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The article "Age and outcomes in people with type 2 diabetes admitted to hospital with COVID-19: A cohort study" published in Diabetic Medicine explores the impact of age on outcomes for individuals with type 2 diabetes hospitalized with COVID-19. The study found that younger individuals (<50 years) with type 2 diabetes had a higher prevalence of adverse cardio-metabolic risk factors, complications, and mortality compared to older individuals (≥50 years). The findings highlight the importance of primary and secondary prevention of type 2 diabetes, especially in high-risk cohorts like young individuals with diabetes. [Extracted from the article]

Objective: To estimate a stillbirth rate at 24 or more gestational weeks in 2015–2016 and to explore potentially preventable causes in China. Design: A multi‐centre cross‐sectional study. Setting: Ninety‐six hospitals distributed in 24 (of 34) provinces in China. Population: A total of 75 132 births at 24 completed weeks of gestation or more. Methods: COX Proportional Hazard Models were performed to examine risk factors for antepartum and intrapartum stillbirths. Population attributable risk percentage was calculated for major risk factors. Correspondence analysis was used to explore region‐specific risk factors for stillbirths. Main outcome measures: Stillbirth rate and risk factors for stillbirth. Results: A total of 75 132 births including 949 stillbirths were used for the final analysis, giving a weighted stillbirth rate of 13.2 per 1000 births (95% CI 7.9–18.5). Small for gestational age (SGA) and pre‐eclampsia/eclampsia increased antepartum stillbirths by 26.2% and 11.7%, respectively. Fetal anomalies increased antepartum and intrapartum stillbirths by 17.9% and 7.4%, respectively. Overall, 31.4% of all stillbirths were potentially preventable. Advanced maternal age, pre‐pregnant obesity, chronic hypertension and diabetes mellitus were important risk factors in East China; low education and SGA were major risk factors in Northwest, Southwest, Northeast and South China; and pre‐eclampsia/eclampsia and intrapartum complications were significant risk factors in Central China. Conclusions: The prevalence of stillbirth was 13.2 per 1000 births in China in 2015–2016. Nearly one‐third of all stillbirths may be preventable. Strategies based on regional characteristics should be considered to reduce further the burden of stillbirths in China. The stillbirth rate was 13.2 per 1000 births in China in 2015–2016 and nearly one‐third of all stillbirths may be preventable. The stillbirth rate was 13.2 per 1000 births in China in 2015–2016 and nearly one‐third of all stillbirths may be preventable. [ABSTRACT FROM AUTHOR]

Fire causes dramatic energy and matter exchanges between biosphere and atmosphere on a regional to global scale. Predicting fires, however, is hindered by the complex interplay of fire, climate, and vegetation. Paleo‐fire records provide critical information beyond instrumental records that cover only the past few decades and may be used to assess the role of fire in large‐scale and long‐term environmental changes. Here we present a 22,000‐year multiproxy record of fire regime from a sediment core retrieved offshore South Java, Indonesia. We use microcharcoal in combination with two molecular markers of burning, levoglucosan and polycyclic aromatic hydrocarbons, to reconstruct fire occurrence as well as fire intensity in the past. We show that fire occurrence and intensity were high during the Last Glacial Maximum (LGM; around 21,000 years ago) and low during the Heinrich Stadial 1 and the early Holocene. Both fire regime and vegetation in tropical regions with high annual rainfall were primarily controlled by rainfall seasonality. However, fire additionally stabilized the savannah (rainforest)‐dominated ecosystem during the LGM (early Holocene) but caused transitions between the two vegetation types during the deglaciation and the late Holocene. Key Points: Microcharcoal reflects regional fire occurrence, while the ratio between two novel molecular markers reflects past fire intensityRainfall seasonality controlled both fire regime and vegetationFires of different frequencies and intensities were capable of either stabilizing or destabilizing savannah/rainforest vegetation [ABSTRACT FROM AUTHOR]

Hypoglycaemia is a key barrier to achieving euglycaemic control in people who are hospitalized. Inpatient hypoglycaemia has been linked to adverse clinical outcomes, including mortality and longer stay in hospital. A number of studies have applied mathematical tools and statistical models to predict inpatient hypoglycaemia and identify factors that may result in hypoglycaemic events. Several different approaches have been tested to prevent inpatient hypoglycaemia. These can be categorized as human intervention, computerized methods or application of medical devices. In this review we provide an overview of the epidemiology of inpatient hypoglycaemia and its impact on patients and hospitals. We also discuss the existing methodology used to predict inpatient hypoglycaemia and the limited number of trials performed to prevent inpatient hypoglycaemia. The review highlights the urgent need for evidence‐based methods to reduce inpatient hypoglycaemia. What's new?: We identified 4572 references in the literature on the prediction, prevention and management of inpatient hypoglycaemia, but only 49 papers were directly relevant to the review.Whilst several papers show an association between hypoglycaemia and subsequent negative clinical and economic impact, there is no evidence that this impact can be reversed by preventing inpatient hypoglycaemia.Several papers have identified multiple predictors of hypoglycaemia through multivariate regression modelling; however, no prospective model has been tested to give an individualized prediction of hypoglycaemia at the point of admission, enabling preventative strategies to be employed.Future research should be conducted to identify prospective predictors of inpatient hypoglycaemia with the aim of developing evidence‐based tools to prevent hypoglycaemia. [ABSTRACT FROM AUTHOR]

Summary: Previously, we have demonstrated that human tissue kallikrein 1 (hKLK1) improves age‐related erectile dysfunction (ED). Autophagy has been implicated in age‐related diseases, including ED. However, the molecular mechanisms underlying hKLK1‐mediated amelioration of age‐related ED via regulation of autophagy remains unknown. To explore the potential mechanism, male wild‐type Sprague‐Dawley rats (WTR) and transgenic rats harboring human KLK1 (TGR) were bred till 4 or 18 months of age and divided into three groups: young WTR (yWTR) as the control group, aged WTR (aWTR) group, and aged TGR (aTGR) group. The erectile function of each rat was evaluated using cavernous nerve electrostimulation. The ratio of intracavernous pressure/mean arterial pressure (ICP/MAP) and total ICP were also measured. Western blotting, immunohistochemistry, and transmission electron microscopy were performed to detect the levels of autophagy. The expression levels of related signaling pathways were determined by western blotting and immunohistochemistry. We found that hKLK1 improved the impaired erectile function of aged rats. Compared to the yWTR and aTGR groups, the aWTR group showed reduced smooth muscle/collagen ratio, fewer autophagosomes, and lower expression of Beclin 1 and LC3‐II, which indicate impaired smooth muscle function and low level of autophagy in the smooth muscle cells. Moreover, the PI3K/Akt/mTOR signaling pathway, which is considered to be a negative regulator of autophagy, was upregulated in the aWTR group. hKLK1 may partially restore erectile function in aged transgenic rats by upregulating protective autophagy via the PI3K/Akt/mTOR pathway. These observations indicate that hKLK1 is a potential gene therapy candidate for age‐related ED. [ABSTRACT FROM AUTHOR]

Summary: The endeavours to reveal the tracheal system of insects and some arachnids has a long history. The traditional way to observe a tracheal system in an insect body is by utilising the glycerin immersion method. In this study, we developed the lactic acid immersion method, which reveals a more complete tracheal system. By mounting various types of live specimens or body parts directly into lactic acid, multiple intact and complex tracheal systems were clearly visualised. The lactic acid immersion contributed to revealing tracheal systems by penetrating body tissue while reserving enough time for observation before the penetration of the tracheae. Preliminary comparisons were conducted between lactic acid and other mediae, including glycerin. It turned out that lactic acid immersion provides better details and more distinct structures. In our test, the optimal time for observing the tracheal system was 10–25 min after the organism was immersed in lactic acid. [ABSTRACT FROM AUTHOR]

The relationship between gene polymorphisms and the pathogenesis of cerebral palsy (CP) is uncovering recently. Here, we suggested that single nucleotide polymorphisms (SNPs) of MLEC gene might take part in the pathogenesis of CP. We genotyped and analyzed 6 SNP positions of MLEC gene in 916 CP patients and 957 healthy people, which are from the Chinese Han population. The results indicated significant associations between the risk of CP and rs10431386 [allele: P‐value = .006, odds ratio (OR) = 1.587, 95% confidence interval (CI) = 1.198‐1.967] and rs7964786 [allele: P‐value = .005, OR = 1.956, 95% CI = 1.238‐2.519] SNP positions of MLEC gene. Further investigations revealed that C alleles of rs10431386 and rs7964786 inhibit the expression of MLEC in blood of CP patients and macrophage cell line. in vitro experiments revealed that MLEC promotes M1 to M2 macrophage polarization. The results of in vitro studies suggest that C alleles of rs10431386 and rs7964786 on MLEC promotes CP by inhibiting M1 to M2 macrophage polarization. Generally, this work suggested the contribution of MLEC gene polymorphisms to the pathogenesis of CP. [ABSTRACT FROM AUTHOR]

Aim To compare bolus insulin delivery patterns during closed-loop home studies in adults with suboptimally [HbA1c 58–86 mmol/mol (7.5%–10%)] and well-controlled [58 mmol/mol (< 7.5%)] Type 1 diabetes. Methods Retrospective analysis of daytime and night-time insulin delivery during home use of closed-loop over 4 weeks. Daytime and night-time controller effort, defined as amount of insulin delivered by closed-loop relative to usual basal insulin delivery, and daytime bolus effort, defined as total bolus insulin delivery relative to total daytime insulin delivery were compared between both cohorts. Correlation analysis was performed between individual bolus behaviour (bolus effort and frequency) and daytime controller efforts, and proportion of time spent within and below sensor glucose target range. Results Individuals with suboptimally controlled Type 1 diabetes had significantly lower bolus effort (P = 0.038) and daily bolus frequency (P < 0.001) compared with those with well-controlled diabetes. Controller effort during both daytime (P = 0.007) and night-time (P = 0.005) were significantly higher for those with suboptimally controlled Type 1 diabetes. Time when glucose was within the target range (3.9–10.0 mmol/L) during daytime correlated positively with bolus effort (r = 0.37, P = 0.016) and bolus frequency (r = 0.33, P = 0.037). Time when glucose was below the target range during daytime was comparable in both groups (P = 0.36), and did not correlate significantly with bolus effort (r = 0.28, P = 0.066) or bolus frequency (r = –0.21, P = 0.19). Conclusion More frequent bolusing and higher proportion of insulin delivered as bolus during hybrid closed-loop use correlated positively with time glucose was in target range. This emphasises the need for user input and educational support to benefit from this novel therapeutic modality. [ABSTRACT FROM AUTHOR]

Background Allergic rhinitis ( AR) is a complex disease, in which gene-environment interactions contribute to its pathogenesis. Epigenetic modifications such as DNA methylation play an important role in the regulation of gene function. As IL13, a pleiotropic cytokine, may be important in conferring susceptibility to AR, the aim of the present work was to assess the relationship between a CpG island methylation status at the upstream of IL13 gene and house dust mite ( HDM)-sensitized AR in Han Chinese subjects. Methods A total of 60 patients with HDM-sensitized AR and 65 control subjects were enrolled as two independent cohorts from Beijing and Liaoning. Mass ARRAY Epi TYPER and pyrosequencing was used to systematically screen the status of DNA methylation in peripheral blood leucocytes. IL13 mRNA expression was measured by real-time quantitative PCR. Electrophoretic mobility shift assay was used to assess the function of methylation site. Results The mean level of methylation was decreased in the AR patient group compared with the control group ( P = 0.01). Two of a total of 33 IL13CpG units analysed (CpG units 24 : 25 : 26 and 38 : 39) showed significant differences in methylation status between the AR patient group and the control group, with DNA hypomethylation at CpG38 significantly associated with higher risk of HDM-sensitized AR in both independent cohorts and a combined cohort (Beijing: OR = 1.24, 95% CI = 1.01-1.52, P = 0.036; Liaoning: OR = 1.62, 95% CI = 1.11-2.38, P = 0.013; Combined: OR = 1.31, 95% CI = 1.10-1.56, P = 0.002). Methylation level of CpG38 correlated negatively with both IL13 mRNA expression and serum total IgE level and affected the binding affinity of SP1. Conclusions DNA hypomethylation of IL13 gene may be associated with increased risk of AR from HDM sensitization. [ABSTRACT FROM AUTHOR]

We adapted DSC and drop tube processing techniques to investigate the solidification behavior of (Ge) and CuAl2 phases in the Al-Cu-Ge ternary alloy comparatively. For the DSC sample only undercooled to 32 K with a low cooling rate, (Ge) phase is the leading nucleating phase and then CuAl2 phase nucleates. Primary (Ge) block, (Ge+CuAl2) and (Ge+Al) pseudobinary eutectics coexist in the microstructure. In the drop tube, the more competitive nucleation and growth of (Ge) and CuAl2 phases are caused primarily by high cooling rate and then secondly by large undercooling. On condition that undercooling and cooling rate exceed critical values, simultaneous nucleation of (Ge) and CuAl2 phases from the alloy melt and subsequently their independent growth contribute to the formation of anomalous (Ge+CuAl2) pseudobinary eutectic grain. Under such condition, a small amount of ternary eutectic grain forms due to the late exclusion of Al solute. [ABSTRACT FROM AUTHOR]

Peri-eutectic transition was investigated in terms of the dependence of crystallization behavior on undercooling in Cu-Ag-Ge ternary alloy composed of (Ag), ζ(Cu5Ge), and ε2(Cu3Ge) phases. (Ag + ε2) pseudobinary eutectic is the product of both peri-eutectic and subsequent pseudobinary eutectic transitions. Nanoscale structure of anomalous (Ag + ε2) pseudobinary eutectic forms at the maximum undercooling, which is ascribed to the independent nucleation and growth from the liquid. The decrease of (Ag + ε2) pseudobinary eutectic at a high undercooling is due to that the phase transition happening at the beginning solidification stage proceeds more thoroughly at a higher undercooling. [ABSTRACT FROM AUTHOR]

Alteration of human leukocyte antigen (HLA) expression, such as decreased HLA I (HLA-A, -B and -C) antigens and elevated nonclassical HLA I antigens (HLA-E, -F and -G), was reported to have an unfavorable prognosis in various cancers. In our study, HLA-F expression in 105 primary esophageal squamous cell carcinoma (ESCC) lesions and 62 case-matched adjacent normal tissues, and HLA I antigens among 68 cases were analyzed by immunohistochemistry. Data revealed that HLA-F expression was observed in 58.1% (61/105) of the ESCC lesions and in 54.8% (34/62) of the normal esophageal tissues. Among the 62 case-matched samples, HLA-F expression (lesion vs. normal tissue) was upregulated, unchanged and downregulated in 13 (21.0%), 6 (9.6%) and 43 (69.4%) cases, respectively. Patients with HLA-F positive had a worse survival than those with HLA-F negative ( p = 0.040). Patients with upregulated HLA-F expression (lesion vs. normal tissue) had significantly worse survival than those with HLA-F unchanged and downregulated ( p = 0.010). Furthermore, decreased HLA I expression was observed in 41.2% (28/68) patients and was with worse prognosis in comparison to those with preserved HLA I expression ( p = 0.001). Multivariate analysis using Cox's proportional hazards model revealed that upregulated HLA-F expression ( p = 0.026) and downregulated HLA I expression ( p = 0.013) could be an independent unfavorable prognostic factor. In conclusion, our study provided the evidence that alteration of HLA I and HLA-F antigen expression was associated with survival in patients with ESCC. [ABSTRACT FROM AUTHOR]

In this paper we report a chemical method named coordination reaction method to synthesize ZnO nanowire arreys. ZnO nanowires with the diameter about 80nm were successfully fabricated in the channels of the porous anodic alumina (PAA) template by the above coordination reaction method. The microstructures of ZnO/PAA assembly were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD). The results showed that the ZnO nanowires can be uniformly assembled into the nanochannels of PAA template. The growth mechanism of ZnO nanowires and the conditions of the coordination reaction are discussed. Photoluminescence (PL) measurement shows that the ZnO/PAA assembly system has a blue emission band caused by the various defects of ZnO. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Interleukin 1 receptor antagonist (IL-1Ra) is an important anti-inflammatory molecule encoded by the IL1RN gene. The polymorphism of IL1RN characterized by variable numbers of an 86 bp tandem repeat (VNTR) sequence in intron 2 has been described. Moreover, frequencies of the IL1RN alleles vary among different ethnics. In the present study, we analysed the IL1RN polymorphism in intron 2 in 256 Chinese Han and 252 Chinese She individuals. Four alleles including IL1RN*1, *2, *3 and IL1RN*4 were identified in this study. Data revealed that the distribution of the IL-1RN genotypes and allele was significantly different between the two Chinese populations ( P < 0.001). Among them, 66.8% (171/256) and 86.5% (218/252) were homozygous for the allele IL-1RN*1 in Chinese Han and She individuals respectively. Homozygosity for allele IL-1RN*2 was only observed in Chinese Han with the percentage of 0.8% (2/256). Heterozygosity for IL-1RN*1/2, IL1RN*1/3 and IL1RN*1/4 was 30.9% (79/256), 0.4% (1/256) and 1.2% (3/256) in Chinese Han, whereas only heterozygosity for IL-1RN*1/2 was found in Chinese She (13.5%, 34/252). Frequencies of the most common allele IL-1RN*1 and IL-1RN*2 were 83.0% and 16.2% for Chinese Han and 93.3% and 6.7% for Chinese She respectively. The rare allele IL-1RN*3 and IL-1RN*4 was only observed in the Chinese Han population with the frequency of 0.2% and 0.6% respectively. Our findings suggested that the ethnic background plays an important role in IL-1Ra gene variation in different populations. [ABSTRACT FROM AUTHOR]

Although recent studies have suggested that the microfilament (MF) cytoskeleton of plant cells participates in the response to salt stress, it remains unclear as to whether the MF cytoskeleton actually plays an active role in a plant’s ability to withstand salt stress. In the present study, we report for the first time the role of MFs in salt tolerance of Arabidopsis thaliana. Our experiments revealed that Arabidopsis seedlings treated with 150 mm NaCl maintained MF assembly and bundle formation, whereas treatment with 250 mm NaCl initially induced MF assembly but subsequently caused MF disassembly. A corresponding change in the fluorescence intensity of MFs was also observed; that is, a sustained rise in fluorescence intensity in seedlings exposed to 150 mm NaCl and an initial rise and subsequent fall in seedlings exposed to 250 mm NaCl. These results suggest that MF assembly and bundles are induced early after salt stress treatment, while MF polymerization disappears after high salt stress. Facilitation of MF assembly with phalloidin rescued wild-type seedlings from death, whereas blocking MFs assembly with latrunculin A and cytochalasin D resulted in few survivors under salt stress. Pre-treatment of seedlings with phalloidin also clearly increased plant ability to withstand salt stress. MF assembly increased survival of Arabidopsis salt-sensitive sos2 mutants under salt stress and rescued defective sos2 mutants. Polymerization of MFs and its role in promoting survival was also found in plants exposed to osmotic stress. These findings suggest that the MF cytoskeleton participates and plays a vital role in responses to salt and osmotic stress in Arabidopsis. [ABSTRACT FROM AUTHOR]

Although many screening criteria have been suggested to distinguish between genotypes for their salt tolerance under controlled environmental conditions, there is a need to test these criteria in the field. Saline soils are often complex and, therefore, unlikely to show a simple relationship to controlled conditions. To address this deficit, different agronomic and physiological screening criteria for salt tolerance in wheat at different stages were examined under both field and controlled conditions. Four wheat genotypes differing in their salt-tolerance levels were grown in salt-affected soil at two different locations and also under greenhouse conditions. Dry weight and leaf area of the upper and lower two leaves of the main stem and total dry weight at Zadoks scale 47 were measured in plants grown under field conditions. The concentrations of Cl−, Na+, K+ and Ca2+ in the upper and lower two leaves of the main stem at Zadoks scale 47 and different yield components were measured in plants grown under both conditions. Our results indicate that measurements derived from the upper two leaves of the main stem were generally more effective as screening criteria than those from the lower two leaves. Correlation coefficients between grain yield and either dry weight or leaf area of the upper two leaves of the main stem indicated that dry weight is inferior to leaf area as a screening criterion under field conditions. Number of sterile spikelets per plant performed well under both conditions, whereas the number of spikelets per plant and 1000-grain weight failed to distinguish the differences of salt-tolerance levels among genotypes accurately. Weight and number of grains per plant and number of fertile spikes per plant were poor criteria under controlled conditions, but effective under field conditions. The maintenance of low Cl− and Na+ concentrations in the upper two leaves offered the best guide to salt tolerance under both conditions. Potassium concentration was a poor criterion compared with the selectivity of K+ over Na+, which was useful under both field and controlled conditions. Calcium concentration and Ca2+ over Na+ selectivity in the upper and/or lower two leaves of the main stem were also effective in ranking genotypes according to their salt tolerance under both field and controlled conditions. Therefore, we conclude that simple measurements of the upper two leaves of the main stem including a straightforward measurement of leaf area, visually estimating the number of sterile spikelets, and a quick, practical determination of Na+ and Ca2+ concentration constitute effective criteria to screen wheat genotypes for salt tolerance under both field and controlled conditions. [ABSTRACT FROM AUTHOR]

Aim: Previous studies have shown that tenuigenin, a crude extract of Polygala tenuifolia Willd. that is commonly used in traditional Chinese herbal medicine for memory loss, can reduce the secretion of Aβ from cultured cells. However, the mechanism underlying this effect and the active compound derived from tenuigenin is unknown. In this study, a purified component of tenuigenin, tenuifolin, was examined and revealed to be an effective compound in vitro. Methods: Aβ secretion from three sets of COS-7 cells, each carrying a plasmid expressing a different form of APP was examined following the treatment with tenuifolin. Initially, tenuifolin was determined to have no inherent toxicity to either the transfected or wild type cells at the effective concentrations. Cells were then treated with 0.5–2.0 μg mL−1 tenuifolin for 12 h and their media were examined via an ELISA for Aβ1-40 and Aβ-42. Results: We found that treatment with 2.0 μg mL−1 tenuifolin significantly decreased Aβ secretion from COS-7 cells without altering the ratio of Aβ1-40 and Aβ-42. This effect is most probably due to inhibition of the β-site APP cleaving enzyme as Aβ secretion was not inhibited from cells expressing the C99 fragment. Conclusion: Tenuifolin is an effective compound from tenuigenin. We believe that this finding should lead the way for future experiments to determine the exact mechanism for tenuifolin’s effect on Aβ secretion. [ABSTRACT FROM AUTHOR]

The article investigates the mechanical and fracture behaviors of thermoplastic polyolefin (TPO)/clay nanocomposites. Results of tensile tests revealed the capacity of organically modified montmorillonite to enhance the stiffness and tensile strength of TPO. Essential work of fracture measurements showed an increase in fracture toughness of the TPO/clay nanocomposites as clay content or elastomer increases.

A new balanced planar ultra-wideband (UWB) antenna is proposed. First, a novel uniplanar broadband balun transition is presented. Then, a balanced UWB planar dipole antenna fed by the proposed balun is studied, and has a measured bandwidth from 2.8 to 11.2 GHz for the return loss better than -10 dB. © 2006 Wiley Periodicals, Inc. Microwave Opt Technol Lett 49: 114–118, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.22040 [ABSTRACT FROM AUTHOR]

St John's wort extract (SJW; Hypericum perforatum L.) is taken extensively as a putative herbal antidepressant. It has been shown to induce the activity of cytochrome P-450 3A4 (CYP3A4) and to increase the clearance of numerous drugs and steroids such as cortisol and ethinyl estradiol. This study was conducted to determine if SJW exposure also alters the concentrations of circulating androgenic steroid hormones. The study was conducted using healthy volunteers (6M, 6F) studied before and after a 14-day treatment period with a SJW preparation previously demonstrated to induce the activity of CYP3A4. Plasma concentrations of testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and the combined concentrations of androsterone sulfate (AoS) and epiandrosterone sulfate (epiAoS) were measured by immunoassay methods. The results of analysis demonstrated that SJW did not significantly alter the majority of the androgens studied (p > 0.05) although the combined concentrations of the 5alpha-reduced steroids, AoS and epiAoS, significantly declined following treatment in all subjects (p = 0.02), and in males (p = 0.04). Furthermore, the testosterone to DHT ratio was increased in both men and women. Although the latter increase did not reach statistical significance, it is also consistent with the possible inhibition of 5alpha-reductase by SJW. It is concluded that despite significant induction of CYP3A4, short term administration of SJW does not significantly alter the concentrations of most circulating androgens in men and women but may produce a dimunition in some of the circulating 5alpha-reduced androgens. [ABSTRACT FROM AUTHOR]

Post-phloem sugar transport in developing tomato (Lycopersicon esculentum Mill. cv. Flora-Dade) fruit follows an apoplastic route during the rapid phase of sugar accumulation. The pathway is characterized by sugar retrieval by the storage parenchyma cells from the fruit apoplast. Two tomato genotypes differing in fruit hexose content were compared in terms of the transport and transfer processes controlling fruit sugar levels. The genotypic difference in fruit sugar content was independent of photoassimilate export from source leaves. Discs of pericarp tissue were cultured in a medium based on analyses of the fruit apoplastic sap. The cultured discs maintained a composition, a relative growth rate and a respiration rate similar to those of the pericarp tissue of intact fruit. Estimates of hexose fluxes into metabolic and storage pools suggested that membrane transport regulated the genotypic difference in hexose accumulation. Short-term [14C]hexose uptake experiments demonstrated a genotypic difference in Vmax for glucose, fructose and 3-O-methylglucose, and this difference was abolished in the presence of the inhibitor p-chloromercuribenzenesulphonic acid (PCMBS). The results support the hypothesis that the activity of energized hexose carriers on the plasma membranes of storage parenchyma cells is a significant determinate of the genotypic difference in hexose accumulation. [ABSTRACT FROM AUTHOR]

To detect the associated factors of FHD based on a big data using Bayesian network, and quantitatively analyse the risk ratio of combined multiple factors. Learning process of Bayesian network was composed of two parts: structure learning and parameter estimation. When the number of births was combined with abortion or with a spouse who smoked, we found the RR for FHD was greater (RR = 1.96 or 1.63). [Extracted from the article]

Aim: To investigate whether oral microbiome diversity is associated with all-cause mortality in the general US population and in individuals with chronic diseases., Materials and Methods: We included 8224 individuals with oral microbiome diversity data from the National Health and Nutrition Examination Survey (2009-2012), representing 164,000,205 US adults, using a survey-weighted analysis method. Cox regression analyses were performed to identify the association between oral microbiome diversity and all-cause mortality., Results: During a survey-weighted mean follow-up period of 8.86 years, 429 all-cause deaths (survey-weighted number: 7,124,920) occurred in 8224 participants. Cox regression analysis revealed that higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk. Significant differences in all-cause mortality risk were observed among the different clusters based on oral microbiome β-diversity (log-rank p < 0.001). Subgroup analyses revealed that the oral microbiome diversity was independently associated with all-cause mortality in individuals with diabetes mellitus and hypertension. A multivariate logistic regression model showed that current smoking and antibiotic use were significantly associated with lower oral microbiome α diversity., Conclusions: Higher oral microbiome diversity was significantly associated with a lower all-cause mortality risk in the general US population and in individuals with diabetes mellitus and hypertension., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We aimed to investigate the associations of long-term exposure to ambient formaldehyde with hypertension and angina pectoris symptoms in Chinese adults., Methods and Results: Participants' information was obtained from the WHO SAGE (World Health Organization Study on Global Aging and Adult Health) study. The Cox proportional hazards regression model was applied to estimate the associations of formaldehyde with hypertension and angina pectoris symptoms. Mediating effect analysis was used to investigate the mediating effect of hypertension between formaldehyde exposure and angina pectoris symptoms. Long-term exposure to formaldehyde was positively associated with the risk of angina pectoris symptoms (hazard ratio [HR], 1.66 [95% CI, 1.29-2.13], per interquartile range [IQR], 3.33, 10 15 molecules/cm 2 ) and hypertension (HR, 1.17 [95% CI, 1.02-1.34], per IQR, 3.34, 10 15 molecules/cm 2 ). The associations between formaldehyde and angina pectoris symptoms were greater in participants aged ≥65 years (HR, 1.90 [95% CI, 1.29-2.80]) and in rural areas (HR, 2.71 [95% CI, 1.54-4.77]), whereas the associations of formaldehyde with hypertension were stronger in men (HR, 1.27 [95% CI, 1.02-1.58]), rural areas (HR, 1.22 [95% CI, 0.94-1.59]), and in ever smokers (HR, 1.33 [95% CI, 1.02-1.72]). The mediation effect analysis indicated that 18.44% (95% CI, 2.17-37.65) of the association between formaldehyde exposure and angina pectoris symptoms was mediated by hypertension., Conclusions: Long-term exposure to ambient formaldehyde was positively associated with hypertension and angina pectoris symptoms. The effects of formaldehyde may be modified by age, sex, urbanicity, and smoking status. Hypertension might play a mediating effect in formaldehyde-induced angina pectoris symptoms.

Background: Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non-HIV populations generalize to people with HIV is not well understood., Methods and Results: PRSs for CAD (GPS Mult ) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low-to-moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPS Mult was associated with plaque presence with odds ratio (OR) per SD in GPS Mult of 1.42 (95% CI, 1.20-1.68; P =3.8×10 -5 ), stenosis >50% (OR, 2.39 [95% CI, 1.48-3.85]; P =3.4×10 -4 ), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23-1.72]; P =9.6×10 -6 ). Effects were consistent in subgroups of age, sex, 10-year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPS Mult to established risk factors increased the C-statistic for predicting plaque presence from 0.718 to 0.734 ( P =0.02). Furthermore, a PRS for low-density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01-1.44; P =0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01-1.45; P =0.04) per SD., Conclusions: Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low-to-moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low-density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low-density lipoprotein cholesterol in HIV-associated CAD., Registration: URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Background: Medial temporal lobe atrophy (MTA) is a diagnostic marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the accuracy of quantitative MTA (QMTA) in diagnosing early AD is unclear. This study aimed to investigate the accuracy of QMTA and its related components (inferior lateral ventricle [ILV] and hippocampus) with MTA in the early diagnosis of MCI and AD., Methods: This study included four groups: normal (NC), MCI stable (MCIs), MCI converted to AD (MCIs), and mild AD (M-AD) groups. Magnetic resonance image analysis software was used to quantify the hippocampus, ILV, and QMTA. MTA was rated by two experienced neurologists. Receiver operating characteristic area under the curve (AUC) analysis was performed to compare their capability in differentiating AD from NC and MCI, and optimal thresholds were determined using the Youden index., Results: QMTA distinguished M-AD from NC and MCI with higher diagnostic accuracy than MTA, hippocampus, and ILV (AUC NC  = 0.976, AUC MCI  = 0.836, AUC MCIs  = 0.894, AUC MCIc  = 0.730). The diagnostic accuracy of QMTA was superior to that of MTA, the hippocampus, and ILV in differentiating MCI from AD. The diagnostic accuracy of QMTA was found to remain the best across age, sex, and pathological subgroups analyzed. The sensitivity (92.45%) and specificity (90.64%) were higher in this study when a cutoff value of 0.635 was chosen for QMTA., Conclusions: QMTA may be a better choice than the MTA scale or the associated quantitative components alone in identifying AD patients and MCI individuals with higher progression risk., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Bladder cancer is a common tumour worldwide and exhibits a poor prognosis. Fibronectin leucine rich transmembrane protein 2 (FLRT2) is associated with the regulation of multiple tumours; however, its function in human bladder cancer remain unclear. Herein, we found that FLRT2 level was reduced in human bladder cancer and that higher FLRT2 level predicted lower survival rate. FLRT2 overexpression inhibited, while FLRT2 silence facilitated tumour cell growth, migration and invasion. Mechanistic studies revealed that FLRT2 elevated acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, increased lipid peroxidation and subsequently facilitated ferroptosis of human bladder cancer cells. In summary, we demonstrate that FLRT2 elevates ACSL4 expression to facilitate lipid peroxidation and subsequently triggers ferroptosis, thereby inhibiting the malignant phenotype of human bladder cancer cells. Overall, we identify FLRT2 as a tumour suppressor gene., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose: The aim of this study was to investigate the effects of maternal pulmonary arterial hypertension (PAH) on fetal hemodynamics in the third trimester and to identify hemodynamic indicators associated with adverse maternal and fetal outcomes., Methods: We recruited 48 pregnant women with PAH in the third trimester and 32 women with normal pregnancies as controls matched for age and gestational week. Fetal growth and hemodynamic parameters were assessed by two-dimensional and color Doppler. All cases were followed up until delivery and maternal and fetal outcomes were collected. High throughput sequencing method was used to determine differential miRNA patterns in plasma exposed to pulmonary arterial hypertension (PAH) in pregnant women. We then performed the validated of key differentially expressed miRNAs by real-time PCR., Results: Compared with the normal and mild PAH groups, resistance index (RI), pulsatility index (PI) of the fetal umbilical artery (UA) and quantitative ductus venosus (QDV) blood flow were increased in subjects with moderate to severe PAH, while PI and the ratio of peak systolic velocity (PSV) to end-diastolic velocity (EDV) (S/D) of the middle cerebral artery (MCA) were decreased. Compared with the normal group, subjects in the mild and moderate PAH groups had lower neonatal weight, shorter neonatal height, and higher preterm birth rates. In addition, miRNA sequencing data showed that PAH affected the levels of 23 miRNAs in plasma. At the same time, we showed that PAH significantly decreased the level of miR-1255a and increased the level of miR-548ar-3p by real-time PCR., Conclusion: In the group of pregnant women with moderate to severe pulmonary hypertension, there was a higher proportion of preterm births and low birth weight babies. Hemodynamic changes in the fetal UA, MCA, and ductus venosus (DV) during late pregnancy were associated with adverse fetal outcomes. At the same time, miRNA sequencing results showed that miR-1255a and miR-548ar-3p may play an important role in the development of PAH., (© 2023 Wiley Periodicals LLC.)

Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Methamphetamine (METH) use disorder is a chronic, relapsing disorder and involves frequent failures of self-control of drug seeking and taking. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compounds of green tea, which has shown great therapeutic effectiveness in neurological disorders. However, it is still unknown whether and how EGCG affects METH seeking behaviour. Here, we show nanostructured EGCG/ascorbic acid nanoparticles (EGCG/AA NPs) dose-dependently reduced METH self-administration (SA) under fixed-ratio 1 (FR1) and progressive ratio (PR) reinforcement schedules in mice and shifted METH dose-response curves downward. Furthermore, EGCG/AA NPs decreased drug- and cue-induced METH seeking. In addition, we found that METH SA led to a decrease in inhibitory postsynaptic currents (IPSCs) and increase in the AMPAR/NMDAR ratio and excitation/inhibition (E/I) ratio in ex vivo midbrain slices from ventral tegmental area (VTA) dopamine neurons. EGCG/AA NPs enhanced Gamma-aminobutyric acid (GABA)ergic inhibition and normalized the E/I ratio. EGCG restored the balance between excitation and inhibition in VTA dopamine neurons, which may contribute to the attenuation of METH SA. These findings indicate that EGCG is a promising pharmacotherapy for METH use disorder., (© 2023 Society for the Study of Addiction.)

Background High and low birth weight are independently associated with increased cardiovascular disease risk in adulthood. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with preleukemic somatic mutations, predicts incident cardiovascular disease independent of traditional cardiovascular risk factors. Whether birth weight predicts development of CHIP later in life is unknown. Methods and Results A total of 221 047 adults enrolled in the UK Biobank with whole exome sequences and self-reported birth weight were analyzed. Of those, 22 030 (11.5%) had low (<2.5 kg) and 29 292 (14.7%) high birth weight (>4.0 kg). CHIP prevalence was higher among participants with low (6.0%, P =0.049) and high (6.3%, P <0.001) versus normal birth weight (5.7%, ref.). Multivariable-adjusted logistic regression analyses demonstrated that each 1-kg increase in birth weight was associated with a 3% increased risk of CHIP (odds ratio, 1.03 [95% CI, 1.00-1.06]; P =0.04), driven by a stronger association observed between birth weight and DNMT3A CHIP (odds ratio, 1.04 per 1-kg increase [95% CI, 1.01-1.08]; P =0.02). Mendelian randomization analyses supported a causal relationship of longer gestational age at delivery with DNMT3A CHIP. Multivariable Cox regression demonstrated that CHIP was independently and additively associated with incident cardiovascular disease or death across birth weight groups, with highest absolute risks in those with CHIP plus high or low birth weight. Conclusions Higher birth weight is associated with increased risk of developing CHIP in midlife, especially DNMT3A CHIP. These findings identify a novel risk factor for CHIP and provide insights into the relationships among early-life environment, CHIP, cancer, and cardiovascular disease.

Aims: To investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission., Materials and Methods: Retrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression., Results: In total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment., Conclusions: Hospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Microglial hyperactivation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild-type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48-linked polyubiquitination in microglia. The loss of Parkin activity in LPS-induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin-induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin-mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Aim: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD-19., Materials and Methods: We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID-19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all-cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID-19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer., Results: Among 2951 CORONADO, 3387 ABCD COVID-19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all-cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66-3.83), OR 1.24 (95% CI 1.00-1.56) and OR 1.66 (95% CI 1.40-1.95) in the CORONADO, the ABCD COVID-19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all-cause death during hospital stay in the CORONADO, the ABCD COVID-19 diabetes national audit and the AMERICADO studies: adjusted OR ( adj OR) 2.57 (95% CI 1.69-3.92), adj OR 1.22 (95% CI 1.00-1.52) and adj OR 1.33 (95% CI 1.15-1.53), respectively. In meta-analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all-cause death during hospital stay of 2.05 (95% CI 1.42-2.97), which decreased to 1.62 (95% CI 1.19-2.119) after adjustment for age and sex, and to 1.50 (1.12-2.02) after hypertension and CVD were further added to the model., Conclusion: Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID-19., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair., Objectives: To investigate the effect and potential mechanism of ALCAR in the treatment of NED., Materials and Methods: Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro., Results: We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site., Discussion and Conclusion: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED., (© 2022 American Society of Andrology and European Academy of Andrology.)

Prostate adenocarcinoma (PRAD) occurs only in males and has a higher incidence rate than other cancers. NPM1 is a nucleocytoplasmic shuttling protein that participates in the development of multiple tumours. The aim of this research was to explore the effect of the upregulation or downregulation of the NPM1 protein on the malignancy of prostate cancer and its possible signalling pathway. Prostate adenocarcinoma cell lines were used in this study, including RWPE-1, PC3, LNCap, and 22RV1 cells. Our research revealed that NPM1 was widely expressed in the PRAD cell lines, as determined by western blotting, and that the levels of NPM1 protein were positively correlated with the degree of malignancy of the PRAD cell lines. Through interference and overexpression experiments, we found that PC3 cell growth was inhibited after NPM1 knockdown and that this inhibition was partly reversed by CTNNB1 overexpression; in contrast, PC3 cells growth was promoted after NPM1 overexpression, and this promotion was partly reversed by CTNNB1 knockdown, suggesting that NPM1 and CTNNB1 play important roles in the progression of prostate cancer cells via the Wnt/β-catenin signalling pathway. NPM1 may serve as an important biomarker and candidate therapeutic for patients with prostate cancer., (© 2022 John Wiley & Sons Australia, Ltd.)

The regulation of renal function by circadian gene BMAL1 has been recently recognized; however, the role and mechanism of BMAL1 in renal ischaemia-reperfusion injury (IRI) are still unknown. The purpose of this study was to clarify the pathophysiological role of BMAL1 in renal IRI. We measured the levels of BMAL1 and mitochondrial biogenesis-related proteins, including SIRT1, PGC-1α, NRF1 and TFAM, in rats with renal IRI. In rats, the level of BMAL1 decreased significantly, resulting in inhibition of SIRT1 expression and mitochondrial biogenesis. In addition, under hypoxia and reoxygenation (H/R) stimulation, BMAL1 knockdown decreased the level of SIRT1 and exacerbated the degree of mitochondrial damage and apoptosis. Overexpression of BMAL1 alleviated H/R-induced injury. Furthermore, application of the SIRT1 inhibitor EX527 not only reduced the activities of SIRT1 and PGC-1α but also further aggravated mitochondrial dysfunction and partially reversed the protective effect of BMAL1 overexpression. Moreover, whether in vivo or in vitro, the application of SIRT1 agonist resveratrol rescued the mitochondrial dysfunction caused by H/R or IRI by activating mitochondrial biogenesis. These results indicate that BMAL1 is a key circadian gene that mediates mitochondrial homeostasis in renal IRI through the SIRT1/PGC-1α axis, which provides a new direction for targeted therapy for renal IRI., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Renal cell carcinoma (RCC) is the most common form of kidney cancer, with a high recurrence rate and metastasis capacity. Circular RNAs (circRNAs) have been suggested to act as the critical regulator in several diseases. This study is designed to investigate the role of circCSNK1G3 on RCC progression. We observed a highly expression of circCSNK1G3 in RCC tissues compared with normal tissues. The aberrantly circCSNK1G3 promoted the tumour growth and metastasis in RCC. In the subsequent mechanism investigation, we discovered that the tumour-promoting effects of circCSNK1G3 were, at least partly, achieved by up-regulating miR-181b. Increased miR-181b inhibits several tumour suppressor gene, including CYLD, LATS2, NDRG2 and TIMP3. Furthermore, the decreased TIMP3 leads to the enhanced epithelial to mesenchymal transition (EMT) process, thus promoting the cancer metastasis. In conclusion, we identified the oncogenic role of circCSNK1G3 in RCC progression and demonstrated the regulatory role of circCSNK1G3 induced miR-181b expression, which leads to TIMP3-mediated EMT process, thus resulting in tumour growth and metastasis in RCC. This study reveals the promise of circCSNK1G3 to be developed as a potential diagnostic and prognostic biomarker in the clinic. And the roles of circCSNK1G3 in cancer research deserve further investigation., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: The population with diabetes mellitus-induced erectile dysfunction is increasing rapidly, but current drugs are not effective in treating erectile dysfunction. Studies of the traditional Chinese medicine extract berberine on diabetes and its complications provide us with new ideas., Objectives: To evaluate the therapeutic effect and potential mechanism of berberine on the erectile function of diabetic rats., Materials and Methods: Fifty male Sprague-Dawley rats were randomly grouped, and 42 rats were injected intraperitoneally with streptozotocin to establish a diabetes model. Erectile dysfunction rats were screened out through the apomorphine test and randomly divided into the diabetes mellitus and berberine groups, and these animals were administered berberine (200 mg/kg/day) and normal saline by gavage for 4 weeks. Primary corpus cavernous smooth muscle cells from healthy rats were cultured and treated with berberine., Results: Fasting blood glucose in the diabetes mellitus group was significantly increased, while berberine showed no significant effect on glucose. Erectile function was obviously impaired in the diabetes mellitus group, and berberine administration partially rescued this impairment. The expression of sphingosine kinase 1, S1PR2, and sphingosine-1-phosphate in the diabetes mellitus group was increased. Berberine partially inhibited the expression of sphingosine kinase 1 and S1PR2, but the decrease in sphingosine-1-phosphate was not significant. Moreover, mitogen-activated protein kinase pathway factor expression was upregulated and eNOS activity was decreased in the diabetes mellitus group. Berberine treatment could partially reverse these alterations. Severe fibrosis and apoptosis were detected in diabetic rats, accompanied by higher expression of TGFβ1, collagen I/IV, Bax/Bcl-2, and caspase 3 than in the other groups. However, supplementation with berberine inhibited the expression of these proteins and attenuated fibrosis and apoptosis., Conclusions: Berberine ameliorated erectile dysfunction in rats with diabetes mellitus, possibly by improving endothelial function and inhibiting apoptosis and fibrosis by suppressing the sphingosine kinase 1/sphingosine-1-phosphate/S1PR2 and mitogen-activated protein kinase pathways., (© 2021 American Society of Andrology and European Academy of Andrology.)

N 6 -methyladenosine (m 6 A) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that m 6 A methyltransferase METTL3 ('writer') and demethylase FTO ('eraser') play critical roles in heart-related disease. However, in the heart, the function of m 6 A 'reader', such as YTH (YT521-B homology) domain-containing proteins remains unclear. Here, we report that the defect in YTHDC1 but not other YTH family members contributes to dilated cardiomyopathy (DCM) in mice. Cardiac-specific conditional Ythdc1 knockout led to obvious left ventricular chamber enlargement and severe systolic dysfunction. YTHDC1 deficiency also resulted in the decrease of cardiomyocyte contractility and disordered sarcomere arrangement. By means of integrating multiple high-throughput sequence technologies, including m 6 A-MeRIP, RIP-seq and mRNA-seq, we identified 42 transcripts as potential downstream targets of YTHDC1. Amongst them, we found that Titin mRNA was decorated with m 6 A modification and depletion of YTHDC1 resulted in aberrant splicing of Titin. Our study suggests that Ythdc1 plays crucial role in regulating the normal contractile function and the development of DCM. These findings clarify the essential role of m 6 A reader in cardiac biofunction and provide a novel potential target for the treatment of DCM., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Bladder cancer (BC) is a major disease of the genitourinary tract, and chemotherapy is one of the main treatments commonly used at present. SC66 is a new type of allosteric AKT inhibitor that is reported to play an effective inhibitory role in the progression of many other types of tumours, but there is no reported research on its role in BC. In this study, we found that SC66 significantly inhibited the proliferation and EMT-mediated migration and invasion of T24 and 5637 cells. In addition, experiments confirmed that SC66 achieved its antitumour effect by inducing cell apoptosis and affecting the cell cycle. Luciferase assays confirmed that SC66 exerted an antitumour effect through the AKT/β-catenin signalling pathway, and this inhibitory effect was reversed after the addition of the β-catenin signalling pathway activator, CHIR-99021. In addition, animal studies have shown that, compared with the control group, the experimental group with SC66 intraperitoneal injection showed significantly reduced the tumour weight and volume in nude mice with T24 tumours and that SC66 combined with cisplatin achieved better inhibition on tumours. Western blot analysis and immunohistochemistry staining confirmed that SC66 inhibited the EMT process in vivo and induced apoptosis through the AKT/β-catenin signalling pathway. In conclusion, our study demonstrated that SC66 exerts a significant antitumour effect through the AKT/β-catenin signalling pathway, thereby providing a new potential treatment for BC., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Renal ischaemia/reperfusion (I/R) injury may induce kidney damage and dysfunction, in which oxidative stress and apoptosis play important roles. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are reported to be closely related to renal I/R, but the specific molecular mechanism is still unclear. The purpose of this research was to explore the regulatory effect of lncRNA TUG1 on oxidative stress and apoptosis in renal I/R injury. This research revealed that in renal I/R injury and hypoxia/reperfusion (H/R) injury in vitro, the expression level of lncRNA TUG1 was upregulated, and oxidative stress levels and apoptosis levels were negatively correlated with the expression level of lncRNA TUG1. Using bioinformatics databases such as TargetScan and microRNA.org, microRNA-144-3p (miR-144-3p) was predicted to be involved in the association between lncRNA TUG1 and Nrf2. This study confirmed that the level of miR-144-3p was significantly reduced following renal I/R injury and H/R injury in vitro, and miR-144-3p was determined to target Nrf2 and inhibit its expression. In addition, lncRNA TUG1 can reduce the inhibitory effect of miR-144-3p on Nrf2 by sponging miR-144-3p. In summary, our research shows that lncRNA TUG1 regulates oxidative stress and apoptosis during renal I/R injury through the miR-144-3p/Nrf2 axis, which may be a new treatment target for renal I/R injury., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The aim of this study was to characterize the variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalized patients with type 2 diabetes or new-onset hyperglycaemia, and to determine patient-related characteristics associated with higher variability of insulin requirements. We retrospectively analysed data from two fully closed-loop inpatient studies involving adults with type 2 diabetes or new-onset hyperglycaemia requiring insulin therapy. The coefficient of variation quantified day-to-day variability of exogenous insulin requirements during up to 15 days using fully automated closed-loop insulin delivery. Data from 535 days in 67 participants were analysed. The coefficient of variation of day-to-day exogenous insulin requirements was 30% ± 16%, and was higher between nights than between any daytime period (56% ± 29% overnight [11:00 pm to 4:59 am] compared with 41% ± 21% in the morning [5:00 am to 10:59 am], 39% ± 15% in the afternoon [11:00 am to 4:59 pm] and 45% ± 19% during the evening [5:00 pm to 10:59 pm]; all P < 0.01). There is high day-to-day variability of exogenous insulin requirements in inpatients, particularly overnight, and diabetes management approaches should account for this variability., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background Several randomized trials have compared the patency of coronary artery bypass conduits. All of the published studies, however, have performed pairwise comparisons and a comprehensive evaluation of the patency rates of all conduits has yet to be published. We set out to investigate the angiographic patency rates of all conduits used in coronary bypass surgery by performing a network meta-analysis of the current available randomized evidence. Methods and Results A systematic literature search was conducted for randomized controlled trials comparing the angiographic patency rate of the conventionally harvested saphenous vein, the no-touch saphenous vein, the radial artery (RA), the right internal thoracic artery, or the gastroepiploic artery. The primary outcome was graft occlusion. A total of 4160 studies were retrieved of which 14 were included with 3651 grafts analyzed. The weighted mean angiographic follow-up was 5.1 years. Compared with the conventionally harvested saphenous vein, both the RA (incidence rate ratio [IRR] 0.54; 95% CI, 0.35-0.82) and the no-touch saphenous vein (IRR 0.55; 95% CI, 0.39-0.78) were associated with lower graft occlusion. The RA ranked as the best conduit (rank score for RA 0.87 versus 0.85 for no-touch saphenous vein, 0.23 for right internal thoracic artery, 0.29 for gastroepiploic artery, and 0.25 for the conventionally harvested saphenous vein). Conclusions Compared with the conventionally harvested saphenous vein, only the RA and no-touch saphenous vein grafts are associated with significantly lower graft occlusion rates. The RA ranks as the best conduit. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42020164492.