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Abstract Background Dietary imbalance, such as a lower proportion of complex carbohydrates and a higher protein diet, may contribute to gestational diabetes mellitus (GDM) risks through their metabolisms. However, there is a lack of knowledge regarding the association between butyrate, iso-butyrate, and GDM, which are metabolisms of the two primary nutrients above. This study aimed to clarify the association of butyrate and iso-butyrate with GDM. Methods A nested case–control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2017 to 2018. Totally, 99 singleton women were involved (GDM: n = 49, control: n = 50). All participants provided blood samples twice (in their first and second trimesters). Gas chromatography-mass spectrometry (GC-MS) was used for butyrate and iso-butyrate detection. Unconditional logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. Results The results showed that butyrate in the first trimester was negatively correlated with GDM (odds ratio (OR): 0.00, 95% confidential interval (CI): 0.00–0.21, P = 0.008), and iso-butyrate in the second trimester was positively related to GDM (OR: 627.68, 95% CI: 40.51–9724.56, P

Cementitious materials are the main binders used in mine filling and play a critical role in determining the mechanical properties of cemented tailings backfill (CTB). But, the materials typically account for over 60% of total filling expenses. The objective of this study is to utilize solid waste cinders as a substitute for certain cement-like materials, aiming to lower the cost of filling while maintaining the strength characteristics of CTB. Through measuring the fluidity and strength characteristics of slurry with different CC replacement levels, and the microstructure analysis of backfill, the study finds that: 1) The addition of CC can improve the fluidity of ultra-fine tailings filling slurry and adding 1 ∼ 2 mm CC can both improve the fluidity of CTB and the compressive strength of CTB. 2) The strength of the filling body can be improved by replacing 20% of the cementitious material with CC when the surface pore size of CC with porous structure is similar to the median particle size of the tailings. 3) The lower packing density of CC and the hydrophilic mineral components on the surface reduced the interfacial tension between solid and liquid, which enhanced the dispersion ability of CC in the slurry. 4) Coal cinders replace part of cement-like materials to reduce filling costs and solid waste emissions.

The impact of climate warming on wetland ecosystems is a current focal point in ecological research. In this study, the Napahai wetland, a typical plateau wetland in northwest Yunnan Province, was selected as the study site to understand the growth and survival strategies of emergent plants in a plateau wetland under climate warming conditions. Open-top chambers (OTCs) were used to simulate warming in three treatments (i.e., control group, 2.0 ± 0.5°C, and 4.0 ± 0.5°C) in order to study the responses of the functional traits of the dominant emergent plant Schoenoplectus tabernaemontani to simulated warming. The results showed that simulated warming significantly reduced the photosynthetic carbon assimilation capacity and biomass accumulation of S. tabernaemontani, as well as its nitrogen content and vascular bundle density, while it significantly increased the vascular bundle size. The growing season accumulated temperature (AT) and the mean temperature of the hottest month (WT) were the main temperature factors influencing the functional traits of S. tabernaemontani. In summary, simulated warming significantly affected the functional traits of S. tabernaemontani, which demonstrated effective adaptation to warming conditions. As the temperature rises and the light and productivity decrease, S. tabernaemontani prioritizes the supply of limited resources to the underground part to ensure the biomass supply of the reproductive structure. This study provides a case for revealing the response patterns and ecological adaptation strategies of plateau wetland plants to climate warming.

Abstract Background Periodontitis is a highly prevalent oral disease characterized by bacterium-induced periodontal inflammation and alveolar bone destruction. Osteoblast function is impaired in periodontitis with a global proteome change. METTL3 is the pivotal methyltransferase of N 6-methyladenosine (m6A) that is recently proved to exert a crucial role in osteoblast differentiation. This study aims to investigate the role of METTL3 in osteoblast ribosome biogenesis in periodontitis progression. Results METTL3 was knocked down in osteoblasts, and the downregulated genes were enriched in ribosome and translation. METTL3 knockdown inhibited ribosome biogenesis and oxidative phosphorylation in LPS-stimulated osteoblasts, whereas METTL3 overexpression facilitated ribosomal and mitochondrial function. Mechanistically, METTL3 mediated osteoblast biological behaviors by activating Wnt/β-catenin/c-Myc signaling. METTL3 depletion enhanced the mRNA expression and stability of Dkk3 and Sostdc1 via YTHDF2. In periodontitis mice, METTL3 inhibitor SAH promoted alveolar bone loss and local inflammatory status, which were partially rescued by Wnt/β-catenin pathway activator CHIR-99021 HCl. Conclusions METTL3 promoted ribosome biogenesis and oxidative phosphorylation by activating Wnt/β-catenin/c-Myc signaling in LPS-treated osteoblasts and alleviated the inflammatory alveolar bone destruction in periodontitis mice.

Abstract Lifestyle recovery captures the collective effects of population activities as well as the restoration of infrastructure and business services. This study uses a novel approach to leverage privacy-enhanced location intelligence data, which is anonymized and aggregated, to characterize distinctive lifestyle patterns and to unveil recovery trajectories after 2017 Hurricane Harvey in Harris County, Texas (USA). The analysis integrates multiple data sources to record the number of visits from home census block groups (CBGs) to different points of interest (POIs) in the county during the baseline and disaster periods. For the methodology, the research utilizes unsupervised machine learning and ANOVA statistical testing to characterize the recovery of lifestyles using privacy-enhanced location intelligence data. First, primary clustering using k-means characterized four distinct essential and non-essential lifestyle patterns. For each primary lifestyle cluster, the secondary clustering characterized the impact of the hurricane into four possible recovery trajectories based on the severity of maximum disruption and duration of recovery. The findings further reveal multiple recovery trajectories and durations within each lifestyle cluster, which imply differential recovery rates among similar lifestyles and different demographic groups. The impact of flooding on lifestyle recovery extends beyond the flooded regions, as 59% of CBGs with extreme recovery durations did not have at least 1% of direct flooding impacts. The findings offer a twofold theoretical significance: (1) lifestyle recovery is a critical milestone that needs to be examined, quantified, and monitored in the aftermath of disasters; (2) spatial structures of cities formed by human mobility and distribution of facilities extend the spatial reach of flood impacts on population lifestyles. These provide novel data-driven insights for public officials and emergency managers to examine, measure, and monitor a critical milestone in community recovery trajectory based on the return of lifestyles to normalcy.

BackgroundReproduction-related congenital birth defects (RCBDs), including Klinefelter syndrome (KS), Turner syndrome (TS), and urogenital congenital anomalies (UCA), can lead to severe physical and psychosocial disorders. The global impact of RCBDs on children and adults is unknown, which limits high-quality development of populations and increases in life expectancy per capita.MethodsAnnual incidence rates, prevalence rates (PR), and disability-adjusted life year (DALY) rates were collected for KS, TS, and UCA for 204 countries and territories, including at birth, for children younger than 1 year, and age-standardized (AS) for all ages. Linear regression was used to calculate their estimated annual percentage changes (EAPCs). Finally, the relationships between EAPCs of each indicator and sociodemographic index (SDI) was investigated using Pearson correlation analysis.ResultsGlobally, the age-standardized prevalence rate (ASPR) trend is decreasing in KS and TS and increasing in UCA. The DALY rates for children younger than 1 year were on a downward trend in KS and UCA, while they were still rising for TS. The AS-DALY rates were all on a downward trend in KS, TS, and UCA. The DALY rates of KS, TS and UCA were found higher in high-income countries in North America. In addition, the burdens of TS and UCA went down with increasing SDI, whereas the burden of KS increased with increasing SDI.ConclusionThe global burdens of RCBDs have decreased since 1990. This finding can help policymakers implement cost-effective interventions to reduce the burdens of RCBDs.

The weak bedding plane and the water-softening coal will lead to the decrease in mechanical properties, which has an important influence on the stability of underground reservoirs and the prevention and control of water inrush accidents in coal mine. To study the comprehensive influence of bedding and soaking on the mechanical properties of coal, the uniaxial compression deformation and failure characteristics of coal under different soaking conditions were analyzed through a non-destructive soaking test and uniaxial compression test and based on the Digital image correlation method (DIC). The mechanical property parameters and surface strain field information of axial parallel and vertical bedded coal samples in the natural state, natural water absorption and forced water absorption were obtained. The results shown that the water absorption characteristics of coal shown obvious stratification differences, and the mechanical properties were affected by the combined effects of stratification and soaking. The specific results were as follows, ① Capillary action led to stronger water adsorption in axial parallel-bedded coal than in axial vertical-bedded coal, and the natural limiting water absorption rate of axial parallel-bedded coal was 2.2 times higher than that of axial vertical-bedded coal. ② The uniaxial compressive strength and elastic modulus of coal were mainly affected by bedding and supplemented by soaking. The failure mode was related to the direction of bedding. The failure mode of axial vertical coal was shear failure, while that of axial parallel coal was split failure. ③ The coal failure was a process of transformation from uniform to non-uniform deformation. After water soaking, the coal appeared strain concentration area earlier, its compaction stage was prolonged, and the elastic deformation stage was shortened. The research results were helpful to further understand the water soaking characteristics, mechanical properties, and rupture evolution of axial parallel and vertical bedded coals, and can be used as a reference for the protection and stability analysis of reserved coal pillars in underground reservoirs.

Abstract Body talk has received increasing research attention in recent years, with accumulating evidence supporting the link between body talk and eating and body image disturbances. However, research on body talk in China is still relatively scarce and generally focused on fat talk, especially in women, and much remains unknown about muscle talk and positive body talk for both Chinese women and men. To promote a better understanding of body talk in the Chinese context, the present study adapted the Body Talk Scale (BTS) into Chinese Mandarin (i.e., C-BTS) and evaluated the factor structure and psychometric properties of the C-BTS in Chinese adult women and men. The English version of the BTS was translated into Chinese Mandarin with standard procedures. With 300 Chinese women (M age = 29.48 years, SD = 7.26) and 300 men (M age = 29.36 years, SD = 6.81), we examined the factor structure and gender invariance of the C-BTS, as well as internal consistency reliability, test–retest reliability, and construct validity, including convergent, concurrent, and incremental validity of the C-BTS. The results indicated that, consistent with the development study of the BTS, the C-BTS had three subscales (i.e., Negative Fat Talk, Negative Muscle Talk, and Positive Body Talk) and good reliability and validity. The findings demonstrate that the C-BTS can be a useful measure of body talk in both Chinese women and men.

Pre-grouting is an effective method to reinforce fractured coal in front of working faces. The mining of adjacent working faces after grouting can cause early damage to the grouting cemented coal. To explore the mechanical properties of grouting cemented coal with different degrees of early damage, we designed and built a grouting equipment that was used on fractured coal to produce grouting cemented coal. In total, 0%, 20%, 40%, and 60% of the uniaxial compressive strength of complete coal were applied to the grouting cemented coal to produce early damage. The uniaxial compressive test, digital image correlation technology (DIC), acoustic emission (AE), and scan electron microscopy (SEM) were used to explore the changes in the mechanical properties of the grouting cemented coal with different early disturbance, and the surface and internal failure modes of the samples were investigated. The results show that with an increase in the early damage degree from 0% to 60%, the strength of the grouting cemented coal samples first increased and then decreased. Moreover, when the damage degree was 40%, the strength of the grouting cemented coal reached a maximum, which increased by 24.38% compared to that of the grouting cemented coal without damage. Under the low degree of damage, the samples exhibited tensile failure. As the damage degree increases, the samples’ failure mode changes to shear and mixed failure mode, and the breakdown speed increases. Internal crack propagation mostly occurred during the failure stage. As the damage degree increased, the failure stage increased, and the grouting cemented coal exhibited plastic characteristics. However, when the early damage degree increased to 60%, the samples exhibited typical brittle failure characteristics. The microstructure results show that the low degree of early damage for the samples is conducive to the infiltration of the slurry in coal, improving the grouting reinforcement effect. A large degree of early damage can lead to internal structural damage and strength degradation in grouting cemented coal.

Temporomandibular joint discs (TMJ discs) are unable to repair themselves in disease states, while induced stem cell differentiation is a common method to repair tissue defects. Nowadays, kinds of stem cells are attempted for tissue regeneration of TMJ disc, but these methods have several downsides, which limit their wide application. The proliferation and differentiation ability of human induced pluripotent stem cells (hiPSC) provides a new research direction for TMJ disc tissue regeneration. In this study, we investigated the feasibility of induced differentiation of hiPSC into TMJ disc cells in vitro and the differentiation efficiency of different methods to clarify the possibility and conditions of hiPSC application in TMJ disc tissue engineering. We collected sheep TMJ disc cells cultures for adding in hiPSC culture environment and treated hiPSC by both direct induction and Transwell co-culture for 7 days, 14 days and 21 days. The secretion of extracellular matrix in TMJ disc cells was detected by Sirius Red and Safranin O staining. Collagen Ⅰ and Collagen Ⅱ were qualitatively detected by immunohistochemical staining. The expression of extracellular matrix genes (type I collagen (COL1A1), type II collagen(COL2), glycosaminoglycan (GAG)), chondrogenic differentiation gene SOX9 and pluripotency gene OCT4 were detected by RT-qPCR. Our results showed that hiPSC had the ability to differentiate to TMJ disc cells by direct induction in TMJ disc cell culture medium and by Transwell co-culture method. The highest degree of differentiation was observed after 14 days of direct induction, while Transwell co-culture showed significant differentiation at different times and with different major directions. Meanwhile, Transwell co-culture not only differentiates hiPSC but also promotes the growth and proliferation of TMJ disc cells. Our study is valuable to investigate the possibility of differentiation of hiPSC toward TMJ disc cells and to determine the time of differentiation. It provides new ideas for the selection of seed cells for TMJ disc tissue engineering.

How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.

IntroductionCurrently, the treatment strategies for angular pregnancy in the first trimester after assisted reproduction technology (ART) are unclear. Improper treatment will cause unnecessary losses to patients, especially infertile patients, after ART. The purpose of this study was to clarify the pregnancy outcomes of expectant treatment for angular pregnancy post-ART and to provide a basis for the formulation of clinical treatment strategies.MethodThis retrospective case series study was performed at the Reproductive Medicine Center of a university hospital. Maternal data and pregnancy outcomes were collected and analyzed for all patients diagnosed with angular pregnancies after ART between January 2016 and August 2021. The outcomes included live birth, term birth, premature birth, early pregnancy loss, fetal death, placental abruption, uterine rupture, maternal death, and hysterectomy.ResultsA total of 78 patients were analyzed in this study, of whom 54 (69.2%) had live births, 44 (56.4%) had term births, 21 (26.9%) had an early pregnancy loss, 1 (1.3%) had mid-trimester missed abortion, 1 (1.3%) underwent mid-trimester labor induction due to fetal malformation, and 1 (1.3%) underwent uterine rupture. There were no cases of maternal death, placental abruption, or hysterectomies.DiscussionAngular pregnancy after ART is not as dangerous as that described in previous studies; most cases could be treated expectantly under close-interval follow-up and obtain live birth.

Abstract Background Some concern has been expressed regarding the negative effects of low-level ionizing radiation exposure in the context of radiological evaluation prior to IVF/ICSI treatment, but the available evidence is limited and conflicting. The aim of this study is to evaluate pregnancy and neonatal outcomes of couples who did chest computed tomography (CT) prior to IVF/ICSI. Methods This was a retrospective cohort study of 2680 IVF/ICSI fresh embryo transfer cycles conducted from January 2019 – August 2020. Fertility outcomes were compared between couples that had or had not undergone CT examination within 3 months prior to the date of oocyte retrieval and sperm collection. Miscarriage was the primary study outcome, while secondary outcomes included the number of oocytes collected, oocyte maturation, normal fertilization, number of good quality cleavage stage embryos, blastocyst formation, implantation, clinical pregnancy, ectopic pregnancy, live birth, multiple birth, Cesarean section rates, gestational weeks, maternal obstetric complications, birth weight, newborn sex ratio, and birth defect incidence. Propensity score matching was used to control for potential confounding variables. Results Of the 2680 cycles included in this study, couples underwent CT examination in 731 cycles. After 1:1 propensity score matching, 670 cycles were included in each group. When comparing demographic and fertility-related variables between groups that had and had not undergone CT examination after propensity score matching, we detected no significant differences in miscarriage rates (16.99% vs. 15.77%, OR = 1.10, 95CI% = 0.74 to 1.68). Similarly, both groups exhibited comparable oocyte and embryonic development, implantation rates (41.99% vs. 40.42%, OR = 1.07, 95%CI = 0.87 to 1.31), clinical pregnancy rates (45.67% vs. 44.48%, OR = 1.05, 95%CI = 0.85 to 1.30), ectopic pregnancy rates (2.94% vs. 1.68%, OR = 1.78, 95%CI = 0.59 to 5.36), live birth rates (36.57% vs. 35.67%, OR = 1.04, 95%CI = 0.83 to 1.30), multiple birth rates, Cesarean section rates, gestational weeks, maternal obstetric complication rates, and neonatal outcomes. Conclusions Chest CT examination before IVF/ICSI has no impact on pregnancy and neonatal outcomes associated with fresh embryo transfer. Trial registration Not applicable.

The UNESCO label of World Heritage can attract a high number of tourists to heritage properties for their Outstanding Universal Values (OUV). Although international studies have demonstrated the World Heritage system can contribute to stimulating cultural tourism and boosting the local economy, how this heritage-led development process promotes urban conservation and morphological changes in cities is yet to be explored adequately. This paper aims to explore the urban morphology of a historic Chinese city after its inscription on the UNESCO World Heritage List, taking the Old Town of Lijiang as case. The methods of spatial plan analysis and discourse analysis are used to analyse the data. The research findings have demonstrated that, theoretically, the Conzenian approach of urban morphology can be an effective framework for World Heritage OUV-monitoring. Methodologically, the analysis of spatial plans and multi-stakeholder interviews can reveal local urban morphology from macro to micro levels. Case-specifically in Lijiang, urban physical characteristics and building structures have been well maintained while traditional social fabric and neighbourhood networks have almost vanished. This research has incorporated the urban morphology approach into (world) heritage management in China, as well as worldwide, in order to maintain the balance between urban conservation and economic growth.

The alleviation effect of Lacticaseibacillus rhamnosus MP108-containing products on diarrhea caused by Enterotoxic Escherichia coli was evaluated. Six-week-old male BALB/c mice were randomly divided into blank group, model group, MP108 probiotic product group, and high-dose MP108 probiotic product group, and probiotic interventions lasted for two weeks. After the experiment, the fecal water content, serum diarrhea-related proteins, inflammatory factors, pathological changes of jejunum tissue, and gut microbial alterations were evaluated. The results showed that both the MP108 product group and the high-dose MP108 product group relieved diarrhea symptoms caused by Enterotoxic Escherichia coli (ETEC) via reducing jejunum damage, decreasing the levels of serum inflammatory factors, suppressing the expressions of serum ferritin (ST) and Toll-like receptor 4 (TLR4), and increasing aquaporin 3 (AQP3) levels. Intestinal flora analysis showed that L. rhamnosus MP108 product restored the intestinal microecology and increased the proportions of short-chain fatty acid-producing bacteria including Akkermansia, Ruminococcaceae, Lachnospiraceae. Collectively, L. rhamnosus MP108 probiotic products relieve diarrhea by regulating the expression of diarrhea-related proteins and inflammatory factors and modulating gut microbiota.

Abstract This study evaluated the impact of elevated body mass index (BMI) on short- and long-term outcomes of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments. A total of 7229 patients undergoing IVF/ICSI fresh cycles and subsequent frozen embryo transfer cycles from 2014 to 2020 were divided into normal (18.5–24.9 kg/m2) and high BMI (≥ 25 kg/m2) groups. Ovarian response, pregnancy outcomes, and safety of both mother and fetus were the main outcome measures. Furthermore, multivariate analysis was used to determine whether BMI was associated with cumulative live birth rate (CLBR). Results showed that for younger women (

Abstract Background Next-generation sequencing provides comprehensive information about individuals’ genetic makeup and is commonplace in precision oncology practice. Due to the heterogeneity of individual patient’s disease conditions and treatment journeys, not all targeted therapies were initiated despite actionable mutations. To better understand and support the clinical decision-making process in precision oncology, there is a need to examine real-world associations between patients’ genetic information and treatment choices. Methods To fill the gap of insufficient use of real-world data (RWD) in electronic health records (EHRs), we generated a single Resource Description Framework (RDF) resource, called PO2RDF (precision oncology to RDF), by integrating information regarding genes, variants, diseases, and drugs from genetic reports and EHRs. Results There are a total 2,309,014 triples contained in the PO2RDF. Among them, 32,815 triples are related to Gene, 34,695 triples are related to Variant, 8,787 triples are related to Disease, 26,154 triples are related to Drug. We performed two use case analyses to demonstrate the usability of the PO2RDF: (1) we examined real-world associations between EGFR mutations and targeted therapies to confirm existing knowledge and detect off-label use. (2) We examined differences in prognosis for lung cancer patients with/without TP53 mutations. Conclusions In conclusion, our work proposed to use RDF to organize and distribute clinical RWD that is otherwise inaccessible externally. Our work serves as a pilot study that will lead to new clinical applications and could ultimately stimulate progress in the field of precision oncology.

Abstract Computational drug repurposing methods adapt Artificial intelligence (AI) algorithms for the discovery of new applications of approved or investigational drugs. Among the heterogeneous datasets, electronic health records (EHRs) datasets provide rich longitudinal and pathophysiological data that facilitate the generation and validation of drug repurposing. Here, we present an appraisal of recently published research on computational drug repurposing utilizing the EHR. Thirty-three research articles, retrieved from Embase, Medline, Scopus, and Web of Science between January 2000 and January 2022, were included in the final review. Four themes, (1) publication venue, (2) data types and sources, (3) method for data processing and prediction, and (4) targeted disease, validation, and released tools were presented. The review summarized the contribution of EHR used in drug repurposing as well as revealed that the utilization is hindered by the validation, accessibility, and understanding of EHRs. These findings can support researchers in the utilization of medical data resources and the development of computational methods for drug repurposing.

IntroductionSesame seeds have become an irreplaceable source of edible oils and food products with rich nutrients and a unique flavor, and their metabolite contents and physiological functions vary widely across different seed coat colors. Although the quantitative trait loci (QTLs) for genetic variation in seed coat color have been extensively investigated, the identification of unique genetic loci for intermediate colors such as brown has not been reported due to their complexity.MethodsHere, we crossed the white sesame ‘Yuzhi No. 8’ (YZ8) and the brown sesame ‘Yanzhou Erhongpi’ (YZEHP) to construct a recombinant inbred line (RIL) population with consecutive self-fertilization for ten generations.ResultsThe selfed F1 seeds were brown which was controlled by a dominant gene. Based on the genotyping by whole-genome resequencing of the RILs, a major-effect QTL for brown coat color was identified through both bulk segregant analysis (BSA) and genetic linkage mapping in sesame, which was located within a 1.19 Mb interval on chromosome 6 (qBSCchr6). Moreover, we found that the YZEHP seed coat initially became pigmented at 20 days post-anthesis (DPA) and was substantially colored at 30 DPA. We screened 13 possible candidate genes based on the effects of genetic variants on protein coding and predicted gene functions. Furthermore, qRT‒PCR was used to verify the expression patterns of these genes in different post-anthesis developmental periods. We noted that in comparison to YZ8 seeds, YZEHP seeds had expression of SIN_1023239 that was significantly up-regulated 2.5-, 9.41-, 6.0-, and 5.9-fold at 15, 20, 25, and 30 DPA, respectively, which was consistent with the pattern of brown seed coat pigment accumulation.DiscussionThis study identified the first major-effect QTL for the control of the brown seed coat trait in sesame. This finding lays the foundation for further fine mapping and cloning as well as investigating the regulatory mechanism of seed coat color in sesame.

To improve the utilization value of raspberry leaves, the extraction and purification conditions of phenolic compounds from raspberry leaves were optimized, and the contents of phenolic compounds and the biological activities of extracts were studied. After steam explosion pretreatment at 115 °C for 15 min, raspberry leaf extract with a total phenolic content (TPC) of 136.30~140.51 mg GAE/g was obtained via homogenization and ultrasound-assisted extraction. In addition, the adsorption relationship between raspberry leaf polyphenols and middle polar XDA-6 macroporous resin was best described by the Langmuir model, and tended to be monolayer adsorption. Its adsorption kinetics best resembled the pseudo second-order kinetic model, and it was speculated that this was influenced by multiple factors. According to the optimal integrated extraction–purification process, the TPC of the extracts increased to 738.98 mg GAE/g after one application of purification and 905.27 mg GAE/g after two applications of purification. Moreover, the latter case showed the highest antioxidant activity and α-glucosidase inhibition activity, and the content of the most typical compound, quercetin-3-glucuronide, reached 199.69 mg/g. SE has a double-edged effect, and is more conducive to the release of active substances as a pre-treatment method. This study provides a theoretical basis for the efficient use of raspberry leaves, further improving their medicinal and economic value.

The mechanisms behind the oncogenic role of the PIK3CA helical domain mutant is poorly understood. Here, the authors show that its oncogenic function depends on the release of p85β from mutated p110α, its translocation to the nucleus and the consequent increased activity of EZH proteins.

Abstract Background The emerging epitranscriptome plays an essential role in female fertility. As the most prevalent internal mRNA modification, N6-methyladenine (m6A) methylation regulate mRNA fate and translational efficiency. However, whether m6A methylation was involved in the aging-related ovarian reserve decline has not been investigated. Herein, we performed m6A transcriptome-wide profiling in the ovarian granulosa cells of younger women (younger group) and older women (older group). Results m6A methylation distribution was highly conserved and enriched in the CDS and 3’UTR region. Besides, an increased number of m6A methylated genes were identified in the older group. Bioinformatics analysis indicated that m6A methylated genes were enriched in the FoxO signaling pathway, adherens junction, and regulation of actin cytoskeleton. A total of 435 genes were differently expressed in the older group, moreover, 58 of them were modified by m6A. Several specific genes, including BUB1B, PHC2, TOP2A, DDR2, KLF13, and RYR2 which were differently expressed and modified by m6A, were validated using qRT-PCR and might be involved in the decreased ovarian functions in the aging ovary. Conclusions Hence, our finding revealed the transcriptional significance of m6A modifications and provide potential therapeutic targets to promote fertility reservation for aging women.

Treatments targeted for gut microbial regulation are newly developed strategies in constipation management. In this study, the alleviating effects of gut micro-ecologically regulatory treatments on constipation in mice were investigated. Male BALB/c mice were treated with loperamide to induce constipation, and then the corresponding intervention was administered in each group, respectively. The results showed that administration of mixed probiotics (MP), a 5-fold dose of postbiotics (P5), both synbiotics (S and S2), as well as mixed probiotics and postbiotics (MPP) blend for 8 days shortened the time to the first black stool, raised fecal water content, promoted intestinal motility, and increased serum motilin level in loperamide-treated mice. Furthermore, these treatments altered gut microbial composition and metabolism of short-chain fatty acids (SCFA). Based on linear regression analysis, SCFA was positively correlated with serum motilin except for isobutyrate. It suggested gut microbial metabolites affected secretion of motilin to increase gastrointestinal movement and transportation function and thus improved pathological symptoms of mice with constipation. In conclusion, the alteration of gut micro-ecology is closely associated with gastrointestinal function, and it is an effective way to improve constipation via probiotic, prebiotic, and postbiotic treatment.

Salmonella enterica serovar Typhimurium (S. Typhimurium) has evolved mechanisms to evade the host’s nutritional immunity and thus promote bacterial growth by using the iron in the host. However, the detailed mechanisms of S. Typhimurium induce dysregulation of iron homeostasis and whether Lactobacillus johnsonii L531 can alleviate the iron metabolism disorder caused by S. Typhimurium has not been fully elucidated. Here, we show that S. Typhimurium activated the expression of iron regulatory protein 2 (IRP2), transferrin receptor 1, and divalent metal transporter protein 1 and suppressed the expression of iron exporter ferroportin, which resulted in iron overload and oxidative stress, inhibiting the key antioxidant proteins NF-E2-related factor 2, Heme Oxygenase-1, and Superoxide Dismutase in vitro and in vivo. L. johnsonii L531 pretreatment effectively reversed these phenomena. IRP2 knockdown inhibited iron overload and oxidative damage induced by S. Typhimurium in IPEC-J2 cells, while IRP2 overexpression promoted iron overload and oxidative damage caused by S. Typhimurium. Interestingly, the protective effect of L. johnsonii L531 on iron homeostasis and antioxidant function was blocked following IRP2 overexpression in Hela cells, demonstrating that L. johnsonii L531 attenuates disruption of iron homeostasis and consequent oxidative damage caused by S. Typhimurium via the IRP2 pathway, which contributes to the prevention of S. Typhimurium diarrhea in mice.

Serious environmental problems occur as a result of the unconscious production and use of energy. Hence, there is a strong need to develop an effective energy culture to provide sustainability for the energy investments. This study aims to identify the influence directions of dimensions and criteria for energy culture in emerging economies for sustainable energy investments. For this purpose, a multi-criteria decision-making model is proposed based on 2-tuple linguistic values and interval-valued intuitionistic fuzzy sets. The weighting results of energy culture are also evaluated for E7 economies. The findings demonstrate that energy companies should consider investing in technologies, assets, and objects which enable to reproduce energy usage. Furthermore, the analysis revealed that there is a misalignment of practices with material culture and norms what creates the potential for behavior change of consumers. Finally, the potential of bigger countries for investment opportunities in sustainable energies has been disclosed by ranking emerging economies. The results let us provide insights into development of energy investments by considering strategic priorities of energy culture in emerging economies. The novelty of this paper is to define a set of criteria and dimensions for the strategic priorities of energy culture in emerging economies and construct a novel decision-making technique with DEMATEL and TOPSIS based on 2-tuple and interval-valued intuitionistic fuzzy sets.

DNMT3A mutations play a prominent role in clonal hematopoiesis and myeloid neoplasms with arginine (R)882 as a hotspot, however the clinical implications of R882 vs. non-R882 mutations in myeloid neoplasms like myelodysplastic syndrome (MDS) is unclear. By data mining with publicly accessible cancer genomics databases and a clinical genomic database from a tertiary medical institution, DNMT3A R882 mutations were found to be enriched in AML (53% of all DNMT3A mutations) but decreased in frequency in clonal hematopoiesis of indeterminate potential (CHIP) (10.6%) or other myeloid neoplasms including MDS (27%) (p50 months, p=.009) than non-R882 mutant MDS cases. DNMT3A R882 mutation is an independent risk factor for worse PFS, and importantly the differences in the risk of AML transformation between R882 vs. non-R882 mutant patients cannot be explained by different treatment approaches. Interestingly the higher risk of AML transformation and the worse PFS in DNMT3A R882 mutant MDS cases are mitigated by coexisting SF3B1 or SRSF2 mutations. The unique clinicopathologic features of DNMT3A R882 mutant MDS shed light on the prognostic and therapeutic implications of DNMT3A R882 mutations.

Abstract Glioma is one of the most commonly diagnosed intracranial malignant tumors with extremely high morbidity and mortality, whose treatment was seriously limited because of the unclear molecular mechanism. In this study, in order to identify a novel therapeutic target for glioma treatment, we explored the functions and mechanism of MEX3A in regulating glioma. The immunohistochemical staining of MEX3A in glioma and normal tissues revealed the upregulation of MEX3A and further indicated the relationship between high MEX3A expression and higher malignancy as well as poorer prognosis of glioma. In vitro loss-of-function and gain-of-function experiments comprehensively demonstrated that MEX3A may promote glioma development through regulating cell proliferation, cell apoptosis, cell cycle, and cell migration. In vivo experiments also suggested the inhibition of glioma growth by MEX3A knockdown. Moreover, our mechanistic study identifies CCL2 as a potential downstream target of MEX3A, which possesses similar regulatory effects on glioma development with MEX3A and could attenuate the promotion of glioma induced by MEX3A overexpression. Overall, MEX3A was identified as a potential tumor promoter in glioma development and therapeutic target in glioma treatment.

Abstract Background Next-generation sequencing provides comprehensive information about individuals’ genetic makeup and is commonplace in oncology clinical practice. However, the utility of genetic information in the clinical decision-making process has not been examined extensively from a real-world, data-driven perspective. Through mining real-world data (RWD) from clinical notes, we could extract patients’ genetic information and further associate treatment decisions with genetic information. Methods We proposed a real-world evidence (RWE) study framework that incorporates context-based natural language processing (NLP) methods and data quality examination before final association analysis. The framework was demonstrated in a Foundation-tested women cancer cohort (N = 196). Upon retrieval of patients’ genetic information using NLP system, we assessed the completeness of genetic data captured in unstructured clinical notes according to a genetic data-model. We examined the distribution of different topics regarding BRCA1/2 throughout patients’ treatment process, and then analyzed the association between BRCA1/2 mutation status and the discussion/prescription of targeted therapy. Results We identified seven topics in the clinical context of genetic mentions including: Information, Evaluation, Insurance, Order, Negative, Positive, and Variants of unknown significance. Our rule-based system achieved a precision of 0.87, recall of 0.93 and F-measure of 0.91. Our machine learning system achieved a precision of 0.901, recall of 0.899 and F-measure of 0.9 for four-topic classification and a precision of 0.833, recall of 0.823 and F-measure of 0.82 for seven-topic classification. We found in result-containing sentences, the capture of BRCA1/2 mutation information was 75%, but detailed variant information (e.g. variant types) is largely missing. Using cleaned RWD, significant associations were found between BRCA1/2 positive mutation and targeted therapies. Conclusions In conclusion, we demonstrated a framework to generate RWE using RWD from different clinical sources. Rule-based NLP system achieved the best performance for resolving contextual variability when extracting RWD from unstructured clinical notes. Data quality issues such as incompleteness and discrepancies exist thus manual data cleaning is needed before further analysis can be performed. Finally, we were able to use cleaned RWD to evaluate the real-world utility of genetic information to initiate a prescription of targeted therapy.

This study aims to evaluate the innovation adoption performance of the renewable energy alternatives. Within this context, a new model is created that consists of two different stages. Firstly, the decision combinations of innovation adoption life cycle patterns are identified by considering integer code series. On the other side, in the second stage, the innovation adoption life cycle performance of the renewable energy alternatives is ranked. In this framework, interval type-2 (IT2) fuzzy technique for order preference by similarity to ideal solution (TOPSIS) methodology is taken into consideration based on alpha cut levels. Moreover, a comparative evaluation is also conducted by considering IT2 fuzzy VIseKriterijumska Optimizacija I Kompromisno Resenje (VIKOR). It is identified that the analysis results are quite coherent and reliable. The findings demonstrate that solar energy is the most appropriate renewable energy type to make innovation. Additionally, wind and geothermal energies are also other significant renewable energy types that have a great innovation potential. However, it is also concluded that biomass and hydroelectric energy have lower importance in comparison with the others. Another important point is that the ranking results are quite similar for different alpha cuts. This condition indicates that the analysis results are coherent and reliable. It is obvious that making investment to solar energy alternatives provides opportunity to adopt technologic innovation more easily. Therefore, it is recommended that investors should give priority to solar energy projects so that it can be more possible to increase the efficiency and the profitability of the investments.

Halomonas bluephagenesis is a halophilic platform bacterium for next generation industrial biotechnology. Here, the authors employ a stimulus response-based flux-tuning method for coproduction of bioplastic PHB and ectoine under open unsterile and continuous growth conditions.

Background: In vitro maturation (IVM) is a technology designed to obtain mature oocytes following culture of immature cumulus–oocyte complexes (COC) in vitro. IVM is characterized by minimal patient stimulation, making it attractive for patients with excessive AFC or those requiring immediate fertility preservation. However, the clinical uptake of IVM has been slow, primarily due to lower embryo yield and live birth rate relative to IVF, therefore improving IVM culture is required. Aim: To assess whether supplementation of IVM culture medium with the novel in-house engineered TGFβ proteins cumulin and super-GDF9 improves subsequent embryo development. Method: Immature mouse COCs were cultured by standard IVM or bi-phasic IVM ± cumulin or super-GDF9. Following IVM, cumulus expansion was scored and COCs were fertilized, and cultured to assess embryo development. Differential staining was performed on day 6 blastocysts following bi-phasic IVM to assess cell allocation. In a separate experiment, hyperspectral imaging of autofluorescence was carried out on oocytes and cumulus cells following standard IVM ± cumulin to assess the molecular composition of these cells. Results: Both cumulin and super-GDF9 in standard IVM significantly increased cumulus expansion (P

Purpose The depth and breadth of clinical data within electronic health record (EHR) systems paired with innovative machine learning methods can be leveraged to identify novel risk factors for complex diseases. However, analysing the EHR is challenging due to complexity and quality of the data. Therefore, we developed large electronic population-based cohorts with comprehensive harmonised and processed EHR data.Participants All individuals 30 years of age or older who resided in Olmsted County, Minnesota on 1 January 2006 were identified for the discovery cohort. Algorithms to define a variety of patient characteristics were developed and validated, thus building a comprehensive risk profile for each patient. Patients are followed for incident diseases and ageing-related outcomes. Using the same methods, an independent validation cohort was assembled by identifying all individuals 30 years of age or older who resided in the largely rural 26-county area of southern Minnesota and western Wisconsin on 1 January 2013.Findings to date For the discovery cohort, 76 255 individuals (median age 49; 53% women) were identified from which a total of 9 644 221 laboratory results; 9 513 840 diagnosis codes; 10 924 291 procedure codes; 1 277 231 outpatient drug prescriptions; 966 136 heart rate measurements and 1 159 836 blood pressure (BP) measurements were retrieved during the baseline time period. The most prevalent conditions in this cohort were hyperlipidaemia, hypertension and arthritis. For the validation cohort, 333 460 individuals (median age 54; 52% women) were identified and to date, a total of 19 926 750 diagnosis codes, 10 527 444 heart rate measurements and 7 356 344 BP measurements were retrieved during baseline.Future plans Using advanced machine learning approaches, these electronic cohorts will be used to identify novel sex-specific risk factors for complex diseases. These approaches will allow us to address several challenges with the use of EHR.

Abstract Background Existing resources to assist the diagnosis of rare diseases are usually curated from the literature that can be limited for clinical use. It often takes substantial effort before the suspicion of a rare disease is even raised to utilize those resources. The primary goal of this study was to apply a data-driven approach to enrich existing rare disease resources by mining phenotype-disease associations from electronic medical record (EMR). Methods We first applied association rule mining algorithms on EMR to extract significant phenotype-disease associations and enriched existing rare disease resources (Human Phenotype Ontology and Orphanet (HPO-Orphanet)). We generated phenotype-disease bipartite graphs for HPO-Orphanet, EMR, and enriched knowledge base HPO-Orphanet + and conducted a case study on Hodgkin lymphoma to compare performance on differential diagnosis among these three graphs. Results We used disease-disease similarity generated by the eRAM, an existing rare disease encyclopedia, as a gold standard to compare the three graphs with sensitivity and specificity as (0.17, 0.36, 0.46) and (0.52, 0.47, 0.51) for three graphs respectively. We also compared the top 15 diseases generated by the HPO-Orphanet + graph with eRAM and another clinical diagnostic tool, the Phenomizer. Conclusions Per our evaluation results, our approach was able to enrich existing rare disease knowledge resources with phenotype-disease associations from EMR and thus support rare disease differential diagnosis.

At present, the polarization of online public opinion is becoming more frequent, and individuals actively participate in attitude interactions more and more frequently. Thus, online views have become the dominant force in current public opinion. However, the rapid fermentation of polarized public opinion makes it very easy for actual topic views to go to extremes. Significantly, negative information seriously affects the healthy development of the social opinion ecology. Therefore, it is beneficial to maintain national credibility, social peace, and stability by exploring the communication structure of online public opinions, analyzing the logical model of extreme public attitudes, and guiding the communication of public opinions in a timely and reasonable manner. Starting from the J–A model and BA network, this paper explores the specific attributes of individuals and opinion network nodes. By incorporating parameters such as individual conformity and the strength of individual online relationships, we established a model of online group attitude polarization, then conducted simulation experiments on the phenomenon of online opinion polarization. Through simulations, we found that individual conformity and the difference in environmental attitude greatly influence the direction of opinion polarization events. In addition, crowd mentality makes individuals spontaneously choose the side of a particular, extreme view, which makes it easier for polarization to form and reach its peak.

Cancer vaccine is widely considered as a powerful tool in immunotherapy. In particular, the effective antigen processing and presentation natures of dendritic cell (DC) have made it a promising target for the development of therapeutic vaccine for cancer treatment. Here in our study, a versatile cancer cell membrane (CCM) coated calcium carbonate (CC) nanoparticles (MC) that capable of generating in situ tumor-associated antigens (TAAs) for DC vaccination is developed. Low-dose doxorubicin hydrochloride (Dox) could be encapsulated in the CC core of MC to trigger immunogenic cell death (ICD) while chlorins e6 (Ce6), a commonly adopted photosensitizer, was loaded in the CCM of MC for effective photodynamic therapy (PDT) through the generation of reactive oxygen species (ROS) to finally construct the vaccine (MC/Dox/Ce6). Most importantly, our in-depth study revealed the treatment of MC/Dox/Ce6 was able to elicit TAAs population and DC recruitment, triggering the following immune response cascade. In particular, the recruited DC cells could be stimulated in situ for effective vaccinations. Both in vitro and in vivo experiments suggested the capability of this all-in-one DDS to enhance DCs maturation to finally result in effective inhibition of both primary and distant growth of breast cancer upon single administration of low dose Dox and Ce6.

Summary: Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals. : Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine. Keywords: oocyte, nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN), SIRT2, female fertility, infertility, reproductive aging, aging, embryo development, in vitro fertilization

Abstract Background The use of knowledge models facilitates information retrieval, knowledge base development, and therefore supports new knowledge discovery that ultimately enables decision support applications. Most existing works have employed machine learning techniques to construct a knowledge base. However, they often suffer from low precision in extracting entity and relationships. In this paper, we described a data-driven sublanguage pattern mining method that can be used to create a knowledge model. We combined natural language processing (NLP) and semantic network analysis in our model generation pipeline. Methods As a use case of our pipeline, we utilized data from an open source imaging case repository, Radiopaedia.org , to generate a knowledge model that represents the contents of medical imaging reports. We extracted entities and relationships using the Stanford part-of-speech parser and the “Subject:Relationship:Object” syntactic data schema. The identified noun phrases were tagged with the Unified Medical Language System (UMLS) semantic types. An evaluation was done on a dataset comprised of 83 image notes from four data sources. Results A semantic type network was built based on the co-occurrence of 135 UMLS semantic types in 23,410 medical image reports. By regrouping the semantic types and generalizing the semantic network, we created a knowledge model that contains 14 semantic categories. Our knowledge model was able to cover 98% of the content in the evaluation corpus and revealed 97% of the relationships. Machine annotation achieved a precision of 87%, recall of 79%, and F-score of 82%. Conclusion The results indicated that our pipeline was able to produce a comprehensive content-based knowledge model that could represent context from various sources in the same domain.

Sleep quality, diet quality, and physical activity are significant factors influencing physical and mental health. However, few studies have explored their underlying mechanisms, especially among the elderly population in East Asia, where people have food culture and lifestyles distinct from those living in Western countries. Therefore, the current study aimed to explore the relationships among sleep quality, diet quality, physical activity, and physical and mental health in a Chinese elderly sample. Sleep quality, diet quality, physical activity, physical health, and mental health were investigated among 313 Chinese elderly (aged 51–92 years, M = 67.90, SD = 7.94). Mediation analysis was used to examine the empirical model based on previous theories and literature. Close positive relationships were observed between all factors investigated (r = 0.22~0.73, p < 0.001). The relationships between sleep quality and physical and mental health were partially mediated by diet quality and physical activity. In clinical interventions, sleep quality, diet quality, and physical activity can be targeted to improve physical and mental health among the older adult populations.

The FHY3/FAR1 transcription factor family, derived from transposases, plays important roles in light signal transduction, and in the growth and development of plants. However, the homologous genes in tea plants have not been studied. In this study, 25 CsFHY3/FAR1 genes were identified in the tea plant genome through a genome-wide study, and were classified into five subgroups based on their phylogenic relationships. Their potential regulatory roles in light signal transduction and photomorphogenesis, plant growth and development, and hormone responses were verified by the existence of the corresponding cis-acting elements. The transcriptome data showed that these genes could respond to salt stress and shading treatment. An expression analysis revealed that, in different tissues, especially in leaves, CsFHY3/FAR1s were strongly expressed, and most of these genes were positively expressed under salt stress (NaCl), and negatively expressed under low temperature (4 °C) stress. In addition, a potential interaction network demonstrated that PHYA, PHYC, PHYE, LHY, FHL, HY5, and other FRSs were directly or indirectly associated with CsFHY3/FAR1 members. These results will provide the foundation for functional studies of the CsFHY3/FAR1 family, and will contribute to the breeding of tea varieties with high light efficiency and strong stress resistance.

BACKGROUND:It is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes. METHODS AND FINDINGS:We analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes. CONCLUSIONS:We demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery.

Obesity is a risk factor for many human diseases. However, the underlying molecular causes of obesity are not well understood. Here, we report that protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat diet-induced obesity. Those mice avoid many deleterious side effects of high-fat diet-induced obesity, displaying improved peripheral insulin sensitivity, lower blood glucose and insulin levels. Compared to wild type littermates, PTPRT knockout mice show reduced food intake. Consistently, STAT3 phosphorylation is up-regulated in the hypothalamus of PTPRT knockout mice. These studies implicate PTPRT-modulated STAT3 signaling in the regulation of high-fat diet-induced obesity.