Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.

Pro-inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro-inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF-κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF-κB regulated pro-inflammatory response of microglia induced by low glucose.

Pumping Small Molecules Selectively through an Energy-Assisted Assembling Process at Nonequilibrium States.

In living organisms, precise control over the spatial and temporal distribution of molecules, including pheromones, is crucial. This level of control is equally important for the development of artificial active materials. In this study, we successfully controlled the distribution of small molecules in the system at nonequilibrium states by actively transporting them, even against the apparent concentration gradient, with high selectivity. As a demonstration, in the aqueous solution of acid orange (AO7) and TMC10COOH, we found that AO7 molecules can coassemble with transient anhydride (TMC10CO)2O to form larger assemblies in the presence of chemical fuel 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC). This led to a decrease in local free AO7 concentration and caused AO7 molecules from other locations in the solution to move toward the assemblies. Consequently, AO7 accumulates at the location where EDC was injected. By continuously injecting EDC, we could maintain a stable high value of the apparent AO7 concentration at the injection point. We also observed that this process which operated at nonequilibrium states exhibited high selectivity.

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and ß-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.

Clonal spread of blaNDM-1-carrying Salmonella enterica serovar Typhimurium clone ST34 and wide spread of IncHI2/ST3-blaNDM-5 plasmid in China.

OBJECTIVES: To characterize blaNDM-carrying Salmonella recovered from a pig slaughterhouse. METHODS: In this study, 46 environment samples were collected from a slaughterhouse in China, and screened for carbapenem-resistant Enterobacterales. WGS, antimicrobial susceptibility testing and conjugation experiments were carried out to identify the isolates' resistance phenotypes and genetic characteristics. The phylogenetic relatedness of the Salmonella isolates obtained in this study and Salmonella (ST34 and ST29) in GenBank was determined. RESULTS: Two ST34 Salmonella Typhimurium and one ST29 Salmonella Stanley, recovered from three environmental samples (6.52%), were positive for blaNDM-1 and blaNDM-5, respectively. The two ST34 S. Typhimurium strains exhibited a close relationship (10-36 SNPs) with two human-derived blaNDM-1-bearing isolates from China (Hong Kong and Guangxi Province) and two blaNDM-negative ST34 Salmonella strains from the UK. The blaNDM-1 genes were located on IncHI2/ST3 plasmids. The capture of blaNDM-1 by the IncHI2/ST3 plasmid seems to be due to homologous recombination mediated by circular structures, as the genetic arrangements of the blaNDM-1 gene contain two IS26 elements of the same orientation. The blaNDM-5 gene was also carried by the IncHI2/ST3 plasmid, which shares highly similar structures with other blaNDM-5-bearing IncHI2/ST3 plasmids from other sources (fish, chicken, duck, human). CONCLUSIONS: This is the first report of a blaNDM-5-carrying IncHI2/ST3 plasmid in Salmonella. The clonal spread of NDM-1-producing ST34 S. Typhimurium across human and animal-associated environments, and the widespread dissemination of epidemic blaNDM-5-carrying IncHI2/ST3 plasmids among Enterobacteriaceae in China indicate the potential of further dissemination of blaNDM among Salmonella, which poses a threat to public health.

Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

ENHANCED DISEASE SUSCEPTIBILITY 1 promotes hydrogen peroxide scavenging to enhance rice thermotolerance.

Heat stress is a major factor limiting the production and geographic distribution of rice (Oryza sativa), and breeding rice varieties with tolerance to heat stress is of immense importance. Although extensive studies have revealed that reactive oxygen species (ROS) play a critical role in rice acclimation to heat stress, the molecular basis of rice controlling ROS homeostasis remains largely unclear. In this study, we discovered a novel heat-stress-responsive strategy that orchestrates ROS homeostasis centering on an immune activator, rice ENHANCED DISEASE SUSCEPTIBILITY 1 (OsEDS1). OsEDS1, which confers heat stress tolerance, promotes hydrogen peroxide (H2O2) scavenging by stimulating catalase activity through the OsEDS1-catalase association. The loss-of-function mutation in OsEDS1 causes increased sensitivity to heat stress, whereas the overexpression of OsEDS1 enhances thermotolerance. Furthermore, overexpression lines greatly improved rice tolerance to heat stress during the reproductive stage, which was associated with substantially increased seed setting, grain weight, and plant yield. Rice CATALASE C (OsCATC), whose activity is promoted by OsEDS1, degrades H2O2 to activate rice heat stress tolerance. Our findings greatly expand our understanding of heat stress responses in rice. We reveal a molecular framework that promotes heat tolerance through ROS homeostasis regulation, suggesting a theoretical basis and providing genetic resources for breeding heat-tolerant rice varieties.

Phylogenomic insights into the historical biogeography, character-state evolution, and species diversification rates of Cypripedioideae (Orchidaceae).

Cypripedioideae (slipper orchids; Orchidaceae) currently consist of ∼200 herbaceous species with a strikingly disjunctive distribution in tropical and temperate regions of both hemispheres. In this study, an updated phylogeny with representatives from all five cypripedioid genera was presented based on maximum likelihood and Bayesian inference of plastome and low-copy nuclear genes. Phylogenomic analyses indicated that each genus is monophyletic, but some relationships (e.g., those among Cypripedium sects. Acaulia, Arietinum, Bifolia, Flabellinervia, Obtusipetala and Palangshanensia) conflict with those in previous studies based on Sanger data. Cypripedioideae appeared to have arisen in South America and/or the adjacent Qinghai-Tibet Plateau and Hengduan Mountains ∼35 Mya. We inferred multiple dispersal events between East Asia and North America in Cypripedium, and between mainland Southeast Asia and the Malay Archipelago in Paphiopedilum. In the Americas, divergences among four genera (except Cypripedium) occurred around 31-20 Mya, long before the closure of the Isthmus of Panama, indicating the importance of long-distance dispersal. Evolutionary patterns between morphological and plastome character evolution suggested several traits, genome size and NDH genes, which are likely to have contributed to the success of slipper orchids in alpine floras and low-elevation forests. Species diversification rates were notably higher in epiphytic clades of Paphiopedilum than in other, terrestrial cypripedioids, paralleling similar accelerations associated with epiphytism in other groups. This study also suggested that sea-level fluctuations and mountain-building processes promoted the diversification of the largest genera, Paphiopedilum and Cypripedium.

Enantioselective adsorption of ibuprofen enantiomers using chiral-active carbon nanoparticles induced S-α-methylbenzylamine.

The chiral media is crucial to the chiral recognition and separation of enantiomers. In this study, we report the preparation of novel chiral carbon nanoparticles (CCNPs) via surface passivation using glucose as the carbon source and S-(-)-α-methylbenzylamine as the chiral ligand. The structures of the obtained CCNPs are characterized via FT-IR, Raman spectroscopy, DLS, XPS, XRD, TEM, and zeta potential analysis. These CCNPs could be employed as the chiral adsorbent and used for the enantioselective adsorption of the ibuprofen enantiomers. The results demonstrated that the CCNPs could selectively adsorb R-enantiomer from ibuprofen racemate solution and give an enantiomeric excess (e.e.) of about 50% under an optimal adsorption condition. Moreover, the regeneration efficiency of the CCNPs remained above e.e. of 43% after the fifth cycle. The present work confirmed that the prepared CCNPs show great potential in the enantioselective separation of ibuprofen racemate.

Effective doses of ciprofol combined with alfentanil in inhibiting responses to gastroscope insertion, a prospective, single-arm, single-center study.

BACKGROUND: Ciprofol is a novel intravenous sedative and anesthetic. Studies have shown that it features a rapid onset of action, a fast recovery time, slight inhibition of respiratory and cardiovascular functions, and a low incidence of adverse reactions. This study aims to explore the median effective dose (ED50) and the 95% effective dose (ED95) of ciprofol in inhibiting responses to gastroscope insertion when combined with a low dose of alfentanil, and to evaluate its safety, to provide a reference for the rational use of ciprofol in clinical practices. METHODS: We included 25 patients aged 18-64 years of either sex who underwent gastroscopy under intravenous general anesthesia, with a Body Mass Index (BMI) 18-28 kg/m2, and an American Society of Anesthesiologists (ASA) grade I or II. In this study, the dose-finding strategy of ciprofol followed a modified Dixon's up-and-down method with an initial dose of 0.30 mg/kg and an increment of 0.02 mg/kg. Ciprofol was administered after intravenous injection of 7 µg/kg of alfentanil, and 2 min later a gastroscope was inserted. When the insertion response of one participant was positive (including body movement, coughing, and eye opening), an escalation of 0.02 mg/kg would be given to the next participant; otherwise, a de-escalation of 0.02 mg/kg would be administered. The study was terminated when negative response and positive response alternated 8 times. A Probit model was used to calculate the ED50 and ED95 of ciprofol in inhibiting responses to gastroscope insertion when combined with alfentanil. Patients' recovery time, discharge time, vital signs and occurrence of adverse reactions were recorded. RESULTS: The ED50 of single-dose intravenous ciprofol injection with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Patients' recovery time and discharge time were 11.04 ± 1.49 min and 9.64 ± 2.38 min, respectively. The overall incidence of adverse reactions was 12%. CONCLUSION: The ED50 of ciprofol combined with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Ciprofol showed a low incidence of anesthesia-related adverse events. TRIAL REGISTRATION: http://www.chictr.org.cn (ChiCTR2200061727).

Functional analysis of three odorant receptors in Plutella xylostella response to repellent activity of 2,3-dimethyl-6-(1-hydroxy)-pyrazine.

Plutella xylostella is an important pest showing resistance to various chemical pesticides, development of botanical pesticides is an effective strategy to resolve above problem and decrease utilization of chemical pesticides. Previous study showed that 2,3-dimethyl-6-(1-hydroxy)-pyrazine has significant repellent activity to P. xylostella adult which mainly effect to the olfactory system, however the molecular targets and mechanism are still unclear. Based on the RNA-Seq and RT-qPCR data, eight ORs (Odorant receptor) in P. xylostella were selected as candidate targets response to repellent activity of 2,3-dimethyl-6-(1-hydroxy)-pyrazine. Here, most of the ORs in P. xylostella were clustered into three branches, which showed similar functions such as recognition, feeding, and oviposition. PxylOR29, PxylOR31, and PxylOR46 were identified as the potential molecular targets based on the results of repellent activity and EAG response tests to the adults which have been injected with dsRNA, respectively. Additionally, the three ORs were higher expressed in antenna of P. xylostella, followed by those in the head segment. Furthermore, it was found that the bindings between these three ORs and 2,3-dimethyl-6-(1-hydroxy)-pyrazine mainly depend on the hydrophobic effect of active cavities, and the binding to PxylOR31 was more stabler and easier with an energy of -16.34 kcal/mol, together with the π-π T-shaped interaction at PHE195 site. These findings pave the way for the complete understanding of pyrazine repellent mechanisms.

The Cys-2088-Arg mutation in the ACCase gene and enhanced metabolism confer cyhalofop-butyl resistance in Chinese sprangletop (Leptochloa chinensis).

Acetyl-CoA carboxylase (ACCase)-inhibiting herbicides are among the most commonly used herbicides to control grassy weeds, especially Leptochloa chinensis, in rice fields across China. Herein, we collected a suspected resistant (R) population of L. chinensis (HFLJ16) from Lujiang county in Anhui Province. Whole plant dose response tests showed that, compared with the susceptible (S) population, the R population showed high resistance to cyhalofop-butyl (22-fold) and displayed cross-resistance to metamifop (9.7-fold), fenoxaprop-P-ethyl (18.7-fold), quizalofop-P-ethyl (7.6-fold), clodinafop-propargyl (12-fold) and clethodim (8.4-fold). We detected an amino acid substitution (Cys-2088-Arg) in the ACCase of resistant L. chinensis. However, ACCase gene expression levels were not significantly different (P > 0.05) between R plants and S plants, without or with cyhalofop-butyl treatment. Furthermore, pretreatment with piperonyl butoxide (PBO, a cytochrome P450 monooxygenase (CYP450) inhibitor) or 4-chloro-7-nitrobenzoxadiazole (NBD-Cl, a glutathione-S-transferase (GST) inhibitor), inhibited the resistance of the R population to cyhalofop-butyl significantly (by approximately 60% and 26%, respectively). Liquid chromatography tandem mass spectrometry analysis showed that R plants metabolized cyhalofop-butyl and cyhalofop acid (its metabolite) significantly faster than S plants. Three CYP450 genes, one GST gene, and two ABC transporter genes were induced by cyhalofop-butyl and were overexpressed in the R population. Overall, GST-associated detoxification, CYP450 enhancement, and target-site gene mutation are responsible for the resistance of L. chinensis to cyhalofop-butyl.

Fenoxaprop-P-ethyl, mesosulfuron-ethyl, and isoproturon resistance status in Beckmannia syzigachne from wheat fields across Anhui Province, China.

Severe infestations of American sloughgrass (Beckmannia syzigachne (Steud.) Fernald) in wheat fields throughout Anhui Province, China, pose a significant threat to local agricultural production. This study aims to evaluate the susceptibility of 37 B. syzigachne populations collected from diverse wheat fields in Anhui Province to three commonly used herbicides: fenoxaprop-P-ethyl, mesosulfuron-ethyl, and isoproturon. Single-dose testing revealed that out of the 37 populations, 31, 26, and 11 populations had either evolved or were evolving resistance to fenoxaprop-P-ethyl, mesosulfuron-ethyl, and isoproturon, respectively. Among them, 25 populations displayed concurrent resistance to both fenoxaprop-P-ethyl and mesosulfuron-ethyl, while eight exhibited resistance to all three tested herbicides. Whole-plant bioassays confirmed that approximately 84% of the fenoxaprop-P-ethyl-resistant populations manifested high-level resistance (resistance index (RI) ≥10); 62% of the mesosulfuron-ethyl-resistant populations and 82% of the isoproturon-resistant populations exhibited low- to moderate-level resistance (2 ≤ RI <10). Three distinct target-site mutations were identified in 27% of fenoxaprop-P-ethyl-resistant populations, with no known resistance mutations detected in the remaining herbicide-resistant populations. The inhibition of cytochrome P450s (P450s) and/or glutathione S-transferases (GSTs) substantially increased susceptibility in the majority of resistant populations lacking mutations at the herbicide target site. In conclusion, resistance to fenoxaprop-P-ethyl and mesosulfuron-ethyl was widespread in B. syzigachne within Anhui Province's wheat fields, while resistance to isoproturon was rapidly evolving due to its escalating usage. Target-site mutations were present in approximately one-third of fenoxaprop-P-ethyl-resistant populations, and alternative mechanisms involving P450s and/or GSTs could explain the resistance observed in most of the remaining populations.

Complementary use of visual and olfactory cues to assess capture of Bactrocera dorsalis (Hendel): Implementation and field verification via an IoT-based automatic monitoring system.

This study examined the effect of combining visual and olfactory cues to attract oriental fruit flies (OFFs). Six different colored light-emitting diodes (LEDs) served as a visual attractant and methyl eugenol served as olfactory bait to lure male flies. An internet of things (IoT)-based pest monitoring system, consisting of sensor nodes, a gateway, and automatic counting traps, was deployed in the field to automatically collect environmental data and pest counts. The results of the calibrated experiments indicated that green, yellow, or red LEDs exhibited better performance in attracting flies than white, purple, or blue LEDs or no LEDs. With an accurate combination of visual and olfactory cues, the proposed IoT-based pest monitoring system may be an effective tool in agricultural pest management, given its advantages for efficiently capturing OFFs in a labor and time saving manner, providing accurate information regarding increases in pest populations, and enabling long-term, real-time data collection.

An investigation study on the interpretation of ultrasonic medical reports using OpenAI's GPT-3.5-turbo model.

OBJECTIVES: Ultrasound medical reports are an important means of diagnosing diseases and assessing treatment effectiveness. However, their professional terms and complex sentences often make it difficult for ordinary people to understand. Therefore, this study explores the clinical value of using artificial intelligence systems based on ChatGPT to interpret ultrasound medical reports. METHODS: In this study, a combination of online and offline questionnaires were used to survey both physicians and non-medical individuals. The questionnaires evaluated ChatGPT's interpretation of ultrasound reports from both professional and comprehensibility perspectives, and the results were analyzed using Excel spreadsheets. Additionally, a portion of the research content was evaluated using the Likert Scale 5-point method in the questionnaire. RESULTS: According to survey results, 67.4% of surveyed doctors believe that using ChatGPT for interpreting ultrasound medical reports can help improve work efficiency. At the same time, 69.72% of non-medical professionals believe it is necessary to enhance their understanding of medical ultrasound reports through ChatGPT interpretation, and 62.58% support the application of ChatGPT to ultrasound medical reports. The non-medical group's understanding of ultrasound medical reports significantly improved (p < 0.01) after implementing ChatGPT, However, 67.49% of the general public are concerned about ChatGPT's imperfect functionality, which may cause misleading information. This reflects that the public's trust in new technology is not high enough, and they are also worried about possible privacy leaks and security issues with ChatGPT technology. CONCLUSIONS: The higher acceptance and support of non-medical individuals for the interpretation of medical reports by ChatGPT might be due to the system's natural language processing abilities that allow them to better understand and evaluate report contents. However, the expertise and experience of physicians are still irreplaceable. This suggests that the ChatGPT-based ultrasound medical report interpretation system has certain clinical value and application prospects, but further optimization is necessary to address its shortcomings in data quality and professionalism. This study provides a reference and inspiration for promoting the application and development of ultrasound technology and artificial intelligence systems in the medical field.

Efficacy of metformin combined with vitamin D in the treatment of polycystic ovarian syndrome: A meta-analysis.

Polycystic ovary syndrome (PCOS), as an endocrine and metabolic disorder, affects approximately 6% -20% of women of childbearing age. This study aims to assess the therapeutic effects of Metformin combined with vitamin D in PCOS patients. Eight databases were searched to obtain randomized controlled trials, both domestically and internationally, on the effects of Metformin combined with vitamin D in patients with PCOS. Data analysis was performed using RevMan 5.3 software. Nine studies were ultimately included in this meta-analysis. Six studies reported the homeostatic model assessment for insulin resistance of the test group and the control group, which was significantly lower (SMD: -0.23; 95% Cl: -0.42,-0.04; P<0.05) than the control group, body mass index (BMI) (SMD: -1.86; 95% Cl: -2.77,-0.96; P<0.01), Serum 25 (OH) D (SMD: 14.28; 95% Cl: 12.26,16.29; P<0.01), testosterone (SMD: -0.11; 95% Cl: -0.15,-0.07; P<0.01) and regulated menstrual cycles (OR: 1.27; 95% Cl: 0.99,1.63; P=0.063). Our meta-analysis of nine trials demonstrates significant reductions in insulin resistance, BMI, and testosterone levels, along with increased serum vitamin D levels and improved menstrual cycle regulation after Metformin and vitamin D treatment. These findings suggest the potential of this combined therapy in managing the multifaceted aspects of PCOS.

Le syndrome des ovaires polykystiques (SOPK), en tant que trouble endocrinien et métabolique, touche environ 6 à 20 % des femmes en âge de procréer. Cette étude vise à évaluer les effets thérapeutiques de la metformine associée à la vitamine D chez les patients atteints du SOPK. Huit bases de données ont été consultées pour obtenir des essais contrôlés randomisés, tant au niveau national qu'international, sur les effets de la metformine associée à la vitamine D chez les patients atteints du SOPK. L'analyse des données a été réalisée à l'aide du logiciel RevMan 5.3. Neuf études ont finalement été incluses dans cette méta-analyse. Six études ont rapporté l'évaluation du modèle homéostatique pour la résistance à l'insuline du groupe test et du groupe témoin, qui était significativement inférieure (DMS : -0,23 ; IC à 95 % : -0,42, -0,04 ; P <0,05) par rapport au groupe témoin, la masse corporelle indice (IMC) (DMS : -1,86 ; Cl 95 % : -2,77, -0,96 ; P<0,01), Sérum 25 (OH) D (SMD : 14,28 ; Cl 95 % : 12,26,16,29 ; P<0,01), testostérone (DMS : -0,11 ; Cl à 95 % : -0,15, -0,07 ; P<0,01) et cycles menstruels régulés (OR : 1,27 ; Cl à 95 % : 0,99, 1,63 ; P=0,063). Notre méta-analyse de neuf essais démontre des réductions significatives de la résistance à l'insuline, de l'IMC et des taux de testostérone, ainsi qu'une augmentation des taux sériques de vitamine D et une amélioration de la régulation du cycle menstruel après un traitement à la metformine et à la vitamine D. Ces résultats suggèrent le potentiel de cette thérapie combinée dans la gestion des aspects multiformes du SOPK.

Hedgehog interacting protein activates sodium-glucose cotransporter 2 expression and promotes renal tubular epithelial cell senescence in a mouse model of type 1 diabetes.

AIMS/HYPOTHESIS: Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (HhipRT-KO), hypothesising that local deficiency of HHIP in the renal tubules would attenuate tubular cell senescence, thereby preventing DKD tubulopathy. METHODS: Low-dose streptozotocin was employed to induce diabetes in both HhipRT-KO and control (Hhipfl/fl) mice. Transgenic mice overexpressing Hhip in renal proximal tubular cells (RPTC) (HhipRPTC-Tg) were used for validation, and primary RPTCs and human RPTCs (HK2) were used for in vitro studies. Kidney morphology/function, tubular senescence and the relevant molecular measurements were assessed. RESULTS: Compared with Hhipfl/fl mice with diabetes, HhipRT-KO mice with diabetes displayed lower blood glucose levels, normalised GFR, ameliorated urinary albumin/creatinine ratio and less severe DKD, including tubulopathy. Sodium-glucose cotransporter 2 (SGLT2) expression was attenuated in RPTCs of HhipRT-KO mice with diabetes compared with Hhipfl/fl mice with diabetes. In parallel, an increased tubular senescence-associated secretory phenotype involving release of inflammatory cytokines (IL-1ß, IL-6 and monocyte chemoattractant protein-1) and activation of senescence markers (p16, p21, p53) in Hhipfl/fl mice with diabetes was attenuated in HhipRT-KO mice with diabetes. In contrast, HhipRPTC-Tg mice had increased tubular senescence, which was inhibited by canagliflozin in primary RPTCs. In HK2 cells, HHIP overexpression or recombinant HHIP increased SGLT2 protein expression and promoted cellular senescence by targeting both ataxia-telangiectasia mutated and ataxia-telangiectasia and Rad3-related-mediated cell arrest. CONCLUSIONS/INTERPRETATION: Tubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.

Synergistic Enzyme-Mimetic Catalysis-Based Non-Thermal Sonocavitation and Sonodynamic Therapy for Efficient Hypoxia Relief and Cancer Ablation.

Non-invasive cancer treatment strategies that enable local non-thermal ablation, hypoxia relief, and reactive oxygen species (ROS) production to achieve transiently destroying tumor tissue and long-term killing tumor cells would greatly facilitate their clinical applications. However, continuously generating oxygen cavitation nuclei, reducing the transient cavitation sound intensity threshold, relieving hypoxia, and improving its controllability in the ablation area still remains a significant challenge. Here, in this work, an Mn-coordinated polyphthalocyanine sonocavitation agent (Mn-SCA) with large d-π-conjugated network and atomic Mn-N sites is identified for the non-thermal sonocavitation and sonodynamic therapy in the liver cancer ablation. In the tumor microenvironment, the catalytical generation of oxygen assists cavitation formation and generates microjets to ablate liver cancer tissue and relieve hypoxia, this work reports for the first time to utilize the enzymatic properties of Mn-SCA to lower the cavitation threshold in situ. Moreover, under pHIFU irradiation, high reactive oxygen species (ROS) production can be achieved. The two merits in liver cancer ablation are demonstrated by cell destruction and high tumor inhibition efficiency. This work will help deepen the understanding of cavitation ablation and the sonodynamic mechanisms related to the nanostructures and guide the design of sonocavitation agents with high ROS production for solid tumor ablation.

Phylogeny, biogeography, and character evolution of the genus Sophora s.l. (Fabaceae, Papilionoideae).

The papilionoid legume genus Sophora (Fabaceae) exhibits a worldwide distribution, but a phylogenetic framework to understand the evolution of this group is lacking to date. Previous studies have demonstrated that Sophora is not monophyletic and might include Ammodendron, Ammothamnus, and Echinosophora, but the relationships among these four genera (defined as Sophora s.l.) are unclear. Here we used a nuclear DNA dataset (ETS, ITS, SQD1) and a plastid DNA dataset (matK, rbcL, rpl32-trnL, trnL-F) of 654 accession sequences to reconstruct the phylogenetic relationships, estimate the divergence times and ancestral range of Sophora s.l., and infer the evolution of chromosome number and morphological characteristics. Our major aim was to reconstruct phylogenetic relationships to test monophyly and elucidate relationships within the genus. Our results indicated that Ammodendron, Ammothamnus, and Echinosophora are embedded within Sophora s.s. and that nine well-supported clades can be recognized within comprise Sophora s.l. Ancestral character state estimation revealed that the most recent common ancestor of Sophora s.l. was a deciduous shrub that lacks rhizome spines and has unwinged legumes. Divergence times estimation and ancestral area reconstruction showed that Sophora s.l. originated in Central Asia and/or adjacent Southeast China in the early Oligocene (ca. 31 Mya) and dispersed from these regions into East and South Asia's adjacent areas and North America via the Bering land bridge. The analyses also supported a South American origin for S. sect. Edwardsia, which experienced rapid radiation with its major lineages diversifying over a relatively narrow timescale (8 Mya).

Coexistence of 1 Tbps classical optical communication and quantum key distribution over a 100.96 km few-mode fiber.

The integration of quantum key distribution (QKD) and classical optical communication has attracted widespread attention. In this Letter, we experimentally demonstrate a real-time co-propagation of 1 Tbps for 10 classical channels with one discrete-variable QKD channel in the weakly coupled few-mode fiber (FMF). Based on the selection of optimal device parameters and wavelength assignment of classical channels, as well as the optimization of equipment performance, a secure key rate of as high as 2.7 kbps of coexistence transmission of QKD and classical optical communication can be achieved using a 100.96 km weakly coupled FMF. Therefore, this study is a step toward realizing long-distance quantum-classical coexistence transmission.

Unconventional Polarization-Switching Mechanism in (Hf, Zr)O_{2} Ferroelectrics and Its Implications.

HfO_{2}-based ferroelectric thin films are promising for their application in ferroelectric devices. Predicting the ultimate magnitude of polarization and understanding its switching mechanism are critical to realize the optimal performance of these devices. Here, a generalized solid-state variable cell nudged elastic band method is employed to predict the switching pathway associated with domain-wall motion in (Hf,Zr)O_{2} ferroelectrics. It is found that the polarization reversal pathway, where threefold coordinated O atoms pass across the nominal unit-cell boundaries defined by the Hf/Zr atomic planes, is energetically more favorable than the conventional pathway where the O atoms do not pass through these planes. This finding implies that the polarization orientation in the orthorhombic Pca2_{1} phase of HfO_{2} and its derivatives is opposite to that normally assumed, predicts the spontaneous polarization magnitude of about 70 µC/cm^{2} that is nearly 50% larger than the commonly accepted value, signifies a positive intrinsic longitudinal piezoelectric coefficient, and suggests growth of ferroelectric domains, in response to an applied electric field, structurally reversed to those usually anticipated. These results provide important insights into the understanding of ferroelectricity in HfO_{2}-based ferroelectrics.