Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines.

Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.

Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors.

Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.

Serum interleukin-6, interleukin-17A, and tumor necrosis factor-alpha in patients with recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis remains the most common disease of the oral mucosa. The aim of this study was to investigate the clinical significance of serum interleukin-6, interleukin-17A, and tumor necrosis factor-alpha in recurrent aphthous stomatitis. METHODS: Using flow cytometry analysis, we detect the level of serum interleukin-2, interleukin-6, interleukin-17A, tumor necrosis factor-alpha, and interferon-gamma in 127 patients with recurrent aphthous stomatitis and 20 healthy control cases; compare; and analyze the correlation of each index. RESULTS: The levels of serum interleukin-2, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma in the recurrent aphthous stomatitis group were higher than in the control group, and the differences were statistically significant (P < .05). There was no significant difference in interleukin-17A between the two groups. CONCLUSION: The levels of serum interleukin-6 and tumor necrosis factor-alpha in recurrent aphthous stomatitis patients were significantly increased. Considering that serum TNF-α was mostly within the normal range, its role in the pathology of RAS needed to be further explored.

Ultrasonic diagnosis of asymptomatic rupture of uterine in second trimester of pregnancy after laparoscopic surgery for interstitial pregnancy: a case report.

BACKGROUND: Uterine rupture is a rare, life-threatening event in obstetrics that may be fatal for the mother and fetus. Therefore, obstetricians need to pay attention to and should consider the antenatal diagnosis of uterine rupture in women having its risk factors. Successful conservative management for asymptomatic uterine rupture due to previous laparoscopic surgery for interstitial pregnancy has already been reported but remains understudied. CASE PRESENTATION: A 39-year-old woman was diagnosed asymptomatic uterine rupture at 22 weeks gestation by a routine second-trimester ultrasound scan. She had a history of laparoscopic salpingectomy with cornual wedge resection for interstitial pregnancy 10 months before this pregnancy. Refusing doctor's twice advice of terminating the pregnancy, the patient insisted carrying on the pregnancy, and followed up by ultrasound and magnetic resonance imaging. Fetal growth was appropriate, fetal movements were good and the patient had no symptoms, without uterine contraction or amniotic fluid loss throughout follow-up period. Caesarean section was carried out at 34 + 1 weeks with a good maternal and neonatal outcome. CONCLUSIONS: A previous history of laparoscopic salpingectomy with cornual wedge resection could be a risk factor for uterine rupture in pregnant women. Sonographers should be alert to this potential risk in pregnant women with a history of laparoscopic salpingectomy with cornual wedge resection even in asymptomatic patients.

Enhance the effectiveness of clinical laboratory critical values initiative notification by implementing a closed-loop system: A five-year retrospective observational study.

BACKGROUND: Accurate and timely clinical laboratory critical values notification are crucial steps in supporting effective clinical decision making, thereby improving patient safety. METHODS: A closed-loop laboratory critical value notification system was developed by a multidisciplinary team of clinicians, laboratorians, administrators, and information technology experts. All the laboratory critical values that occurred at Beijing Tsinghua Changgung Hospital (BTCH, Beijing, China) from 2015 to 2019 were analyzed and studied retrospectively. RESULTS: The total number (ratio) of institutional laboratory critical values to all reported items at BTCH from 2015 to 2019 was 38 020/7 706 962 (0.49%). Percentage distribution points of critical value boundaries based on patients' test reports are 0.007% ~ 6.04% for low boundaries and 71.70% ~ 99.99% for high boundaries. After the intervention, the timely notification ratio, notification receipt ratio, and timely notification receipt ratio of critical values of ED, IPD, and total patients had increased, with a significant difference (P < .001). Five quality indicators, such as notification ratio, timely notification ratio, notification receipt ratio, timely notification receipt ratio, and clinician response ratio over a 5-year period, were 100%, 94%, 97%, 92%, and 99%, respectively. CONCLUSIONS: We enhanced the effectiveness of clinical laboratory critical values initiative notification by implementing a closed-loop system and intervening. Clinical critical values and quality indicators should be analyzed and monitored to avoid adversely affecting patient care.

Comprehensive analysis of Cry1Ac protoxin activation mediated by midgut proteases in susceptible and resistant Plutella xylostella (L.).

Insecticidal Cry toxins produced by Bacillus thuringiensis (Bt) have been widely used to control agricultural pests in both foliage sprays and transgenic crops. Nevertheless, rapid evolution of insect resistance to Cry toxins requires elucidation of the molecular mechanisms involved in Cry resistance. Two proposed models have been described to explain the toxicity of Cry proteins, the classic model states that Cry protoxin is activated by midgut proteases resulting in activated toxin that binds to receptors and forms a pore in the midgut cells triggering larval death, and the newly proposed dual model of the mode of action of Bt Cry toxins states that protoxin and activated toxins may have different mechanisms of action since several resistant strains to activated Cry toxins are still susceptible to the same Cry-protoxin. Protoxin activation by midgut proteases is a key step in both models. Herein, we evaluated Cry1Ac protoxin activation in a susceptible Plutella xylostella (L.) strain (DBM1Ac-S) and in the near-isogenic strain (NIL-R) with high field-evolved Cry1Ac resistance. Previous work showed that Cry1Ac resistance in NIL-R correlates with reduced binding to midgut receptors due to enhanced MAPK signaling pathway and down regulation of ABCC2 receptor. However, reduced midgut trypsin levels and altered midgut protease gene transcription were also observed in the Cry1Ac-resistant field isolated strain that is parent of the NIL-R strain. Therefore, we analyzed the midgut protease activities in both DBM1Ac-S and NIL-R strains. Detection of enzymatic activities showed that caseinolytic protease, trypsin and chymotrypsin activities were not significantly different between the susceptible and resistant strains. Furthermore, treatment with different trypsin or chymotrypsin inhibitors, such as Nα-tosyl-l-lysine chloromethyl ketone (TLCK) or Np-tosyl-L-phenylalanine chloromethyl ketone (TPCK) did not affect the susceptibility to Cry1Ac protoxin of the DBM1Ac-S and NIL-R larvae. Bioassay results indicated that the NIL-R larvae showed similar resistant levels to both Cry1Ac protoxin and trypsin-activated toxin. Taken together, our results demonstrated that high-level field-evolved Cry1Ac resistance in the NIL-R strain is independent of Cry1Ac protoxin activation and the specific protoxin mechanism of action. This discovery will strengthen our comprehensive understanding of the complex mechanistic basis of Bt resistance in different insects.

Forty-five consecutive cases of complicated monochorionic multiple pregnancy treated with microwave ablation: A single-center experience.

OBJECTIVE: To describe our preliminary experience in the application of microwave ablation for selective fetal reduction in complicated monochorionic multiple pregnancies. METHODS: In this prospective study, 45 consecutive complicated monochorionic multiple pregnancies that underwent microwave ablation for selective fetal reduction from July 2015 to February 2017 were analyzed from the first case onward. All patients were managed at the Peking University Third Hospital in Beijing, China. RESULTS: There were 45 cases (twins in 40 and triplets in five) treated by microwave ablation. The median gestational age at surgery was 21.3 weeks (range, 15.9-25.7 wk), with a mean total ablation time of 8.5 ± 4.2 (7.2-9.7) minutes. There were 12 (26.7%) cases of postprocedural fetal loss. Thirty-three women delivered alive at a median gestational age of 37.6 weeks (range, 28.6-40.4 wk). There were no neonatal deaths in our cohort, and the overall survival rate was 73.3% (33/45). Preterm premature rupture of membranes occurred in 9 (20.0%) cases with a median of 7.0 weeks (range, 0.9-16.3 wk) after the surgery. None of the surviving cotwins had evidence of thermal injury or neurological abnormalities. CONCLUSION: Microwave ablation appears to be a safe and effective method for selective feticide in complicated monochorionic pregnancies.

Comparative analysis of calculating sigma metrics by a trueness verification proficiency testing-based approach and an internal quality control data inter-laboratory comparison-based approach.

INTRODUCTION: Two methods were compared for evaluating the sigma metrics of clinical biochemistry tests using two different allowable total error (TEa) specifications. MATERIALS AND METHODS: The imprecision (CV%) and bias (bias%) of 19 clinical biochemistry analytes were calculated using a trueness verification proficiency testing (TPT)-based approach and an internal quality control data inter-laboratory comparison (IQC)-based approach, respectively. Two sources of total allowable error (TEa), the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) and the People's Republic of China Health Industry Standard (WS/T 403-2012), were used to calculate the sigma metrics (σCLIA, σWS/T ). Sigma metrics were calculated to provide a single value for assessing the quality of each test based on a single concentration level. RESULTS: For both approaches, σCLIA  > σWS/T in 18 out of 19 assays. For the TPT-based approach, 16 assays showed σCLIA  > 3, and 12 assays showed σWS/T  > 3. For the IQC-based approach, 19 and 16 assays showed σCLIA  > 3 and σWS/T  > 3, respectively. CONCLUSIONS: Both methods can be used as references for calculating sigma metrics and designing QC schedules in clinical laboratories. Sigma metrics should be evaluated comprehensively by different approaches.

A comparison study between wide-range and high-sensitivity C-reactive protein assays (Roche Cobas c702) for low C-reactive protein concentration in patients with cardiovascular risk.

BACKGROUND: Low concentration C-reactive protein (CRP) has favorable prognostic significance in patients with cardiovascular risks. METHODS: We compared the wr-CRP method with the hs-CRP method both on Roche Cobas c702 analyzer for the determination of low CRP concentration (<20 mg/L) including 200 patients treated in Cardiology Department in Beijing Tsinghua Changgung Hospital (Beijing, China) from December 2018 to March 2019. RESULTS: The two methods were highly correlated (Spearman's rho = 0.995). Deming regression was used to fit the regression analysis model, giving a slope of 1.058 with an intercept of 0.008. The median method difference (wr-CRP - hr-CRP) was 0.120 mg/L (95% CI, 0.086-0.200 mg/L), and the median percent differences were 7.34% (95% CI, 4.27%-8.47%). The percent bias between both methods at the given cutoff CRP values of 1, 3, and 10 mg/L evaluated by Deming regression was 6.60%, 6.07%, and 5.88%, respectively, all of which were less than the acceptable standard (12.50%). The percentage of sample results concordant by both methods for the risk stratification was 96.0% (kappa = 0.937, P < 0.001). CONCLUSIONS: Roche wr-CRP and hs-CRP assays are highly concordant in determining low concentration CRP. Wr-CRP may be used as an alternative to hs-CRP assay on Roche Cobas c702 analyzer to assess the cardiovascular risk, considering its convenience and lower costs.

Characterization of immune-related PGRP gene expression and phenoloxidase activity in Cry1Ac-susceptible and -resistant Plutella xylostella (L.).

Peptidoglycan recognition proteins (PGRPs) are important recognition receptors which play a critical role in signal identification and transmission in Toll or immune deficiency (IMD) pathways, particularly when pathogens evade and circumvent reactive oxygen species. Antimicrobial peptides (AMPs) synthesis can be activated by these signals to further eliminate pathogens. In this study, we cloned and characterized three different PGRP genes in Plutella xylostella strains, DBM1Ac-S, DBM1Ac-R and a field strain (DBMF). The results showed that PGRP1 belongs to the PGRP-SA family, PGRP2 to PGRP-LB, and PGRP3 to PGRP-LF. Moreover, PGRP1 expressed the highest transcript level, followed by PGRP3 and PGRP2, in two tissues including the gut and the larval carcass tissues of the DBM1Ac-S strain. Furthermore, altered expression levels of PGRP1-3 genes were detected in both gut and carcass tissues. Moreover, the DBM1Ac-R strain had the highest phenol oxidase (PO) activity among these three strains. The characterization of PGRP gene expression and PO activity in DBM1Ac-S, DBM1Ac-R and DBM-F provides insights into their important physiological roles in the immune system of P. xylostella exposed to Bt Cry1Ac toxin.

Quantitative analysis of cellular proteome alterations of Pseudomonas putida to naphthalene-induced stress.

OBJECTIVE: To investigate whether genes other than the operons nahAaAbAcAdBFCED and nahGTHINLOMKJ of Pseudomonas putida are involved in the tolerance of the bacterium to naphthalene. RESULTS: Cellular responses of P. putida ND6 grown with 2 and 4 g naphthalene/l were investigated using a quantitative proteomic-based approach. Comparative analysis of the proteome data identified that the expression levels of 22 proteins involved in heat shock and universal stress response, naphthalene degradation, cell envelope synthesis, and motility were up-regulated; while the expression levels of 26 proteins involved in protein and fatty acid synthesis, carbon compound, nucleotide, and amino acid metabolism, and small molecule transport were down-regulated. CONCLUSION: Our findings offer insights into the cellular response of P. putida to high naphthalene concentrations at the protein level.

Superoxide is an Intrinsic Signaling Molecule Triggering Muscle Hypertrophy.

Aims: Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide (O2•-) and hydrogen peroxide and thereby to specifically explore the role of O2•- in muscle hypertrophy in C2C12 cells and mice. Results: TM can linearly regulate intracellular O2•- levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in O2•- levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced O2•- increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging O2•- with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, whereas the restoration of O2•- levels with a O2•- generator promotes muscle hypertrophy independent of SOD1 activity. Innovation and Conclusion: These findings suggest that O2•- is an endogenous initiator of myofiber hypertrophy and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating O2•- levels in vivo.

[Umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations].

OBJECTIVE: To evaluate the clinical effect and safety of umbilical cord ligation in the fetocide of complicated monochorionic multiple gestations. METHODS: From January 2009 to December 2012, clinical data of 18 women with complicated monochorionic multiple gestations who experienced intrauterine percutaneous umbilical cord ligation in Peking University Third Hospital were collected. Among the patients, 6 were selective intrauterine growth restriction (1 with type I, 4 with type II, 1 with type III); 4 were acrania or hydropic twins; 4 were acardiac twins, 2 were complicated triplet gestation; 1 was twin-twin transfusion syndrome with right ventricular dysplasia and 1 was monochorionic diamniotic (MCDA) with caesarean section history. The procedure was performed under both endoscopic and sonographic guidance. The gestational age at the time of the procedure were 17-27(+6) weeks. The procedure and perinatal outcome were analyzed. RESULTS: (1) The procedure was performed successfully in all the 18 cases. The average duration of the procedure was 63 min (24-156 min). The blood loss was 7.6 ml (5-20 ml). The mean gestational age at the time of the procedure was 20 weeks (17-27(+) weeks). The average birth weight of the neonates was 2441 g (1000-3400 g) .(2) There were 206 fetuses survived. Two fetuses had cardiac anomalies and were terminated in the following 2-3 weeks.Intrauterus fetal demise occured in 3 twin reverse arterial perfusion syndrome (TRAP) cases 3-14 weeks after the procedure.1 case delivered as early preterm birth at 28 weeks and the neonate died of respiratory distress syndrome (RDS) and hypoxie-ischemicen-cephalopathy (HIE) .Fourteen neonates were in healthy and normal development by 3-51 months' follow-up.(3) Fourteen cases delivered at more than 28 weeks (28-38 weeks, averagely 33(+1) weeks). The gestational weeks were prolonged by 5-21 weeks (averagely 13(+4) weeks). Among them, 3 case were early preterm birth (28-33 weeks) and 3 were late preterm birth (34-36 weeks). CONCLUSION: Percutaneous umbilical cord ligation is a reliable technique for the fetocide of complicated monochrionic mutilple gestations, especially for monochronic monoamniotic pregnancies.

A new species of Pseudopoda (Araneae, Sparassidae) from China, with the description of different and distinctive internal ducts of the female vulva.

One new species of the genus Pseudopoda Jäger, 2000, Pseudopodadeformis Gong & Zhong, sp. nov. (♂, ♀), is described and documented with digital images from Shennongjia Forestry District, Hubei Province, China, based on morphology and DNA barcodes. This new species is separated from other Pseudopoda species by the unique type of internal ducts of the female vulva that are curved longitudinally, forming a narrow triangle or trapezoidal shape. In addition, DNA barcodes for this species are provided.

Plasmonic scattering imaging of single Cu2-xSe nanoparticle for Hg2+ detection.

The development of new efficient contrast nanoprobe has been greatly concerned in the field of scattering imaging for sensitive and accurate detection of trace analytes. In this work, the non-stoichiometric Cu2-xSe nanoparticle with typical localized surface plasmon resonance (LSPR) properties originating from their copper deficiency as a plasmonic scattering imaging probe was developed for sensitive and selective detection of Hg2+ under dark-field microscopy. Hg2+ can compete with Cu(I)/Cu(II) which were sources of optically active holes coexisting in these Cu2-xSe nanoparticles for its higher affinity with Se2-. The plasmonic properties of Cu2-xSe were adjusted effectively. Thus, the color scattering images of Cu2-xSe nanoparticles was changed from blue to cyan, and the scattering intensity was obviously enhanced with the dark-field microscopy. There was a linear relationship between the scattering intensity enhancement and the Hg2+ concentration in the range of 10-300 nM with a low detection limit of 1.07 nM. The proposed method has good potential for Hg2+ detection in the actual water samples. This work provides a new perspective on applying new plasmonic imaging probe for the reliable determination of trace heavy metal substances in the environment at a single particle level.

Sympathetic blockage attenuates fasting-induced hepatic steatosis.

Although the central nervous system coordinates whole-body metabolism, the neural mechanism for hepatic steatosis remains unclear. This study is aimed to explore the neural mechanism of fasting-induced hepatic steatosis. Mice were pretreated with 6-hydroxydopamine to block sympathetic nerve activity before fasting, and to explore the potential effects of chemical sympathectomy on fasting-induced hepatic steatosis and transcriptional changes. Twenty-four hours fasting led to obvious hepatic steatosis, low-core temperature, and similar effects to cold-induced white adipose lipolysis. The alterations in hepatic mRNA expression revealed that the hepatic lipid accumulation did not result from an increase in hepatic lipogenesis or a decrease in fatty acid oxidation but from enhanced fatty acid uptake as indicated by upregulation of CD36. Blockage of the sympathetic nervous system via chemical sympathectomy attenuated fasting-induced hepatic steatosis and suppressed CD36 upregulation in the liver, but did not obviously alter the expression of genes associated with lipogenesis or fatty acid oxidation. These findings indicate that the sympathetic nervous system orchestrates the mechanism for fasting-induced hepatic steatosis via modulating CD36 expression and adipose fat trafficking into the liver, which provides clues to reveal new targets for fatty liver diseases.

Circadian transcriptional pathway atlas highlights a proteasome switch in intermittent fasting.

While intermittent fasting is a safe strategy to benefit health, it remains unclear whether a "timer" exists in vivo to record fasting duration and trigger a transcriptional switch. Here, we map a circadian transcriptional pathway atlas from 600 samples across four metabolic tissues of mice under five feeding regimens. Results show that 95.6% of detected canonical pathways are rhythmic in a tissue-specific and feeding-regimen-specific manner, while only less than 25% of them induce changes in transcriptional function. Fasting for 16 h initiates a circadian resonance of 43 pathways in the liver, and the resonance punctually switches following refeeding. The hepatic proteasome coordinates the resonance, and most genes encoding proteasome subunits display a 16-h fasting-dependent transcriptional switch. These findings indicate that the hepatic proteasome may serve as a fasting timer and a coordinator of pathway transcriptional resonance, which provide a target for revealing the underlying mechanism of intermittent fasting.

First description of the female of Sinopodayichangensis Zhu, Zhong & Yang, 2020 (Araneae, Sparassidae).

Sinopodayichangensis Zhu, Zhong & Yang, 2020 was described from a single male from Qiaoliao Village, Hubei Province, China. To date, no additional specimens have been recorded. The female is reported for the first time from the type locality. Detailed morphological descriptions of the female, with photographs of living specimens and copulatory organs, are provided.

Redescription of Pseudopoda taibaischana (Araneae, Sparassidae), with the first description of the female.

Pseudopoda taibaischana Jäger, 2001 (Sparassidae) is redescribed based on new material from the type locality in Taibaishan Nation Forest Park of Shaanxi Province, China. The female is described and illustrated for the first time, and a redescription is provided for the male.

MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host.

The arms race between entomopathogenic bacteria and their insect hosts is an excellent model for decoding the intricate coevolutionary processes of host-pathogen interaction. Here, we demonstrate that the MAPK signaling pathway is a general switch to trans-regulate differential expression of aminopeptidase N and other midgut genes in an insect host, diamondback moth (Plutella xylostella), thereby countering the virulence effect of Bacillus thuringiensis (Bt) toxins. Moreover, the MAPK cascade is activated and fine-tuned by the crosstalk between two major insect hormones, 20-hydroxyecdysone (20E) and juvenile hormone (JH) to elicit an important physiological response (i.e. Bt resistance) without incurring the significant fitness costs often associated with pathogen resistance. Hormones are well known to orchestrate physiological trade-offs in a wide variety of organisms, and our work decodes a hitherto undescribed function of these classic hormones and suggests that hormonal signaling plasticity is a general cross-kingdom strategy to fend off pathogens.