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Objective: Tangbi capsule (TBC) is a traditional Chinese medicine prescription, which has the potential to improve the vascular insufficiency of lower extremities and limb numbness in diabetes. However, the potential mechanism remains unknown. This study aims to investigate the pharmacological effects and mechanism of TBC on rats with diabetic lower extremities arterial disease (LEAD). Methods: The mechanism of TBC on diabetic LEAD was investigated through metabolomics and transcriptomics analysis, and the main components of TBC were determined by mass spectrometry. The efficacy and mechanism of TBC on diabetic LEAD rats were investigated through in vitro experiments, histopathology, blood flow monitoring, western blot, and real-time polymerase chain reaction. Results: Mass spectrometry analysis identified 31 active chemical components in TBC including (2R)-2,3-Dihydroxypropanoic acid, catechin, citric acid, miquelianin, carminic acid, salicylic acid, formononetin, etc. In vitro analysis showed that TBC could reduce endothelial cell apoptosis and promote angiogenesis. Histopathological analysis showed that TBC led to an obvious improvement in diabetic LEAD as it improved fibrous tissue proliferation and reduced arterial wall thickening. In addition, TBC could significantly increase the expression levels of HIF-1α, eNOS, and VEGFA proteins and genes while reducing that of calpain-1 and TGF-ß, suggesting that TBC can repair vascular injury. Compared with the model group, there were 47 differentially expressed genes in the whole blood of TBC groups, with 25 genes upregulated and 22 downregulated. Eighty-seven altered metabolites were identified from the serum samples. Combining the changes in differentially expressed genes and metabolites, we found that TBC could regulate arginine biosynthesis, phenylalanine metabolism, pyrimidine metabolism, arachidonic acid metabolism, pyrimidine metabolism, arachidonic acid metabolism, nucleotide metabolism, vitamin B6 metabolism and other metabolic pathways related to angiogenesis, immune-inflammatory response, and cell growth to improve diabetic LEAD. Conclusion: TBC improved vascular endothelial injury, apoptosis, lipid accumulation, liver and kidney function, and restored blood flow in the lower extremities of diabetic LEAD rats. The mechanism of TBC in the treatment of diabetic LEAD may be related to the modulation of inflammatory immunity, lipid metabolism, and amino acid metabolism. This study presented preliminary evidence to guide the use of TBC as a therapy option for diabetic LEAD.
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Stable, efficient, and economical bifunctional electrocatalysts for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) are needed for rechargeable Zn-air batteries. In this study, a directional electron transfer pathway is exploited in a spatial heterojunction of CoyNix@FeâNâC heterogeneous catalyst for effective bifunctional electrolysis (OER/ORR). Thereinto, the Co/Ni alloy is strongly coupled to the FeâNâC support through Co/NiâN bonds. DFT calculations and experimental findings confirm that Co/NiâN bonds play a bridging role in the directional electron transfer from Co/Ni alloy to the FeâNâC support, increasing the content of pyridinic nitrogen in the ORR-active support. In addition, the discovered directional electron transfer mechanism enhances both the ORR/OER activity and the durability of the catalyst. The Co0.66Ni0.34@FeâNâC with the optimal Ni/Co ratio exhibits satisfying bifunctional electrocatalytic performance, requiring an ORR half-wave potential of 0.90 V and an OER overpotential of 317 mV at 10 mA cm-2 in alkaline electrolytes. The assembled rechargeable zinc-air batteries (ZABs) incorporating Co0.66Ni0.34@FeâNâC cathode exhibits a charge-discharge voltage gap comparable to the Pt/C||IrO2 assembly and high robustness for over 60 h at 20 mA cm-2.
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The drivers of changes in gut microbiota under arsenic exposure and the mechanism by which microbiota affect arsenic metabolism are still unclear. Here, C57BL/6 mice were exposed to 0, 5, or 10 ppm NaAsO2 in drinking water for 6 months. The results showed that arsenic exposure induced liver injury and increased the abundance of folic acid (FA)/vitamin B12 (VB12)- and butyrate-synthesizing microbiota. Statistical analysis and in vitro cultures showed that microbiota were altered to meet the demand for FA/VB12 by arsenic metabolism and to resist the toxicity of unmetabolized arsenic. However, at higher arsenic levels, changes of these microbiota were inconsistent. A 3D molecular simulation showed that arsenic bound to methionine synthase (MTR), which was confirmed by SEC-UV-DAD (1 µM recombinant human MTR was purified with 0 or 2 µM NaAsO2 at room temperature for 1 h) and fluorescence-labeled arsenic co-localization (primary hepatocytes were exposed to 0, 0.5, or 1 µM ReAsH-EDT2 for 24 h) in non-cellular and cellular systems. Mechanistically, the arsenic-MTR interaction in the liver interferes with the utilization of FA/VB12, which increases arsenic retention and thus results in a substantial increase in the abundance of butyrate-synthesizing microbiota compared to FA/VB12-synthesizing microbiota. By exposing C57BL/6J mice to 0 or 10 ppm NaAsO2 with or without FA (6 mg/L) and VB12 (50 µg/L) supplementation in their drinking water for 6 months, we constructed an FA/VB12 intervention mouse model and found that FA/VB12 supplementation blocked the disturbance of gut microbiota, restored MTR levels, promoted arsenic metabolism, and alleviated liver injury. We demonstrate that the change of gut microbiota is a response to arsenic metabolism, a process influenced by the arsenic-MTR interaction. This study provides new insights for understanding the relationship between gut microbiota and arsenic metabolism and present therapeutic targets for arseniasis.
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5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase , Arsênio , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Arsênio/metabolismo , Arsênio/toxicidade , Camundongos , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Masculino , Ácido Fólico/metabolismo , Vitamina B 12/metabolismoRESUMO
To investigate the influence of different rhenium contents on the helium desorption behavior in tungsten-rhenium alloys, pure tungsten and tungsten-rhenium alloys were irradiated with helium under the same conditions. All irradiated samples were characterized using TDS and DBS techniques. The results indicate that the addition of rhenium can reduce the total helium desorption quantity in tungsten-rhenium alloys and slightly accelerate the reduction in the concentration of vacancy-type defects accompanying helium dissociation. The desorption activation energy of helium is approximately 2 eV at the low-temperature peak (~785 K) and about 4 eV at the high-temperature peak (~1475 K). An increase in rhenium content causes the desorption peak to shift towards higher temperatures (>1473 K), which is attributed to the formation of the stable complex structures between rhenium and vacancies. Besides, the migration of He-vacancy complexes towards traps and dynamic annealing processes both lead to the recovery of vacancy-type defects, resulting in a decrease in the positron annihilation S parameters.
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Photoelectrochemical water splitting on n-type semiconductors is highly dependent on catalysis of the rate-determining reaction of O2 evolution. Conventionally, in electrochemistry and photoelectrochemistry O2 evolution is catalyzed by metal oxide catalysts like IrO2 and RuO2, whereas noble metals such as Pt are considered unsuitable for this purpose. However, our study finds that Pt, in its single-atom form, exhibits exceptional cocatalytic properties for photoelectrochemical water oxidation on a TiO2 photoanode, in contrast to Pt in a nanoparticle form. The decoration of Pt single atoms onto TiO2 yields a remarkable current density of 5.89 mA cm-2 at 1.23 VRHE, surpassing bare TiO2 (or Pt nanoparticle decorated TiO2) by 2.52 times. Notably, this enhancement remains consistent over a wide pH range. By accompanying theoretical work, we assign this significant enhancement to an improved charge transfer and separation efficiency along with accelerated kinetics in the oxygen evolution reaction facilitated by the presence of Pt single atoms on the TiO2 surface.
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BACKGROUND: Malancao (MLC) is a traditional Chinese medicine with a long history of utilization in treating ulcerative colitis (UC). Nevertheless, the precise molecular mechanisms underlying its efficacy remain elusive. This study leveraged ultra-high-performance liquid chromatography coupled with exactive mass spectrometry (UHPLC-QE-MS), network pharmacology, molecular docking (MD), and gene microarray analysis to discern the bioactive constituents and the potential mechanism of action of MLC in UC management. AIM: To determine the ingredients related to MLC for treatment of UC using multiple databases to obtain potential targets for fishing. METHODS: This research employs UHPLC-QE-MS for the identification of bioactive compounds present in MLC plant samples. Furthermore, the study integrates the identified MLC compound-related targets with publicly available databases to elucidate common drug disease targets. Additionally, the R programming language is utilized to predict the central targets and molecular pathways that MLC may impact in the treatment of UC. Finally, MD are conducted using AutoDock Vina software to assess the affinity of bioactive components to the main targets and confirm their therapeutic potential. RESULTS: Firstly, through a comprehensive analysis of UHPLC-QE-MS data and public database resources, we identified 146 drug-disease cross targets related to 11 bioactive components. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis highlighted that common disease drug targets are primarily involved in oxidative stress management, lipid metabolism, atherosclerosis, and other processes. They also affect AGE-RAGE and apoptosis signaling pathways. Secondly, by analyzing the differences in diseases, we identified key research targets. These core targets are related to 11 active substances, including active ingredients such as quercetin and luteolin. Finally, MD analysis revealed the stability of compound-protein binding, particularly between JUN-Luteolin, JUN-Quercetin, HSP90AA1-Wogonin, and HSP90AA1-Rhein. Therefore, this suggests that MLC may help alleviate intestinal inflammation in UC, restore abnormal lipid accumulation, and regulate the expression levels of core proteins in the intestine. CONCLUSION: The utilization of MLC has demonstrated notable therapeutic efficacy in the management of UC by means of the compound target interaction pathway. The amalgamation of botanical resources, metabolomics, natural products, MD, and gene chip technology presents a propitious methodology for investigating therapeutic targets of herbal medicines and discerning novel bioactive constituents.
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Epidemiological evidence showed that serum high perfluorooctane sulfonate (PFOS) levels are associated with multiple eye related diseases, but the potential underlying molecular mechanisms remain poorly understood. Zebrafish and photoreceptor cell (661w) models were used to investigate the molecular mechanism of PFOS induced eye development defects. Our results showed a novel molecular mechanism of PFOS-induced inflammation response-mediated photoreceptor cell death associated with eye development defects. Inhibition of Caspase-8 activation significantly decreased photoreceptor cell death in PFOS exposure. Mechanistically, Toll-like receptor 4 (TLR4) mediates activation of Caspase-8 promote activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome to elicit maturation of interleukin-1 beta (IL-1ß) via Caspase-1 activation, facilitating photoreceptor cell inflammation damage in PFOS exposure. In addition, we also made a novel finding that Caspase-3 activation was increased via Caspase-8 activation and directly intensified cell death. Our results show the important role of Caspase-8 activation in PFOS induced eye development defects and highlight Caspase-8 mediated activation of the NLRP3 inflammation triggers activation of Caspase-1 and promote the maturation of IL-1ß in retinal inflammatory injury.
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Ácidos Alcanossulfônicos , Caspase 8 , Fluorocarbonos , Inflamassomos , Larva , Proteína 3 que Contém Domínio de Pirina da Família NLR , Peixe-Zebra , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Caspase 8/metabolismo , Caspase 8/genética , Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Larva/efeitos dos fármacos , Interleucina-1beta/metabolismo , Olho/efeitos dos fármacos , Poluentes Químicos da Água/toxicidadeRESUMO
Sweat gland (SwG) regeneration is crucial for the functional rehabilitation of burn patients. In vivo chemical reprogramming that harnessing the patient's own cells in damaged tissue is of substantial interest to regenerate organs endogenously by pharmacological manipulation, which could compensate for tissue loss in devastating diseases and injuries, for example, burns. However, achieving in vivo chemical reprogramming is challenging due to the low reprogramming efficiency and an unfavorable tissue environment. Herein, this work has developed a functionalized proteinaceous nanoformulation delivery system containing prefabricated epidermal growth factor structure for on-demand delivery of a cocktail of seven SwG reprogramming components to the dermal site. Such a chemical reprogramming system can efficiently induce the conversion of epidermal keratinocytes into SwG myoepithelial cells, resulting in successful in situ regeneration of functional SwGs. Notably, in vivo chemical reprogramming of SwGs is achieved for the first time with an impressive efficiency of 30.6%, surpassing previously reported efficiencies. Overall, this proteinaceous nanoformulation provides a platform for coordinating the target delivery of multiple pharmacological agents and facilitating in vivo SwG reprogramming by chemicals. This advancement greatly improves the clinical accessibility of in vivo reprogramming and offers a non-surgical, non-viral, and cell-free strategy for in situ SwG regeneration.
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Reprogramação Celular , Animais , Humanos , Camundongos , Reprogramação Celular/efeitos dos fármacos , Fator de Crescimento Epidérmico/química , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Regeneração/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/citologia , Nanopartículas/químicaRESUMO
Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6â¯J female mice were randomly allocated to three groups: the control group, F-53B 0.8⯵g/kg/day group, and F-53B 8⯵g/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8⯵g/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8⯵g/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.
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Inflamassomos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Placenta , Animais , Feminino , Gravidez , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placenta/efeitos dos fármacos , Placenta/patologia , Camundongos , Inflamassomos/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/patologia , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Fluorocarbonos/toxicidade , Transdução de Sinais/efeitos dos fármacosRESUMO
Sebaceous glands (SGs), as holocrine-secreting appendages, lubricate the skin and play a central role in the skin barrier. Large full-thickness skin defects cause overall architecture disruption and SG loss. However, an effective strategy for SG regeneration is lacking. Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine. Recently, considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological, structural and functional features of their in vivo counterparts. Engineering approaches empower researchers to manipulate cell behaviors, the surrounding environment and cell-environment crosstalk within the culture system as needed. These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids. This review aims to provide an overview of recent advancements in SG organoid engineering. It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized, innervated, immune-interactive and lipogenic SG organoids. We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.
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Objective: Moderate-to-severe pain is the most common clinical symptom in patients with hepatocellular carcinoma (HCC).This trial aimed to analyze the clinical efficacy of Transcutaneous electrical acupoint stimulation (TEAS) in patients of HCC with severe pain and provide a reliable reference for optimizing the clinical diagnostic and therapeutic strategies of HCC. Methods: A total of 104 eligible patients were randomly allocated to experimental and control groups in a ratio of 1:1.The treatment was administered for 1 week continuously. Patients in both groups were followed up 1 week after the end of the treatment.The primary outcome measure was the Numerical Rating Scale (NRS) score, whereas the secondary outcome measures included Brief Pain Inventory BPI-Q3, Q4, Q5 scores, analgesic dose, frequency of opioid-induced gastrointestinal side effects, Karnofsky Performance Status (KPS), Quality of Life Scale - Liver Cancer (QOL-LC), and Brief Fatigue Inventory (BFI) scores. Results: The NRS scores of experimental group was significantly lower after treatment and at the follow-up than baseline (average P<0.01), there were also statistical differences between the groups at the above time points (average P<0.01). BPI-Q3, -Q4, and -Q5 scores in the experimental group were decreased after treatment when compared with those before treatment (average P<0.01). Furthermore, there were significant improvements of gastrointestinal side effects, KPS, QOL-LC and BPI in the experimental group after treatment, and the above results were statistically significant compared to the control group. Conclusion: 7-day TEAS treatment can significantly enhance the analgesic effect and maintain for the following week, also reduce the incidence of gastrointestinal side effects caused by opioids, and improve the quality of life of patients with moderate-to-severe HCC-related pain, which has reliable safety and certain clinical promotion value.
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The purpose of this study was to reveal the spatial and temporal evolution patterns of habitat quality in karst counties of Guizhou plateau and its driving factors and to provide scientific basis for balanced ecological conservation and sustainable development of karst regions. Using DEM data, meteorological data, socio-economic data, and four periods of land use data in 1989, 2003, 2010, and 2020, the InVEST model was used to analyze the spatial and temporal evolution characteristics of habitat quality in Puding County from 1989 to 2020 and to quantitatively detect the driving forces of its spatial divergence. The results were as follows:â Arable land and forest land were the main land use types in Puding County, which constituted the surface cover landscape matrix. Land use changes from 2003-2010 were the most significant, among which forest land had the largest increase of 86.42%; arable land was the most severely lost land use type, with an area decrease of 157.57 km2, mainly flowing to forest land and construction land. â¡ From 1989 to 2020, the average value of habitat quality index in Puding County increased from 0.60 to 0.73. Spatially, the distribution pattern of "high-low-high" was generally from northeast to southwest, with the high value areas of habitat quality mainly distributed in the woodland and grassland areas in the northeast and the low value areas concentrated in the construction land in the central and south areas. ⢠Land use type was the primary factor affecting the spatial and temporal distribution of habitat quality, with an explanation of 91.00%. In the interaction detection, the interaction of any two influencing factors was greater than that of individual factors alone, and the interaction between land use type and average annual precipitation was the strongest, reaching 96.00%; the interaction with lithological factors reached 94.00%, with natural and human factors jointly dominating the spatial and temporal changes in habitat quality. From the results of this study, we concluded that the habitat quality of Puding County was generally good from 1989 to 2020, and the relationship between land use type changes and habitat quality was close. Optimizing the land use structure and reducing the influence of human activities are important to improve the habitat quality of Puding County.
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BACKGROUND: Obesity, a chronic metabolic disorder, is related to cardiovascular diseases, diabetes, cancer, and reproductive disorders. The relationship between obesity and male infertility is now well recognized, but the mechanisms involved are unclear. We aimed to observe the effect of obesity on spermatogenesis and to investigate the role of histone ubiquitination and acetylation modifications in obesity-induced spermatogenesis disorders. METHODS: Thirty male C57BL/6J mice were randomly divided into two groups. The control group was fed with a general maintenance diet (12% fat), while a high-fat diet (HFD) group was fed with 40% fat for 10 weeks; then, they were mated with normal females. The fertility of male mice was calculated, testicular and sperm morphology were observed, and the expression levels of key genes and the levels of histone acetylation and ubiquitination modification during spermatogenesis were detected. RESULTS: The number of sperm was decreased, as well as the sperm motility, while the number of sperm with malformations was increased. In the testes, the mRNA and protein expression levels of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), chromosome region maintenance-1 protein (CRM1), high-mobility group B2 (HMGB2), phosphoglycerate kinase 2 (PGK2), and testicular angiotensin-converting enzyme (tACE) were decreased. Furthermore, obesity led to a decrease in ubiquitinated H2A (ubH2A) and reduced levels of histone H3 acetylation K18 (H3AcK18) and histone H4 acetylation K5, K8, K12, and K16 (H4tetraAck), which disrupted protamine 1 (Prm1) deposition in testis tissue. CONCLUSION: These results suggest that low levels of histone ubiquitination and acetylation are linked with obesity-induced disorders during spermatogenesis, contributing to a better understanding of obesity-induced damage to male reproduction.
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Microbial interactions can lead to different colonization outcomes of exogenous species, be they pathogenic or beneficial in nature. Predicting the colonization of exogenous species in complex communities remains a fundamental challenge in microbial ecology, mainly due to our limited knowledge of the diverse mechanisms governing microbial dynamics. Here, we propose a data-driven approach independent of any dynamics model to predict colonization outcomes of exogenous species from the baseline compositions of microbial communities. We systematically validate this approach using synthetic data, finding that machine learning models can predict not only the binary colonization outcome but also the post-invasion steady-state abundance of the invading species. Then we conduct colonization experiments for commensal gut bacteria species Enterococcus faecium and Akkermansia muciniphila in hundreds of human stool-derived in vitro microbial communities, confirming that the data-driven approaches can predict the colonization outcomes in experiments. Furthermore, we find that while most resident species are predicted to have a weak negative impact on the colonization of exogenous species, strongly interacting species could significantly alter the colonization outcomes, e.g., Enterococcus faecalis inhibits the invasion of E. faecium invasion. The presented results suggest that the data-driven approaches are powerful tools to inform the ecology and management of microbial communities.
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Enterococcus faecium , Microbiota , Humanos , Fezes/microbiologia , Interações Microbianas , Enterococcus faecalisRESUMO
Trading water for carbon has cautioned large-scale afforestation in global drylands. However, model simulations suggested that the consumption of soil water could be partially offset by increasing precipitation due to vegetation feedback. A systematic meta-analysis of long-term and large-scale field observations is urgently required to address the abovementioned limitations, and the implementation of large-scale afforestation since 1978 in northern China provides an ideal example. This study collected data comprising 1226 observations from 98 sites in northern China to assess the variation in soil water content (SWC) with stand age after afforestation and discuss the effects of tree species, precipitation and conversions of land use types on SWC. We found that the SWC has been decreased by coniferous forest and broadleaf forest at rates of 0.6 and 3.2 mm decade-1, respectively, since 1978. There is a significant declining trend of SWC with the stand age of plantations, and the optimum growth stage for plantation forest is 0-20 a in northern China. However, we found increases in SWC for the conversion from grassland to forest and in the low-precipitation region, both are corresponding to the increased SWC in coniferous forest. Our study implies that afforestation might lead to a soil water deficit crisis in northern China in the long term at the regional scale but depends on prior land use types, tree taxa and the mean annual precipitation regime, which sheds light on decision-making regarding ecological restoration policies and water resource management in drylands.
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Neutron irradiation (E ≥ 1â
MeV) and 400â
keV Kr+ ion irradiation tests were carried out and compared to study the formation and growth mechanism of dislocation loops in zirconium alloys. The results show that, as the irradiation reached 1.9 × 1025â
n/m2 and 1.0 × 1020â
Kr+/m2, a large number of -type dislocation loops and a small amount of large-sized
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Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.
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Arsênio , Ácido Ascórbico , Dioxigenases , Transtornos do Metabolismo de Glucose , Animais , Camundongos , Arsênio/toxicidade , Ácido Ascórbico/uso terapêutico , Dioxigenases/metabolismo , DNA , Metilação de DNA , Proteínas de Ligação a DNA , Glucose/metabolismo , Transtornos do Metabolismo de Glucose/induzido quimicamente , Transtornos do Metabolismo de Glucose/genética , Transtornos do Metabolismo de Glucose/metabolismo , Fígado/metabolismoRESUMO
BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.
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Hepatite B Crônica , Humanos , Masculino , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Estudos Retrospectivos , Cirrose Hepática , Curva ROC , Alanina Transaminase , Vírus da Hepatite B , Antígenos E da Hepatite BRESUMO
The applications of hierarchically porous metal-organic frameworks (HP-MOFs) against traditional microporous counterparts for oxidative desulfurization (ODS) have triggered wide research interests due to their highly exposed accessible active sites and fast mass transfer of substrate molecules, particularly for the large-sized refractory sulfur compounds. Herein, a series of hierarchically porous amino-functionalized Zr-MOFs (HP-UiO-66-NH2-X) network with controllable mesopore sizes (3.5-9.2 nm) were firstly prepared through a template-free method, which were further utilized as anchoring support to bind the active phosphomolybdic acid (PMA) via the strong host-guest interaction to catalyze the ODS reaction. Benefitting from the hierarchically porous structure, accessible active sites and the strong host-guest interaction, the resultant PMA/HP-UiO-66-NH2-X exhibited excellent ODS performance, of which, the PMA/HP-UiO-66-NH2-9 with an appropriate mesopore size (4.0 nm) showed the highest catalytic activity, achieving a 99.9% removal of dibenzothiophene (DBT) within 60 min at 50 °C, far exceeding the microporous sample and PMA/HP-UiO-66. Furthermore, the scavenger experiments confirmed that â¢OH radical was the main reactive species and the density functional theory (DFT) calculations revealed that electron transfer (from amino group to PMA) made PMA react more easily with oxidant, thereby generating more â¢OH radical to promote the ODS reaction. Finally, from the industrial point of view, the powdered MOF nanoparticles (NPs) were in situ grown on the carboxymethyl cellulose (CMC) substrates and shaped into monolithic MOF-based catalysts, which still exhibited satisfying ODS performance in the case of model real fuel with good reusability, indicating its potential industrial application prospect.
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Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.