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The influence of external strain on the gate leakage current of AlGaN/GaN high-electron-mobility transistors was studied. The magnitude of the leakage current increased by 39% under 0.1% tensile strain but decreased by 23% under −0.1% compressive strain. The leakage current obeyed the Poole–Frenkel conduction mechanism, demonstrating a decrease/increase in the barrier height for electron emission from the trap state into the continuum dislocation state. Furthermore, the magnitude of critical reverse stressing voltage for the onset of degradation induced by the inverse piezoelectric effect became lower/higher under tensile/compressive strain compared with that of the initial state, which was attributed to the modification of the total stress in the film. In addition, using the transient current method, it was established that the detrapping time constant for the traps in the AlGaN barrier increased as a result of the tensile strain, which is ascribed to movement of the dislocation level away from the conduction band. [ABSTRACT FROM AUTHOR]

Following publication of the original article [1], the authors reported an error in [ABSTRACT FROM AUTHOR]

Background: Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells. Methods: We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and 13C6 metabolites tracing analysis, and then confirmed the results using patient tissue protein samples through Western Blotting. Bioinformatics analysis and transfection assay were used to confirm the upstream target of the low levels of pyruvate status in CCA. The regulation of cMyc by HDAC3 was studied through immunoprecipitation and Western Blotting. Results: We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation. Conclusions: Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies. [ABSTRACT FROM AUTHOR]

Few studies have focused on frailty as a predictor of mortality and readmission among inpatients in the acute care setting, especially over long follow-up periods. We conducted this study to determine the impact of the frailty on subsequent mortality and readmission in this setting. This study was a prospective observational study conducted in the acute geriatric wards, with a three-year follow-up duration. We assessed frailty via the 36-item Frailty Index (FI), and a cut-off value of 0.25 was used to identify the presence or absence of frailty. We collected survival and readmission information through telephone interviews at 12, 24, and 36 months. We used the Cox regression model to examine the association between frailty and outcomes interested (death and readmission). The present study included 271 patients (mean age: 81.1 years old; 20.3% females), of whom 21.4% died during the 3-year follow-up period. One hundred and thirty-three patients (49.1%) were identified as being frail. The prevalence of frailty was similar in men and women (46.8% vs.58.2%, P = 0.130). Compared with non-frail patients, death and hospital readmission rates of frail patients were increased. Frailty was an independent predictor of 3-year death (adjusted hazard ratio (HR): 2.09; 95% confidence interval (CI): 1.20 to 3.63) and readmission (adjusted HR: 1.40; 95% CI: 1.04 to 1.88) after adjusting for several potential confounders. Frailty is prevalent among older inpatients and is a valuable predictor of 3-year mortality and hospital readmission in an acute care setting. [ABSTRACT FROM AUTHOR]

The gate defect of the ferroelectric HfO2-based Si field-effect transistor (Si FeFET) plays a dominant role in its reliability issue. The first-principles calculations are an effective method for the atomic-scale understanding of gate defects. However, the first-principles study on the defects of FeFET gate stacks, i.e., the metal/orthorhombic-Hf0.5Zr0.5O2/SiOx/Si structure, has not been reported so far. The key challenge is the construction of metal/orthorhombic-Hf0.5Zr0.5O2/SiOx/Si gate stack models. Here, the atomic structure and defect property of orthorhombic-Hf0.5Zr0.5O2/SiO2/Si gate stack are systematically studied by first-principles calculations. We use the Hf0.5Zr0.5O2(130) high-index crystal face as the orthorhombic ferroelectric layer and construct a robust atomic structure of the orthorhombic-Hf0.5Zr0.5O2/SiO2/Si gate stack without any gap states based on the electron counting rule. The calculated band offsets show that this gate structure is of type-I band alignment. Furthermore, the formation energies and charge transition levels (CTLs) of defects reveal that the oxygen vacancy defects are more favorable to form compared with other defects such as oxygen interstitial and Hf/Zr vacancy, and their CTLs are mainly localized near the Si conduction band minimum and valence band maximum, in agreement with the reported experimental results. The oxygen vacancy defects are responsible for charge trapping/de-trapping behavior in Si FeFET. This work provides an insight into gate defects and paves the way to carry out the first-principles study of ferroelectric HfO2-based Si FeFET. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway up-regulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA. [ABSTRACT FROM AUTHOR]

The trap characteristics and polarization effect on the trapping behavior in Hf0.5Zr0.5O2 ferroelectric field-effect transistors were analyzed. The current transient that corresponds to the trapping/detrapping of charge carriers was measured and the exact time constant spectra were extracted. In accordance with the different time constants and activation energies as well as the dependence of the trapping behavior on the filling conditions, traps that originated from the oxygen vacancies in the Hf0.5Zr0.5O2 layer and from the Si/SiO2 interface trap states were identified. The detrapping peaks in time constant spectra showed a consistent changing trend with the variation of remanent polarization, confirming that the positive polarization enhanced the trapping of charge carriers injected from channel side to the ferroelectric layer. [ABSTRACT FROM AUTHOR]

[Display omitted] • A particle stress model at subgrid scale is proposed to consider the effect of gas flow on particle motion. • Anisotropic behaviors of gas-particle interactions are described by a second-order moment model. • Large eddy simulation is used to simulate numerically dense particle flow in a small-scale fluidized bed. • Bubblelike granular temperature is 11.2 times larger than particle granular temperature at 4u mf. • The evolution of core-annular flow structure and gulf-stream of particle flow patterns are obtained. Large eddy simulation of dense particle flow in fluidized bed is an advanced strategy to acquire a better understanding mechanism of gas-particle two-phase turbulent flow. A novelty particle stress model at subgrid scale level based on the Euler-Euler two-fluid frame is proposed to consider the effect of gas flow on particle dynamics. Anisotropic dispersion of interactions between gas and particle is modeled by a developed second-order moment approach, the four-way coupling is used to combine the particle–particle collisions by using the particle granular temperature based on the kinetic theory of granular flow. Numerical simulation is carried out in a small-scale fluidized bed and predictions are well agreed with the experimental data. Results show that the evolution of core-annular flow structure is captured. Increased superficial gas velocity is favorable for the enhancement of bubble hydrodynamics and anisotropic particle dispersions. At the 4u mf , Bubblelike granular temperature is 11.2 times larger than particle granular temperature, and mean and standard deviation values of axial particle velocity are approximately 2.2 times and 1.5 times larger than those of 2u mf. Bubble motions have a great effect on the heterogeneous flow pattern, particle dynamics and the redistribution of particle Reynolds stresses. [ABSTRACT FROM AUTHOR]

In this study, the current-transient method has been conducted to investigate the trap states in p-GaN gate high-electron-mobility transistors (HEMTs) under reverse gate stress. An irregular threshold voltage shift under reverse gate bias has been observed through the pulsed transfer measurements with different delay times. It suggests that both the hole insufficiency and hole trapping are generated during the reverse gate pulse bias. With proper selection of the delay time based on the pulsed characterizations, the hole detrapping can be effectively evaluated after the hole recovery is completed. In addition, by subtracting the trapping behavior caused by the measurement condition, the actual detrapping transient under reverse gate filling voltages can be obtained with the current-transient method. Three traps have been observed with the energy levels of 0.484, 0.390, and 0.235 eV. The identification of hole traps may provide a basis on the understanding of threshold voltage instability and further improvement of the reliability of p-GaN gate HEMTs. [ABSTRACT FROM AUTHOR]

The change of electrical properties of flexible low-temperature polysilicon (LTPS) thin-film transistors (TFTs) under biaxial bending strains was studied. Biaxial strains were applied using a ring-on-ring bending test rig. The magnitude of the strain was determined by theoretical calculations and finite-element simulations. With an increase in strain, the transfer curve shifted to a negative bias. At a biaxial strain level of 12%, the threshold voltage decreased by 27%, the field-effect mobility decreased by 13%, and the subthreshold slope increased by 25%. It had a more significant effect on the property changes than the uniaxial strain; this difference may be attributed to additional trap states generated by the biaxial strain. The analysis showed that the trap density increased when the strain level increased. The contributions of the increases in the grain-boundary trap state density and the interface trap state density to the degradation in the electrical properties were derived to be 10% and 90%, respectively. After removal of the biaxial bending strains, the electrical performance showed recovery behavior, but the performance could not return fully to its original state. [ABSTRACT FROM AUTHOR]

In this work, the current transient method was conducted for trap analysis in the p-GaN gate high-electron-mobility transistors (HEMTs) in the OFF-state. Based on the traditional detrapping transient measurements, the pure recovery transients can be isolated by subtracting the undetected part caused by the measurement conditions. A comparison of the measured and actual recovery transients under different drain filling voltages was presented. It suggested that this method can be effective to analyze the unregular transient curves and distinguish the charge trapping type preliminarily. In addition, three traps were identified based on the time constant spectra and the hidden absolute amplitudes of traps can be corrected using the differential amplitude spectra. The information of trap levels in the buffer layer and AlGaN barrier layer was revealed, consisting of three electron traps with energy levels of 0.313, 0.265, and 0.467 eV. The identification of the traps may provide a physical foundation for better understanding of the drain-induced trapping effect during the OFF-state in p-GaN HEMTs. [ABSTRACT FROM AUTHOR]

[Display omitted] • A SGS particle kinetic energy mode is proposed for modeling and simulation of particle slug flow. • A large eddy simulation is used to solve the hydrodynamic parameters of particle dispersion behavior. • Distinctively heterogenous flow structures and the effect of gas flow on particle motions are revealed. • Bubblelike vertical Reynolds stress at x/W = 0.28 is 4.0 times larger than that of the lateral x-direction. • Dominant frequencies of slug flow are 10.8 Hz, 7.7 Hz in center region, and 4.6 Hz, 1.7 Hz at walls. In this study, an investigation on particle hydrodynamic behaviors of gas-particle slug flow is modeled and numerically simulated. A novelty particle kinetic energy model at subgrid-scale level is developed to consider the effect of gas turbulence on particle movement and a four-way coupling approach is combined. Anisotropic particle dispersions and the multiphase interactions is revealed by using a second-order moment turbulence model and large eddy simulation is performed to solve the Euler-Euler two-fluid transport equations, Predictions are well agreed with the experimental data and reported results by discrete particle model built-in the multiphase flow model with interphase exchanges code. Bubble motions have great effects on the particle dynamics due to bubble entrainment. Flow patterns of particle circulation are generated between higher and lower concentrations. The largest frequency of power spectrum density at center of top surface is approximately 4.5 times larger than that of wall region. Bubblelike granular temperatures are much larger than smaller-scale particle granular temperature. At the top surface, maximum value of vertical bubblelike Reynolds stress is found at x/W = 0.28, it is 4.0 times larger than that of the lateral x-direction. In addition, the mean values, and the standard deviation of SGS particle kinetic energy at center are both approximately 3.5 times larger than those of z = 10.0 cm. For particle shear stress at middle section, maximum ratios of mean value and standard deviation at central regions to those of walls reach up to 8.0 and 11.0. [ABSTRACT FROM AUTHOR]

Background and purpose: Motoric cognitive risk (MCR) syndrome characterized by subjective cognitive complaints and slow gait has been proposed and validated as a pre‐dementia syndrome. The overall and specific ethnic prevalence of MCR and the associated factors are poorly understood in middle‐aged to older community‐dwelling residents in west China. Methods: The present study included 6091 samples from the prospective cohort study, West China Health and Aging Trend (WCHAT). Multidimensional factors of demography, lifestyle, social support, anthropometrics and body components, and clinical status were investigated and analyzed by univariate and multivariate logistic regression models. Lasso regression and K‐fold cross‐validation were conducted to construct the most predictive model with fitted factors. Results: The overall prevalence of MCR was 9.74%, and ethnically the prevalence was 14.25% in Tibetan, 11.03% in Yi, 10.72% in Han, 5.18% in Uighur and 4.55% in Qiang, respectively. In the adjusted models, the positively associated risk factors included diabetes mellitus (odds ratio [OR] = 1.51, p = 0.007), osteoarthritis (OR = 1.50, p = 0.002), depression (OR = 1.36, p = 0.005), poor sleep (OR = 1.21, p = 0.045), comorbidity (OR = 1.49, p = 0.001) and falls in the last 12 months (OR = 1.34, p = 0.031). Of note, every 1‐unit increase of value in stroke was associated with an approximate 3‐fold higher risk of having MCR, whilst in high‐density lipoprotein with a 30% lower risk of MCR,respectively. Conclusions: Profiles of MCR from the aspects of ethnicity and the presenium stage need further exploration. It is a promising strategy to apply MCR as a primary prevention tool to prevent dementia. [ABSTRACT FROM AUTHOR]

• A multi-hazard coupling tank failure prediction model is developed. • The mutual amplification effect between earthquake and fire is quantified. • Non-linear dynamic superposition of consequence under the earthquake-fire sequence is investigated. • A dynamic graph-based accident consequence assessment methodology is proposed. As a typical high-risk area, nature hazards acting on chemical industrial parks (CIPs) can result in catastrophic multi-hazard coupling scenarios (MHCSs). Existing research mainly adopts a linear superposition method based on simplified assumptions to analyze the coupling amplified effects of multi-hazard. Therefore, the complicated nonlinearity of consequence superposition has not been intensively studied. In this study, a new dynamic graph-based methodology is established to investigate the nonlinear superposition mechanism, by addressing the failure consequence assessment of multi-hazard. A typical MHCS of the earthquake-fire sequence is adopted to demonstrate the proposed methodology, and the failure prediction model of earthquake-damaged tanks subjected to the earthquake-fire sequence is numerically developed to calculate the failure consequence more accurately. The results indicate that the seismic damage significantly reduces the fire resistance of steel cylinder tanks. Compared to intact tanks, the time to failure of seismic damaged tanks is reduced by up to 8.48 min at most, exacerbating the escalation of domino effects. The consequence modeling without the consideration of fire resistance attenuation may be severely underestimated by a factor of 1.35 to 2.13. This method can be used to predict the dynamic consequence of the typical MHCSs and mitigate such accidents via more flexible adjustment of emergency decision-making at each evolution stage. [ABSTRACT FROM AUTHOR]

A subgrid scale particle kinetic turbulent energy model coupled with a second order moment model is developed to describe the particle hydrodynamic characteristics in dense gas-particle fluidized bed. Anisotropic behaviors of particle dispersions and interactions between gas and particle are fully revealed by means of two-phase Reynolds stresses transport eqs. A four-way coupling strategy for the consideration of particle-particle collisions is modeled by frictional granular temperature transport equation. Simulation results by large eddy simulation are validated by experimental measurement with acceptable agreement. Heterogenous flow structures, anisotropic characteristics of particle dispersions and wider-size distribution behaviors of bubbles are indicated. At the height of 0.2 m, the largest dominant frequency of porosity is 25.0 Hz at lateral 0.375 cm away from center, it is approximately 5.0 times larger than that of lateral 9.375 cm. Compared to 0.45 m, the standard deviations of 82.5 cm/s at lateral region is approximately 1.5 times larger than that of center region. [Display omitted] • LES-SOM four-way coupling modeling and simulation is good agreement with measurements. • Anisotropic characteristics of particle dispersions and heterogenous flow structures are revealed. • Maximum and minimum dominant frequency of porosity is 25.0 Hz and 45.0 Hz at height of 0.2 m. • Maximum and minimum standard deviation of particle vertical velocity are 82.5 cm/s and 7.9 cm/s. • Distributions of particle velocity and porosity deviate from the normal distributions. [ABSTRACT FROM AUTHOR]

• Proposed LES-SOM four-way coupling is validated successfully by experimental data. • Evolution of coherent structures and vortices enhanced turbulence diffusion and mixing. • Instantaneous axial and tangential particle velocity are followed by the normal distribution. • Axial-tangential correlations of particle fluctuations at inlet shear region are approximately 6.0 times larger than those of developed flow. • Core-annular flow structure of radial particle concentration is observed at r/R=0.9∼1.0. A novelty particle subgrid scale model is established to model the effect of gas flow on particle motion behaviors and a four-way coupling method to describe the particle-particle collisions by granular temperature equation is also developed. Menthane-central jets of particle-laden swirling flow in coaxial chamber are modeled by a multiphase second-order moment model and numerically predicted by the large-eddy simulation. Simulation results of two-phase hydrodynamics are in good agreement with experimental measurement. Evolution of coherent structure, recirculation region, periodic vortices formation, breakup, coalescence and pair, stronger mixing are captured and analyzed successfully. Compared to gas-annular flow, it is benefit for the stabilization of flame due to the strongly radial spread of particle dispersions and mixing momentum exchanges. The core-annular flow structures of particle concentration are observed, and instantaneous particle velocity are complied with the normal distribution. At shear layers of core-jetting regions of X/R=0.56, correlations of axial-tangential gas and particle fluctuation velocities are approximately 3.0 and 6.0 times larger than those of far downstream flows. [ABSTRACT FROM AUTHOR]

A new particle subgrid scale model is proposed to consider the effect of gas flow on particle motions. Multiphase gas-particle turbulent flow is modeled by a second-order moment two-phase turbulence model involving a four-way coupling strategy to describe the interactions among gas-particle, particle-gas and particle-particle collisions. A large eddy simulation algorithm is developed to solve the hydrodynamic parameters of confined swirling and non-swirling particle-laden flow in coaxial chamber. Results show that predictions are well agreed with experimental data. Vortex structures and vortices distributions of gas and particle flow are quietly different. Coherent structures of swirling particle flows are not observed, and length of recirculation region is almost one quarter of non-swirling flow. Compared to developed flow region of non-swirling flow, standard deviation values of granular temperature at near entrance decreased by 5.5 times. Dominant frequencies of particle number density of non-swirling and swirling flows are 18 Hz and 10 Hz. Particle dispersions exhibit anisotropic characteristics, and their distributions are not in accordance with the normal distribution. The 2D turbulence model needs to be further improved due to the failure of describing vortex stretch in this job. • A new particle subgrid scale model is proposed to consider the effect of gas flow on particles. • Coherent structure and vortices of confined particle-laden flow are revealed by large eddy simulation. • Recirculation length of non-swirling flow is almost 4.0 times larger than that of swirling flow. • Standard deviations of granular temperature of non-swirling flow have decreased by 6.5 times. • Dominant frequencies of particle number density are 18 Hz and 10 Hz in non-swirling and swirling flow. [ABSTRACT FROM AUTHOR]

The newly proposed combustion model, the second-order moment (SOM) turbulent combustion model is validated a-priori using the DNS database of combustion. It is found that the assumption of neglecting the density fluctuation and the third-order fluctuation correlation terms is acceptable. The fluctuation averaged closure method for the mean reaction-rate coefficient can be a promising method. The comparison of the terms in the correlation equations indicates that the chemical reaction term plays a dominant role, followed by the production term and the diffusion term. The predicted production term is in good agreement with the exact production term. The validation of the dissipation term shows that the performance of the closure is not promising but can be acceptable due to its less contribution. The predicted reaction terms are validated and discussed. Two modified reaction-term closure methods are proposed for different fluctuation correlation equations. It is concluded that the SOM combustion model is a promising one for the future development of turbulent combustion models. [ABSTRACT FROM AUTHOR]

• Berberine have therapeutic effects in mice experimental colitis. • Berberine could promote the growth of Bacteroides fragilis in vivo and vitro. • Bacteroides fragilis inhibit the secretion of IL-6 by dendritic cells in vitro. Berberine (BBR), a compound long used in traditional Chinese medicine, has been reported to have therapeutic effects in treating ulcerative colitis (UC), attributed to its anti-inflammatory properties and restorative potential of tight junctions (TJs). However, the mechanism by which BBR affects intestinal bacteria and immunity is still unclear. This study investigated the effects of BBR on intestinal bacteria and the inflammatory response in dextran sulfate sodium (DSS)-induced colitis mice. Immunohistochemistry (IHC) and electron microscopy were used to detect intestinal TJs. Microflora analysis was used to screen for bacteria regulated by BBR. The results showed that BBR had increased colonic epithelium zonula occludens proteins-1 (ZO-1) and occludin expression and reduced T-helper 17/T regulatory ratio in DSS-induced mice. Mechanically, BBR eliminated DSS-induced intestinal flora disturbances in mice, particularly increased Bacteroides fragilis (B. fragilis) in vivo and in vitro. B. fragilis decreased the interleukin-6 induced by dendritic cells through some heat-resistant component rather than nucleic acids or proteins. Overall, these data suggest that BBR had a moderating effect on DSS-induced colitis. This compound may regulate intestinal immune cell differentiation by affecting the growth of B. fragilis , providing new insights into the potential application of BBR in UC. [ABSTRACT FROM AUTHOR]

• Thiomyristoyl reduces ulcerative colitis (UC) progression by inhibiting metabolic reprogramming and T helper 17 (Th17) differentiation. • TM prevented Th17 differentiation by reducing the expression of related transcription factors, promoting acetylation of Lactate dehydrogenase A (LDHA). • Sirtuin 2 may be a potential target for UC treatment. The pathogenesis of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) has not been fully elucidated. However, a strong correlation between IBD and high T helper 17 (Th17) levels has been found. Sirtuin 2 (SIRT2) has recently been found to play an important role in metabolic reprogramming, but its potential anti-inflammatory properties remain unclear. The expression levels of SIRT2 and glucose metabolism-related proteins in peripheral blood mononuclear cells (PBMCs) of IBD patients and healthy volunteers were detected. Human PBMCs were differentiated into Th17 cells in vitro and were treated with TM simultaneously. The ratio of Th17 cells and apoptotic cells and the production of Interleukin (IL)-17A and the expression levels of transcription factors of classical signaling pathway related to Th17 differentiation were determined. The acetylation of LDHA and glucose metabolism was assessed. Subsequently, C57BL/6J colitis mice induced by 2.5% dextran sulfate sodium salt (DSS) were treated with or without TM, Disease activity index, T cell subsets in the mice spleen, relevant inflammatory cytokines in serum, specific mRNA, and proteins in mice colon were evaluated respectively. SIRT2 and glucose metabolism-related proteins in PBMCs of patients were overexpressed. Compared with the positive control group, human PBMCs treated with TM had lower levels of IL-17A, percentage of Th17 cells, levels of phospho-signal transducer and activator of transcription (p-STAT) 3 and phospho-nuclear transcription factor-κB (p-NF-κB), but higher levels of acetylated LDHA. Compared with colitis mice, TM-treated colitis mice had longer colons, reduced weight-losses, and lower disease activity index and histopathologic scores. Interestingly, although the expression levels of interferon (IFN)-γ, IL-17A, and retinoic acid receptor-related orphan receptor (ROR)-γt were inhibited in the colons of TM-treated colitis mice, the expression of forkhead box protein P3 (FOXP3) didn't change. Consistently, relative to the high percentage of splenic Th17 cells in colitis mice, the percentage of splenic Th17 cells in TM-treated colitis mice was as normal as PBS-treated mice, while the percentage of Treg cells was not affected. Additionally, the TM group had reduced levels of IL-23 and hypoxia inducible factor-1 α (HIF-1α), and an increased level of IL-10 in the colon, compared with the colitis group. Our results indicate that TM reduces UC progression by reducing metabolic reprogramming and T cell differentiation. Specifically, TM prevented Th17 differentiation by reducing the expression of related transcription factors and promoting acetylation of LDHA (weakening glycolysis). SIRT2 may be a potential target for IBD treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the associations between parity (the number of offspring a female has borne) and cognitive function, depression, and chronic comorbidity in Western China., Methods: A total of 846 women aged 50-55 years were included in the current analysis. Cognitive status was measured using a 10-item short portable mental status questionnaire (SPMSQ). Depressive symptoms were assessed using the 15-item geriatric depression scale (GDS-15). Other characteristics were self-reported. The associations between parity and cognitive decline, depression, and chronic comorbidity were analyzed using univariable and multivariable models. Multivariable models were adjusted for age, ethnic group, occupation, marital status, educational level, lifestyle factors, and sleeping time., Results: Among the enrolled women, 26.71% were either childless or had one child, 47.40% had two children, 18.32% had three children, and 7.57% had ≥4 children. Compared to women with low parity, women with two or more children exhibited a higher risk of cognitive decline. Moreover, having four or more children was significantly associated with depression and chronic comorbidity. After adjusting covariates, women with three or more children exhibited a higher risk of cognitive decline than those with low parity. However, high parity was not significantly associated with depression or chronic comorbidity after adjustment for covariates., Conclusion: Our study showed that ≥3 children was associated with cognitive decline in women. Longitudinal studies are needed to evaluate this conclusion and to investigate the mechanisms involved. More importantly, families and societies should pay more attention to women's long-term health outcomes related to fertility., (© 2024 International Federation of Gynecology and Obstetrics.)

The aim of this study was to investigate a novel FBN1 gene mutation in a pediatric patient with Marfan syndrome (MFS) to provide a theoretical basis for genetic counseling. The subject was a 5-month-old male infant. With informed consent from the proband and his family, 2 mL of peripheral venous blood was collected from the patient, his father, mother, and sister. DNA was extracted using a DNA extraction kit with EDTA-K as an anticoagulant. The extracted DNA was subjected to minigene transcription and bioinformatics analysis. For minigene construction, wild-type and mutant minigenes were inserted into pcMINI and pcMINI-C vectors, respectively. Four recombinant vectors were transfected into the HeLa and 293T cell lines. After transfection for 48 hours, RNA was extracted from eight samples. DNA was also extracted from the family members' samples to construct a library. Target regions were captured using the SureSelect Human All Exon V6 (Agilent) kit and were sequenced with Illumina NovaSeq (sequencing read length 2×150 bp). Bioinformatic analysis identified the c.8226+5del mutation as a variant of uncertain clinical significance (VOUS). Literature and database reviews confirmed that this mutation had not been previously reported, identifying it as a novel mutation. The study identified a novel FBN1 mutation, c.8226+5del, that may be associated with clinical features such as low-set ears and distinctive facial characteristics in the proband. This mutation likely affects normal mRNA splicing, altering the structure and function of Exon 64 and potentially contributing to the development of autosomal dominant MFS., Competing Interests: The authors have no conflicts of interest to disclose., (2024, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Introduction: Motoric cognitive risk syndrome (MCR), characterized by subjective cognitive complaints and slow gait in older populations, is associated with sleep duration. However, the association between MCR and daytime nap duration has not been thoroughly explored., Methods: Baseline data from the China Health and Retirement Longitudinal Study (CHARLS) were used in this study. MCR was defined as the coexistence of subjective cognitive complaints and objective slow gait speed without a history of dementia or mobility disability. Daytime nap duration was categorized into four groups: no napping, short napping (<30 min), moderate napping (30-89 min) and extended napping (≥90 min). Multivariable logistic regression models were used to explore the association of daytime napping duration and MCR., Results: A total of 4230 individuals aged ≥60 were included in the current analysis, of which 463 were diagnosed with MCR. Moderate napping of 30-89 min per day was found to be significantly associated with lower odds of MCR compared with the reference group of no napping. In subgroup analysis, individuals with sleep durations of <7 h per night had lower odds of MCR in the model that adjusted for all potential confounders with ≥30 min daytime nap duration compared with no napping. Interestingly, for people with a night sleep duration of 7-8 h, only those with a moderate nap of 30-89 min had lower odds of MCR than non-nappers after adjustment for potential confounders., Conclusion: A moderate nap of 30-89 min could lower the odds of MCR, especially for older adults with a night sleep duration of ≤8 h., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In this article, we present a transient temperature detection device for silicon carbide (SiC) Schottky barrier diodes (SBDs) based on thermal reflection theory. We constructed a thermal reflection temperature measurement device based on a 530-nm green laser. This device is more suitable for transient temperature measurement of SiC SBDs than previous thermal reflection equipment. The accuracy of temperature measurement by our device was confirmed by comparison with the results of infrared thermal imaging. The high temporal resolution characteristics of the thermal reflection technology allowed the detection of millisecond-level transient temperature changes in SiC SBDs. In addition, we investigated the complementarity of transient temperature change curves during heating and cooling processes, as well as the reasons for the differences between these curves. Finally, we used the structural function method combined with the Bayesian deconvolution algorithm to obtain the thermal resistance along the heat flow path of the device and validated the results using an established thermal resistance testing method., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys 108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7 ). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A , which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7 , which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

Background: Honokiol (HKL), a natural extract of the bark of the magnolia tree and an activator of the mitochondrial protein sirtuin-3 (SIRT3), has been proposed to possess anti-inflammatory effects. This study investigated the inhibitory effects of HKL on T helper (Th) 17 cell differentiation in colitis., Methods: Serum and biopsies from 20 participants with ulcerative colitis (UC) and 18 healthy volunteers were collected for the test of serum cytokines, flow cytometry analysis (FACS), and relative messenger RNA (mRNA) levels of T cell subsets, as well as the expression of SIRT3 and phosphorylated signal transducer and activator of transcription/retinoic acid-related orphan nuclear receptor γt (p-STAT3/RORγt) signal pathway in colon tissues. In vitro, naïve clusters of differentiation (CD) 4 + T cells isolated from the mouse spleen differentiated to subsets including Th1, Th2, Th17, and regulatory T (Treg) cells. Peripheral blood monocytes (PBMCs) from healthy volunteers were induced to the polarization of Th17 cells. After HKL treatment, changes in T cell subsets, related cytokines, and transcription factors were measured. The dextran sulfate sodium (DSS)-induced colitis and interleukin (IL)-10-deficient mice were intraperitoneally injected with HKL. These experiments were conducted to study the effect of HKL on the development, cytokines, and expression of signaling pathway proteins in colitis., Results: Patients with UC had higher serum IL-17 and a higher proportion of Th17 differentiation in blood compared with healthy participants; while IL-10 level and the proportion of Treg cells were lower. Higher relative mRNA levels of RORγt and a lower SIRT3 expression in colon tissues were observed. In vitro, HKL had little effect on the differentiation of naïve CD4+ T cells to Th1, Th2, or Treg cells, but it downregulated IL-17 levels and the Th17 cell ratio in CD4+ T cells from the mouse spleen and human PBMCs under Th17 polarization. Even with a STAT3 activator, HKL still significantly inhibited IL-17 levels. In DSS-induced colitis mice and IL-10 deficient mice treated with HKL, the length of the colon, weight loss, disease activity index, and histopathological scores were improved, IL-17 and IL-21 levels, and the proportion of Th17 cells were decreased. Sirtuin-3 expression was increased, whereas STAT3 phosphorylation and RORγt expression were inhibited in the colon tissue of mice after HKL treatment., Conclusions: Our study demonstrated that HKL could partially protect against colitis by regulating Th17 differentiation through activating SIRT3, leading to inhibition of the STAT3/RORγt signaling pathway. These results provide new insights into the protective effects of HKL against colitis and may facilitate the research of new drugs for inflammatory bowel disease., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Objectives: Motoric cognitive risk (MCR) syndrome is a type of pre-dementia. It is defined as the co-occurrence of subjective cognitive complaints and a slow gait speed. A recent study found that handgrip strength (HGS) asymmetry is associated with an increased risk of neurodegenerative disorders. We aimed to investigate the associations of HGS weakness and asymmetry separately and together with MCR incidence among older Chinese adults., Methods: Data from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study were used. HGS values <28 kg for male participants and <18 kg for female participants were considered HGS weaknesses. HGS asymmetry was assessed by the ratio of nondominant to dominant HGS. We used 3 different cutoff values of HGS ratio to define asymmetry, including 10%, 20%, and 30%. Specifically, HGS ratios <0.90 or >1.10 (10%), <0.80 or >1.20 (20%), and <0.70 or >1.30 (30%) were classified as asymmetry. The participants were classified into 4 groups: neither weakness nor asymmetry (neither), asymmetry only, weakness only, and weakness and asymmetry (both). The association between baseline HGS status and 4-year incidence of MCR was examined using logistic regression analyses., Results: A total of 3,777 participants 60 years and older were included in the baseline analysis. The prevalence of MCR at the baseline was 12.8%. Participants with asymmetry only, weakness only, and both showed significantly increased risk of MCR. After excluding participants with MCR at baseline, 2,328 participants were included in the longitudinal analysis. There were 111 MCR cases (4.77%) over the 4-year follow-up period. Participants with HGS weakness and asymmetry together at baseline had increased odds of incident MCR (HGS ratio at 10%: odds ratio [OR] 4.48, p < 0.001; HGS ratio at 20%: OR 5.43, p < 0.001; HGS ratio at 30%: OR 6.02, p < 0.001)., Discussion: These results show that the presence of both HGS asymmetry and weakness is associated with MCR incidence. The early recognition of HGS asymmetry and weakness may be helpful in the prevention and treatment of cognitive dysfunction., (© 2023 American Academy of Neurology.)

Introduction: Night sleep duration and total sleep duration are associated with frailty. However, the association between daytime nap duration and the risks of frailty has not been explored thoroughly., Methods: This study used data from the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 60 years and older at baseline were included in this study. Individuals with daytime nap duration were categorized into four groups: no napping, short napping (< 30 min), moderate napping (30-89 min), and extended napping (≥90 min). Frailty was assessed using a modified Physical Frailty Phenotype (PFP) scale. Non-frail participants at baseline were followed up for 4 years. The association between nap duration and risks of frailty at baseline and incident frailty was evaluated by logistic regression and discrete-time Cox regression analyses, respectively., Results: In total, 5,126 participants were included in this study. For individuals with night sleep duration of ≥9 h, short nappers showed higher odds [odds ratio (OR) = 4.08, 95% confidence interval (CI): 1.30-12.78] for frailty compared with non-habitual nappers at baseline, while moderate nappers were less likely to be frail (OR = 0.18, 95% CI: 0.04-0.73). In the follow-up study, short nappers showed higher risks for frailty compared with participants of the no napping group with night sleep duration of < 6 h [hazard ratio (HR) = 1.91, 95% CI: 1.07-3.43] or 6-9 h (HR = 1.97, 95% CI: 1.18-3.30). Compared with short nappers, older adults with extended napping (HR = 0.41, 95% CI: 0.22-0.77) showed lower risks for frailty in those with night sleep duration of 6-9 h. For individuals with night sleep duration of ≥9 h, moderate napping (HR = 0.20, 95% CI: 0.05-0.77) decreased the risks for frailty compared with short napping., Conclusion: Among older adults with night sleep duration of < 9 h, short nappers posed higher risks for frailty compared with non-habitual nappers. Extended naps for those with a night sleep duration of 6-9 h or moderate naps for those with night sleep duration of ≥9 h could lower the risk of frailty compared with short naps. Future studies on the timing, purpose, frequency, and quality of daytime napping and objectively measured nap duration are needed to explore the association between daytime napping and risks of frailty., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Zhou, Ge, Lin and Dong.)

Objective: Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract, and its molecular mechanisms have not been fully clarified. This study aimed to evaluate the immune infiltration pattern of esophageal cancer through a gene co-expression network, and to provide biomarkers for immunotherapy of esophageal cancer., Methods: We downloaded RNA-seq data of ESCC samples from GSE53625 and GSE66258 datasets, then assessed the immune score and tumor purity through the ESTIMATE algorithm. Next, a co-expression network was constructed by the weighted gene co-expression network analysis, and the key co-expressed immune- related genes were identified on the basis of existing human immune-related genes. Afterward, we utilized bioinformatics algorithms including GSVA, CIBERSORT, and ssGSEA to clarify the relationship between hub genes and immune infiltration patterns. Finally, these hub genes were used to evaluate the sensitivity to immunotherapy by the subclass mapping algorithm, which were further validated by digital pathology through the Hover- Net algorithm., Results: Sixteen immune-related genes with robust expression characteristics were identified and used to build gene signatures. The expression of gene signature was significantly related to the immune infiltration pattern and immunotherapy sensitivity prediction in patients with esophageal cancer. Consistent with previous studies, genetic changes at the level of somatic mutations such as NFE2L2 were revealed., Conclusion: A total of 16 immune-related genes with the total expression gene signature can be used as biomarkers for immunotherapy of esophageal squamous cell carcinoma. Its molecular mechanisms deserve further study to guide clinical treatment in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Frailty is a geriatric syndrome characterized by a decline in physiological reserves, and multiple factors contribute to the occurrence and development of frailty. Growing evidence supports a strong link and overlap between frailty and cognitive impairment, but the mechanisms involved have not yet been fully elucidated., Aim: To identify associations between 12 plasma cognition-related biomarkers and frailty in community-dwelling older adults., Methods: A total of 375 participants (age 70.9 ± 5.8, 165 men and 210 women) were included in this study. Frailty was assessed using the modified Fried frailty phenotype. Participants were divided into not-frail group (n = 313) and frail group (n = 62). Twelve plasma cognitive biomarkers were detected by enzyme-linked immunosorbent assay (ELISA). Multinomial logistic regression was used to explore the association between different biomarkers and frailty status., Results: Among the 12 biomarkers, only pTau was higher in frail individuals than in their not-frail peers (471.3 ± 58.1 pg/mL vs. 451.9 ± 61.1 pg/mL, p = 0.022). No other biomarkers had any significant association with frailty, including total-Tau (tTau), neurofilament light (NFL), amyloid-β 40 (Aβ40), amyloid-β 40 (Aβ42), S100 calcium binding protein B (S100B), visinin-like protein 1 (VLP-1), Alzheimer-associated neuronal thread protein (AD7cNTP), β-amyloid precursor protein (βAPP), chitinase-3-like-1 (CHI3L1), soluble complement receptor 1 (sCR1) and heart-type fatty acid binding protein (hFABP). Furthermore, pTau was compared between negative and positive subject groups for each individual criterion of frailty. Significantly higher levels of pTau were observed in those who were positive for the criteria of low grip strength (451.2 ± 61.4 pg/mL vs. 469.1 ± 57.6 pg/mL, p = 0.019), exhaustion (451.2 ± 61.6 pg/mL vs. 466.4 ± 58.4 pg/mL, p = 0.035) and low physical activity (451.1 ± 60.7 pg/mL vs. 465.7 ± 60.7 pg/mL, p = 0.034) when compared to those who were negative for each corresponding criterion. Finally, in the multivariable-adjusted analysis, the association between pTau and frailty was statistically significantly associated (OR: 1.40, 95% CI: 1.04-1.89), even after adjusting., Conclusions: The present study found a potential association between pTau and frailty. Future works should monitor the longitudinal trajectory of changes of pTau concentrations in frailty older adults. A better understanding of the molecular mechanisms behind will contribute to biomarker research in frailty., (© 2022. The Author(s).)

Introduction: Motoric cognitive risk syndrome (MCR) is characterized by subjective cognitive complaints (SCCs) and slow gait (SG). Metabolomics and lipidomics may potentiate disclosure of the underlying mechanisms of MCR., Methods: This was a cross-sectional study from the West China Health and Aging Trend cohort study (WCHAT). The operational definition of MCR is the presence of SCCs and SG without dementia or mobility disability. The test and analysis were based on untargeted metabolomics and lipidomics, consensus clustering, lasso regression and 10-fold cross-validation., Results: This study enrolled 6,031 individuals for clinical analysis and 577 plasma samples for omics analysis. The overall prevalence of MCR was 9.7%, and the prevalence of MCR-only, assessed cognitive impairment-only (CI-only) and MCR-CI were 7.5, 13.3, and 2.1%, respectively. By consensus clustering analysis, MCR-only was clustered into three metabolic subtypes, MCR-I, MCR-II and MCR-III. Clinically, body fat mass (OR = 0.89, CI = 0.82-0.96) was negatively correlated with MCR-I, and comorbidity (OR = 2.19, CI = 1.10-4.38) was positively correlated with MCR-III. Diabetes mellitus had the highest ORs above 1 in MCR-II and MCR-III (OR = 3.18, CI = 1.02-9.91; OR = 2.83, CI = 1.33-6.04, respectively). The risk metabolites of MCR-III showed relatively high similarity with those of cognitive impairment. Notably, L-proline, L-cystine, ADMA, and N1-acetylspermidine were significantly changed in MCR-only, and PC(40:3), SM(32:1), TG(51:3), eicosanoic acid(20:1), methyl-D-galactoside and TG(50:3) contributed most to the prediction model for MCR-III., Interpretation: Pre-dementia syndrome of MCR has distinct metabolic subtypes, and SCCs and SG may cause different metabolic changes to develop MCR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Sun, Liu, Ge, Lu, Liu, Zhou, Liu, Dong, Yue, Xue, Dai and Dong.)

The immune system of centenarians remains active and young to prevent cancer and infections. Aging is associated with inflammaging, a persistent low-grade inflammatory state in which CD4 + T cells play a role. However, there are few studies that have been done on the CD4 + T cell subsets in centenarians. Herein, the changes in CD4 + T cell subsets were investigated in centenarians. It was found that with aging, the old adults had higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines in plasma. The levels of CRP, IL-12, TNF-α, IFN-γ, IL-6 and IL-10 were further increased in centenarians compared to old adults. While the levels of IL-17A, IL-1β, IL-23 and TGF-β in centenarians were closer to those in young adults. The total CD4 + , CD8 + , Th17 and Treg cells from peripheral blood mononuclear cells (PBMCs) were similar among the three groups. It was observed that the ratio of Th17/Treg cells was elevated in old adults compared to young adults. The ratio was not further elevated in centenarians but rather decreased. In addition, the ex vivo PBMCs differentiation assay showed that increased Th17 cells in centenarians tended to secrete fewer proinflammatory cytokines, while decreased Treg cells in centenarians were prone to secrete more anti-inflammatory cytokines. These observations suggested centenarians alleviated inflammaging by decreasing the ratio of Th17/Treg cells and changing them into anti-inflammatory secretory phenotypes, which provided a novel mechanism for anti-aging research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Ge, Zhang, Wu, Leng, Gan, Mou, Zhou, Valencia, Hao, Zhu, Dong and Dong.)

Endothelial senescence is believed to constitute the initial pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). MicroRNA-335-5p (miR-335-5p) expression is significantly up-regulated in oxidative stress-induced endothelial cells (ECs). Sirtuin7 (SIRT7) is considered to prevent EC senescence, yet data on its response to ASCVD risk factors are limited. The present study analyzed the elevated levels of miR-335-5p and the decreased levels of SIRT7 in human umbilical vein endothelial cells (HUVECs), and found that high glucose, tumor necrosis factor-α (TNF-α), and H2O2 are the three contributing factors that induced cellular senescence. The current study also assessed premature endothelial senescence and decreased proliferation, adhesion, migration, and nitric oxide (NO) secretion in HUVECs with these risk factors together with SIRT7-siRNA transfection. It found that the miR-335-5p inhibitor attenuated the down-regulation of SIRT7 expression induced by oxidative stress in HUVECs, and SIRT7 overexpression exerts a rescue effect against miR-335-5p-induced endothelial dysfunction. Furthermore, the direct binding of miR-335-5p to SIRT7 was observed in human embryonic kidney cells 293T (HEK 293T). Therefore, it can be inferred that miR-335-5p down-regulates the expression of SIRT7 in human cells. Current findings may provide deeper insights into the underlying mechanisms of endothelial senescence and potential therapeutic targets of ASCVD as well as other age-related diseases., (© 2022 The Author(s).)

It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes the brain pathophysiology of neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation. If not all, gut microbiota-induced systemic chronic inflammation (GM-SCI) mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging. To illustrate the immune roles of the BBB in pathophysiology affected by inflammatory or "leaky" IB resulting from GM and their metabolites, we reviewed the selected publications, including the role of the BBB as the immune barrier, systemic chronic inflammation and inflammation influences on BBB permeability, NF&ND, and brain aging. To add depth to the bridging role of systemic chronic inflammation, a plausible mechanism indispensable for BBB corruption was highlighted; namely, BBB maintenance cues are affected by inflammatory cytokines, which may help to understand how GM and its metabolites play a major role in NF&ND and aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mou, Du, Zhou, Yue, Hu, Liu, Chen, Lin, Zhang, Xiao and Dong.)

Background: Sarcopenia is associated with cognitive impairment in older adults. However, the underlying mechanisms are not fully understood., Aim: To explore the mediating role of nutritional status in the relationship between sarcopenia and cognitive impairment., Methods: Three thousand eight hundred and ten participants (mean age 61.94 ± 8.01 years) from the West China Health and Aging Trend (WCHAT) study were included. We defined sarcopenia using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Cognitive status and nutritional status were measured using the Short Portable Mental Status Questionnaire (SPMSQ) and the Mini Nutritional Assessment Short Form (MNA-SF). Relationships between sarcopenia, nutritional status, and cognitive function were explored using multiple linear regression. Two mediation models were generated to examine whether nutritional status mediates the association between sarcopenia and cognitive function using PROCESS macro version 3.5., Results: The study involved 3147 (82.6%) non-sarcopenic, 387 (10.2%) sarcopenic, and 276 (7.2%) severely sarcopenic individuals. In mediation model 1, sarcopenia (β = 0.208, 95% CI 0.072 to 0.344, P = 0.0028) was significantly associated with cognitive impairment, and nutritional status mediated this association (indirect effect = 0.162, bootstrap 95% CI 0.116 to 0.212). Mediation model 2 indicated that nutritional status exhibited a full mediating effect regarding the association between sarcopenia and cognitive impairment (indirect effect = 0.131, bootstrap 95% CI: 0.08 to 0.188; direct effect = 0.046, bootstrap 95% CI - 0.115 to 0.21) and a partial mediating effect regarding the association between severe sarcopenia and cognitive impairment (indirect effect = 0.21, bootstrap 95% CI: 0.143 to 0.283; direct effect = 0.476, bootstrap 95% CI: 0.234-0.724)., Conclusions: The relationship between sarcopenia and cognitive impairment was significantly mediated by nutritional status. Early nutritional interventions may prevent cognitive decline in sarcopenic older adults., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To investigate the association between sleep duration and cognitive frailty among older adults dwelling in western China., Methods: We used the baseline data from West China Health and Aging Trend (WCHAT) study. Sleep duration was classified as short sleep duration (< 6 h), normal sleep duration (6-8 h) and long sleep duration (≥ 9 h). Fried frailty criteria and Short Portable Mental Status Questionnaire were used to measure cognitive frailty. Multinomial logistic regression was conducted to estimate odds ratio (OR) and 95% confidence interval (CI)., Results: A total of 4093 older adults (age = 67.8 ± 5.9 years, 1708 males and 2385 females) were included in the analysis. The prevalence of cognitive frailty was 11.8% among older adults in western China. Approximately 11.9% participants had short sleep duration (< 6 h); 22.2% had a long sleep duration (≥ 9 h). After adjusting for covariates, only long sleep duration was significantly associated with high risk of cognitive frailty (OR = 2.07, 95%CI = 1.60-2.68, P <  0.001) in western China older adults compared to normal sleep duration., Conclusions: Long sleep duration was significantly related to cognitive frailty in older adults. Intervention for long sleep duration may be helpful to prevent cognitive frailty., Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800018895 ., (© 2021. The Author(s).)

Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases 1,2 . Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (T H 17) cell differentiation stimulator, STAT3 3,4 , is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes T H 17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects T H 17 cell differentiation. Overactivation of T H 17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.

Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutation within phenylalanine hydroxylase (PAH) gene. Loss-of-function of PAH leads to accumulation of phenylalanine in the blood/body of an untreated patient, which damages the developing brain, causing severe mental retardation. Current gene therapy strategies based on adeno-associated vector (AAV) delivery of PAH gene were effective in male animals but had little long-term effects on blood hyperphenylalaninemia in females. Here, we designed a gene therapy strategy using AAV to deliver a human codon-optimized phenylalanine amino lyase in a liver-specific manner. It was shown that PAL was active in lysing phenylalanine when it was expressed in mammalian cells. We produced a recombinant adeno-associated vector serotype 8 (AAV8) viral vector expressing the humanized PAL under the control of human antitrypsin (hAAT) promoter (AAV8-PAL). A single intravenous administration of AAV8-PAL caused long-term correction of hyperphenylalaninemia in both male and female PKU mice (strain Pah enu2 ). Besides, no obvious liver injury was observed throughout the treatment process. Thus, our results established that AAV-mediated liver delivery of PAL gene is a promising strategy in the treatment of PKU., (© 2020 The Authors.)

Background: Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells., Methods: We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and 13 C 6 metabolites tracing analysis, and then confirmed the results using patient tissue protein samples through Western Blotting. Bioinformatics analysis and transfection assay were used to confirm the upstream target of the low levels of pyruvate status in CCA. The regulation of cMyc by HDAC3 was studied through immunoprecipitation and Western Blotting., Results: We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation., Conclusions: Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.

Background: Inflammatory bowel disease (IBD)-associated dysbiosis is characterized by a loss of Faecalibacterium prausnitzii, whose supernatant exerts an anti-inflammatory effect. However, the anti-inflammatory substances in F. prausnitzii supernatant and the mechanism in ameliorating colitis in IBD have not yet been fully investigated., Methods: Experimental colitis models were induced and evaluated by clinical examination and histopathology. Levels of cytokines and ratio of T cells were detected by enzyme-linked immunosorbent assay and flow cytometry analysis, respectively. F. prausnitzii supernatant was separated by macroporous resins. After extraction, the substances in supernatant were identified by gas chromatography-mass spectrometer. T-cell differentiation assay was conducted in vitro. Changes in signaling pathways were examined by immunoblot, immunohistochemistry, and immunofluorescent staining., Results: We found that the supernatant of F. prausnitzii could regulate T helper 17 cell (Th17)/regulatory T cell (Treg) differentiation. Then, we identified butyrate produced by F. prausnitzii that played the anti-inflammatory effects by inhibiting interleukin (IL)-6/signal transducer and the activator of transcription 3 (STAT3)/IL-17 pathway and promoting forkhead box protein P3 (Foxp3). Finally, we demonstrated that the target of butyrate was histone deacetylase 1 (HDAC1)., Conclusions: It is butyrate, instead of other substances produced by F. prausnitzii, that maintains Th17/Treg balance and exerts significant anti-inflammatory effects in colorectal colitis rodents, by inhibiting HDAC1 to promote Foxp3 and block the IL-6/STAT3/IL-17 downstream pathway. F. prausnitzii could be an option for further investigation for IBD treatment. Targeting the butyrate-HDAC1-T-cell axis offers an effective novel approach in the treatment of inflammatory disease., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Metastasis is the most important feature of gastric cancer (GC) and the most widely recognized reason for GC-related deaths. Unfortunately, the underlying mechanism behind this metastasis remains unknown. Mounting evidence suggests the dynamic regulatory role of sirtuin2 (SIRT2), a histone deacetylase (HDAC), in cell migration and invasion. The present study aims to evaluate the biological function of SIRT2 in GC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in GC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 overexpression marginally promoted proliferation in GC cell lines, SIRT2 knockdown or treatment with SirReal2 decreased the migration and invasion of GC cells. We demonstrated both in vitro and in vivo that SirReal2 could inhibit the deacetylation activity of SIRT2 and its downstream target PEPCK1, which is related to mitochondrial metabolism and RAS/ERK/JNK/MMP-9 pathway. Taken together, these results demonstrate for the first time that SirReal2 selectively targets SIRT2 and decreases migration as well as invasion in human GC cells. SirReal2 therefore shows promise as a new drug candidate for GC therapy., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)