Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.

Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here, we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes ("spermatoproteasomes") contain a spermatid/sperm-specific α subunit α4 s/PSMA8 and/or the catalytic ß subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.

Typical value ranges and signal patterns in patients with neurogenic bladder: Quality control in urodynamics using an air-charged catheter system.

PURPOSE: To establish typical value ranges (TVRs) of the air-charged catheter (ACC) system, and analyze the typical signal patterns (TSPs) of cough under different bladder volumes for quality control of a urodynamic study using the ACC system. MATERIALS AND METHODS: The urodynamic traces of 1977 patients with neurogenic bladder (NB) were analyzed for intravesical pressure (pves ), abdominal pressure (pabd ), and detrusor pressure (pdet ) in the cough test at our center from July 2017 to December 2021. The pdet cough signals were described and classified. The pdet cough signal patterns in different bladder volumes and postures were analyzed. RESULTS: The 50% range of the initial resting pves , pabd , and pdet in the supine and sitting positions were 7-15, 7-14, and 0-0 cmH2 O, and 24-33, 24-33, and 0-0 cmH2 O, respectively. The cough amplitudes for pves and pabd were similar in the 50% range, as follows: 10-27 and 8-25 cmH2 O in the supine position, respectively; and 18-43 and 17-40 cmH2 O in the sitting position, respectively. The cough amplitude of pves and pabd was not related to bladder volume (p > 0.05). The cough spikes of pdet were divided into three types: type I, in which pdet has a minimal change (<5 cmH2 O); type II, a monophasic cough spike, in which could be a positive (IIa, ≥5 cmH2 O) or negative spike (IIb, ≥5 cmH2 O); and type III, a biphasic spike, in which could be a positive-to-negative biphasic (IIIa) or negative-to-positive spike (IIIb). Under different bladder volumes, the cough signals of pdet were all expressed as type I, II, or III, and the cough signals were unrelated to bladder volume (p > 0.05). CONCLUSIONS: TVRs of the initial resting state in patients with NB were established to provide guidance for quantitative quality control of the ACC system. The TSPs of the pdet cough signal under different bladder volume and posture were described, which could be used for qualitative quality control of the ACC system.

Inhibitory effects of a smartphone-controlled wearable transcutaneous tibial nerve stimulation device on bladder reflexes in anesthetized cats.

OBJECTIVES: To explore the inhibitory effects of a novel, smartphone-controlled, and wearable tibial nerve stimulation device on nonnociceptive and nociceptive bladder reflexes in anesthetized cats and to compare the stimulus results of two current waveforms outputted by this new stimulator. MATERIALS AND METHODS: A novel, intelligent tibial nerve stimulator was put on the ankles of 14 cats and controlled by a mobile application. Cystometrograms (CMGs) were performed repeatedly by infusing 0.9% normal saline (NS) and 0.5% acetic acid (AA) through a urethral catheter. Inhibitory effects were explored by measuring the bladder capacity (BC) in two areas: (1) on nonnociceptive bladder reflex (infused with NS) and on nociceptive bladder reflex (filled with AA to induce overactive bladder [OAB] model); and (2) under the stimulation of two different current waveforms (waveforms A and B). RESULTS: In Group 1, the BC of AA-induced OAB (41.48 ± 8.40%) was significantly different compared with the capacity of a NS-infused bladder (104.89 ± 1.32%, p < 0.05). Both NS-filled (151.35 ± 5.71%, p < 0.05) and AA-instilled (71.41 ± 9.34%, p < 0.05) bladder volumes significantly increased after tibial nerve stimulation (TNS). In Group 2, the BC increased to 166.18 ± 15.17% (p = 0.026) and 127.64 ± 13.00% (p = 0.239), respectively, after TNS with waveforms A and B current. CONCLUSIONS: Results revealed that this novel, smartphone-based, wearable, and wireless tibial nerve stimulation system could inhibit the micturition reflex on physiological condition, serving as a potential option for OAB treatment. In addition, the waveforms of stimulation current had an important influence on the effects of TNS.

From blue to cyan emission: Ce3+ and Tb3+ co-doped silicon phosphate phosphors with high thermal stability.

A series of Ca15(PO4)2(SiO4)6:xCe3+,yTb3+ phosphors have been prepared by a high-temperature solid-state reaction. Under the excitation of near-UV with 371 nm wavelength, Ca15(PO4)2(SiO4)6:xCe3+ phosphors exhibit strong blue emission with a broad peak at 432 nm. Based on the photoluminescence of Ca15(PO4)2(SiO4)6:xCe3+ phosphors, the coordination environment around Ce3+ ions and the concentration quenching mechanism are inferred. With the doping of Tb3+ ions into Ca15(PO4)2(SiO4)6:1.33%Ce3+, the luminescence color from blue to cyan can be well tuned. By measuring the luminescence intensity and lifetime of the as-prepared phosphors, it can be judged that there exists an energy transfer from Ce3+ to Tb3+. To achieve white light, the optimal Ca15(PO4)2(SiO4)6:1.33%Ce3+, 9%Tb3+ phosphors are mixed with commercial SrAlSiN3:Eu2+ powders and finally warm white light emission could be obtained. The results show that Ca15(PO4)2(SiO4)6:xCe3+,yTb3+ phosphors have potential applications in warm white light-emitting diodes.

Quercetin Treatment Improves Renal Function and Protects the Kidney in a Rat Model of Adenine-Induced Chronic Kidney Disease.

BACKGROUND The aim of this study was to examine the effects of the natural flavonoid, quercetin, in a rat model of adenine-induced chronic kidney disease. MATERIAL AND METHODS Forty male Wister rats were divided into four groups: normal (no adenine or quercetin) (n=10); untreated model (treated withadenine but not quercetin) (n=10); quercetin-treated model (5 mg/kg/day for 21 days) (n=10); quercetin-treated model (10 mg/kg/day for 21 days) (n=10). Urine and blood samples were collected and rat kidneys were examined histologically. RESULTS Comparison of the findings of the model rats treated with quercetin (n=20) with non-treated model rats (n=10) showed reduced levels of fibroblast growth factor 23 (FGF23): normal group, 19.6 pg/ml; untreated group, 73.6 pg/ml; quercetin-treated group (5 mg/kg), 34.25 pg/ml; and quercetin-treated group (10 mg/kg), 21.3 pg/ml. Quercetin-treated model rats had reduced serum levels of parathyroid hormone (PTH), inorganic phosphate, increased urine protein-to-creatinine ratio, increased urine antioxidants, serum lactate dehydrogenase (LDH), and interleukin (IL)-8 when compared with the untreated model group and the control group. Quercetin treatment 10 mg/kg (n=10) reduced the levels of creatinine, blood urea nitrogen (BUN), and urinary uric acid. Renal histopathology in model rats treated with quercetin (n=20) showed reduced inflammation compared with the untreated model rats (n=10). CONCLUSIONS In a rat model of adenine-induced chronic kidney disease, treatment with quercetin improved renal function, reduced oxidative stress factors, serum levels of FGF23, and kidney inflammation.

[Purple sweet potato anthocyanins attenuates steatohepatitis induced by high fat diet combined with carbon tetrachloride in rats].

OBJECTIVE: To explore the mechanism of purple sweet potato anthocyanins through NF-κB pathway in attenuating steatohepatitis induced by high fat diet combined with carbon tetrachloride in rats. METHODS: Seventy male rats were randomly divided into control group( n = 10) and high-fat diet group( n = 60), models were prepared by highfat diet and intraperitoneal injection of carbon tetrachloride and olive oil( 50 : 50) 2 mL/kg, two times a week. After 10 weeks of feeding, the weight variations of all rats were tested before and after modeling. The colorimetric technique was used to test the concentration of serum ALT, AST, TG, and TC. A total of 58 rats were succeeded in modeling, the random choice of 50 rats were divided into model group, purple sweet potato anthocyanin low dose group( 60 mg/kg), middle dose group( 120 mg/kg), high dose group( 240 mg/kg), positive drug group( 150 mg/kg), 10 rats in each group. After 8 weeks of continuous administration, the method of colorimetric technique was used to test the concentration of ALT, AST, TG, TC, HDL and LDL. The method of ELISA kit was used to test the levels of the pro-inflammatory factors TNF-α, IL-1ß and the levels of the anti-inflammatory IL-4, IL-13. The Real-time PCR was used to test the expression of TNF-α, IL-1ß, IL-4, IL-13, PPAR-γ and HMGB-1 mRNA of rats liver. The western blotting method was adopted to test the level of IκB phosphorylation in liver tissues as well as the PPAR-γ and HMGB-1 protein expression. RESULTS: After modeling, the body weight of rats increased( P < 0. 05), the concentration of serum insulin AST, ALT, TG, TC, and LDL all increased significantly( P < 0. 05), the concentration of HDL decreased obviously( P < 0. 05). Compared with control group, the expression of TNF-α, IL-1ß and HMGB-1 in model group were increased significantly( P < 0. 05), the expression of IL-4, IL-13 and PPAR-γ were decreased significantly( P < 0. 05), the expression of pIκB and NF-κB in the model group increased significantly( P < 0. 05). Compared with the model group, the expression level of NF-κB in the high dose purple sweet potato anthocyanin group decreased obviously, and the phosphorylation degree of IκB decreased( P < 0. 05), the mRNA expression of TNF-α, IL-1ß and HMGB-1 in liver tissue was significantly decreased( P < 0. 05), and the mRNA expression of IL-4, IL-13 and PPAR-γ were significantly increased( P < 0. 05). The purple sweet potato anthocyanin low dose group, middle dose group, high dose group and positive drugs group all improved the above indexes in different degrees. The effect of the high dose group was significantly higher than that of the low dose and medium dose group, but equivalent to that of the positive drug group. CONCLUSION: Purple sweet potato anthocyanins through NF-κB pathway have a role in attenuating steatohepatitis induced by high fat diet combined with carbon tetrachloride in rats.

Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling.

Recent research indicates that the C-terminal Eps15 homology domain 1 is associated with epithelial growth factor receptor-mediated endocytosis recycling in non-small-cell lung cancer. The aim of this study was to determine the clinical significance of Eps15 homology domain 1 gene expression in relation to phosphorylation of epithelial growth factor receptor expression in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Eps15 homology domain 1, RAB11FIP3, and phosphorylation of epithelial growth factor receptor expression via immunohistochemistry. The clinical significance was assessed via a multivariate Cox regression analysis, Kaplan-Meier curves, and the log-rank test. Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor were upregulated in 60.46% (185/306) and 53.92% (165/306) of tumor tissues, respectively, as assessed by immunohistochemistry. The statistical correlation analysis indicated that Eps15 homology domain 1 overexpression was positively correlated with the increases in phosphorylation of epithelial growth factor receptor ( r = 0.242, p < 0.001) and RAB11FIP3 ( r = 0.165, p = 0.005) expression. The multivariate Cox proportional hazard model analysis demonstrated that the expression of Eps15 homology domain 1 alone is a significant prognostic marker of breast cancer for the overall survival in the total, chemotherapy, and human epidermal growth factor receptor 2 (-) groups. However, the use of combined expression of Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor markers is more effective for the disease-free survival in the overall population, chemotherapy, and human epidermal growth factor receptor 2 (-) groups. Moreover, the combined markers are also significant prognostic markers of breast cancer in the human epidermal growth factor receptor 2 (+), estrogen receptor (+), and estrogen receptor (-) groups. Eps15 homology domain 1 has a tumor suppressor function, and the combined marker of Eps15 homology domain 1/phosphorylation of epithelial growth factor receptor expression was identified as a better prognostic marker in breast cancer diagnosis. Furthermore, RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor.

A computational study of self-assembled hexapeptide inhibitors against amyloid-ß (Aß) aggregation.

The fibrillation and deposition of amyloid-ß (Aß) peptides in human brains are pathologically linked to Alzheimer's disease (AD). Development of different inhibitors (peptides, organic molecules, and nanoparticles) to prevent Aß aggregation becomes a promising therapeutic strategy for AD treatment. We recently propose a "like-interacts-like" design principle to computationally design/screen and experimentally validate a new set of hexapeptide inhibitors with completely different sequences from the Aß sequence. These hexapeptide inhibitors inhibit Aß aggregation and reduce Aß-induced cytotoxicity. However, inhibitory mechanisms of these hexapeptides and the underlying interactions between hexapeptides and Aß remain unclear. Herein we apply multi-scale computational methods (quantum-chemical calculations, molecular docking and explicit-solvent molecular dynamic simulation) to explore the structure, dynamics, and interaction between 3 identified hexapeptides (CTLWWG, GTVWWG, and CTIYWG) and different Aß-derived fragments and an Aß17-42 pentamer. When interacting with 6 Aß-derived fragments, 3 hexapeptide inhibitors show stronger interactions with two lysine-included fragments (16KLVFFA21 and 27NKGAII33) than other fragments, indicating different sequence-specific interactions with Aß. When interacting with the Aß17-42 pentamer, the 3 peptides show similar binding modes and interaction mechanisms by preferentially binding to the edge of the Aß17-42 pentamer to potentially block the Aß elongation pathway. This work provides structural-based binding information on further modification and optimization of these peptide inhibitors to experimentally enhance their inhibitory abilities against Aß aggregation.

Optogenetic Neuromodulation in Inflammatory Pain.

Inflammatory pain is one of the most prevalent forms of pain and negatively influences the quality of life. Neuromodulation has been an expanding field of pain medicine and is accepted by patients who have failed to respond to several conservative treatments. Despite its effectiveness, neuromodulation still lacks clinically robust evidence on inflammatory pain management. Optogenetics, which controls particular neurons or brain circuits with high spatiotemporal accuracy, has recently been an emerging area for inflammatory pain management and studying its mechanism. This review considers the fundamentals of optogenetics, including using opsins, targeting gene expression, and wavelength-specific light delivery techniques. The recent evidence on application and development of optogenetic neuromodulation in inflammatory pain is also summarised. The current limitations and challenges restricting the progression and clinical transformation of optogenetics in pain are addressed. Optogenetic neuromodulation in inflammatory pain has many potential targets, and developing strategies enabling clinical application is a desirable therapeutic approach and outcome.

The Clinical and Pathological Effects of Serum C3 Level and Mesangial C3 Intensity in Patients with IgA Nephropathy.

Objective: To investigate the clinical and pathological effects of serum C3 level, mesangial C3 deposition intensity and blood lipid on IgA nephropathy. Methods: According to the deposition intensity of immunofluorescence (IF) complement C3 in mesangial region, a total of 151 patients were divided into: (1) negative group (65 cases), (2) weak positive group (51 cases), and (3) strong positive group (35 cases). According to the level of serum C3, the patients were divided into two groups: (1) 33 patients with decreased serum C3 (<85 mg/dL); (2) 118 patients with normal serum C3. The clinicopathological data of the patients were analyzed retrospectively according to the groups. Results: (1) With the increase of C3 deposition in mesangial region, the mean value of serum C3 level decreased, and the difference was statistically significant (P=0.001). (2) Compared with the normal serum C3 group, the blood urea nitrogen (BUN), serum creatinine (Scr), and albumin (Alb) in the serum C3 decreased group were higher, and the differences were statistically significant (P < 0.05), while the fasting blood glucose (FBG), low-density lipoprotein (LDL), triglyceride and 24-hr urinary protein (24hUTP) were lower, which difference was statistically significant (P < 0.05). (3) Compared with negative group and weak positive group, BUN, uric acid (UA), and Scr were higher in the strong positive group with C3 deposition, while eGFR was lower, with statistical significance (P < 0.05). However, C3 deposition in the mesangial region was related to T and enhanced mesangial C3 deposition was associated with more severe tubular atrophy and/or interstitial fibrosis, with statistically significant differences (P=0.001). Conclusion: Patients with strong mesangial C3 deposition and elevated lipid levels had more severe tubule atrophy and/or interstitial fibrosis, as well as more severe pathological lesions, suggesting that activation of the complement system is involved in the pathogenesis of IgA nephropathy and increases the metabolic burden of the kidney.

Monoterpenoid indole alkaloids from Melodinus axillaris W.T.Wang exhibit anti-inflammatory activities by inhibiting the NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Melodinus axillaris W.T.Wang has been widely used as an important medicine in China. In the folk of China, its whole plant has been used for fractures, rheumatic heart disease, testitis, hernia, abdominal pain, and dyspepsia, etc. Despite its extensive use, there is a shortage of literature investigating the specific bioactive compounds and underlying mechanisms responsible for their anti-inflammatory effects. This knowledge gap serves as the primary impetus for conducting this study, which aims to shed light on the previously unexplored therapeutic potential of M. axillaris. AIM OF THE STUDY: This study aims to investigate the material basis and potential mechanism of anti-inflammatory activity of M. axillaris. MATERIALS AND METHODS: Compounds were isolated from the 95% ethanol extract of M. axillaris using a systematic phytochemical method. The structures were established by extensive spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, ECD calculation, and DP4+ analysis. The anti-inflammatory activities of ethanol extract and compounds from M. axillaris were tested by an inflammation model of LPS-stimulated RAW264.7 cells in vitro. Western blot analysis was employed to evaluate the expressions of COX-2, iNOS, and NF-κB signaling pathways, aiming to elucidate the underlying mechanisms. RESULTS: Eleven undescribed monoterpenoid indole alkaloids (MIAs), axillines A-K (1-11), along with thirteen known analogs were isolated from M. axillaris. Compound 1 was the first representative of vincadine alkaloid with unprecedented 6/5/9/6/6 skeletons. Compounds 1-11 and ethanol extract showed significant anti-inflammatory effects in vitro. Among them, compound 2 had the best activity of inhibiting NO release (IC50 = 3.7 ± 0.9 µM). Additionally, subsequent Western blot analysis revealed that 2 could significantly inhibit the up-regulation of NF-κB signaling pathways, iNOS, and COX-2 in LPS-stimulated RAW264.7 cells, thereby demonstrating its anti-inflammatory activity. CONCLUSION: This study provides support for the traditional use of M. axillaris in terms of its anti-inflammatory properties and highlights the potential of MIAs as promising candidates for further development as anti-inflammatory drugs.

CAP2 contributes to Parkinson's disease diagnosed by neutrophil extracellular trap-related immune activity.

Introduction: Neutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis. Methods: Through differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. Results: Our findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. Discussion: In conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.

Metformin inhibits proliferation and promotes apoptosis of HER2 positive breast cancer cells by downregulating HSP90.

PURPOSE: To investigate the effects and the possible molecular mechanisms of metformin on HER2 positive breast cancer cells. METHODS: SK-BR-3 HER2 positive breast cancer cells were treated with different concentrations of metformin. The growth inhibitory rate of the cells was calculated by MTT assay, apoptosis was detected by flow cytometry, and the expression level of heat shock protein 90 (HSP90) was performed by Western blot analysis. A control group consisted of cells treated with PBS. RESULTS: With increased concentrations of metformin, cell growth inhibitory rates increased. The growth inhibitory rates with 0.5 mM, 2mM or 8mM metformin were significantly higher compared with the control group (p<0.05). Apoptosis in the metformin treated cells was also significantly higher compared with the control group (p=0.003). The expression level of HSP90 in the metformin group was significantly lower than that in the control group. CONCLUSION: Metformin can inhibit the proliferation and promote apoptosis of HER2 positive breast cancer cells,which is maybe related to inhibition of HSP90.

Exposure to real-ambient particulate matter induced vascular hypertrophy through activation of PDGFRß.

BACKGROUND: Vascular toxicity induced by particulate matter (PM) exposure exacerbates the onset and development of cardiovascular diseases; however, its detailed mechanism remains unclear. Platelet-derived growth factor receptor ß (PDGFRß) acts as a mitogen for vascular smooth muscle cells (VSMCs) and is therefore essential for normal vasoformation. However, the potential effects of PDGFRß on VSMCs in PM-induced vascular toxicity have not yet been elucidated. METHODS: To reveal the potential roles of PDGFRß signalling in vascular toxicity, individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models and PDGFRß overexpression mouse models were established in vivo, along with in vitro VSMCs models. RESULTS: Vascular hypertrophy was observed following PM-induced PDGFRß activation in C57/B6 mice, and the regulation of hypertrophy-related genes led to vascular wall thickening. Enhanced PDGFRß expression in VSMCs aggravated PM-induced smooth muscle hypertrophy, which was attenuated by inhibiting the PDGFRß and janus kinase 2 /signal transducer and activator of transcription 3 (JAK2/STAT3) pathways. CONCLUSION: Our study identified the PDGFRß gene as a potential biomarker of PM-induced vascular toxicity. PDGFRß induced hypertrophic effects through the activation of the JAK2/STAT3 pathway, which may be a biological target for the vascular toxic effects caused by PM exposure.

Real-ambient particulate matter exposure-induced FGFR1 methylation contributes to cardiac dysfunction via lipid metabolism disruption.

Particulate matter (PM)-induced cardiometabolic disorder contributes to the progression of cardiac diseases, but its epigenetic mechanisms are largely unknown. This study used bioinformatic analysis, in vivo and in vitro multiple models to investigate the role of PM-induced cardiac fibroblast growth factor 1 (FGFR1) methylation and its impact on cardiomyocyte lipid metabolic disruption. Bioinformatic analysis revealed that FGFR1 was associated with cardiac pathologies, mitochondrial function and metabolism, supporting the possibility that FGFR1 may play regulatory roles in PM-induced cardiac functional impairment and lipid metabolism disorders. Individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models were used to expose C57/BL6 mice for six and fifteen weeks. The results showed that PM induced cardiac lipid metabolism disorder, DNA nucleotide methyltransferases (DNMTs) alterations and FGFR1 expression declines in mouse heart. Lipidomics analysis revealed that carnitines, phosphoglycerides and lysophosphoglycerides were most significantly affected by PM exposure. At the cellular level, AC16 cells treated with FGFR1 inhibitor (PD173074) led to impaired mitochondrial and metabolic functions in cardiomyocytes. Inhibition of DNA methylation in cells by 5-AZA partially restored the FGFR1 expression, ameliorated cardiomyocyte injury and mitochondrial functions. These changes involved alterations in AMP-activated protein kinase (AMPK)-peroxisome proliferator activated receptors gamma, coactivator 1 alpha (PGC1α) pathways. Bisulfite sequencing PCR (BSP) and DNA methylation specific PCR (MSP) confirmed that PM exposure induced FGFR1 gene promoter region methylation. These results suggested that, by inducing FGFR1 methylation, PM exposure would affect cardiac injury and deranged lipid metabolism. Overexpression of FGFR1 in mouse heart using adeno-associated virus 9 (AAV9) effectively alleviated PM-induced cardiac impairment and metabolic disorder. Our findings identified that FGFR1 methylation might be one of the potential indicators for PM-induced cardiac mitochondrial and metabolic dysfunction, providing novel insights into underlying PM-related cardiotoxic mechanisms.

Cold stress selectively unsilences tandem repeats in heterochromatin associated with accumulation of H3K9ac.

Knobs are cytologically observable major interstitial heterochromatin present on maize nuclei, which consist of highly tandem-repetitive elements that are always silenced. Here we investigated the genome-wide change of H3K9ac, an active chromatin mark, during cold stress using chromatin immunoprecipitation sequencing (ChIP-Seq) and identified differential cold-induced H3K9ac enrichment at repetitive sequences in maize. More detailed analysis of two knob-associated tandem-repetitive sequences, 180-bp and TR-1, demonstrated that cold activated their transcription and this cold-induced transcriptional activation of repetitive sequences is selective, transient, and associated with an increase in H3K9ac and a reduction in DNA methylation and H3K9me2. Furthermore, knob sequence expression is accompanied by localized chromatin remodelling and silencing is recovered upon prolonged treatment. In addition, no evidence of copy number change and rearrangement of these repetitive elements are found in plants subjected to cold stress. These results suggest that cold-mediated unsilencing of heterochromatic tandem-repeated sequences, accompanied with epigenetic regulation, might play an important role in the adaptation of plants to cold stimuli.

Isogeometric Analysis of Graphene-Reinforced Functionally Gradient Piezoelectric Plates Resting on Winkler Elastic Foundations.

In this paper, the refined plate theory (RPT), Hamilton's principle, and isogeometric analysis (IGA) are applied to investigate the static bending, free vibration and buckling behaviors of functionally graded graphene-platelet-reinforced piezoelectric (FG-GRP) plates resting on a Winkler elastic foundation. The graphene platelets (GPLs) are distributed in polyvinylidene fluoride (PVDF) as a power function along the plate thickness direction to generate functionally gradient materials (FGMs). The modified Halpin-Tsai parallel model predicts the effective Young's modulus of each graphene-reinforced piezoelectric composite plate layer, and the rule of the mixture can be used to calculate the effective Poisson's ratio, mass density, and piezoelectric properties. Under different graphene distribution patterns and boundary conditions, the effects of a plate's geometric dimensions, GPLs' physical properties, GPLs' geometric properties and the elastic coefficient of the Winkler elastic foundation on deflections, frequencies and bucking loads of the FG-GRP plates are investigated in depth. The convergence and computational efficiency of the present IGA are confirmed versus other studies. Furthermore, the results illustrate that a small amount of GPL reinforcements can improve the FG-GRP plates' mechanical properties, i.e., GPLs can improve the system's vibration and stability characteristics. The more GPL reinforcements spread into the surface layers, the more effective it is at enhancing the system's stiffness.

Role of STAT3 Expression in Thyroid Cancer: A Meta-Analysis and Systematic Review Based on the Chinese Population.

Background: Signal transduction and activator of transcription 3 (STAT3) is an oncogene with transcriptional activity. In recent years, there have been several studies concerning the clinicopathological significance of the expression of the STAT3 protein in thyroid cancer. However, the results are still inconsistent. In this study, we conducted a meta-analysis to evaluate the relationship between the expression of STAT3 protein and thyroid cancer susceptibility and its clinicopathological characteristics. Methods: We searched the China National Knowledge Infrastructure (CNKI) database, Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wanfang, PubMed, and EMBASE. The time frame of the publication search was from the establishment of each of the databases until December 2021. We performed a meta-analysis to quantitatively evaluate the relationship between the expression of the STAT3 protein in thyroid cancer and its clinicopathological characteristics. Results: A total of eight articles were included in the meta-analysis, covering 448 thyroid cancer patients and 227 controls. Results indicated that the expression of STAT3 protein in thyroid cancer tissue is highly expressed (OR = 14.41, 95% CI (6.94, 29.91), p < 0.001). Besides, we also discovered that STAT3 protein is negatively correlated with thyroid cancer tumor diameter and TNM stage (OR = 0.13, 95% CI (0.05, 0.33), p < 0.001; OR = 0.40, 95% CI (0.24, 0.67), p < 0.001) and positively correlated with lymph node metastasis (OR = 2.83, 95% CI (1.08, 7.46), p = 0.035). However, STAT3 expression is not related to gender (OR = 0.88, 95% CI (0.54, 1.44), p = 0.609), age (OR = 0.54, 95% CI (0.21, 1.36), p = 0.191), capsular invasion (OR = 2.98, 95% CI (0.23, 38.29), p = 0.403), or tumor multiplicity (OR = 0.25, 95% CI (0.003, 19.28), p = 0.533). Conclusions: This study reveals that STAT3 protein expression is significantly related to the susceptibility and clinicopathological characteristics of thyroid cancer. It also suggests that STAT3 may be a potential predictor of the clinical progression of thyroid cancer.

3D localization based on anatomical LANDmarks in the treatment of pulmonary nodules.

Background: Various methods exist for locating lung nodules, each with its own advantages and disadvantages. Aiming to find a more accurate, safe, effective, economical and practical method for locating lung nodules, this study evaluated the safety and feasibility of a precise three-dimensional (3D) method for positioning small pulmonary nodules based on anatomical landmarks. Methods: From June 2019 to December 2021, 120 patients with 131 pulmonary nodules who underwent video-assisted thoracoscopic surgery at the University of Hong Kong-Shenzhen Hospital were included in the study. Surgical data such as the positioning time, accuracy rate, pathological result, localization-related complication rate and length of postoperative hospital stay were retrospectively reviewed and analyzed. During surgery, pulmonary nodules were accurately located by the 3D positioning method based on anatomical landmarks and then removed to determine the pathology. Results: A total of 120 patients, including 35 males and 85 females, were included, and the median age was 53 years [interquartile range (IQR), 41-63 years]. No mortality or major morbidity occurred within 30 days. The median localization time was 11 minutes (IQR, 8-14 minutes). The accuracy of localization was 98.5%. The median diameter of the pulmonary nodules was 8 mm (IQR, 7-13 mm), and the median distance from the visceral pleura was 6 mm (IQR, 2-10 mm). No location-related complications occurred. The median length of postoperative hospital stay was 5 days (IQR, 3-7 days). Conclusions: The proposed positioning method is accurate, safe and feasible for selected patients with pulmonary nodules. Compared with other preoperative and intraoperative positioning methods, it can significantly reduce localization-related complications.

Research on the Synergistic Effect of Total Ionization and Displacement Dose in GaN HEMT Using Neutron and Gamma-Ray Irradiation.

This paper studies the synergistic effect of total ionizing dose (TID) and displacement damage dose (DDD) in enhancement-mode GaN high electron mobility transistor (HEMT) based on the p-GaN gate and cascode structure using neutron and 60Co gamma-ray irradiation. The results show that when the accumulated gamma-ray doses are up to 800k rad(Si), the leakage-current degradations of the two types of GaN HEMTs with 14 MeV neutron irradiation of 1.3 × 1012 n/cm2 and 3 × 1012 n/cm2 exhibit a lower degradation than the sum of the two separated effects. However, the threshold voltage shifts of the cascode structure GaN HEMT show a higher degradation when exposed to both TID and DDD effects. Moreover, the failure mechanisms of the synergistic effect in GaN HEMT are investigated using the scanning electron microscopy technique. It is shown that for the p-GaNHEMT, the increase in channel resistance and the degradation of two-dimensional electron gas mobility caused by neutron irradiation suppresses the increase in the TID leakage current. For the cascode structure HEMT, the neutron radiation-generated defects in the oxide layer of the metal-oxide-semiconductor field-effect transistor might capture holes induced by gamma-ray irradiation, resulting in a further increase in the number of trapped charges in the oxide layer.