Analyzing genetic diversity in luffa and developing a Fusarium wilt-susceptible linked SNP marker through a single plant genome-wide association (sp-GWAS) study.

BACKGROUND: Luffa (Luffa spp.) is an economically important crop of the Cucurbitaceae family, commonly known as sponge gourd or vegetable gourd. It is an annual cross-pollinated crop primarily found in the subtropical and tropical regions of Asia, Australia, Africa, and the Americas. Luffa serves not only as a vegetable but also exhibits medicinal properties, including anti-inflammatory, antidiabetic, and anticancer effects. Moreover, the fiber derived from luffa finds extensive applications in various fields such as biotechnology and construction. However, luffa Fusarium wilt poses a severe threat to its production, and existing control methods have proven ineffective in terms of cost-effectiveness and environmental considerations. Therefore, there is an urgent need to develop luffa varieties resistant to Fusarium wilt. Single-plant GWAS (sp-GWAS) has been demonstrated as a promising tool for the rapid and efficient identification of quantitative trait loci (QTLs) associated with target traits, as well as closely linked molecular markers. RESULTS: In this study, a collection of 97 individuals from 73 luffa accessions including two major luffa species underwent single-plant GWAS to investigate luffa Fusarium wilt resistance. Utilizing the double digest restriction site associated DNA (ddRAD) method, a total of 8,919 high-quality single nucleotide polymorphisms (SNPs) were identified. The analysis revealed the potential for Fusarium wilt resistance in accessions from both luffa species. There are 6 QTLs identified from 3 traits, including the area under the disease progress curve (AUDPC), a putative disease-resistant QTL, was identified on the second chromosome of luffa. Within the region of linkage disequilibrium, a candidate gene homologous to LOC111009722, which encodes peroxidase 40 and is associated with disease resistance in Cucumis melo, was identified. Furthermore, to validate the applicability of the marker associated with resistance from sp-GWAS, an additional set of 21 individual luffa plants were tested, exhibiting 93.75% accuracy in detecting susceptible of luffa species L. aegyptiaca Mill. CONCLUSION: In summary, these findings give a hint of genome position that may contribute to luffa wild resistance to Fusarium and can be utilized in the future luffa wilt resistant breeding programs aimed at developing wilt-resistant varieties by using the susceptible-linked SNP marker.

The prognostic value of the NPT test combined with amplitude integrated electroencephalogram in children with VE and its bioreliability analysis.

Background: Viral encephalitis (VE) is one of the common diseases of children with intracranial infection, it has come on urgent, progress is fast, and the clinical features of severe cases may even lead to disability, death, and other serious adverse prognostic outcomes, so seek in early diagnosis and prognosis of efficiency of the relevant indicators to stop in time and take effective means to prevent the further development is of great significance. Neopterin (NPT), as a factor that plays an important role in the process of validation development, has been relatively rarely studied in children with VE. Methods: In this study, 127 cases of children with VE were retrieved from the TCGA database by bioinformatics, and their amplitude integrated electroencephalogram (AEEG) related information was collected at the same time. The neurodevelopmental status of VE children was evaluated according to the Gesell scale and divided into the good group (n=88) and the poor group (n=39). The differences in NPT expression and AEEG score between them were observed. In addition, the clinical data of 100 children without VE were screened from the database, and the differences in NPT expression and AEEG score between VE children and non-VE children were compared. The ROC curve was used to evaluate the clinical efficacy of NPT combined with AEEG in diagnosis and prognosis prediction. Kaplan-Meier was used to observe the effect of NPT high expression and low expression on poor prognosis of VE children.

Histopathology and quantification of green fluorescent protein-tagged Fusarium oxysporum f. sp. luffae isolate in resistant and susceptible Luffa germplasm.

Fusarium oxysporum f. sp. luffae (Folu) is a severe plant pathogen that causes vascular wilt and root rot in Luffa plants worldwide. A green fluorescent protein (GFP)-tagged isolate of Folu (Fomh16-GFP) was utilized to investigate the infection progress and colonization of Fomh16-GFP in resistant (LA140) and susceptible (LA100) Luffa genotypes. Seven days post-inoculation (dpi), it was observed that Fomh16-GFP had successfully invaded and colonized the vascular bundle of all LA100 parts, including the roots, hypocotyl, and stem. Pathogen colonization continued to increase over time, leading to the complete wilting of plants by 14-17 dpi. In LA140, the Fomh16-GFP isolate colonized the roots and hypocotyl vascular system at 7 dpi. Nevertheless, this colonization was restricted in the hypocotyl and decreased significantly, and no fungal growth was detected in the vascular system at 21 dpi. Thus, the resistant genotype might trigger a robust defense mechanism. In addition, while the pathogen was present in LA140, the inoculated plants did not exhibit any symptoms until 28 dpi. Quantitative PCR was utilized to measure the Fomh16-GFP biomass in various parts of LA100 and LA140 at different time points. The findings indicated a positive correlation between the quantity of Fomh16-GFP DNA and disease development in LA100. Alternatively, a high amount of Fomh16-GFP DNA was identified in the roots of LA140. Nonetheless, no significant correlations were found between DNA amount and disease progression in LA140. Aqueous extracts from LA140 significantly reduced Fomh16-GFP spore germination, while no significant reduction was detected using LA100 extracts.IMPORTANCEFusarium wilt of Luffa, caused by Fusarium oxysporum f. sp. luffae (Folu), causes great losses in Luffa plants worldwide. This study used a green fluorescent protein (GFP)-tagged isolate of Folu (Fomh16-GFP) to investigate the infection progress and colonization dynamics of Fomh16-GFP in the resistant and susceptible Luffa genotypes, which could be important in understanding the resistance mechanism of Folu in Luffa plants. In addition, our work highlights the correlations between DNA amount and disease progression in resistant plants using real-time PCR. We observed a positive correlation between the quantity of Fomh16-GFP DNA and disease progression in LA100, while no significant correlation was found in LA140. These results could be valuable to further investigate the resistance mechanism of Luffa genotypes against Folu. Gaining a better understanding of the interaction between Folu and Luffa plants is crucial for effectively managing Fusarium wilt and enhancing resistance in Luffa rootstock and its varieties.

Epithelial IL5RA promotes epithelial-mesenchymal transition in pulmonary fibrosis via Jak2/STAT3 cascade.

Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.

Tiotropium reduces clinically important deterioration in patients with mild-to-moderate chronic obstructive pulmonary disease: A post hoc analysis of the Tie-COPD study.

BACKGROUND: Clinically important deterioration (CID) is a composite endpoint used to holistically assess the complex progression of chronic obstructive pulmonary disease (COPD). Tiotropium improves lung function and reduces the rate of COPD exacerbations in patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate). However, whether tiotropium reduces CID risk in patients with mild-to-moderate COPD remains unclear. METHODS: This was a post hoc analysis of the 24-month Tie-COPD study comparing 18 µg tiotropium with placebo in patients with mild-to-moderate COPD. CID was defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 s, an increase of ≥2 unit in COPD Assessment Test (CAT) score, or moderate-to-severe exacerbation. The time to the first occurrence of one of these events was recorded as the time to the first CID. Subgroup analyses were conducted among patients stratified by CAT score, modified Medical Research Council (mMRC) dyspnea score, and GOLD stage at baseline. RESULTS: Of the 841 randomized patients, 771 were included in the full analysis set. Overall, 643 patients (83.4 %) experienced at least one CID event. Tiotropium significantly reduced the CID risk and delayed the time to first CID compared with placebo (adjusted hazard ratio = 0.58, 95 % confidence interval = 0.49-0.68, P < 0.001). Significant reductions in CID risk were also observed in various subgroups, including patients with a CAT score <10, mMRC score <2, and mild COPD. CONCLUSIONS: Tiotropium reduced CID risk in patients with mild-to-moderate COPD, even in patients with fewer respiratory symptoms or mild disease, which highlights tiotropium's effectiveness in treating COPD patients with mild disease. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (Tie-COPD, NCT01455129).

Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: A population-based cohort study of 2 million Swedish children.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder and is associated with an increased risk of iatrogenic preterm birth and adverse infant outcomes. Hence, there are several plausible pathways through which ICP could affect offspring neurodevelopment. However, to the best of our knowledge, no studies have investigated these associations. Thus, we aimed to determine whether ICP is associated with offspring neurodevelopmental conditions. METHODS AND FINDINGS: In this Swedish register-based cohort study, we included singleton non-adopted children born in Sweden between the 1st of January 1987 and the 31st of December 2010, who were resident in Sweden >5 years, with no missing covariate information, which we followed until the 31st of December 2016. Maternal ICP diagnosis and the date of the initial diagnosis during pregnancy were obtained from the National Patient Register. Offspring diagnoses of attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability were obtained from the National Patient Register, and the dispensation of ADHD medications were obtained from the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression while controlling for observed confounders and unobserved confounders shared among full siblings and maternal full cousins. A total of 2,375,856 children were included in the study; 81.6% of them were of Nordic origin, and 51.4% were male. Of these, 10,378 (0.44%) were exposed to ICP. During a median of 18 years follow-up (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition. After adjusting for child's sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, ICP was associated with increased odds of offspring neurodevelopmental conditions (OR 1.22, 95% CI 1.13 to 1.31), particularly among those exposed to early-onset ICP (OR 2.38, 95% CI 1.71 to 3.30) as compared to ICP diagnosed after reaching term (≥37 weeks of gestation) (OR 1.08, 95% CI 0.97 to 1.20). The findings of early-onset ICP were consistent in family-based analyses. Within-family comparisons of full maternal cousins yielded an OR of 2.99 (95% CI 1.48 to 6.04), and comparisons of full siblings showed an OR of 1.92 (95% CI 0.92 to 4.02), though the latter was less precise. The findings were consistent across specific neurodevelopmental conditions and different analytical approaches. The primary limitations of this study included its observational design, the absence of data on ICP therapeutics, and the lack of bile acid measures. CONCLUSIONS: In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP. Further studies are warranted to better understand the role of early-ICP in offspring neurodevelopment.

Domain-Limited Sub-Nanometer Co Nanoclusters in Defective Nitrogen Doped Carbon Structures for Non-Invasive Drug Monitoring.

In this work, sub-nanometer Co clusters anchored on porous nitrogen-doped carbon (C─N─Co NCs) are successfully prepared by high-temperature annealing and pre-fabricated template strategies for non-invasive sensing of clozapine (CLZ) as an efficient substrate adsorption and electrocatalyst. The introduction of Co sub-nanoclusters (Co NCs) provides enhanced electrochemical performance and better substrate adsorption potential compared to porous and nitrogen-doped carbon structures. Combined with ab initio calculations, it is found that the favorable CLZ catalytic performance with C─N─Co NCs is mainly attributed to possessing a more stable CLZ adsorption structure and lower conversion barriers of CLZ to oxidized state CLZ. An electrochemical sensor for CLZ detection is conceptualized with a wide operating range and high sensitivity, with monitoring capabilities validated in a variety of body fluid environments. Based on the developed CLZ sensing system, the CLZ correlation between blood and saliva and the accuracy of the sensor are investigated by the gold standard method and the rat model of drug administration, paving the way for non-invasive drug monitoring. This work provides new insights into the development of efficient electrocatalysts to enable drug therapy and administration monitoring in personalized healthcare systems.

PeCIN8 expression correlates with flower size and resistance to yellow leaf disease in Phalaenopsis orchids.

BACKGROUND: The orchid industry has seen a recent surge in export values due to the floral morphology and versatile applications of orchids in various markets for medicinal, food additive, and cosmetic usages. However, plant-related diseases, including the yellow leaf disease caused by Fusarium solani, have caused significant losses in the production value of Phalaenopsis (up to 30%). RESULTS: In this study, 203 Phalaenopsis cultivars were collected from 10 local orchid nurseries, and their disease severity index and correlation with flower size were evaluated. Larger flowers had weaker resistance to yellow leaf disease, and smaller flowers had stronger resistance. For the genetic relationship of disease resistance to flower size, the genetic background of all cultivars was assessed using OrchidWiz Orchid Database Software and principal component analysis. In addition, we identified the orthologous genes of BraTCP4, namely PeIN6, PeCIN7, and PeCIN8, which are involved in resistance to pathogens, and analyzed their gene expression. The expression of PeCIN8 was significantly higher in the most resistant cultivars (A7403, A11294, and A2945) relative to the most susceptible cultivars (A10670, A6390, and A10746). CONCLUSIONS: We identified a correlation between flower size and resistance to yellow leaf disease in Phalaenopsis orchids. The expression of PeCIN8 may regulate the two traits in the disease-resistant cultivars. These findings can be applied to Phalaenopsis breeding programs to develop resistant cultivars against yellow leaf disease.

Associations between maternal metabolic conditions and neurodevelopmental conditions in offspring: the mediating effects of obstetric and neonatal complications.

BACKGROUND: Maternal pre-gestational diabetes (PGDM), gestational diabetes mellitus (GDM), and overweight/obesity have been associated with increased risks of offspring neurodevelopmental conditions (NDCs) including autism, intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). Less is known about whether and how obstetric and neonatal complications (e.g., preterm birth, neonatal asphyxia) could mediate these associations. METHODS: In this Swedish register-based cohort study, we examined complications during pregnancy, delivery, and the neonatal period as potential mediators of the relationships between maternal metabolic conditions and offspring NDCs. We quantified the extent to which these obstetric and neonatal factors could mediate the associations of maternal metabolic conditions with offspring NDCs by applying parametric regression models for single mediation analyses and weighting-based methods for multiple mediation analyses under counterfactual frameworks. RESULTS: The study sample included 2,352,969 singleton children born to 1,299,692 mothers from 1987-2010 who were followed up until December 31, 2016, of whom 135,832 children (5.8%) were diagnosed with at least one NDC. A substantial portion of the association between maternal PGDM and children's odds of NDCs could be explained by the combined group of obstetric and neonatal complications in the multiple mediation analysis. For instance, these complications explained 44.4% of the relationship between maternal PGDM and offspring ID risk. The proportion of the relationship between maternal overweight/obesity and children's risk of NDCs that could be explained by obstetric and neonatal complications was considerably smaller, ranging from 1.5 to 8.1%. Some complications considered on their own, including pregnancy hypertensive diseases, preterm birth, neonatal asphyxia, and hematological comorbidities, could explain at least 10% of the associations between maternal PGDM and offspring NDCs. Complications during the neonatal period showed a stronger joint mediating effect for the relationship between PGDM and offspring NDCs than those during pregnancy or delivery. CONCLUSIONS: Obstetric and neonatal complications could explain nearly half of the association between maternal PGDM and offspring risk of NDCs. The mediating effects were more pronounced for complications during the neonatal period and for specific complications such as pregnancy hypertensive diseases, preterm birth, neonatal asphyxia, and hematological comorbidities. Effective preventive strategies for offspring NDCs should holistically address both the primary metabolic issues related to PGDM and the wide array of potential complications, especially those in the neonatal period.

Edge-generated N-doped carbon-supported dual-metal active sites for enhancing electrochemical immunoassay.

Development of high-precision human epidermal growth factor receptor 2 (HER2) assay is essential for the early diagnostic and prevention of breast cancer. In this work, an innovative Fe/Mn bimetallic nanozyme at the edge of N-doped carbon defects (FeMn-NCedge) with abundant active sites was prepared through the hydrothermal synthetic method. FeMn-NCedge nanozyme displayed excellent peroxidase-like activity relative to the H2O2-catalyzed 3,3',5,5'-tetramethylbenzidine (TMB) system for generation of the oxidized TMB (oxTMB). As a proof-of-concept application, we constructed an electrochemical immunoassay for the detection of HER2 based on the unique merits of FeMn-NCedge. Initially, a sandwiched immunoreaction was carried out in the microtiter plate coated with monoclonal anti-HER2 capture antibodies using glucose oxidase (GOx)-labeled anti-HER2 as detection antibody. The carried GOx could catalyze glucose to produce H2O2, thus resulting in the formation of oxTMB with the assistance of TMB and FeMn-NCedge nanozyme. The produced oxTMB could be determined on the electrode by the chronoamperometry at an applied potential of +10 mV. Experimental results revealed that the steady-state current increased with the increasing HER2 concentration in the sample, and gave a good linear relationship within the dynamic range of 0.01-10 ng/mL at a limit of detection of 5.4 pg/mL HER2. In addition, good reproducibility, high specificity and acceptable accuracy were acquired for the measurement of human serum samples. Importantly, this method can be extended for quantitative monitoring other disease-related proteins by changing the corresponding antibodies.

Block-Polymer-Restricted Sub-nanometer Pt Nanoclusters Nanozyme-Enhanced Immunoassay for Monitoring of Cardiac Troponin I.

Noble-metal nanozymes have demonstrated great potential in various fields. However, aggregation of single-particle nanoparticles severely affects their exposed catalytically active sites to the extent of exhibiting weak enzyme-like activity. Here, we present an organic block surfactant (polyvinylpyrrolidone, PVP) to construct monodisperse water-stable Pt nanoclusters (Pt NCs) for an enhanced immunoassay of cardiac troponin I (cTnI). The PVP-modified Pt NC nanozyme exhibited up to 16.3 U mg-1 peroxidase-mimicking activity, which was mainly attributed to the ligand modification on the surface and the electron-absorbing effect of the ligand on the Pt NCs. The PVP-modified Pt NCs have a lower OH-transition potential, as determined by density functional theory. Under optimized experimental conditions, the enhanced nanozyme immunoassay strategy exhibited an ultrawide dynamic response range of 0.005-50 ng mL-1 for cTnI targets with a detection limit of 1.3 pg mL-1, far superior to some reported test protocols. This work provides a designable pathway for the design of artificial enzymes with high enzyme-like activity to further expand the practical range of enzyme alternatives.

Random capillary glucose levels throughout pregnancy, obstetric and neonatal outcomes, and long-term neurodevelopmental conditions in children: a group-based trajectory analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with both short- and long-term risks, although it is unknown if risks vary by severity, timing, and duration of gestational hyperglycemia. We aimed to identify trajectories of random capillary glucose (RCG) levels throughout pregnancy and assess their associations with both obstetric/neonatal outcomes and children's risk of neurodevelopmental conditions (NDCs) (i.e., autism, intellectual disability, and attention-deficit/hyperactivity disorders [ADHD]). METHODS: A population-based cohort study was conducted involving 76,228 children born to 68,768 mothers without pregestational diabetes. Group-based trajectory modeling was utilized to identify distinct glucose trajectories across RCG values throughout the course of pregnancy. The associations between these trajectory groups and obstetric/neonatal outcomes as well as children's NDCs were then assessed using generalized estimating equation models with a logit link. The Benjamini-Hochberg (BH) procedure was employed to adjust P-values for multiple comparisons, controlling the false discovery rate (FDR). RESULTS: Five distinct glucose trajectory groups were identified, each with varying percentages diagnosed with GDM. Their associations with obstetric/neonatal outcomes as well as children's NDCs varied. For example, when compared to the "Persistently Low" group, other groups exhibited varying degrees of increased risk for large-for-gestational-age babies, with the exception of the "High in Early Pregnancy" group. Compared to the "Persistently Low" group, all other trajectory groups were associated with NDC outcomes, except the "High in Mid-Pregnancy" group. However, none of the associations with offspring NDCs remained significant after accounting for the FDR correction. CONCLUSIONS: Persistent high glucose levels or moderately elevated glucose levels throughout pregnancy, as well as transient states of hyperglycemia in early or mid-pregnancy, were found to be associated with increased risks of specific obstetric and neonatal complications, and potentially offspring NDCs. These risks varied depending on the severity, timing, duration, and management of hyperglycemia. The findings underscore the need for continuous surveillance and individualized management strategies for women displaying different glucose trajectories during pregnancy. Limitations such as potential residual confounding, the role of mediators, and small sample size should be addressed in future studies.

Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders.

BACKGROUND: Previous studies have suggested that gestational weight gain (GWG) outside an optimal range increases the risks of neurodevelopmental disorders (NDDs) in offspring including autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). The sequential development of the fetal brain suggests that its vulnerability may vary depending on the timing of exposure. Therefore, we aimed to investigate the associations of not only gestational age-standardized total GWG (GWG z-scores) but also the rate of GWG (RGWG) in the second and third trimesters with risks of NDDs in offspring. METHODS: In this population-based cohort study, we used maternal weight data from antenatal care records collected for 57,822 children born to 53,516 mothers between 2007 and 2010 in the Stockholm Youth Cohort. Children were followed from 2 years of age to December 31, 2016. GWG z-scores and RGWG (kg/week) in the second and third trimesters were considered as continuous variables in cox regression models, clustered on maternal identification numbers. Nonlinear relationships were accommodated using restricted cubic splines with 3 knots. RGWG were also categorized according to the 2009 US Institute of Medicine (IOM) guidelines for optimal GWG. According to the IOM guidelines, the optimal rate of GWG for the second and third trimesters for underweight, normal weight, overweight, and obese categories were 0.44-0.58, 0.35-0.50, 0.23-0.33, and 0.17-0.27 kg/week, respectively. RESULTS: During a mean follow-up of 5.4 years (until children were on average 7.4 years old), 2205 (3.8%) children were diagnosed with NDDs, of which 1119 (1.9%) received a diagnosis of ASD, 1353 (2.3%) ADHD, and 270 (0.5%) ID. We observed a J-shaped association between total GWG z-score and offspring risk of NDDs, with higher total GWG (GWG z-score = 2) associated with 19% increased risk of any NDD (95% CI = 3-37%) and lower total GWG (GWG z-score = - 2) associated with 12% increased risk of any NDDs (95% CI = 2-23%), compared to the reference (GWG z-score = 0). In the second trimester, lower RGWG (0.25 kg/week) was associated with a 9% increased risk of any NDD diagnosis (95% CI = 4-15%) compared to the median of 0.57 kg/week, with no apparent relationship between higher RGWG and risk of NDDs. In the third trimester, there was no apparent association between lower RGWG and risk of NDDs, though higher RGWG (1 kg/week) was associated with a 28% increased risk of NDD diagnosis (95% CI = 16-40%), compared to the median (0.51 kg/week). When considering categorized RGWG, we found that slow weight gain in the second trimester followed by rapid weight gain in the third trimester most significantly increased the risk of ADHD (HRadjusted = 1.55, 1.13-2.13) and ID (HRadjusted = 2.53, 1.15-5.55) in offspring. The main limitations of our study are the relatively few years for which detailed GWG data were available and the relatively short follow-up for the outcomes, limiting power to detect associations and misclassifying children who receive an NDD diagnosis later in childhood. CONCLUSIONS: The relationship between maternal weight gain and children's risk of NDDs varied according to timing in pregnancy, with the greatest risks associated with slow weight gain in the second trimester and rapid weight gain in the third trimester.

The efficacy of anastrozole in subfertile men with and without abnormal testosterone to estradiol ratios.

Background: Aromatase inhibitors (AIs), such as anastrozole, have shown effectiveness in treating oligoasthenozoospermia due to abnormal testosterone to estradiol (T/E2) ratio (T/E2 <10). However, its efficacy in subfertile men without abnormal T/E2 ratio (T/E2 >10) remained unevaluated. This retrospective study aimed to investigate whether patients with T/E2 ratio >10 could also benefit from anastrozole treatment. Methods: One hundred and five subfertile patients treated with 1 mg anastrozole daily were included, in which 62 patients had a T/E2 ratio of <10, and 43 patients had this ratio >10. Semen parameters and sex hormone levels (including FSH, LH, PRL, E2 and total T) were measured before and after a three-month treatment. T/E2 ratio and total progressive motility sperm count were calculated from these results. Results: Patients in both groups (T/E2 ratio <10 and >10) showed significant increase in sex hormone levels (FSH, LH and total T), T/E2 ratio and semen parameters (semen volume, sperm concentration, total sperm count, progressive motility and total progressive motility count). The changes of these parameters between two groups were comparable. A subgroup analysis comparing the effect of anastrozole on overweight and normal patients also showed no significant difference. Improvements in semen parameters were seen in some azoospermic and cryptozoospermic patients. Conclusions: The majority of subfertile men with and without abnormal T/E2 ratios responded to anastrozole treatment with significantly improved semen parameters and sex hormone levels. Anastrozole showed potential effectiveness in male subfertile patients with T/E2 >10, to be confirmed by future prospective, randomized, controlled studies.

Sinensetin protects against pulmonary fibrosis via inhibiting Wnt/ß-Catenin signaling pathway.

Pulmonary fibrosis is a fatal lung disease characterized by progressive fibroblast proliferation and extensive extracellular matrix (ECM) deposition. Although great efforts have been placed to understand the pathogenesis and explore therapeutic strategies, the treatment options for pulmonary fibrosis are very limited and the prognosis of pulmonary fibrosis patients remains poor. Sinensetin is a polymethoxylated flavone derived from citrus fruits, and has been characterized with anti-fibrotic property. However, the underlying mechanism is still unclear. In present study, combining in vitro and in vivo models, we revealed for the first time that sinensetin can protect against pulmonary fibrosis via inhibiting glycogen synthase kinase-3ß (GSK-3ß)-mediated Wnt/ß-Catenin signaling pathway. According to our results, the activation of Wnt/ß-Catenin signaling pathway in pulmonary fibrosis is responsible for fibroblast proliferation and differentiation to form ECM-producing myofibroblasts. Sinensetin treatment dephosphorylates and activates GSK-3ß, a component of ß-Catenin destruction complex, which induces ß-Catenin degradation and deactivates Wnt/ß-Catenin-mediated fibroblast proliferation and differentiation. As a result, myofibroblasts formation and ECM production are reduced and the progression of pulmonary fibrosis is suppressed. These results not only advance our knowledge on the pharmacological activities of sinensetin, but also provide novel insights on pulmonary fibrosis treatment.

p21-activated kinase 2 binds to transcription factor SOX2 and up-regulates DEK to promote the progression of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) is a prevalent and progressive subtype of lung cancer. This study aimed to substantiate the regulatory effect of the PAK2/SOX2/DEK axis on the LSCC development. LSCC tissues (n = 83) and adjacent normal tissues were collected and SOX2 expression was determined by qRT-PCR and Western blotting. Correlation between SOX2 expression and the prognosis of LSCC patients was then explored utilizing Kaplan-Meier analysis. Co-immunoprecipitation and glutathione-S-transferase pull-down assays were conducted to validate the binding of SOX2 to DEK. Gain- and loss- of function assays were then performed on LSCC cells, with CCK-8 and Transwell assays applied to detect the malignant behaviors of cells. A mouse xenograft model of LSCC was further established for in vivo validation. The expression levels of SOX2, PAK2 and DEK were up-regulated in LSCC tissues and cells. SOX2 overexpression was correlated with poor prognosis of LSCC patients. Knockdown of SOX2 weakened the viability and the migratory and invasive potential of LSCC cells. Further, PAK2 directly interacted with SOX2. PAK2 overexpression accelerated the malignant phenotypes of LSCC cells through interplay with SOX2. Moreover, SOX2 activated the expression of DEK, and silencing DEK attenuated the malignant behaviors of LSCC cells. In conclusion, PAK2 could bind to the transcription factor SOX2 and thus activate the expression of DEK, thereby driving the malignant phenotypes of LSCC cells both in vivo and in vitro.

Application of Scanning Magnetic Resonance Imaging in the Diagnosis of Prenatal Placental Implantation and Related Care.

In order to solve the problem of scanning magnetic resonance imaging in prenatal diagnosis, the application and research of placental implantation have been proposed. Placental implantation is a serious obstetric emergency, which refers to the abnormal attachment of placental villi caused by the dysplasia of decidual basal layer. A study from the United States showed that the incidence of placental implantation in pregnant women during delivery increased from 9.9/30000 to 11.6/20000 from 2006 to 2019, which increased the risk of prenatal or postpartum hemorrhage, hysterectomy, stillbirth, abdominal organ injury, and so on. Clinically, patients can show severe prenatal or postpartum hemorrhage, postpartum placental retention, uterine perforation, and secondary infection, which may seriously endanger the lives of pregnant mothers and fetuses. Placental implantation can also have no obvious symptoms before delivery, which leads to insufficient prenatal diagnosis. Gielchinsky retrospectively studied 410 patients with placental implantation and found that only 9 patients were detected by prenatal ultrasound or magnetic resonance imaging (MRI), and the detection rate was only 6.6%. It can be seen that if the accurate diagnosis of placental implantation can be made before prenatal or symptoms appear, clinical intervention treatment can be carried out in time to reduce the probability of hysterectomy and improve the examination means of patients' prerecovery. At present, studies at home and abroad suggest that it has good clinical application value and research prospect in the clinical diagnosis of placental implantation.

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy.

BACKGROUND: Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of diseases characterized by exclusive degeneration of peripheral motor nerves, while only 20.0-47.8% of dHMN patients are genetically identified. Recently, GGC expansion in the 5'UTR of NOTCH2NLC has been associated with dHMN. Accordingly, short tandem repeat (STR) should be further explored in genetically unsolved patients with dHMN. METHODS: A total of 128 patients from 90 unrelated families were clinically diagnosed as dHMN, and underwent a comprehensively genetic screening. Skin biopsies were conducted with routine protocols. RESULTS: Most patients showed chronic distal weakness of lower limbs (121/128), while 20 patients initially had asymmetrical involvements, 14 had subclinical sensory abnormalities, 11 had pyramidal impairments, five had cerebellar disturbance, and four had hyperCKmia. The rate of genetic detection was achieved in 36.7% (33/90), and the rate increased to 46.7% (42/90) if patients with variants uncertain significance were included. The most common causative genes included chaperone-related genes (8/33, 24.2%), tRNA synthetase genes (4/33, 12.1%), and cytoskeleton-related genes (4/33, 12.1%). Additionally, two dominant inherited families were attributed to abnormal expansion of GGC repeats in the 5'UTR of NOTCH2NLC; and a patient with dHMN and cerebellar symptoms had CAG repeat expansion in the ATXN2 gene. Skin biopsy from patients with GGC expansion in NOTCH2NLC revealed typical intranuclear inclusions on histological and ultrastructural examinations. INTERPRETATIONS: This study further extends the genetic heterogeneity of dHMN. Given some dHMN patients may be associated with nucleotides repeat expansion, STR screening is necessary to perform in genetically unsolved patients.

High-density genetic map and genome-wide association studies of aesthetic traits in Phalaenopsis orchids.

Phalaenopsis spp. represent the most popular orchids worldwide. Both P. equestris and P. aphrodite are the two important breeding parents with the whole genome sequence available. However, marker-trait association is rarely used for floral traits in Phalaenopsis breeding. Here, we analyzed markers associated with aesthetic traits of Phalaenopsis orchids by using genome-wide association study (GWAS) with the F1 population P. Intermedia of 117 progenies derived from the cross between P. aphrodite and P. equestris. A total of 113,517 single nucleotide polymorphisms (SNPs) were identified in P. Intermedia by using genotyping-by-sequencing with the combination of two different restriction enzyme pairs, Hinp1 I/Hae III and Apek I/Hae III. The size-related traits from flowers were negatively related to the color-related traits. The 1191 SNPs from Hinp1 I/ Hae III and 23 simple sequence repeats were used to establish a high-density genetic map of 19 homolog groups for P. equestris. In addition, 10 quantitative trait loci were highly associated with four color-related traits on chromosomes 2, 5 and 9. According to the sequence within the linkage disequilibrium regions, 35 candidate genes were identified and related to anthocyanin biosynthesis. In conclusion, we performed marker-assisted gene identification of aesthetic traits with GWAS in Phalaenopsis orchids.

Validity of the Handheld Expiratory Flowmeter for COPD Screening in the Primary Care Setting of China.

Purpose: The use of simple and affordable screening tools for chronic obstructive pulmonary disease (COPD) is limited. We aimed to assess the validity of a handheld expiratory flowmeter (Vitalograph Ltd., COPD-6®, Ireland) for COPD screening in Chinese primary care settings. Methods: In our cross-sectional study, subjects were randomly selected in eight primary care settings. Tests with the handheld expiratory flowmeter and the conventional spirometry were sequentially performed on all participants. The correlation between the handheld expiratory flowmeter and the conventional spirometry was determined. Validity was determined by the area under the receiver operator characteristic curve (AUC) of the forced expiratory volume in one second (FEV1)/forced expiratory volume in six seconds (FEV6) that used to detect airway obstruction. The sensitivity, specificity, predictive values, and likelihood ratio were calculated according to different FEV1/FEV6 cut-off points. Results: A total of 229 subjects (15.4%) were diagnosed with airflow limitation by conventional spirometry. FEV1, FEV6, and FEV1/FEV6 measured by the handheld expiratory flowmeter were correlated with FEV1, FVC, and FEV1/FVC measured by the conventional spirometry (r=0.889, 0.835 and 0.647, p<0.001), respectively. AUC of the FEV1/FEV6 to determine airflow obstruction was 0.857 (95% CI: 0.826 to 0.888). No significant difference of AUC was observed between the symptomatic group and the asymptomatic group (AUC=0.869 vs 0.843, P=0.425). A similar phenomenon was found in the AUC of smokers and never-smokers (AUC=0.862 vs 0.840; P=0.515). The cut-off point for FEV1/FEV6 was 0.77 and the corresponding sensitivity and specificity were 71.2% and 89.8%, respectively. Conclusion: The handheld expiratory flowmeter might be used as a screening device for COPD in Chinese primary care settings.