, respectively. The novel strategy was successfully applied to H2O2 and ATP determination in serum samples with recoveries of 97.2-103.8% for H2O2 and 97.6-101.7% for ATP, enriching the avenue to design functional MOFs and providing new avenue of multicomponent bioanalysis.

Effect of hydrogenation on the thermal conductivity of 2D gallium nitride.

The indirect bandgap of two-dimensional GaN hinders its application in the optical field. Hydrogenation can convert the bandgap type of the GaN monolayer from an indirect to a direct one and also tune the bandgap size. The thermal transport, an important property in the application of two-dimensional materials, is also influenced by hydrogenation. By performing first-principles calculations and solving the phonon Boltzmann equation, we investigate the effect of hydrogenation on the thermal conductivity of the GaN monolayer. The results show that hydrogenation will slightly increase the thermal conductivity of the GaN monolayer from 70.62 Wm-1 K-1 to 76.23 Wm-1 K-1 at 300 K. The little effect of hydrogenation on thermal conductivity is mainly dominated by two competing factors: (1) the reduction of ZA mode lifetime due to the breaking of reflection symmetry after hydrogenation and (2) the increased contribution from TA and LA modes due to the reduction of anharmonic scattering caused by the enlarged phonon bandgap after hydrogenation. The results are compared with other two-dimensional materials with hexagonal monolayer structures.

Effectiveness of Wearable Device-based Intervention on Glycemic Control in Patients with Type 2 Diabetes: A System Review and Meta-Analysis.

With the development of flexible electronics and chip technology, the application value of wearable devices in lifelong treatment of chronic diseases is increasing. In view of its rapid development and diversified forms, wearable device-based intervention seems to provide a promising option to solve the problems of long-term glycemic control in type 2 diabetes (T2D). However, to date, it is unclear whether the intervention based on wearable device is effective on glycemic control in patients with T2D. In order to explore whether this choice is effective in glycemic control in patients with T2D, after database search and study screening, 6 studies and 1001 patients were selected from 181studies for this meta-analysis. The results guided that the wearable device-based intervention may be more effective than usual care on glycemic control in patients with T2D. Subgroup analysis showed that when the duration of intervention was equal to or less than 12 weeks, the effect of wearable device-based intervention was significantly different from that of usual care, but when the intervention duration greater than 12 weeks, the effect was not significantly different. The intervention effect of wearable devices with goal-setting or encouragement functions was significantly better than that of usual care, and there was no significant difference between automatic drug delivery wearable devices and usual care. In conclusion, the wearable device-based intervention is effective on glycemic control in patients with T2D. In general, this choice of wearable devices for patients with T2D may be effective to some extent.

Seasonal association between ambient ozone and mortality in Zhengzhou, China.

Different seasonal health effects of ambient ozone (O3) have been reported in previous studies. This might be due to inappropriate adjustment of temperature in different seasons. We used daily data on non-accidental mortality and ambient air pollution in Zhengzhou from January 19, 2013 to June 30, 2015. Season-stratified analyses using generalized additive models were conducted to evaluate the seasonal associations with adjustment of temperature with different lagged days (lag0-1 for warm season, lag0-14 for cold season). We recorded a total of 70,443 non-accidental deaths in Zhengzhou during the study period. Significant associations were observed between ambient O3 and mortality in cold season. Every 10-µg/m3 increment of 24-h O3 of 1-day lagged time was associated with a 1.38% (95% CI 0.60, 2.16%) increase in all cause mortality, 1.35% (95% CI 0.41, 2.30%) increase in cardiovascular mortality, and 1.78% (95% CI 0.43, 3.14%) increase in respiratory mortality. Similar associations were observed when using daily 1- and 8-h maximum concentrations of O3. No significant association was found during warm season. This study suggests a more pronounced ozone-mortality association in cold season in Zhengzhou, and we suggest that different lagged temperatures should be considered when examining the seasonal health effects of ambient ozone.

Combining Global-Constrained Concept Factorization and a Regularized Gaussian Graphical Model for Clustering Single-Cell RNA-seq Data.

Single-cell RNA sequencing technology is one of the most cost-effective ways to uncover transcriptomic heterogeneity. With the rapid rise of this technology, enormous amounts of scRNA-seq data have been produced. Due to the high dimensionality, noise, sparsity and missing features of the available scRNA-seq data, accurately clustering the scRNA-seq data for downstream analysis is a significant challenge. Many computational methods have been designed to address this issue; nevertheless, the efficacy of the available methods is still inadequate. In addition, most similarity-based methods require a number of clusters as input, which is difficult to achieve in real applications. In this study, we developed a novel computational method for clustering scRNA-seq data by considering both global and local information, named GCFG. This method characterizes the global properties of data by applying concept factorization, and the regularized Gaussian graphical model is utilized to evaluate the local embedding relationship of data. To learn the cell-cell similarity matrix, we integrated the two components, and an iterative optimization algorithm was developed. The categorization of single cells is obtained by applying Louvain, a modularity-based community discovery algorithm, to the similarity matrix. The behavior of the GCFG approach is assessed on 14 real scRNA-seq datasets in terms of ACC and ARI, and comparison results with 17 other competitive methods suggest that GCFG is effective and robust.

scEM: A New Ensemble Framework for Predicting Cell Type Composition Based on scRNA-Seq Data.

With the advent of single-cell RNA sequencing (scRNA-seq) technology, many scRNA-seq data have become available, providing an unprecedented opportunity to explore cellular composition and heterogeneity. Recently, many computational algorithms for predicting cell type composition have been developed, and these methods are typically evaluated on different datasets and performance metrics using diverse techniques. Consequently, the lack of comprehensive and standardized comparative analysis makes it difficult to gain a clear understanding of the strengths and weaknesses of these methods. To address this gap, we reviewed 20 cutting-edge unsupervised cell type identification methods and evaluated these methods comprehensively using 24 real scRNA-seq datasets of varying scales. In addition, we proposed a new ensemble cell-type identification method, named scEM, which learns the consensus similarity matrix by applying the entropy weight method to the four representative methods are selected. The Louvain algorithm is adopted to obtain the final classification of individual cells based on the consensus matrix. Extensive evaluation and comparison with 11 other similarity-based methods under real scRNA-seq datasets demonstrate that the newly developed ensemble algorithm scEM is effective in predicting cellular type composition.

CLIP170 inhibits the metastasis and EMT of papillary thyroid cancer through the TGF-ß pathway.

Metastasis poses a significant challenge in combating tumors. Even in papillary thyroid cancer (PTC), which typically exhibits a favorable prognosis, high recurrence rates are attributed to metastasis. Cytoplasmic linker protein 170 (CLIP170) functions as a classical microtubule plus-end tracking protein (+TIP) and has shown close association with cell migration. Nevertheless, the specific impact of CLIP170 on PTC cells remains to be elucidated. Our analysis of the GEO and TCGA databases unveiled an association between CLIP170 and the progression of PTC. To explore the impact of CLIP170 on PTC cells, we conducted various assays. We evaluated its effects through CCK-8, wound healing assay, and transwell assay after knocking down CLIP170. Additionally, the influence of CLIP170 on the cellular actin structure was examined via immunofluorescence; we further investigated the molecular expressions of epithelial-mesenchymal transition (EMT) and the transforming growth factor-ß (TGF-ß) signaling pathways through Western blotting and RT-qPCR. These findings were substantiated through an in vivo nude mouse model of lung metastasis. We observed a decreased expression of CLIP170 in PTC in contrast to normal thyroid tissue. Functionally, the knockdown of CLIP170 (CLIP170KD) notably enhanced the metastatic potential and EMT of PTC cells, both in vitro and in vivo. Mechanistically, CLIP170KD triggered the activation of the TGF-ß pathway, subsequently promoting tumor cell migration, invasion, and EMT. Remarkably, the TGF-ß inhibitor LY2157299 effectively countered TGF-ß activity and significantly reversed tumor metastasis and EMT induced by CLIP170 knockdown. In summary, these findings collectively propose CLIP170 as a promising therapeutic target to mitigate metastatic tendencies in PTC.