DY131 activates ERRγ/TFAM axis to protect against metabolic disorders and acute kidney injury.

Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRγ agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI.

Flavonoid derivative DMXAA attenuates cisplatin-induced acute kidney injury independent of STING signaling.

Cisplatin-induced nephrotoxicity is the main adverse effect of cisplatin-based chemotherapy and highly limits its clinical use. DMXAA, a flavonoid derivative, is a promising vascular disrupting agent and known as an agonist of STING. Although cGAS-STING activation has been demonstrated to mediate cisplatin-induced acute kidney injury (AKI), the role of DMXAA in this condition is unclear. Here, we defined an unexpected and critical role of DMXAA in improving renal function, ameliorating renal tubular injury and cell apoptosis, and suppressing inflammation in cisplatin-induced AKI. Moreover, we confirmed that DMXAA combated AKI in a STING-independent manner, as evidenced by its protective effect in STING global knockout mice subjected to cisplatin. Furthermore, we compared the role of DMXAA with another STING agonist SR717 in cisplatin-treated mice and found that DMXAA but not SR717 protected animals against AKI. To better evaluate the role of DMXAA, we performed transcriptome analyses and observed that both inflammatory and metabolic pathways were altered by DMXAA treatment. Due to the established role of metabolic disorders in AKI, which contributes to kidney injury and recovery, we also performed metabolomics using kidney tissues from cisplatin-induced AKI mice with or without DMXAA treatment. Strikingly, our results revealed that DMXAA improved the metabolic disorders in kidneys of AKI mice, especially regulated the tryptophan metabolism. Collectively, therapeutic administration of DMXAA ameliorates cisplatin-induced AKI independent of STING, suggesting a promising potential for preventing nephrotoxicity induced by cisplatin-based chemotherapy.

Low-intensity pulsed ultrasound at ST36 improves the gastric motility by TNF-α/IKKß/NF-κB signaling pathway in diabetic rats.

BACKGROUND AND AIM: Low-intensity pulsed ultrasound (LIPUS) can effectively regulate the central and peripheral nervous system. However, whether LIPUS could act on acupuncture points to modulate the activity of peripheral nervous has rarely been studied. Our study aimed to investigate whether LIPUS at ST36 could improve gastric emptying in diabetic gastroparesis rats. METHODS: Sprague-Dawley male rats were divided into three groups: control group (CON), diabetic gastroparesis group (DM), and diabetic gastroparesis LIPUS treated group (LIPUS). The body weight and blood glucose were recorded every week. Glucose tolerance, gastric emptying rate, and gastric motility were measured before and after treatment. Gastric motility was assessed by ultrasonic examination and Muscle strip experiment. The expression level of c-Kit was assessed by immunohistochemistry staining. Levels of TNF-α, p-NF-κB p-65, NF-κB p-65, and p-IKKß, IKKß were measured by western blot. RESULTS: We reported LIPUS at an intensity of 0.88 W/cm2 exhibited significant differences in functional recovery of gastric delayed emptying in diabetic rats. Through ultrasound gastric motility functional testing and analysis of gastric antral smooth muscle strips indirectly and directly proved the effectiveness of LIPUS for the recovery of gastric delayed emptying. Pathological analysis and western blot indicated that the mechanism by which LIPUS applied to ST36 improved gastric motility may be partially attributed to the inhibition of the TNF-α/IKKß/NF-κB signaling pathway, thereby rescuing the damaged interstitial cells of Cajal network. CONCLUSION: LIPUS at ST36 improved the gastric motility and rescued the damaged networks of interstitial cells of Cajal. LIPUS may have a promising therapeutic potential for diabetic gastroparesis.

A study on the effect of nutrition education based on the goal attainment theory on oral nutritional supplementation after colorectal cancer surgery.

OBJECTIVE: To investigate their compliance with postoperative oral nutritional supplementation and nutritional outcomes. METHODS: A total of 84 patients with colorectal cancer surgery with NRS-2002 risk score ≥ 3 who were treated with oral nutritional supplementation were selected and divided into control and observation groups according to the random number table method, with 42 cases in each group. The control group received conventional oral nutritional supplementation and dietary nutrition education; the observation group established a nutrition intervention group based on the Goal Attainment Theory and carried out individualized nutrition education based on the Goal Attainment Theory. The nutritional indicators at 1 day postoperative, 7 days postoperative, oral nutritional supplementation adherence scores at 7 and 14 days postoperative, and the attainment rate of trans-oral nutritional intake at 21 days postoperative were compared between the 2 groups of patients. RESULTS: There was no statistically significant difference between the nutritional status indexes of the 2 groups of patients before the intervention, p > 0.05; when comparing the prealbumin of the 2 groups of patients at 7 days postoperatively, the prealbumin level of the patients in the observation group at 7 days postoperatively (200.25 ± 53.25) was better than that of the control group (165.73 ± 43.00), with a p value of 0.002, and the difference was statistically significant (p < 0.05). Comparison of oral nutritional supplementation adherence scores at 7 and 14 days postoperatively showed that ONS treatment adherence scores were better than those of the control group, with statistically significant differences (p < 0.05). When comparing the attainment rate of oral nutritional intake at 21 days after surgery, the difference was statistically significant (p < 0.05). CONCLUSION: Nutritional education based on the Goal Attainment Theory can effectively improve the adherence to oral nutritional supplementation therapy and protein intake attainment rate of colorectal cancer patients after surgery and effectively improve the nutritional status of patients.

Identification of cholesterol metabolism-related subtypes in nonfunctioning pituitary neuroendocrine tumors and analysis of immune infiltration.

OBJECTIVE: This study aimed to investigate the role of cholesterol metabolism-related genes in nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs) invading the cavernous sinus and analyze the differences in immune cell infiltration between invasive and noninvasive NF-PitNETs. METHODS: First, a retrospective analysis of single-center clinical data was performed. Second, the immune cell infiltration between invasive and noninvasive NF-PitNETs in the GSE169498 dataset was further analyzed, and statistically different cholesterol metabolism-related gene expression matrices were obtained from the dataset. The hub cholesterol metabolism-related genes in NF-PitNETs were screened by constructing machine learning models. In accordance with the hub gene, 73 cases of NF-PitNETs were clustered into two subtypes, and the functional differences and immune cell infiltration between the two subtypes were further analyzed. RESULTS: The clinical data of 146 NF-PitNETs were evaluated, and the results showed that the cholesterol (P = 0.034) between invasive and noninvasive NF-PitNETs significantly differed. After binary logistic analysis, cholesterol was found to be an independent risk factor for cavernous sinus invasion (CSI) in NF-PitNETs. Bioinformatics analysis found three immune cells between invasive and noninvasive NF-PitNETs were statistically significant in the GSE169498 dataset, and 34 cholesterol metabolism-related genes with differences between the two groups were obtained 12 hub genes were selected by crossing the two machine learning algorithm results. Subsequently, cholesterol metabolism-related subgroups, A and B, were obtained by unsupervised hierarchical clustering analysis. The results showed that 12 immune cells infiltrated differentially between the two subgroups. The chi-square test revealed that the two subgroups had statistically significance in the invasive and noninvasive samples (P = 0.001). KEGG enrichment analysis showed that the differentially expressed genes were mainly enriched in the neural ligand-receptor pathway. GSVA analysis showed that the mTORC signaling pathway was upregulated and played an important role in the two-cluster comparison. CONCLUSION: By clinical data and bioinformatics analysis, cholesterol metabolism-related genes may promote the infiltration abundance of immune cells in NF-PitNETs and the invasion of cavernous sinuses by NF-PitNETs through the mTOR signaling pathway. This study provides a new perspective to explore the pathogenesis of cavernous sinus invasion by NF-PitNETs and determine potential therapeutic targets for this disease.

Spatial-temporal analysis of HIV/AIDS and syphilis in mainland China from 2007 to 2017.

Human immune deficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and syphilis are the most common sexually transmitted diseases (STDs) worldwide, as well as in China. The objective of this study is to describe the trend of spatial and temporal variation of HIV/AIDS and syphilis in mainland China from 2007 to 2017. Stratified analysis was conducted according to age and the GDP per capita. Estimated Annual Percentage Change (EAPC) was calculated and spatial autocorrelation analysis was used to evaluate the epidemiology and identify clusters. The morbidity of new HIV infection increased from 2.5034/100 000 in 2007 to 6.9247/100 000 in 2017, with an EAPC of 9.84 (95% confidence interval [CI]: 9.07-10.60). From 2007 to 2017, the morbidity of syphilis presented a significant upward trend from 15.8834/100 000 to 34.4867/100 000 (EAPC = 6.48, 95% CI: 4.23-8.73). The number of new HIV infections (205 084) and syphilis (921 279) were highest in the 20-30 years old group, where the incidence decreased with age over 20 years. In general, HIV and syphilis infection had the same incidence trend according to age and time stratification. The morbidity of new HIV infection was mainly reported from Xinjiang and southwestern China. As for syphilis, the highest was found in Zhejiang in Xinjiang and southeast coastal areas. Both HIV and syphilis infection showed a nonrandom positive correlation by Moran's I value. The High-High cluster areas of HIV infection were concentrated in southwestern and eastern China due to syphilis. A highly significant positive correlation was found between gross domestic product per capita and syphilis infection (p < 0.05) but was not associated with HIV infection. The incidence of AIDS/HIV and syphilis is increasing year by year, and a higher prevalence is found in younger individuals. More attention should be paid to HIV infection in the southwest, syphilis in southeast coastal areas, and both the two diseases in Xinjiang.

The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction.

Stimulator of interferon genes (STING) is an important adaptor in cytosolic DNA-sensing pathways. A recent study found that the deletion of STING ameliorated cisplatin-induced acute kidney injury (AKI), suggesting that STING could serve as a potential target for AKI therapy. Up to now, a series of small-molecule STING inhibitors/antagonists have been identified. However, none of the research was performed to explore the role of human STING inhibitors in AKI. Here, we investigated the effect of a newly generated covalent antagonist, H151, which targets both human and murine STING, in cisplatin-induced AKI. We found that H151 treatment significantly ameliorated cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology, and renal inflammation. In addition, tubular cell apoptosis and increased renal tubular injury marker neutrophil gelatinase-associated lipocalin induced by cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by cisplatin was also reversed as evidenced by improved mitochondrial morphology, restored mitochondrial DNA content, and reversed mitochondrial gene expression. Finally, we observed enhanced mitochondrial DNA levels in the plasma of patients receiving platinum-based chemotherapy compared with healthy controls, which could potentially activate STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting STING-mediated inflammation and mitochondrial injury.NEW & NOTEWORTHY Although various stimulator of interferon genes (STING) inhibitors have been identified, no research was performed to investigate the role of human STING inhibitors in AKI. Here, we evaluated the effect of H151 targeting both human and murine STING on cisplatin-induced AKI and observed a protection against renal injury possibly through ameliorating inflammation and mitochondrial dysfunction.

The Vasomotor Response to Dopamine Is Altered in the Rat Model of l-dopa-Induced Dyskinesia.

BACKGROUND: Levodopa (l-dopa) is the frontline treatment for motor symptoms of Parkinson's disease. However, prolonged use of l-dopa results in a motor complication known as levodopa-induced dyskinesia (LID) in ~50% of patients over 5 years. OBJECTIVES: We investigated neurovascular abnormalities in a rat model of LID by examining changes in angiogenesis and dopamine-dependent vessel diameter changes. METHODS: Differences in striatal and nigral angiogenesis in a parkinsonian rat model (6-OHDA lesion) treated with 2 doses of l-dopa (saline, 2, and 10 mg/kg/day subcutaneous l-dopa treatment for 22 days) by 5-bromo-2'-deoxyuridine (BrdU)-RECA1 co-immunofluorescence. Difference in the vasomotor response to dopamine was examined with 2-photon laser scanning microscopy and Dodt gradient imaging. RESULTS: We found that the 10 mg/kg l-dopa dosing regimen induced LID in all animals (n = 5) and induced significant angiogenesis in the striatum and substantia nigra. In contrast, the 2 mg/kg treatment induced LID in 6 out of 12 rats and led to linearly increasing LID severity over the 22-day treatment period, making this a promising model for studying LID progression longitudinally. However, no significantly different level of angiogenesis was observed between LID versus non-LID animals. Dopamine-induced vasodilatory responses were exaggerated only in rats that show LID-like signs compared to the rest of groups. Additionally, in juvenile rats, we showed that DA-induced vasodilation is preceded by increased Ca2+ release in the adjacent astrocytes. CONCLUSION: This finding supports that astrocytic dopamine signaling controls striatal blood flow bidirectionally, and the balance is altered in LID. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Raloxifene in the Treatment of Osteoporosis in Postmenopausal Women with End-Stage Renal Disease: A Systematic Review and Meta-Analysis.

As a selective estrogen receptor modulator (SERM), raloxifene is used in healthy postmenopausal women to prevent bone loss and reduce fractures. However, the benefit of raloxifene is uncertain in the treatment of osteoporosis among patients with end-stage renal disease (ESRD) or those who require maintenance dialysis. We assessed the safety and efficacy of raloxifene in this particular population. Studies were selected from PubMed, Springer, CNKI (Chinese National Knowledge Infrastructure) and Wanfang Database. Randomized controlled trials (RCTs) and prospective studies with control/placebo groups were included. Five studies were included with a total of 244 participants (121 patients in the raloxifene group and 123 patients in the placebo/control group). The median duration of treatment was 12 months. The incidence rate of side effects of raloxifene was 0/121 (0%). There was a significant improvement of lumbar spine bone mineral density (BMD) levels in the raloxifene group compared with the placebo group (MD: 33.88, 95% CI: 10.93, 56.84, p=0.004). There was no significant difference concerning the improvement of femoral neck BMD (MD: 8.42, 95% CI: -10.21, 27.04, p=0.38), intact parathyroid hormone (iPTH) (MD: -12.62, 95% CI: -35.36, 10.13, p=0.28), calcium (MD: -0.08, 95% CI: -0.61, 0.44, p=0.76), phosphorus (MD: 0.18, 95% CI: -0.12, 0.48, p=0.23) or bone alkaline phosphatase (BAP) (MD: -4.33, 95% CI: -14.44, 5.79, p=0.40). Raloxifene seems to be effective in improving the lumbar spine BMD in postmenopausal women with ESRD. More large RCTs are necessary to evaluate the long-term safety of raloxifene in uremic patients.

Diaphragma sellae sinking can predict the onset of hyponatremia after transsphenoidal surgery for pituitary adenomas.

PURPOSE: Sinking of the diaphragma sellae (DS) may stretch the pituitary stalk, which in turn impairs neurohypophyseal function; thus, it may play a role in the development of postoperative hyponatremia. We aimed to assess the factors influencing the development of hyponatremia after transsphenoidal surgery (TSS) for pituitary adenomas and analyze the effect of DS sinking on hyponatremia. METHODS: After applying the inclusion and exclusion criteria, we retrospectively analyzed the clinical data of patients with pituitary adenoma who underwent TSS. The pituitary gland was scanned using a 3.0-T magnetic resonance imaging, and sagittal and coronal images were acquired. We evaluated the following: preoperative and postoperative hypothalamus‒pituitary‒thyroid axis function, hypothalamus‒pituitary‒adrenal axis function, intra-operative cerebrospinal fluid leaks, diabetes insipidus, hyponatremia, time from the day of surgery to the day of discharge, and time of hyponatremia onset. RESULTS: Of the 460 patients who had microscopic TSS for pituitary adenoma, 83 experienced postoperative hyponatremia. Hyponatremia occurred approximately 5.25 days postoperatively and persisted for 5.54 days. The lowest average blood sodium level was 123.9 mEq/L, which occurred at 7.49 days after surgery. Logistic regression analysis showed that the risk of hyponatremia was greater for patients with a significant DS sinking depth, a large pituitary stalk deviation angle difference, and a longer postoperative "measurable pituitary stalk". The difference in blood sodium levels between pre-TSS and 2 days post-TSS was also an independent predictor of postoperative hyponatremia onset. CONCLUSION: DS sinking plays an important role in predicting hyponatremia onset after TSS for pituitary adenomas.

MicroRNA profiling in Chinese children with Henoch-Schonlein purpura and association between selected microRNAs and inflammatory biomarkers.

AIM: This study aimed to profile the microRNA levels in Chinese Henoch-Schonlein purpura (HSP) children and to explore their association with inflammatory factors and T helper 17 (Th17)/regulatory T (Treg). METHODS: Forty-five HSP children and 27 healthy controls were enrolled in this study, and microRNA levels were profiled with a microRNA microarray. The levels of selected microRNAs were determined by quantitative real-time PCR, and the levels of serum IgA, interleukin-6, interleukin-10 and interleukin-17A were detected by enzyme-linked immunosorbent assay. Additionally, Th17 and Treg cells were analysed by flow cytometry. RESULTS: There were 9 up-regulated and 27 down-regulated microRNAs in the PBMCs of Chinese HSP children. Among them, miR-1-3p, miR-19b-1-5p and miR-29b-1-5p were up-regulated, while miR-483-5p and miR-1246 were down-regulated. Additionally, these selected microRNAs could differentiate HSP patients from healthy controls. Interestingly, miR-29b-1-5p was correlated with IgA, miR-19b-1-5p, miR-483-5p and miR-1246 were correlated with interleukin-6, while miR-1-3p and miR-1246 were correlated with Th17/Treg. CONCLUSION: This study reveals that the altered microRNAs could differentiate HSP from the healthy, and were associated with inflammatory factors or Th17/Treg. It is indicated that alteration in these microRNAs may contribute to the HSP pathogenesis and may become therapeutic targets or diagnostic biomarkers for HSP.

Galectin-1 attenuates neurodegeneration in Parkinson's disease model by modulating microglial MAPK/IκB/NFκB axis through its carbohydrate-recognition domain.

The vicious cycle between the chronicactivationofmicroglia and dopamine neurons degeneration is linked with the progression of Parkinson's disease (PD). Targeting microglialactivationhas proven to be a viable option to develop a disease-modified therapy for PD. Galectin-1, which has been reported to have an anti-neuroinflammation effect was used in the present study to evaluate its therapeutic effects on microglia activation and neuronal degeneration in Parkinson's disease model. It was found that galectin-1 attenuated the inflammatory insult and the apoptosis of SK-N-SH human neuroblastoma cells from conditioned medium of activated microglia induced by Lipopolysaccharides (LPS). Nonetheless, galectin-1 administration (0.5 mg/kg) inhibited the microglia activation, improved the motor deficits in PD mice model induced by MPTP (25 mg/kg weight of mouse, i.p.) and prevented the degeneration of dopaminergic neurons in the substantia nigra. Administration of galectin-1 resulted in p38 and ERK1/2 dephosphorylation followed by IκB/NFκB signaling pathway inhibition. Galectin-1 significantly decreased the secretion of pro-inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The protective effects and modulation of the MAPK/IκB/NFκB signaling pathway were abolished with ß-D-galactose which blocked the carbohydrate-recognition domain of galectin-1. The present study demonstrated that galectin-1 inhibited microglia activation and ameliorated neurodegenerative process in PD model by modulating MAPK/IκB/NFκB axis through its carbohydrate-recognition domain.

Static Tactile Sensing for a Robotic Electronic Skin via an Electromechanical Impedance-Based Approach.

Tactile sensing is paramount for robots operating in human-centered environments to help in understanding interaction with objects. To enable robots to have sophisticated tactile sensing capability, researchers have developed different kinds of electronic skins for robotic hands and arms in order to realize the 'sense of touch'. Recently, Stanford Structures and Composites Laboratory developed a robotic electronic skin based on a network of multi-modal micro-sensors. This skin was able to identify temperature profiles and detect arm strikes through embedded sensors. However, sensing for the static pressure load is yet to be investigated. In this work, an electromechanical impedance-based method is proposed to investigate the response of piezoelectric sensors under static normal pressure loads. The smart skin sample was firstly fabricated by embedding a piezoelectric sensor into the soft silicone. Then, a series of static pressure tests to the skin were conducted. Test results showed that the first peak of the real part impedance signal was sensitive to static pressure load, and by using the proposed diagnostic method, this test setup could detect a resolution of 0.5 N force. Numerical simulation methods were then performed to validate the experimental results. The results of the numerical simulation prove the validity of the experiments, as well as the robustness of the proposed method in detecting static pressure loads using the smart skin.

Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma.

BACKGROUND & AIMS: Dietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen. METHODS: We obtained HCC tumor tissues and matched non-tumor liver tissues from 49 patients, collected from 1990 through 2016, at the Qidong Liver Cancer Hospital Institute in China-a high-risk region for aflatoxin exposure (38.2% of food samples test positive for aflatoxin contamination). Somatic variants were identified using GATK Best Practices Pipeline. We validated part of the mutations from whole-genome sequencing and whole-exome sequencing by Sanger sequencing. We also analyzed genomes of 1072 HCCs, obtained from 5 datasets from China, the United States, France, and Japan. Mutations in 49 aflatoxin-associated HCCs and 1072 HCCs from other regions were analyzed using the Wellcome Trust Sanger Institute mutational signatures framework with non-negative matrix factorization. The mutation landscape and mutational signatures from the aflatoxin-associated HCC and HCC samples from general population were compared. We identified genetic features of aflatoxin-associated HCC, and used these to identify aflatoxin-associated HCCs in datasets from other regions. Tumor samples were analyzed by immunohistochemistry to determine microvessel density and levels of CD34 and CD274 (PD-L1). RESULTS: Aflatoxin-associated HCCs frequently contained C>A transversions, the sequence motif GCN, and strand bias. In addition to previously reported mutations in TP53, we found frequent mutations in the adhesion G protein-coupled receptor B1 gene (ADGRB1), which were associated with increased capillary density of tumor tissue. Aflatoxin-associated HCC tissues contained high-level potential mutation-associated neoantigens, and many infiltrating lymphocytes and tumors cells that expressed PD-L1, compared to HCCs not associated with aflatoxin. Of the HCCs from China, 9.8% contained the aflatoxin-associated genetic features, whereas 0.4%-3.5% of HCCs from other regions contained these genetic features. CONCLUSIONS: We identified specific genetic and mutation features of HCCs associated with aflatoxin exposure, including mutations in ADGRB1, compared to HCCs from general populations. We associated these mutations with increased vascularization and expression of PD-L1 in HCC tissues. These findings might be used to identify patients with HCC due to aflatoxin exposure, and select therapies.

Metal-Free Oxidative Thioesterification of Methyl Ketones with Thiols/Disulfides for the Synthesis of α-Ketothioesters.

A direct Csp3-H bond oxidative thioesterification of methyl ketones with aromatic thiols/disulfides promoted by TBAI/K2S2O8 has been developed. The reaction provides successfully a simple and efficient method for the synthesis of functionalized α-ketothioesters of aromatic thiols. This practical methodology exhibits readily available starting materials, large-scale applicability, synthetic application, and broad functional group tolerance. A possible mechanism for the transformation is proposed.

Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice.

Aberrant α-synuclein (α-syn) accumulation has been shown to impair mitochondrial function by reducing mitochondrial membrane potential (MMP). However, the underlying mechanisms remain elusive. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca2+ channels, among which TRPC3 is the only one that is localized in mitochondria and plays a role in maintaining the normal MMP. This raises a possibility that altered TRPC3 expression may play a role in the mitochondrial dysfunction induced by α-syn accumulation. To demonstrate this possibility, we first examined the expressions of mitochondrial TRPC3 in the brains of aging monkeys and α-syn transgenic and wild-type mice. We showed that α-syn levels increased in mitochondria in an age-dependent manner that was positively correlated to an elevation of mitochondrial TRPC3. This correlation was more prominent in the striatum than in the cerebellum, possibly due to the greater age-dependent α-syn accumulation in the striatum than in the cerebellum. We then used primary neurons overexpressing α-syn to investigate the effect of the α-syn-induced elevation of mitochondrial TRPC3 on the MMP and apoptotic cell death. We found that neurons with overexpressed α-syn had increased mitochondrial TRPC3 and decreased MMP, which were accompanied by increased number of apoptotic neurons. Suppressing TRPC3 expression partially reversed the reduction of MMP and alleviated the apoptotic cell death, indicating that the mitochondrial TRPC3 may play a role in the mitochondrial dysfunction in neurons with α-syn accumulation that may occur in not only the aged brain but also the brain with PD.

Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase.

Astrocytes play a critical role in neurovascular coupling by providing a physical linkage from synapses to arterioles and releasing vaso-active gliotransmitters. We identified a gliotransmitter pathway by which astrocytes influence arteriole lumen diameter. Astrocytes synthesize and release NMDA receptor coagonist, D-serine, in response to neurotransmitter input. Mouse cortical slice astrocyte activation by metabotropic glutamate receptors or photolysis of caged Ca(2+) produced dilation of penetrating arterioles in a manner attenuated by scavenging D-serine with D-amino acid oxidase, deleting the enzyme responsible for D-serine synthesis (serine racemase) or blocking NMDA receptor glycine coagonist sites with 5,7-dichlorokynurenic acid. We also found that dilatory responses were dramatically reduced by inhibition or elimination of endothelial nitric oxide synthase and that the vasodilatory effect of endothelial nitric oxide synthase is likely mediated by suppressing levels of the vasoconstrictor arachidonic acid metabolite, 20-hydroxy arachidonic acid. Our results provide evidence that D-serine coactivation of NMDA receptors and endothelial nitric oxide synthase is involved in astrocyte-mediated neurovascular coupling.

Interaction Between IGF1 Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Chinese Children.

BACKGROUND/AIMS: IGF1 is a key regulator in cell proliferation and apoptosis, and the 3' un-translated region (3'UTR) of the gene plays an important role in gene expression. For the first time, we explored the relationship between polymorphisms in the IGF1 3'UTR region and the risk of childhood acute lymphoblastic leukemia (ALL). METHODS: Questionnaires were applied to collect epidemiological data. The genotypes of IGF1 polymorphisms were tested in a population of 744 ALL patients and 1088 cancer-free controls utilizing Taqman. Cell functional studies included real-time PCR, cell culture and transfection and luciferase assays. RESULTS: We found that rs6214 homozygous AA genotype and rs6218 homozygous CC genotype were significantly associated with increased risk of childhood ALL. In addition, rs6218 CC genotype was associated with increased level of IGF1 mRNA in bone marrow, and the mutation in rs6218 led to aberrant binding capacity of hsa-miR-603 and hsa-miR-3941 in the 3'UTR of IGF1. CONCLUSION: Polymorphisms of rs6214 and rs6218 in the 3'UTR of IGF1 are associated with childhood ALL susceptibility, and the polymorphism of rs6218 is related with IGF1 expression at mRNA level.

Serotypes, seasonal trends, and antibiotic resistance of non-typhoidal Salmonella from human patients in Guangdong Province, China, 2009-2012.

BACKGROUND: Non-typhoidal Salmonella is a common cause of infectious diarrhea in humans. Antimicrobial-resistant Salmonella has become a global concern. METHODS: Using laboratory-based surveillance system for Salmonella from September 2009 to December 2012 in Guangdong Province of China. The clinical information and samples of diarrhea patients were collected, according to the surveillance case definition. The lab tests were followed by standardized protocols, including sample isolation, isolates confirmation, serotyping, and antimicrobial susceptibility testing (AST). RESULTS: A total of 1,826 Salmonella isolates were identified from40,572 patients in 28 hospitals in11 prefectures. The isolates ratio was highest in autumn (38.8%, 708/1826) and lowest in winter (6.4%, 117/1826). Children aged <5 years were the group most affected by Salmonella in Guangdong Province accounting for 73% (1,329/1,826), of whom the infants (<1 year) were 81.5% (1084/1329) especially. A total of 108 serotypes were identified among the isolates. S. Typhimurium represented the most common serotype followed by serotype 4,5,12:i:-. S. Typhimurium was also the common serotype followed by S. Enteritidis among infants and children aged 1-3 years old. However, S. Enteritidis became the common serotype followed by S. Typhimurium among children aged 3-5 and >5 years. Resistance to at least one antimicrobial was found in 72% (1321/1,826) of the isolates. Resistance to at least three antimicrobials was found in 46% (850/1,826) of the isolates. Resistance to all 12 antimicrobials screened was observed in 8 isolates (0.44%, 8/1,826). The resistant prevalence to quinolones including nalidixic acid and ciprofloxacin was 61.9% (1131/1826), of which ciprofloxacin resistance rate was 8.05% (147/1826). The prevalence resistance to all three cephalosporin antimicrobials (cefepime, cefotaxime, and caftazidime) in <5 yr age group was accounted for 90% (89/99). CONCLUSIONS: Additional data and more refined methods can improve future surveillance. The invasive Salmonella isolates should also be included to the antibiotic resistance surveillance for clinical care or public health.