Clinical and genetic characterization of Epstein-Barr virus-associated T/NK-cell lymphoproliferative diseases.

BACKGROUND: Epstein-Barr virus (EBV)-associated T-/natural killer (T/NK)-cell lymphoproliferative diseases clinically take on various forms, ranging from an indolent course to an aggressive condition. OBJECTIVE: Clinically, failure to establish precise diagnosis and provide proper treatment makes it difficult to help patients. We sought to better understand the underlying pathogenesis and to identify genetic prognostic factors to achieve better treatment efficacy. METHODS: In this study, 119 cases of EBV-associated lymphoproliferative diseases, including EBV-associated hemophagocytic lymphohistiocytosis (n = 46) and chronic active EBV disease of T/NK cell type (n = 73), were retrospectively examined. RESULTS: Adults aged >20 years at onset accounted for 71.4% of our cohort. About 54.6% patients with unfavorable overall survival developed hemophagocytic lymphohistiocytosis and had higher plasma EBV load. Allogenic hematopoietic stem-cell transplantation was the sole independent favorable factor. We systematically screened germline and somatic aberrations by whole-exome and targeted sequencing. Among 372 antiviral immunity genes, germline variants of 8 genes were significantly enriched. From a panel of 24 driver genes, somatic mutations were frequently identified in dominant EBV-infected T/NK cells. Patients carrying any germline/somatic aberrations in epigenetic modifiers and RIG-I-like receptor (RLR) pathway had worse overall survival than those without 2 type aberrations. Importantly, patients with IFIH1 and/or DDX3X aberrations in the RLR pathway had higher plasma and NK-cell EBV load. Knockdown of DDX3X in NKYS cells downregulated RLR signaling activities and elevated the expression of EBV-encoded oncogenes such as LMP1 and EBNA1. CONCLUSION: Genetic defects were prevalent in adult EBV-associated hemophagocytic lymphohistiocytosis patients and patients with chronic active EBV disease of T/NK cell type; these defects were associated with unfavorable prognosis. These findings can help clinicians work out more precise staging of the condition and provide new insights into these EBV-associated diseases.

Nitrate reduction to nitrogen in wastewater using mesoporous carbon encapsulated Pd-Cu nanoparticles combined with in-situ electrochemical hydrogen evolution.

The conversion of NO3--N to N2 is of great significance for zero discharge of industrial wastewater. Pd-Cu hydrogenation catalysis has high application prospects for the reduction of NO3--N to N2, but the existing form of Pd-Cu, the Pd-Cu mass ratio and the H2 evolution rate can affect the coverage of active hydrogen (*H) on the surface of Pd, thereby affecting N2 selectivity. In this work, mesoporous carbon (MC) is used as support to disperse Pd-Cu catalyst and is applied in an in-situ electrocatalytic H2 evolution system for NO3--N removal. The Pd-Cu particles with the average size of 6 nm are uniformly encapsulated in the mesopores of MC. Electrochemical in-situ H2 evolution can not only reduce the amount of H2 used, but the H2 bubbles can also be efficiently dispersed when PPy coated nickel foam (PPy/NF) is used as cathode. Moreover, the mesoporous structure of MC can further split H2 bubbles, reducing the coverage of *H on Pd. The highest 77% N2 selectivity and a relatively faster NO3--N removal rate constant (0.10362 min-1) can be achieved under the optimal conditions, which is superior to most reported Pd-Cu catalytic systems. The prepared catalyst is further applied to the denitrification of actual deplating wastewater. NO3--N with the initial concentration of 650 mg L-1 can be completely removed after 180 min of treatment, and the TN removal can be maintained at 72%.

Constructing High-performance Cobalt-based Environmental Catalysts from Spent Lithium-Ion Batteries: Unveiling Overlooked Roles of Copper and Aluminum from Current Collectors.

Converting spent lithium-ion batteries (LIBs) cathode materials into environmental catalysts has drawn more and more attention. Herein, we fabricated a Co3O4-based catalyst from spent LiCoO2 LIBs (Co3O4-LIBs) and found that the role of Al and Cu from current collectors on its performance is nonnegligible. The density functional theory calculations confirmed that the doping of Al and/or Cu upshifts the d-band center of Co. A Fenton-like reaction based on peroxymonosulfate (PMS) activation was adopted to evaluate its activity. Interestingly, Al doping strengthened chemisorption for PMS (from -2.615 eV to -2.623 eV) and shortened Co-O bond length (from 2.540 Å to 2.344 Å) between them, whereas Cu doping reduced interfacial charge-transfer resistance (from 28.347 kΩ to 6.689 kΩ) excepting for the enhancement of the above characteristics. As expected, the degradation activity toward bisphenol A of Co3O4-LIBs (0.523 min-1) was superior to that of Co3O4 prepared from commercial CoC2O4 (0.287 min-1). Simultaneously, the reasons for improved activity were further verified by comparing activity with catalysts doped Al and/or Cu into Co3O4. This work reveals the role of elements from current collectors on the performance of functional materials from spent LIBs, which is beneficial to the sustainable utilization of spent LIBs.

How to handle a delayed or missed dose of edoxaban in patients with non-valvular atrial fibrillation? A model-informed remedial strategy.

AIMS: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for the long-term prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOAC therapy has been unsatisfactory and decreases over time. Remedial strategies are currently used to address the non-adherence events. Current recommendations, however, are generic and not well supported by evidence. The aim of this study was to explore appropriate remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through Monte Carlo simulation. METHODS: Six regimens were compared with the current recommendations of the European Heart Rhythm Association (EHRA) guide based on total deviation time. Both edoxaban plasma concentration and intrinsic Factor Xa activity were considered. Monte Carlo simulations were performed using RxODE based on a published population pharmacokinetic/pharmacodynamic (PK/PD) model. RESULTS: The proposed remedial strategies were different than the EHRA recommendations and were related to the delay time. However, it was found that the missed dose can be administered immediately if the delay time is within 11 h. When the delay is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred. CONCLUSION: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which can help maximise its therapeutic effect.

Abatement of Aromatic Contaminants from Wastewater by a Heat/Persulfate Process Based on a Polymerization Mechanism.

A novel approach to the abatement of pollutants consisting of their conversion to separable solid polymers is explored by a heat/persulfate (PDS) process for the treatment of high-temperature wastewaters. During this process, a simultaneous decontamination and carbon recovery can be achieved with minimal use of PDS, which is significantly different from conventional degradation processes. The feasibility of this process is demonstrated by eight kinds of typical organic pollutants and by a real coking wastewater. For the treatment of the selected pollutants, 30.2-91.9% DOC abatement was achieved with 24.8-91.2% carbon recovery; meanwhile, only 5.2-47.0% of PDS was consumed compared to a conventional degradation process. For the treatment of a real coking wastewater, 71.0% DOC abatement was achieved with 66.0% carbon recovery. With phenol as a representative compound, our polymerization-based heat/PDS process is applicable in a wide pH range (3.5-9.0) with a carbon recovery of >87%. Both SO4•- and HO• can be initiators for polymerization, with different contribution ratios under various conditions. Phenol monomers are semioxidized to form phenolic radicals, which are polymerized via chain transfer or chain growth processes to form separable solid phenol polymers, benzenediol polymers, and cross-linked polymers.

Highly Dispersed FeAg-MCM41 Catalyst for Medium-Temperature Hydrogen Sulfide Oxidation in Coke Oven Gas.

The traditional hydrolysis-cooling-adsorption process for coke oven gas (COG) desulfurization urgently needs to be improved because of its complex nature and high energy consumption. One promising alternative for replacing the last two steps is selective catalytic oxidation. However, most catalysts used in selective catalytic oxidation require a high temperature to achieve effective desulfurization. Herein, a robust 30Fe-MCM41 catalyst is developed for direct desulfurization at medium temperatures after hydrolysis. This catalyst exhibits excellent stability for over 300 h and a high breakthrough sulfur capacity (2327.6 mgS gcat-1). Introducing Ag into the 30Fe-MCM41 (30Fe5Ag-MCM41) catalyst further enhances the H2S removal efficiency and sulfur selectivity at 120 °C. Its outstanding performance can be attributed to the synergistic effect of Fe-Ag clusters. During H2S selective oxidation, Fe serves as the active site for H2S adsorption and dissociation, while Ag functions as the catalyst promoter, increasing Fe dispersion, reducing the oxidation capacity of the catalyst, improving the desorption capacity of sulfur, and facilitating the reaction between active oxygen species and [HS]. This process provides a potential route for enhancing COG desulfurization.

Aberrant Spontaneous Brain Activity and its Association with Cognitive Function in Non-Obese Nonalcoholic Fatty Liver Disease: A Resting-State fMRI Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been proven to be associated with an increased risk of cognitive impairment and dementia, and this association is more significant in non-obese NAFLD populations, but its pathogenesis remains unclear. Our study aimed to explore the abnormalities of spontaneous brain activity in non-obese NAFLD patients by resting-state fMRI (RS-fMRI) and their relationship with cognitive function. METHODS: 19 non-obese NAFLD, 25 obese NAFLD patients, and 20 healthy controls (HC) were enrolled. All subjects underwent RS-fMRI scan, psychological scale assessment, and biochemical examination. After RS-fMRI data were preprocessed, differences in low-frequency fluctuation amplitude (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were compared among the three groups. Furthermore, the relationship between RS-fMRI indicators and cognitive and clinical indicators were performed using correlation analysis. RESULTS: The cognitive function was declined in both NAFLD groups. Compared with obese NAFLD patients, non-obese NAFLD patients showed increased ALFF and ReHo in the left middle temporal gyrus (MTG), increased ReHo in the sensorimotor cortex and reduced FC between left MTG and right inferior frontal gyrus (IFG). Compared with HC, non-obese NAFLD patients showed increased ALFF and ReHo in the left calcarine cortex and fusiform gyrus (FG), decreased ALFF in the bilateral cerebellum, and reduced FC between left FG and right IFG and left angular gyrus. In addition to the same results, obese patients showed increased activity in different regions of the bilateral cerebellum, while decreased ALFF in the right superior frontal gyrus and ReHo in the right orbitofrontal cortex (OFC). Correlation analysis showed that in non-obese patients, the ALFF values in the FG and the FC values between the left MTG and the right IFG were associated with cognitive decline, insulin resistance, and fasting glucose disorder. CONCLUSIONS: Non-obese NAFLD patients showed abnormal local spontaneous activity and FC in regions involved in the sensorimotor, temporo-occipital cortex, cerebellum, and reward system (such as OFC), some of which may be the potential neural mechanism difference from obese NAFLD patients. In addition, the temporo-occipital cortex may be a vulnerable target for cognitive decline in non-obese NAFLD patients.

A preoperative predictive model for stage IV endometriosis.

This was a retrospective study that evaluated a total of 280 patients who underwent surgery for complete removal of endometriosis to develop and validate the predictive model for stage IV endometriosis. The differences between stage I-III and stage IV endometriosis were performed by logistic regression. A model for the prediction of stage IV endometriosis was constructed, which was subsequently validated. The independent variables were visual analogue scale (VAS)≥4 [3.855, 95% confidence interval (CI): 1.675-8.871, p = 0.002], painful nodularity on uterosacral ligaments (13.954, 95% CI: 1.658-117.423, p = 0.015), and bilateral endometriosis (5.933, 95% CI: 1.931-18.225, p = 0.002). The AUC of the model was 0.777, with a sensitivity of 71.9% and specificity of 76.3% for stage IV endometriosis. Therefore, a complete collection of patient information prior to surgery, asking about pain and VAS scores, careful completion of pelvic examinations, and application of imaging techniques are conducive to better diagnosis and prediction of advanced endometriosis.IMPACT STATEMENTWhat is already known on this subject? Endometriosis, a chronic disease causing pain and infertility, is characterised by endometrial-like tissue outside the uterine cavity, which is often treated via surgery at present. Considering the risks of surgery, it is necessary to identify patients with stage IV endometriosis through non-invasive predictive models for adequate preparation for surgery. However, there is no reliable non-invasive predictive model now, despite utilisation of patient medical history, symptoms especially pain-related ones, pelvic examinations, laboratory examinations, and images in the preoperative diagnosis of endometriosis in the clinic.What do the results of this study add? A model developed based on three simple, accessible and non-invasive indicators displays good performance in predicting stage IV endometriosis.What are the implications of these findings for clinical practice and/or further research? It is conducive to diagnosing and predicting advanced endometriosis before surgery, so as to reduce the difficulty and improve the safety of surgery.

Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental validation.

CONTEXT: Dihydromyricetin (DMY) is extracted from vine tea, a traditional Chinese herbal medicine with anti-cancer, liver protection, and cholesterol-lowering effects. OBJECTIVE: This study investigated the mechanism of DMY against hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Potential DMY, HCC, and cholesterol targets were collected from relevant databases. PPI networks were created by STRING. Then, the hub genes of co-targets, screened using CytoHubba. GO and KEGG pathway enrichment, were performed by Metascape. Based on the above results, a series of in vitro experiments were conducted by using 40-160 µM DMY for 24 h, including transwell migration/invasion assay, western blotting, and Bodipy stain assay. RESULTS: Network pharmacology identified 98 common targets and 10 hub genes of DMY, HCC, and cholesterol, and revealed that the anti-HCC effect of DMY may be related to the positive regulation of lipid rafts. Further experiments confirmed that DMY inhibits the proliferation, migration, and invasion of HCC cells and reduces their cholesterol levels in vitro. The IC50 is 894.4, 814.4, 467.8, 1,878.8, 151.8, and 156.9 µM for 97H, Hep3B, Sk-Hep1, SMMC-7721, HepG2, and Huh7 cells, respectively. In addition, DMY downregulates the expression of lipid raft markers (CAV1, FLOT1), as well as EGFR, PI3K, Akt, STAT3, and Erk. DISCUSSION AND CONCLUSION: The present study reveals that DMY suppresses EGFR and its downstream pathways by reducing cholesterol to disrupt lipid rafts, thereby inhibiting HCC, which provides a promising candidate drug with low toxicity for the treatment of HCC.

[Structural characterization of PCP-â from Poria as vaccine adjuvant and its hydrolytic oligosaccharide].

Poria is an important medical herb in clinic. The authors isolated a polysaccharide(PCP-Ⅰ) from Poria in previous studies, which is composed of galactose, mannose, fucose and glucose. PCP-Ⅰ exhibited significant adjuvant effects on H1N1 influenza vaccine, hepatitis B surface antigen and anthrax protective antigen, and its adjuvant activity was stronger than aluminium adjuvant. However, little is known about the chemical structure of PCP-Ⅰ at present. In this study, weak acid hydrolysis was used to obtain the backbone oligosaccharide of PCP-Ⅰ. Then periodate oxidation, Smith degradation, methylation analysis, Fourier transform infrared spectroscopy(FT-IR), nuclear magnetic resonance(NMR) and gas chromatography-mass spectrometry(GC-MS) were performed to investigate the chemical structural features of PCP-Ⅰ and its hydrolytic oligosaccharide(PCP-Ⅰ-hy-1). These results suggested that the backbone of PCP-Ⅰ was composed of galactose with α anomeric carbon and ß anomeric carbon. The linking residues of galactan are(1→),(l→6) and(1→2,6).

[Serum metabolomics study of Psoraleae Fructus in improving learning and memory ability of APP/PS1 mice].

This study aimed to investigate the mechanism of Psoraleae Fructus in improving the learning and memory ability of APP/PS1 mice by serum metabolomics, screen the differential metabolites of Psoraleae Fructus on APP/PS1 mice, and reveal its influence on the metabolic pathway of APP/PS1 mice. Thirty 3-month-old APP/PS1 mice were randomly divided into a model group and a Psoraleae Fructus extract group, and another 15 C57BL/6 mice of the same age were assigned to the blank group. The learning and memory ability of mice was evaluated by the Morris water maze and novel object recognition tests, and metabolomics was used to analyze the metabolites in mouse serum. The results of the Morris water maze test showed that Psoraleae Fructus shortened the escape latency of APP/PS1 mice(P<0.01), and increased the number of platform crossing and residence time in the target quadrant(P<0.01). The results of the novel object recognition test showed that Psoraleae Fructus could improve the novel object recognition index of APP/PS1 mice(P<0.01). Eighteen differential metabolites in serum were screened out by metabolomics, among which the levels of arachidonic acid, tryptophan, and glycerophospholipid decreased after drug administration, while the levels of glutamyltyrosine increased after drug administration. The metabolic pathways involved included arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and glycerolipid metabolism. Therefore, Psoraleae Fructus can improve the learning and memory ability of APP/PS1 mice, and its mechanism may be related to the effects in promoting energy metabolism, reducing oxidative damage, protecting central nervous system, reducing neuroinflammation, and reducing Aß deposition. This study is expected to provide references for Psoraleae Fructus in the treatment of Alzheimer's disease(AD) and further explain the mechanism of Psoraleae Fructus in the treatment of AD.

Interaction of SOX5 with SOX9 promotes warfarin-induced aortic valve interstitial cell calcification by repressing transcriptional activation of LRP6.

Calcific aortic valve disease (CAVD) is an important health burden due to its increasing prevalence and lack of available approaches. Osteogenic transdifferentiation of aortic valve interstitial cells (AVICs) contributes to valve calcification. SRY-related HMG-box transcription factor 5 (SOX5) is essential for cartilage development. Whether SOX5 is involved in AVIC calcification has not been determined. This study aimed to explore the role of SOX5 in warfarin-induced AVIC calcification. Immunostaining showed decreased SOX5 in human calcific AV and warfarin induced mouse calcific AV tissues compared with human noncalcific AV and control mouse AV tissues. In calcific human AVICs (hAVICs) and porcine AVICS (pAVICs), both knockdown and overexpression of SOX5 inhibited calcium deposition and osteogenic marker gene expression. Protein expression assays and ChIP assays showed that overexpression of SOX5 led to increased recruitment of SOX5 to the SOX9 promoter and resulted in increased mRNA and protein expression of SOX9. Coimmunoprecipitation and immunofluorescence showed that SOX5 binds to SOX9 with its HMG domain in nucleus. Blue Native PAGE showed overexpression of SOX5 led to multimeric complex formation of SOX5 and resulted in decreased binding of SOX5 to SOX9 similar to the results of knockdown of SOX5. Further ChIP and western blotting assays showed that both knockdown and overexpression of SOX5 resulted in SOX9 initiating transcription of anti-calcific gene LRP6 in warfarin-treated pAVICs. Knockdown of LRP6 rescues the anti-calcification effect of SOX5 overexpression. We found that both loss and gain of function of SOX5 lead to the same phenotype: decreased warfarin induced calcification. The stoichiometry of SOX5 is crucial for cooperation with SOX9, SOX9 nuclear localization and subsequent binding of SOX9 to LRP6 promoter. These results suggest that SOX5 is a potential target for the development of anti-calcification therapy.

Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation.

BACKGROUND: Circular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure. METHODS: RNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments. RESULTS: Here, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/ß-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 - + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin-proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with ß-catenin protein was enhanced via suppressing the ß-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus. CONCLUSION: Our findings manifested a novel circMTCL1-C1QBP-ß-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC.

The causal association between smoking, alcohol consumption and risk of bladder cancer: A univariable and multivariable Mendelian randomization study.

Smoking and alcohol consumption are associated with bladder cancer risk in observational studies. We conducted a two-sample univariable and multivariable Mendelian randomization (MR) analysis to determine whether those associations are causal. We used 21, 126, 360, 39 single nucleotide polymorphisms (SNPs) as instrumental variables for number of cigarettes per day, lifetime smoking index, smoking initiation, and drinks per week, respectively. A total of 1115 cases with bladder cancer and 174 006 noncases from FinnGen consortium and 2883 cases with bladder cancer and 417 955 noncases from UK Biobank study were obtained. Genetic predisposition to cigarettes per day, lifetime smoking index and smoking initiation were positively associated with an increased risk of bladder cancer in both the FinnGen and UK Biobank consortium. The summary odds ratio (OR) of bladder cancer was 1.79 (95% confidence interval [CI], 1.31-2.45; P = .0002), 2.38 (95% CI, 1.45-3.88; P = .0005) and 1.91 (95% CI, 1.46-2.50; P = 1.59 × 10-06 ) for one SD increase in the number of cigarettes per day, lifetime smoking index and smoking initiation, respectively. The genetically instrumented number of drinks per week was not associated with bladder cancer (OR = 0.69; 95% CI, 0.44-1.10; P = .1237). Estimates were consistent in multivariable MR analyses by the adjustments of body mass index and education. Our study suggests a causal potential of the association of smoking but not alcohol consumption with bladder cancer according to current evidence.

Both indirect maternal and direct fetal genetic effects reflect the observational relationship between higher birth weight and lower adult bone mass.

BACKGROUND: Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass. METHODS: We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables. RESULTS: In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, ß-coefficient= 0.17, P < 2.00 × 10-16; lateral spine, ß-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) (lumbar spine, ß-coefficient= - 0.01, P = 2.27 × 10-14; lateral spine, ß-coefficient = - 0.05, P = 0.001), and decrease adult bone mineral density (BMD) (lumbar spine, ß-coefficient = - 0.04, P = 0.007; lateral spine; ß-coefficient = - 0.03, P = 0.02; heel, ß-coefficient = - 0.06, P < 2.00 × 10-16), and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area (lumbar spine; ß-coefficient = 0.15, P = 1.26 × 10-6, total hip, ß-coefficient = 0.15, P = 0.005; intertrochanteric area, ß-coefficient = 0.13, P = 0.0009; trochanter area, ß-coefficient = 0.11, P = 0.03) but lower BMD (lumbar spine, ß-coefficient = - 0.10, P = 0.01; lateral spine, ß-coefficient = - 0.12, P = 0.0003, and heel ß-coefficient = - 0.11, P = 3.33 × 10-13). In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD (ß-coefficient = - 0.001, P = 0.04). CONCLUSIONS: The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.

A high-performance SNP panel developed by machine-learning approaches for characterizing genetic differences of Southern and Northern Han Chinese, Korean, and Japanese individuals.

Population stratification analyses targeting genetically closely related East Asians have revealed that distinguishable differentiation exists between Han Chinese, Korean, and Japanese individuals, as well as between southern (S-) and northern (N-) Han Chinese. Previous studies offer a number of choices for ancestry informative single nucleotide polymorphisms (AISNPs) to discriminate East-Asian populations. In this study, we collected and examined the efficiency of 1185 AISNPs using frequency and genotype data from various publicly available databases. With the aim to perform fine-scale classification of S-Han, N-Han, Korean, and Japanese subjects, machine-learning methods (Softmax and Random Forest) were used to screen a panel of highly informative AISNPs and to develop a superior classification model. Stepwise classification was implemented to increase and balance the discrimination in the process of AISNP selection, first discriminating Han, Korean, and Japanese individuals, and then characterizing stratification between S-Han and N-Han. The final 272-AISNP panel is an alternative optimization of various previous works, which promises reliable and >90% accuracy in classification of the four East-Asian groups. This AISNP panel and the machine-learning model could be a useful and superior choice in medical genome-wide association studies and in forensic investigations for unknown suspect identity.

Detection of cytomegalovirus (CMV) by digital PCR in stool samples for the non-invasive diagnosis of CMV gastroenteritis.

BACKGROUND: CMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research. METHODS: In this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure. RESULTS: Twenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R2 = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/µL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation. CONCLUSION: The combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making.

Mechanical Insights into Activation of Peroxides by Quinones: Formation of Oxygen-Centered Radicals or Singlet Oxygen.

In this work, the mechanism of the activation of peroxides by quinones has been investigated through quantum chemical calculations. Hydrogen peroxide (H2O2), peroxomonosulfate (PMS), peracetic acid (PAA), and CH3OOH were chosen as the model peroxides and p-benzoquinone (p-BQ) and tetrachloro-1,4-benzoquinone (TCBQ) as the model quinones. The nucleophilic attack of peroxides can occur on the carbonyl and olefinic carbons of quinones. For p-BQ, the nucleophilic attack of HO2-, CH3OO-, PMS, and PAA might prefer to occur on the carbonyl carbons, which have more positive atomic charges. Then, further transformation could not be induced from the addition of HO2- and CH3OO- to p-BQ. Comparatively, singlet oxygen (1O2) could be generated in the cases of PMS and PAA. For TCBQ, the chlorine atoms cause the olefinic carbons to carry more positive atomic charges, and then, HO2- preferred to add to the olefinic carbons, which might induce the formation of the hydroxyl radical (•OH). The activation of PMS by TCBQ was similar to that by p-BQ, with the kinetical feasibility of 1O2 formation. These findings may provide some theoretical insights into the reaction of peroxides with quinones, especially into the interconnection between the substitutes and the formation of oxygen-centered radicals (e.g., •OH) and 1O2.

Performance of toluene oxidation on different morphologies of α-MnO2 prepared using manganese-based compound high-selectively recovered from spent lithium-ion batteries.

The proper disposals of spent lithium-ion batteries (LIBs) and volatile organic compounds (VOCs) both have a significant impact on the environment and human health. In this work, different morphologies of α-MnO2 catalysts are synthesized using a manganese-based compound as the precursor which is high-selectively recovered from spent lithium-ion ternary batteries. Different synthesis methods including the co-precipitation method, hydrothermal method, and impregnation method are used to prepare different morphologies of α-MnO2 catalysts and their catalytic activities of toluene oxidation are investigated. Experimental results show that MnO2-HM-140 with stacked nanorods synthesized using the hydrothermal method exhibits the best catalytic performance of toluene oxidation (T90 of 226 °C under the WHSV of 60,000 mL g-1·h-1), which could be attributed to its better redox ability at low temperature and much more abundant adsorbed oxygen species at low temperature. The adsorption abilities of toluene and the replenish rate of surface lattice oxygen can be enhanced due to the increase of oxygen vacancies on the surface of MnO2-HM-140. Furthermore, the results of in-situ DRIFTS and TD/GC-MS imply that benzoate species are the main intermediate groups and then the reaction pathway of toluene oxidation on the surface of MnO2-HM-140 is proposed.

Optimization scheme of machine learning model for genetic division between northern Han, southern Han, Korean and Japanese.

Han Chinese, Korean and Japanese are the main populations of East Asia, and Han Chinese presents a gradient admixture from north to south. There are differences among the East Asian populations in genetic structure. To achieve fine-scale genetic classification of southern (S-) and northern (N-) Han Chinese, Korean and Japanese individuals in this study, we collected and analyzed 1185 ancestry informative SNPs (AISNPs) from previous literature reports and our laboratory findings. First, two machine learning algorithms, softmax and randomForest, were used to build genetic classification models. Then, phylogenetic tree, STRUCTURE and principal component analysis were used to evaluate the performance of classification for different AISNP panels. The 234-AISNP panel achieved a fine-scale differentiation among the target populations in four classification schemes. The accuracy of the softmax model was 92%, which realized the accurate classification of the S-Han, N-Han, Korean and Japanese individuals. The two machine learning models tested in this study provided important references for the high-resolution discrimination of close-range populations and will be useful tools to optimize marker panels for developing forensic DNA ancestry inference systems.