Human alveolar echinococcosis is a hard-to-treat and largely untreated parasitic disease with high associated health care costs. The current antiparasitic treatment for alveolar echinococcosis relies exclusively on albendazole, which does not act parasiticidally and can induce severe adverse effects. Alternative, and most importantly, improved treatment options are urgently required. A drug repurposing strategy identified the approved antimalarial pyronaridine as a promising candidate against Echinococcus multilocularis infections. Following a 30-day oral regimen (80 mg kg−1 day−1), pyronaridine achieved an excellent therapeutic outcome in a clinically relevant hepatic alveolar echinococcosis murine model, showing a significant reduction in both metacestode size (72.0%) and counts (85.2%) compared to unmedicated infected mice, which revealed significantly more potent anti-echinococcal potency than albendazole treatment at an equal dose (metacestode size: 42.3%; counts: 4.1%). The strong parasiticidal activity of pyronaridine was further confirmed by the destructive damage to metacestode tissues observed morphologically. In addition, a screening campaign combined with computational similarity searching against an approved drug library led to the identification of pirenzepine, a gastric acid-inhibiting drug, exhibiting potent parasiticidal activity against protoscoleces and in vitro cultured small cysts, which warranted further in vivo investigation as a promising anti-echinococcal lead compound. Pyronaridine has a known drug profile and a long track record of safety, and its repurposing could translate rapidly to clinical use for human patients with alveolar echinococcosis as an alternative or salvage treatment.

A new resolvent-based method is developed to predict the space–time properties of the flow field. To overcome the deterioration of the prediction accuracy with increasing distance between the measurements and predictions in the resolvent-based estimation (RBE), the newly proposed method utilizes the RBE to estimate the relative energy distribution near the wall rather than the absolute energy directly estimated from the measurements. Using this extra information from RBE, the new method modifies the energy distribution of the spatially uniform and uncorrelated forcing that drives the flow system by minimizing the norm of the cross-spectral density tensor of the error matrix in the near-wall region in comparison with the RBE-estimated one, and therefore it is named as the resolvent-informed white-noise-based estimation (RWE) method. For validation, three time-resolved direct numerical simulation (DNS) datasets with the friction Reynolds numbers $Re_\tau = 180$, 550 and 950 are generated, with various locations of measurements ranging from the near-wall region ($y^+ = 40$) to the upper bound of the logarithmic region ($y/h \approx 0.2$, where h is the half-channel height) for the predictions. Besides the RWE, three existing methods, i.e. the RBE, the $\lambda$-model and the white-noise-based estimation (WBE), are also included for the validation. The performance of the RBE and scale-dependent model ($\lambda$-model) in predicting the energy spectra shows a strong dependence on the measurement locations. The newly proposed RWE shows a low sensitivity on $Re_{\tau }$ and the measurement locations, which may range from the near-wall region to the upper bound of the logarithmic region, and has a high accuracy in predicting the energy spectra. The RWE also performs well in predicting the space–time properties in terms of the correlation magnitude and the convection velocity. We further utilize the new method to reconstruct the instantaneous large-scale structures with measurements from the logarithmic region. Both the RWE and RBE perform well in estimating the instantaneous large-scale structure, and the RWE has smaller errors in the estimations near the wall. The structural inclination angles around $15^\circ$ are predicted by the RWE and WBE, which generally recover the DNS results.

In the United States, cardiovascular disease is the leading cause of death and the rate of maternal mortality remains among the highest of any industrialized nation. Maternal cardiometabolic health throughout gestation and postpartum is representative of placental health and physiology. Both proper placental functionality and placental microRNA expression are essential to successful pregnancy outcomes, and both are highly sensitive to genetic and environmental sources of variation. Placental pathologies, such as preeclampsia, are associated with maternal cardiovascular health but may also contribute to the developmental programming of chronic disease in offspring. However, the role of more subtle alterations to placental function and microRNA expression in this developmental programming remains poorly understood. We performed small RNA sequencing to investigate microRNA in placentae from the Rhode Island Child Health Study (n = 230). MicroRNA counts were modeled on maternal family history of cardiovascular disease using negative binomial generalized linear models. MicroRNAs were considered to be differentially expressed at a false discovery rate (FDR) less than 0.10. Parallel mRNA sequencing data and bioinformatic target prediction software were then used to identify potential mRNA targets of differentially expressed microRNAs. Nine differentially expressed microRNAs were identified (FDR < 0.1). Bioinformatic target prediction revealed 66 potential mRNA targets of these microRNAs, many of which are implicated in TGFβ signaling pathway but also in pathways involving cellular metabolism and immunomodulation. A robust association exists between familial cardiovascular disease and placental microRNA expression which may be implicated in both placental insufficiencies and the developmental programming of chronic disease.

Long non-coding RNAs (lncRNAs) exert vital functions in the occurrence and development of various tumours. The aim of this study was to examine the regulatory effect and underlying molecular mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) on the proliferation, invasion and migration of thyroid tumour cells. The expression of SNHG14 in thyroid tumour cell lines was determined using qRT-PCR. CCK-8 and western blot were used to detect the effects of SNHG14 on proliferation and apoptosis of thyroid tumour cells. The effect of SNHG14 on the migration and invasion of thyroid tumour cells was analyzed using immunofluorescence, wound-healing and transwell assays. A targeting relationship between SNHG14 and miR-93-5p was determined using bioinformatics software and luciferase reporter assays. In addition, CCK-8, immunofluorescence, wound-healing and transwell assays were applied to demonstrate that SNHG14 promoted the proliferation, migration and invasion of thyroid tumour cells by targeting miR-93-5p. The biological function of SNHG14 in vivo was explored through a xenograft model and immunohistochemistry. SNHG14 was upregulated in thyroid tumour cells compared with normal cells. Downregulation of SNHG14 effectively reduced the proliferation, migration and invasion of TPC-1 cells, and induced cell apoptosis. Moreover, SNHG14 directly targeted miR-93-5p and there was a negative correlation between them. Further functional experiments illustrated that miR-93-5p overexpression dramatically reversed the promoting role of SNHG14 in proliferation, migration and invasion of TPC-1 cells. Our results demonstrated that SNHG14 promotes the proliferation, invasion and migration of thyroid tumour cells by downregulating miR-93-5p.

Folate status for women during early pregnancy has been investigated, but data for women during mid-pregnancy, late pregnancy or lactation are sparse or lacking. Between May and July 2014, we conducted a cross-sectional study in 1211 pregnant and lactating women from three representative regions in China. Approximately 135 women were enrolled in each stratum by physiological periods (mid-pregnancy, late pregnancy or lactation) and regions (south, central or north). Plasma folate concentrations were measured by microbiological assay. The adjusted medians of folate concentration decreased from 28·8 (interquartile range (IQR) 19·9, 38·2) nmol/l in mid-pregnancy to 18·6 (IQR 13·2, 26·4) nmol/l in late pregnancy, and to 17·0 (IQR 12·3, 22·5) nmol/l in lactation (Pfor trend < 0·001). Overall, lower folate concentrations were more likely to be observed in women residing in the northern region, with younger age, higher pre-pregnancy BMI, lower education or multiparity, and in lactating women who had undergone a Caesarean delivery or who were breastfeeding exclusively. In total, 380 (31·4 %) women had a suboptimal folate status (folate concentration <13·5 nmol/l). Women in late pregnancy and lactating, residing in the northern region, having multiparity and low education level had a higher risk of suboptimal folate status, while those with older age had a lower risk. In conclusion, maternal plasma folate concentrations decreased as pregnancy progressed, and were influenced by geographic region and maternal socio-demographic characteristics. Future studies are warranted to assess the necessity of folic acid supplementation during later pregnancy and lactation especially for women at a higher risk of folate depletion.

The effects of macronutrient intake on obesity are controversial. This research aims to investigate the associations between macronutrient intake and new-onset overweight/obesity. The relationship between the consumption of carbohydrate and total fat and obesity was assessed by the multivariable Cox model in this 11-year cohort, which included 6612 adults (3291 men and 3321 women) who were free of overweight and obesity at baseline. The dietary intake was recorded using a 24-h recall method for three consecutive days. Moreover, substitution models were developed to distinguish the effects of macronutrient composition alteration from energy intake modification. During 7·5 person years (interquartile range 4·3, 10·8) of follow-up, 1807 participants became overweight or obese. After adjusting for risk factors, the hazard ratio (HR) of overweight/obesity in extreme quintiles of fat was 1·48 (quintile 5 v. quintile 1, 95 % CI 1·16, 1·89; Ptrend = 0·02) in women. Additionally, replacing 5 % of energy from carbohydrate with equivalent energy from fat was associated with an estimated 4·3 % (HR 1·043, 95 % CI 1·007, 1·081) increase in overweight/obesity in women. Moreover, dietary carbohydrate was inversely associated with overweight/obesity (quintile 5 v. quintile 1, HR 0·70, 95 % CI 0·55, 0·89; Ptrend = 0·02) in women. Total fat was related to a higher risk of overweight/obesity, whereas high carbohydrate intake was related to a lower risk of overweight/obesity in women, which was not observed in men.

The aim of this network meta-analysis is to compare bone mineral density (BMD) changes among different osteoporosis prevention interventions in postmenopausal women. We searched MEDLINE, Embase and Cochrane Library from inception to 24 February 2019. Included studies were randomised controlled trials (RCT) comparing the effects of different treatments on BMD in postmenopausal women. Studies were independently screened by six authors in three pairs. Data were extracted independently by two authors and synthesised using Bayesian random-effects network meta-analysis. The results were summarised as mean difference in BMD and surface under the cumulative ranking (SUCRA) of different interventions. A total of ninety RCT (10 777 participants) were included. Ca, vitamin D, vitamin K, oestrogen, exercise, Ca + vitamin D, vitamin D + vitamin K and vitamin D + oestrogen were associated with significantly beneficial effects relative to no treatment or placebo for lumbar spine (LS). For femoral neck (FN), Ca, exercise and vitamin D + oestrogen were associated with significantly beneficial intervention effects relative to no treatment. Ranking probabilities indicated that oestrogen + vitamin D is the best strategy in LS, with a SUCRA of 97·29 % (mean difference: +0·072 g/cm2 compared with no treatment, 95 % credible interval (CrI) 0·045, 0·100 g/cm2), and Ca + exercise is the best strategy in FN, with a SUCRA of 79·71 % (mean difference: +0·029 g/cm2 compared with placebo, 95 % CrI –0·00093, 0·060 g/cm2). In conclusion, in postmenopausal women, many interventions are valuable for improving BMD in LS and FN. Different intervention combinations can affect BMD at different sites diversely.

Conotruncal heart defects are considered to be one of the most common types of birth defect worldwide. Genetic disturbances in folate metabolism such as Thymidylate synthase may increase risk for conotruncal heart defects. We evaluated two common Thymidylate synthase polymorphisms, including the 28 bp tandem repeat in the promoter enhancer region of the 5′-untranslated region and the 6 bp deletion in the 3′-untranslated region, as risk factors of conotruncal heart defects including various subtypes of malformations, in a total of 193 mothers with conotruncal heart defect in offspring and 234 healthy controls in the Chinese population. Logistic regression analyses revealed that mothers who were homozygotes with deletion (−/−) had a 1.8-fold (odds ratio: 1.8; 95% confidence interval: 1.0–3.0, p = 0.040) increased risk for conotruncal heart defect in offspring, respectively, when compared with mothers carrying the wild type (+/+) genotype. Consistently, individuals carrying the genotype −/− of the Thymidylate synthase 6 bp deletion also had higher plasma homocysteine levels compared to the mothers carrying the genotype +/+ in the control and conotruncal heart defect groups (p = 0.006 and p = 0.004, respectively). However, our results showed that Thymidylate synthase 28 bp tandem repeat polymorphism was not associated with risk for conotruncal heart defect and plasma homocysteine level. In conclusion, our data suggest that the maternal Thymidylate synthase 6 bp deletion polymorphism might be associated with plasma homocysteine level and risk for conotruncal heart defect in offspring.

Nanopore tuning via atomic layer deposition (ALD) is promising but its conformality on sub-10nm pores and its homogeneity over the whole porous network is still challenging, primarily due to the slow transport within the porous network. Conventional ALD process oftentimes falls into a dilemma: higher temperature and prolonged exposure/purge time are required to overcome the slow transport issue, but higher temperature will cause the instability of surface –OH groups and prolonged exposure/purge time will result in “over purge” at the surface vicinity, leading to another type of non-homogeneity. To resolve this issue, a new dual-stage exposure/purge ALD process was developed. Each exposure/purge step contains a longer exposure/purge stage and a shorter exposure/purge stage, where the longer stage ensures ideal exposure/purge for inner pores, and the shorter stage makes up the surface depletion for the outer pores. By doing so, we’ve been able to extend the ALD nanopore tuning to sub-10nm pores with excellent coating homogeneity and conformality.

The Myanmar snub-nosed monkey Rhinopithecus strykeri was discovered in 2010 on the western slopes of the Gaoligong Mountains in the Irrawaddy River basin in Myanmar and subsequently in the same river basin in China, in 2011. Based on 2 years of surveying the remote and little disturbed forest of the Gaoligong Mountains National Nature Reserve in China, with outline transect sampling and infrared camera monitoring, a breeding group comprising > 70 individuals was found on the eastern slopes of the Gaoligong Mountains in the Salween River Basin. Given the Critically Endangered status of this primate (a total of < 950 individuals are estimated to remain in the wild), efforts to protect the relatively undisturbed habitat of this newly discovered population and to prevent hunting are essential for the long-term survival of this species.

In this present study, the influence of different casting processes on high cycle fatigue behavior of Mg–10Gd–3Y–0.5Zr magnesium alloy was investigated by using porosity-free low-pressure sand-casting (LPS) bars and gravity permanent mold casting (GPM) ingots. The results show that the fatigue properties of both LPS and GPM Mg–10Gd–3Y–0.5Zr alloy in as-cast condition are determined by Mg matrix and eutectic phase. However, the fatigue property improvement for LPS alloy by T6 heat treatment is significantly superior to that of GPM alloy. The different degree of enhancement of fatigue properties for two conditions of the alloy is related to different crack initiation mechanism. The fatigue crack of the LPS alloy initiates from the free surface of the sample, while the crack of the GPM alloy initiates from porosities or inclusions near the surface of the sample. Meanwhile, the crack of slip band has a crucial effect on the fatigue crack initiation of both as-cast and T6 conditions for LPS alloy.

Our experiments show that external focusing and initial laser energy strongly influences filament generated by the femtosecond Ti–sapphire laser in air. The experimental measurements show the filament length can be extended both by increasing the laser energy and focal length of focusing lens. On the other hand, the plasma fluorescence emission can be enhanced by increasing the laser energy with fixed focal length or decreasing the focal length. In addition, the collapse distance measured experimentally are larger than the calculated ones owing to the group-velocity-dispersion effect. In addition, we find that the line widths of the spectral lines from $\text{N}_{2}$ is independent of filament positions, laser energies and external focusing.

Crack propagation behaviors in a precracked single crystal Ag under mode I loading at different temperatures are studied by molecular dynamics simulation. The simulation results show that the crack propagation behaviors are sensitive to external temperature. At 0 K, the crack propagates in a brittle manner. Crack tip blunting and void generation are first observed followed by void growth and linkage with the main crack, which lead to the propagation of the main crack and brittle failure immediately without any microstructure evolution. As the temperature gets higher, more void nucleations and dislocation emissions occur in the crack propagation process. The deformation of the single crystal Ag can be considered as plastic deformation due to dislocation emissions. The crack propagation dynamics characterizing the microstructure evolution of atoms around the crack tip is also shown. Finally, it is shown that the stress of the single crystal Ag changes with the crack length synchronously.

Nosema bombycis, a pathogen of silkworm pebrine, is an obligate unicellular eukaryotic parasite. It is reported that the spore wall proteins have essential functions in the adherence and infection process of microsporidia. To date, the information related to spore wall proteins from microsporidia is still limited. Here, a 44 kDa spore wall protein NbSWP16 was characterized in N. bombycis. In NbSWP16, a 25 amino acids signal peptide and 3 heparin binding motifs were predicted. Interestingly, a region that contains 3 proline-rich tandem repeats lacking homology to any known protein was also present in this protein. The immunofluorescence analysis (IFA) demonstrated that distinct fluorescent signals were detected both on the surface of mature spores and the germinated spore coats. Immunolocation by electron microscopy revealed that NbSWP16 localized on the exospore regions. Finally, spore adherence analysis indicated that spore adherence to host cell was decreased more than 20% by anti-NbSWP16 blocking compared with the negative control in vitro. In contrast with anti-NbSWP16, no remarkable decrement inhibition was detected when antibodies of NbSWP16 and NbSWP5 were used simultaneously. Collectively, these results suggest that NbSWP16 is a new exospore protein and probably be involved in spore adherence of N. bombycis.