Bayesian spatial cluster signal learning with application to adverse event (AE).

There is growing interest in understanding geographic patterns of medical device-related adverse events (AEs). A spatial scan method combined with the likelihood ratio test (LRT) for spatial-cluster signal detection over the geographical region is universally used. The spatial scan method used a moving window to scan the entire study region and collected some candidate sub-regions from which the spatial-cluster signal(s) will be found. However, it has some challenges, especially in computation. First, the computational cost increased when the number of sub-regions increased. Second, the computational cost may increase if a large spatial-cluster pattern is present and a flexible-shaped window is used. To reduce the computational cost, we propose a Bayesian nonparametric method that combines the ideas of Markov random field (MRF) to leverage geographical information to find potential signal clusters. Then, the LRT is applied for the detection of spatial cluster signals. The proposed method provides an ability to capture both locally spatially contiguous clusters and globally discontiguous clusters, and is manifested to be effective and tractable using hypothetical Left Ventricular Assist Device (LVAD) data as an illustration.

Morroniside ameliorates glucocorticoid-induced osteoporosis and promotes osteoblastogenesis by interacting with sodium-glucose cotransporter 2.

CONTEXT: Morroniside (MOR) possesses antiosteoporosis (OP) effects, but its molecular target and relevant mechanisms remain unknown. OBJECTIVE: We investigated the effects of MOR on glucocorticoid-induced OP and osteoblastogenesis and its underlying mechanisms. MATERIALS AND METHODS: The effects of MOR (10-100 µM) on the proliferation and differentiation of MC3T3-E1 cells were studied in vitro. The glucocorticoid-induced zebrafish OP model was treated with 10, 20 and 40 µM MOR for five days to evaluate its effects on vertebral bone density and related osteogenic markers. In addition, molecular targets prediction and molecular docking analysis were carried out to explore the binding interactions of MOR with the target proteins. RESULTS: In cultured MC3T3-E1 cells, 20 µM MOR significantly increased cell viability (1.64 ± 0.12 vs. 0.95 ± 0.16; p < 0.01) and cell differentiation (1.57 ± 0.01 vs. 1.00 ± 0.04; p < 0.01) compared to the control group. MOR treatment significantly ameliorated vertebral bone loss in the glucocorticoid-induced OP zebrafish model (0.86 ± 0.02 vs. 0.40 ± 0.03; p < 0.01) and restored the expression of osteoblast-specific markers, including ALP, Runx2 and Col-І. Ligand-based target prediction and molecular docking revealed the binding interaction between MOR and the glucose pockets in sodium-glucose cotransporter 2 (SGLT2). DISCUSSION AND CONCLUSIONS: These findings demonstrated that MOR treatment promoted osteoblastogenesis and ameliorated glucocorticoid-induced OP by targeting SGLT2, which may provide therapeutic potential in managing glucocorticoid-induced OP.

Gender interactions between vertebral bone mineral density and fat content in the elderly: Assessment using fat-water MRI.

BACKGROUND: Adipose tissue is closely related to bone mass, bone quality, and bone fractures, but the connection between fat and bone is complex and gender-related. Fat-water magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are very useful tools for identifying tissue fat. PURPOSE: To assess gender interactions between bone mineral density (BMD), bone marrow fat, and body mass index (BMI) in the elderly using fat-water MRI and MRS. STUDY TYPE: Prospective/cohort. POPULATION: Sixty-six women and 38 men (mean age, 62.3 years; range, 50-75 years), Asian. FIELD STRENGTH: A 1.5T MR equipped with a body and spine array coil. STEAM MRS and T2 * Dixon were performed. ASSESSMENT: Vertebral bone marrow fat ratio (MFR), BMI, and BMD were measured. Correlations between these variables and differences in bone density in MFR were assessed between participants, divided into three groups based on bone density. STATISTICAL TESTS: Multiple regression; Pearson tests; analysis of covariance; analysis of variance. RESULTS: Multiple regression analysis identified gender, vertebral bone MFR, and BMI as significant predictors of vertebral BMD (P < 0.001). Among the women, vertebral BMD was negatively correlated with vertebral MFR (P = 0.011), but among the men, it was positively correlated with BMI (P = 0.048), although this relationship was confounded by age and MFR. Moreover, vertebral bone marrow fat and BMI were indeed statistically uncorrelated in the elderly (P = 0.357 in women; P = 0.961 in men). DATA CONCLUSION: We found gender interactions between fat and bone in the elderly. Higher bone marrow fat was correlated with lower trabecular BMD in older women but not in men. On the other hand, the positive correlation between BMI and BMD was more pronounced in men than in women. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1382-1389.

Downregulated NOX4 underlies a novel inhibitory role of microRNA-137 in prostate cancer.

Prostate cancer is the second highest caused by cancer-related death among males. microRNAs (miRs) have been reported to participate in carcinogenesis, yet their roles in prostate cancer are rarely studied or investigated. Therefore, the present study attempted to explore the effect of miR-137 in prostate cancer via regulating NADPH oxidase 4 (NOX4). Initially, microarray analysis was performed to obtain prostate cancer-related differentially expressed genes and miRs that regulated NOX4, followed by detecting the expression of miR-137 and NOX4 and its target relationship. Moreover, PC-3 cells were transfected with small interfering RNA (siNOX4) and miR-137 mimic for exploring the effect of miR-137 on glycolysis, cell proliferation, and apoptosis in prostate cancer by evaluating lactate production, glucose uptake, adenosine triphosphate (ATP) production, viability rate, and expression of cleaved caspases 3, 8, and 9, cytochrome c, cleaved poly ADP ribose polymerase (PARP), Bax, and Bcl-2. miR-137 was vital to prostate cancer progression via regulating NOX4. Besides, miR-137 expressed poorly while NOX4 expressed highly in prostate cancer. NOX4 was the target gene of miR-137. Additionally, overexpression of miR-137 and silencing of NOX4 were observed to decrease NOX4 and Bcl-2 protein expression, but increase cleaved caspases 3, 8, and 9, cytochrome c, cleaved-PARP, and Bax protein expression. Furthermore, miR-137 overexpression and NOX4 silencing contributed to decreased lactate production, glucose uptake, ATP production, and cell proliferation, but increased apoptosis rate. Collectively, the present study showed that miR-137 repressed glycolysis in prostate cancer through knockdown of NOX4, which might be a potential theoretical target for prostate cancer treatment.

Interferon-gamma induces autophagy-associated apoptosis through induction of cPLA2-dependent mitochondrial ROS generation in colorectal cancer cells.

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third in males. In this work, we aim to investigate the possible anti-cancer effects of interferon-gamma (IFN-γ) in CRC cells. We observed that IFN-γ induced mitochondria-derived reactive oxygen species (ROS) production in a time-dependent manner in SW480 and HCT116 cell lines. The IFN-γ-induced mitochondrial ROS generation was dependent on the activation of cytosolic phospholipase A2 (cPLA2). In addition, a mitochondria-targeted antioxidant SS31 and/or cPLA2 inhibitor AACOCF3 abolished the IFN-γ-induced ROS production and subsequent autophagy and apoptosis. Moreover, suppression of autophagy by CQ was able to reduce IFN-γ-induced cell apoptosis. Beclin-1 gene silencing resulted in caspase-3 inactivation, decreased Bax/Bcl-2 ratio and less population of apoptotic cells. Collectively, our results suggested that IFN-γ induces autophagy-associated apoptosis in CRC cells via inducing cPLA2-dependent mitochondrial ROS production.

Spatial separation of nitrifiers and denitrifiers promotes selection and enrichment of polyhydroxyalkanoates storing mixed cultures fed by crude glycerol and propionate wastewater.

Polyhydroxyalkanoates (PHA) recovery from industrial wastewater has been highlighted as a promising strategy for a circular bioeconomy. However, the high and varying level of nitrogen in wastewater makes enrichment of mixed microbial culture (MMC) low efficiency. In this study, spatial separation of nitrifiers and denitrifiers was adopted by adding biocarriers in MMC and decreasing the sludge retention time (SRT) to accelerate the enrichment of PHA-storing MMC fed by mixed wastewater containing glycerol and propionate. Nitrifiers and denitrifiers were sustained on biocarriers, obtaining a high total inorganic nitrogen removal and allowing a more efficient selective pressure of a high carbon and nitrogen ratio (C/N) under low SRT conditions. The maximum PHA cell content and relative abundance of PHA-storing bacteria were increased to 60.51 % (SRT 6 d) and 49.62 % (SRT 6 d) with the decrease of SRT, respectively. This study demonstrates an efficient way to highly enrich PHA-storing MMC from crude glycerol, which provide a relevant technical support for high-efficiency enrichment of PHA-storing bacteria in low C/N wastewater.

Enhancing osteoporosis treatment using a targeted, sustained-release drug delivery system based on macrocyclic amphiphile.

Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems.

Defense Regulatory Network Associated with circRNA in Rice in Response to Brown Planthopper Infestation.

The brown planthopper (BPH), Nilaparvata lugens (Stål), a rice-specific pest, has risen to the top of the list of significant pathogens and insects in recent years. Host plant-mediated resistance is an efficient strategy for BPH control. Nonetheless, BPH resistance in rice cultivars has succumbed to the emergence of distinct virulent BPH populations. Circular RNAs (circRNAs) play a pivotal role in regulating plant-environment interactions; however, the mechanisms underlying their insect-resistant functions remain largely unexplored. In this study, we conducted an extensive genome-wide analysis using high-throughput sequencing to explore the response of rice circRNAs to BPH infestations. We identified a total of 186 circRNAs in IR56 rice across two distinct virulence groups: IR-IR56-BPH (referring to IR rice infested by IR56-BPH) and IR-TN1-BPH, along with a control group (IR-CK) without BPH infestation. Among them, 39 circRNAs were upregulated, and 43 circRNAs were downregulated in the comparison between IR-IR56-BPH and IR-CK. Furthermore, in comparison with IR-CK, 42 circRNAs exhibited upregulation in IR-TN1-BPH, while 42 circRNAs showed downregulation. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that the targets of differentially expressed circRNAs were considerably enriched in a multitude of biological processes closely linked to the response to BPH infestations. Furthermore, we assessed a total of 20 randomly selected circRNAs along with their corresponding expression levels. Moreover, we validated the regulatory impact of circRNAs on miRNAs and mRNAs. These findings have led us to construct a conceptual model that circRNA is associated with the defense regulatory network in rice, which is likely facilitated by the mediation of their parental genes and competing endogenous RNA (ceRNA) networks. This model contributes to the understanding of several extensively studied processes in rice-BPH interactions.

Deficiency of Acetyltransferase nat10 in Zebrafish Causes Developmental Defects in the Visual Function.

Purpose: N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification catalyzed by N-acetyltransferase 10 (NAT10), a critical factor known to influence mRNA stability. However, the role of ac4C in visual development remains unexplored. Methods: Analysis of public datasets and immunohistochemical staining were conducted to assess the expression pattern of nat10 in zebrafish. We used CRISPR/Cas9 and RNAi technologies to knockout (KO) and knockdown (KD) nat10, the zebrafish ortholog of human NAT10, and evaluated its effects on early development. To assess the impact of nat10 knockdown on visual function, we performed comprehensive histological evaluations and behavioral analyses. Transcriptome profiling and real-time (RT)-PCR were utilized to detect alterations in gene expression resulting from the nat10 knockdown. Dot-blot and RNA immunoprecipitation (RIP)-PCR analyses were conducted to verify changes in ac4C levels in both total RNA and opsin mRNA specifically. Additionally, we used the actinomycin D assay to examine the stability of opsin mRNA following the nat10 KD. Results: Our study found that the zebrafish NAT10 protein shares similar structural properties with its human counterpart. We observed that the nat10 gene was prominently expressed in the visual system during early zebrafish development. A deficiency of nat10 in zebrafish embryos resulted in increased mortality and developmental abnormalities. Behavioral and histological assessments indicated significant vision impairment in nat10 KD zebrafish. Transcriptomic analysis and RT-PCR identified substantial downregulation of retinal transcripts related to phototransduction, light response, photoreceptors, and visual perception in the nat10 KD group. Dot-blot and RIP-PCR analyses confirmed a pronounced reduction in ac4C levels in both total RNA and specifically in opsin messenger RNA (mRNA). Additionally, by evaluating mRNA decay in zebrafish treated with actinomycin D, we observed a significant decrease in the stability of opsin mRNA in the nat10 KD group. Conclusions: The ac4C-mediated mRNA modification plays an essential role in maintaining visual development and retinal function. The loss of NAT10-mediated ac4C modification results in significant disruptions to these processes, underlining the importance of this RNA modification in ocular development.

Early statin exposure influences cardiac and skeletal development with implications for ion channel transcriptomes in zebrafish.

Statins, widely prescribed for cholesterol management by inhibiting HMG-CoA reductase in the cholesterol biosynthesis pathway, may also influence vertebrate development. In this study, we investigated the developmental effects of two widely used statins, atorvastatin (ATO) and pravastatin (PRA), on zebrafish offspring. For ATO, we administered doses classified as low (1 µM), medium (5 µM), and high (10 µM), while for PRA, the corresponding concentrations were set at low (18 µM), medium (180 µM), and high (270 µM). Our results showed significant reductions in birth and hatching rates, along with decreased body length in offspring at all ATO concentrations and medium to high PRA concentrations. A notable increase in malformation rates, especially in the spine and heart, was observed across all ATO treatments and in medium and high PRA groups. Additionally, we observed reduced heart contraction rates, decreased heart size, lower bone volumes, and diminished expression of mRNA osteogenic markers. Elevated venous sinus-artery bulb (SV-BA) ratios, increased thoracic area, and abnormal cartilage development were also prominent in all ATO-treated groups. Transcriptome analysis revealed alterations in genes predominantly associated with ion channels. These findings provide insights into the potential impacts of specific concentrations of statins on offspring development and highlight potential gene interactions with statins.

Time fused coefficient SIR model with application to COVID-19 epidemic in the United States.

In this paper, we propose a Susceptible-Infected-Removal (SIR) model with time fused coefficients. In particular, our proposed model discovers the underlying time homogeneity pattern for the SIR model's transmission rate and removal rate via Bayesian shrinkage priors. MCMC sampling for the proposed method is facilitated by the nimble package in R. Extensive simulation studies are carried out to examine the empirical performance of the proposed methods. We further apply the proposed methodology to analyze different levels of COVID-19 data in the United States.

A halophilic aerobic-heterotrophic strain Halomonas venusta SND-01: Nitrogen removal by ammonium assimilation and heterotrophic nitrification-aerobic denitrification.

Nitrogen (N) removal from high-salinity wastewater is a major challenge. The aerobic-heterotrophic nitrogen removal (AHNR) process has been demonstrated to be feasible for treating hypersaline wastewater. In this study, Halomonas venusta SND-01, a halophilic strain capable of performing AHNR, was isolated from saltern sediment. The strain achieved ammonium, nitrite, and nitrate removal efficiencies of 98%, 81%, and 100%, respectively. The N balance experiment suggests that this isolate removes N mainly via assimilation. Various functional genes related to N metabolism were found in the genome of the strain, establishing a complex AHNR pathway that includes ammonium assimilation, heterotrophic nitrification-aerobic denitrification, and assimilatory nitrate reduction. Four key enzymes in the N removal process were successfully expressed. The strain exhibited high-adaptability under C/N ratios of 5-15, salinities of 2%-10% (m/v), and pH of 6.5-9.5. Therefore, the strain shows high potential for treating saline wastewater with different inorganic N compositions.

Curcumin alleviated oxidation stress injury by mediating osteopontin in nephrolithiasis rats.

PURPOSE: To explore the role and mechanism of curcumin (Cur) in reducing oxidative stress damage in rats with nephrolithiasis induced by ethylene glycol (EG). METHODS: Thirty male rats were divided into normal control, model, positive (10% potassium citrate), Cur-10 (10 mg/kg curcumin) and Cur-20 (20 mg/kg curcumin) groups. RESULTS: The results of kidney tissue section stained by hematoxylin-eosin and von Kossa showed that curcumin treatment can inhibit the formation of kidney stones. The biochemical test results showed that the urea (Ur), creatinine (Cr), uric acid (UA), inorganic phosphorus and Ca2+ concentrations in urine decreased after being treated with curcumin. There were significant differences between different doses of curcumin (P < 0.05). Compared with the Cur-10 group, Cur-20 had a more significant inhibitory effect on malondialdehyde (MDA) (P < 0.05). In addition, reverse transcription polymerase chain reaction (PCR) detection and immunohistochemical results indicated that the osteopontin (OPN) in the kidney was significantly reduced after curcumin treatment. CONCLUSIONS: Curcumin could reduce the oxidative stress damage caused by EG-induced kidney stones.

Progesterone Changes the Pregnancy-Induced Adaptation of Cardiomyocyte Kv2.1 Channels via MicroRNA-29b.

The cardiovascular system adaptation occurs during pregnancy to ensure adequate maternal circulation. Progesterone (P4) is widely used in hormone therapy to support pregnancy, but little is known about its effects on maternal cardiac function. In this study, we investigated the cardiac repolarization and ion channel expression in pregnant subjects and mice models and studied the effects of P4 administrations on these pregnancy-mediated adaptations. P4 administrations shortened the prolongation of QTC intervals and action potential duration (APD) that occurred during pregnancy, which was mainly attributable to the reduction in the voltage-gated potassium (Kv) current under basal conditions. In vitro studies indicated that P4 regulated the Kv2.1 channel in a bidirectional manner. At a low dose (1 µM), P4 induced upregulation of Kv2.1 through P4 receptor, while at a higher dose (5 µM), P4 downregulated Kv2.1 by targeting microRNA-29b (miR-29b). Our data showed that P4 modulated maternal cardiac repolarization by regulating Kv2.1 channel activity during pregnancy. Kv2.1, as well as miR-29b, might be used as potential therapeutic targets for adaptations of the maternal cardiovascular system or evaluation of progesterone medication during pregnancy.

Emergent bedside real-time three-dimensional transesophageal echocardiography in a patient with cardiac arrest following a caesarean section.

Post-caesarean pulmonary embolism (PE) is associated with significant peri-operative morbidity and mortality. This report describes a case of sudden cardiac arrest 2 days post-caesarean due to massive PE diagnosed via bedside transesophageal echocardiography (TEE). Recognition of the PE at the bifurcation of the right and left pulmonary arteries was achieved by real-time three-dimensional TEE, but not two-dimensional TEE. Extracorporeal membrane oxygenation was immediately established and emergent pulmonary thromboembolectomy was performed. The patient was discharged without residual deficits on Day 22 of hospitalization.

Ag (111) surface for ambient electrolysis of nitrogen to ammonia.

In this paper, the reaction process of N2 convert to NH3 catalyzed by Ag (111) surface was obtained through the construction of Ag (111) surface and computational simulation. The charge transfer in the reaction process and the change of N≡N bond length are described. Since the N2 reduction reaction (NRR) usually occurs under alkaline solution conditions, we calculated and described the coexistence of OH* and N2. At the same time, the co-adsorption structure of OH* and N2 at different adsorption sites was studied.

Mixed-culture biocathodes for acetate production from CO2 reduction in the microbial electrosynthesis: Impact of temperature.

The temperature effect on bioelectrochemical reduction of CO2 to acetate with a mixed-culture biocathode in the microbial electrosynthesis was explored. The results showed that maximum acetate amount of 525.84 ± 1.55 mg L-1 and fastest acetate formation of 49.21 ± 0.49 mg L-1 d-1 were obtained under mesophilic conditions. Electron recovery efficiency for CO2 reduction to acetate ranged from 14.50 ± 2.20% to 64.86 ± 2.20%, due to propionate, butyrate and H2 generation. Mesophilic conditions were demonstrated to be more favorable for biofilm formation on the cathode, resulting in a stable and dense biofilm. At phylum level, the relative abundance of Bacteroidetes phylum in the biofilm remarkably increased under mesophilic conditions, compared with that at psychrophilic and thermophilic conditions. At genus level, the Clostridium, Treponema, Acidithiobacillus, Acetobacterium and Acetoanaerobium were found to be dominated genera in the biofilm under mesophilic conditions, while genera diversity decreased under psychrophilic and thermophilic conditions.

Clinical Experience of Patients With Hepatitis C Treated With Direct-Acting Antivirals After Heart Transplantation.

BACKGROUND: Hepatitis C increases the mortality and morbidity of patients after heart transplant. Direct-acting antivirals (DAAs) are the primary drugs for hepatitis C treatment. However, such drugs are expensive and frequently unaffordable for patients. In DAA treatment, the assessment of drug interaction is crucial. METHODS: We investigated a retrospective case series study from January 2017 to December 2019. Sustained virologic response 12 (SVR12) was used to assess the effectiveness of DAA treatment. Data on patients' demographic information, timing of hepatitis C virus (HCV) infection (before or after heart transplant), HCV genotypes and viral loads, DAAs used (branded drugs or generic drugs), and drug interaction assessments were collected. RESULTS: Fifteen heart transplant patients received hepatitis C treatments during the study period, 11 of whom were infected because their donors had hepatitis C. After DAA treatment, HCV was undetectable in all patients, and 93.3% of them achieved SVR12. Nine patients used the generic sofosbuvir/velpatasvir, and 88.9% of them achieved SVR12. A total of 256 drugs were used with DAAs; 51 records of drug interactions were noted, 3 of which were contraindications, and the remaining records were potential interactions. Patients who used sofosbuvir or elbasvir/grazoprevir experienced fewer drug interactions. CONCLUSIONS: DAA treatment is effective for hepatitis C treatment in patients after heart transplant. Patients who cannot afford branded drugs because of their prices can use generic drugs as an alternative. Drug interactions must be surveyed during DAA treatment.

Quantifying lumbar vertebral perfusion by a Tofts model on DCE-MRI using segmental versus aortic arterial input function.

The purpose of this study was to investigate the influence of arterial input function (AIF) selection on the quantification of vertebral perfusion using axial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In this study, axial DCE-MRI was performed on 2 vertebrae in each of eight healthy volunteers (mean age, 36.9 years; 5 men) using a 1.5-T scanner. The pharmacokinetic parameters Ktrans, ve, and vp, derived using a Tofts model on axial DCE-MRI of the lumbar vertebrae, were evaluated using various AIFs: the population-based aortic AIF (AIF_PA), a patient-specific aortic AIF (AIF_A) and a patient-specific segmental arterial AIF (AIF_SA). Additionally, peaks and delay times were changed to simulate the effects of various AIFs on the calculation of perfusion parameters. Nonparametric analyses including the Wilcoxon signed rank test and the Kruskal-Wallis test with a Dunn-Bonferroni post hoc analysis were performed. In simulation, Ktrans and ve increased as the peak in the AIF decreased, but vp increased when delay time in the AIF increased. In humans, the estimated Ktrans and ve were significantly smaller using AIF_A compared to AIF_SA no matter the computation style (pixel-wise or region-of-interest based). Both these perfusion parameters were significantly greater using AIF_SA compared to AIF_A.