Spt4 is selectively required for transcription of extended trinucleotide repeats.

Lengthy trinucleotide repeats encoding polyglutamine (polyQ) stretches characterize the variant proteins of Huntington's disease and certain other inherited neurological disorders. Using a phenotypic screen to identify events that restore functionality to polyQ proteins in S. cerevisiae, we discovered that transcription elongation factor Spt4 is required to transcribe long trinucleotide repeats located either in ORFs or nonprotein-coding regions of DNA templates. Mutation of SPT4 selectively decreased synthesis of and restored enzymatic activity to expanded polyQ protein without affecting protein lacking long-polyQ stretches. RNA-seq analysis revealed limited effects of Spt4 on overall gene expression. Inhibition of Supt4h, the mammalian ortholog of Spt4, reduced mutant huntingtin protein in neuronal cells and decreased its aggregation and toxicity while not altering overall cellular mRNA synthesis. Our findings identify a cellular mechanism for transcription through repeated trinucleotides and a potential target for countermeasures against neurological disorders attributable to expanded trinucleotide regions.

Towards artificial general intelligence with hybrid Tianjic chip architecture.

There are two general approaches to developing artificial general intelligence (AGI)1: computer-science-oriented and neuroscience-oriented. Because of the fundamental differences in their formulations and coding schemes, these two approaches rely on distinct and incompatible platforms2-8, retarding the development of AGI. A general platform that could support the prevailing computer-science-based artificial neural networks as well as neuroscience-inspired models and algorithms is highly desirable. Here we present the Tianjic chip, which integrates the two approaches to provide a hybrid, synergistic platform. The Tianjic chip adopts a many-core architecture, reconfigurable building blocks and a streamlined dataflow with hybrid coding schemes, and can not only accommodate computer-science-based machine-learning algorithms, but also easily implement brain-inspired circuits and several coding schemes. Using just one chip, we demonstrate the simultaneous processing of versatile algorithms and models in an unmanned bicycle system, realizing real-time object detection, tracking, voice control, obstacle avoidance and balance control. Our study is expected to stimulate AGI development by paving the way to more generalized hardware platforms.

Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes.

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via ß1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9.

BACKGROUND: Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered protein expressed in human tissues, especially in malignant tissues; however, its role in CSC expansion has not been studied. This study aimed to determine the role of TMEM120B in transcriptional coactivator with PDZ-binding motif (TAZ)-mediated CSC expansion and chemotherapy resistance. METHODS: Both bioinformatics analysis and immunohistochemistry assays were performed to examine expression patterns of TMEM120B in lung, breast, gastric, colon, and ovarian cancers. Clinicopathological factors and overall survival were also evaluated. Next, colony formation assay, MTT assay, EdU assay, transwell assay, wound healing assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, RNA-sequencing assay, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of TMEM120B interaction on proliferation, invasion, stemness, chemotherapy sensitivity, and integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography-tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between TMEM120B, myosin heavy chain 9 (MYH9), and CUL9. RESULTS: TMEM120B expression was elevated in lung, breast, gastric, colon, and ovarian cancers. TMEM120B expression positively correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Overexpression of TMEM120B promoted breast cancer cell proliferation, invasion, and stemness by activating TAZ-mTOR signaling. TMEM120B directly bound to the coil-coil domain of MYH9, which accelerated the assembly of focal adhesions (FAs) and facilitated the translocation of TAZ. Furthermore, TMEM120B stabilized MYH9 by preventing its degradation by CUL9 in a ubiquitin-dependent manner. Overexpression of TMEM120B enhanced resistance to docetaxel and doxorubicin. Conversely, overexpression of TMEM120B-∆CCD delayed the formation of FAs, suppressed TAZ-mTOR signaling, and abrogated chemotherapy resistance. TMEM120B expression was elevated in breast cancer patients with poor treatment outcomes (Miller/Payne grades 1-2) than in those with better outcomes (Miller/Payne grades 3-5). CONCLUSIONS: Our study reveals that TMEM120B bound to and stabilized MYH9 by preventing its degradation. This interaction activated the ß1-integrin/FAK-TAZ-mTOR signaling axis, maintaining stemness and accelerating chemotherapy resistance.

Underestimated role of hydroxyl radicals for bromate formation in persulfate-based advanced oxidation processes.

In persulfate-based advanced oxidation processes (PS-AOPs), sulfate radicals (SO4•-) have been recognized to play more important roles in inducing bromate (BrO3-) formation rather than hydroxyl radicals (HO•) because of the stronger oxidation capacity of the former. However, this study reported an opposite result that HO• indeed dominated the formation of bromate instead of SO4•-. Quenching experiments were coupled with electron paramagnetic resonance (EPR) detection and chemical probe identification to elucidate the contributions of each radical species. The comparison of different thermal activated persulfates (PDS and PMS) demonstrated that the significant higher bromate formation in HEAT/PMS ([BrO3-]/[Br-]0 = 0.8), as compared to HEAT/PDS ([BrO3-]/[Br-]0 = 0.2), was attributable to the higher concentration of HO• radicals in HEAT/PMS. Similarly, the bromate formation in UV/PDS ([BrO3-]/[Br-]0 = 1.0), with a high concentration of HO•, further underscored the dominant role of HO•. As a result, we quantified that HO• and SO4•- radicals accounted 66.7% and 33.3% for bromate formation. This controversial result can be reconciled by considering the critical intermediate, hypobromic acid/hypobromate (HOBr/BrO-), involved in the transformation of Br- to BrO3-. HO• radicals have the chemical preference to induce the formation of HOBr/BrO- intermediates (contributing âˆ¼ 60%) relative to SO4•- radicals (contributing âˆ¼ 40%). This study highlighted the dominant role of HO• in the formation of bromate rather than SO4•- in PS-AOPs and potentially offered novel insights for reducing disinfection byproduct formation by controlling the radical species in AOPs.

BAIAP2L1 accelerates breast cancer progression and chemoresistance by activating AKT signaling through binding with ribosomal protein L3.

BAI1-associated protein 2-like 1 (BAIAP2L1), also known as insulin receptor tyrosine kinase substrate, modulates the insulin network; however, its function in breast cancer has not been explored. Immunohistochemical analysis of 140 breast cancer specimens (77 triple-negative and 63 nontriple-negative cases) indicated that BAIAP2L1 expression was higher in breast cancer tissues (56/140, 40%) than in normal breast tissues (28.3%, 15/53; p < 0.001). BAIAP2L1 expression in breast cancer was correlated with triple-negative breast cancer (p = 0.0013), advanced TNM stage (p = 0.001), lymph node metastasis (p = 0.001), and poor patient prognosis (p = 0.001). BAIAP2L1 overexpression could accelerate breast cancer proliferation, invasion, and stemness in vivo and in vitro, possibly through the activation of AKT, Snail, and cyclin D1. Treatment with the AKT inhibitor LY294002 reduced the effects of BAIAP2L1 overexpression on breast cancer cells. BAIAP2L1 may bind to the AA202-288 of ribosomal protein L3 (RPL3) within its SRC homology 3 (SH3) domain, the loss of which may abolish the transduction of the AKT signaling pathway by promoting the degradation of PIK3CA. Moreover, BAIAP2L1 overexpression may induce chemotherapy resistance, with BAIAP2L1 expression being higher in patients with advanced Miller grades than those with lower grades. Our results indicated that BAIAP2L1 promotes breast cancer progression through the AKT signaling pathway by interacting with RPL3 through its SH3 domain.

ZNF500 abolishes breast cancer proliferation and sensitizes chemotherapy by stabilizing P53 via competing with MDM2.

Zinc finger protein 500 (ZNF500) has an unknown expression pattern and biological function in human tissues. Our study revealed that the ZNF500 mRNA and protein levels were higher in breast cancer tissues than those in their normal counterparts. However, ZNF500 expression was negatively correlated with advanced TNM stage (p = 0.018), positive lymph node metastasis (p = 0.014), and a poor prognosis (p < 0.001). ZNF500 overexpression abolished in vivo and in vitro breast cancer cell proliferation by activating the p53-p21-E2F4 signaling axis and directly interacting with p53 via its C2H2 domain. This may prevent ubiquitination of p53 in a manner that is competitive to MDM2, thus stabilizing p53. When ZNF500-∆C2H2 was overexpressed, the suppressed proliferation of breast cancer cells was neutralized in vitro and in vivo. In human breast cancer tissues, ZNF500 expression was positively correlated with p53 (p = 0.022) and E2F4 (p = 0.004) expression. ZNF500 expression was significantly lower in patients with Miller/Payne Grade 1-2 than in those with Miller/Payne Grade 3-5 (p = 0.012). ZNF500 suppresses breast cancer cell proliferation and sensitizes cells to chemotherapy.

Humanized disulfide-stabilized diabody against fibroblast growth factor-2 inhibits PD-L1 expression and epithelial-mesenchymal transition in hepatoma cells through STAT3.

Fibroblast growth factor 2 (FGF2) plays an important role in tumor angiogenesis. Humanized disulfide-stable double-chain antibody against fibroblast growth factor-2 (anti-FGF2 ds-Diabody) is a small molecule antibody with good tissue permeability and low immunogenicity, which has potential in tumor-targeted therapy. This study intended to investigate the effect of anti-FGF2 ds-Diabody on the migration and expression of programmed death-ligand1 (PD-L1) in hepatocellular carcinoma (HCC) cells. The anti-FGF2 ds-Diabody was expressed under methanol induction and purified with Ni2+ -affinity chromatography. Anti-FGF2 ds-Diabody significantly inhibited cell viability and proliferation in SK-Hep1 and HepG2 cells as confirmed by CCK-8 assays and colony formation assays. Western blot assays indicated that the proliferation of SK-Hep1 and HepG2 cells was inhibited by anti-FGF2 ds-Diabody through inhibiting the phosphorylation activation of AKT and MAPK. The results of transwell and western blot assays showed that the migration and invasion of SK-Hep1 and HepG2 cells were suppressed by anti-FGF2 ds-Diabody by affecting the epithelial-mesenchymal transition (EMT) process. Meanwhile, anti-FGF2 ds-Diabody inhibited the expression of PD-L1, and STAT3 participated in this process. Analysis of RT-PCR and Western blot suggested that fibroblast growth factor receptor 4 inhibitor 1 (FGFR4-IN-1) suppressed the expression of PD-L1, while STAT3 overexpression reversed this inhibitory effect. In addition, overexpression of STAT3 promoted migration and invasion and restored the suppressive effect of anti-FGF2 ds-Diabody on EMT. In conclusion, anti-FGF2 ds-Diabody could inhibit the expression of PD-L1 and EMT of hepatoma cells through FGF2/FGFR4/STAT3 axis. These results suggested that anti-FGF2 ds-Diabody has potential clinical application in inhibiting metastasis and immune escape of hepatocellular carcinoma.

Flexible broadcast UWOC system using an LCVR-based tunable optical splitter.

For underwater wireless optical communication (UWOC) systems, using an omnidirectional light source to construct a broadcast system will require considerable energy due to high geometric loss and water attenuation. In addition, high-sensitivity photon detectors usually have a limited dynamic range, therefore limiting communication distance. In this Letter, a broadcast UWOC system, based on liquid crystal variable retarders (LCVRs) and polarization beam splitters (PBSs), is proposed to allocate user power in accordance with user-specific channel conditions. By adjusting the driving alternating current (AC) voltage of LCVRs to change the input light polarization, different proportions of light can be allocated to different PBS ports before broadcasting to different users. In a dual-user transmitter for the proof-of-concept, the output power dynamic range and the additional insertion loss for the first user are 19.17 dB and 0.91 dB, respectively. For the second user, the performance degrades to 17.33 dB and 1.26 dB, respectively. The step size of power adjustment is less than 0.063 dB. To verify the effectiveness of power adjustment in UWOC systems, a 7-m/243.2-Mbps single-user UWOC system is designed with a water attenuation coefficient ranging from 0.50 dB/m to 2.35 dB/m. All bit error rates (BERs) can decrease to below the forward error correction (FEC) limit by adjusting the LCVR driving voltage. The adjustable range of communication distance could be extended from 4.2 m to 13.19 m with a channel attenuation coefficient of 1.44 dB/m. Finally, a dual-user UWOC experiment is conducted and proves that the proposed system can still work in a multi-user system. The proposed system is proven to be effective for improving the anti-jamming capability and flexibility of UWOC networks.

Efficacy of an mHealth App to Support Patients' Self-Management of Hypertension: Randomized Controlled Trial.

BACKGROUND: Hypertension is a significant global disease burden. Mobile health (mHealth) offers a promising means to provide patients with hypertension with easy access to health care services. Yet, its efficacy needs to be validated, especially in lower-income areas with a high-salt diet. OBJECTIVE: This study aims to assess the efficacy of an mHealth app-based intervention in supporting patients' self-management of hypertension. METHODS: A 2-arm randomized controlled trial was conducted among 297 patients with hypertension at the General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, China. Participants selected via convenience sampling were randomly allocated into intervention and control groups. Intervention group participants were trained and asked to use an mHealth app named Blood Pressure Assistant for 6 months. They could use the app to record and upload vital signs, access educational materials, and receive self-management reminders and feedback from health care providers based on the analysis of the uploaded data. Control group participants received usual care. Blood pressure (BP) and 2 questionnaire surveys about hypertension knowledge and lifestyle behavior were used to assess all participants at baseline and 6 months. Data analysis was performed with SPSS software using 2-tailed t tests and a chi-square test. RESULTS: There were no significant differences in baseline characteristics and medication use between the 2 groups (all P>.05). After 6 months, although both groups show a significant pre-post improvement (P<.001 each), the BP control rate (ie, the proportion of patients with a systolic BP of <140 mm Hg and diastolic BP of <90 mm Hg) in the intervention group was better than that in the control group (100/111, 90.1% vs 75/115, 65.2%; P<.001). The mean systolic and diastolic BP were significantly reduced by 25.83 (SD 8.99) and 14.28 (SD 3.74) mm Hg in the intervention group (P<.001) and by 21.83 (SD 6.86) and 8.87 (SD 4.22) mm Hg in the control group (P<.001), respectively. The differences in systolic and diastolic BP between the 2 groups were significant (P<.001 and P=.01, respectively). Hypertension knowledge significantly improved only in the intervention group in both pre-post and intergroup comparisons (both P<.001). However, only intragroup improvement was observed for lifestyle behaviors in the intervention group (P<.001), including medication adherence (P<.001), healthy diet (P=.02), low salt intake (P<.001), and physical exercises (P=.02), and no significant difference was observed in the control group or on intergroup comparisons. CONCLUSIONS: This research shows that the mHealth app-based intervention has the potential to improve patient health knowledge and support self-management among them toward a healthier lifestyle, including medication adherence, low-salt diets, and physical exercises, thereby achieving optimal BP control. Further research is still needed to verify the specific effects of these interventions. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900026437; https://www.chictr.org.cn/showproj.html?proj=38801.

Protoboration of Alkynes and Miyaura Borylation Catalyzed by Low Loadings of Palladium.

The versions of Miyaura borylation and protoboration of alkynes catalyzed by low loadings of palladium (400 mol ppm = 0.04 mol %) have been developed. These transformations have a broad substrate scope, good functional-group compatibility, and gram-scale synthetic ability.

Selenite and Selenate Sequestration during Coprecipitation with Barite: Insights from Mineralization Processes of Adsorption, Nucleation, and Growth.

Coprecipitation of selenium oxyanions with barite is a facile way to sequester Se in the environments. However, the chemical composition of Se-barite coprecipitates usually deviates from that predicted from thermodynamic calculations. This discrepancy was resolved by considering variations in nucleation and growth rates controlled by ion-mineral interactions, solubility, and interfacial energy. For homogeneous precipitation, ∼10% of sulfate, higher than thermodynamic predictions (<0.3%), was substituted by Se(IV) or Se(VI) oxyanion, which was attributed to adsorption-induced entrapment during crystal growth. For heterogeneous precipitation, thiol- and carboxylic-based organic films, utilized as model interfaces to mimic the natural organic-abundant environments, further enhanced the sequestration of Se(VI) oxyanions (up to 41-92%) with barite. Such enhancement was kinetically driven by increased nucleation rates of selenate-rich barite having a lower interfacial energy than pure barite. In contrast, only small amounts of Se(IV) oxyanions (∼1%) were detected in heterogeneous coprecipitates mainly due to a lower saturation index of BaSeO3 and deprotonation degree of Se(IV) oxyanion at pH 5.6. These roles of nanoscale mineralization mechanisms observed during composition selection of Se-barite could mark important steps toward the remediation of contaminants through coprecipitation.

MRI-assessed diaphragmatic function can predict frequent acute exacerbation of COPD: a prospective observational study based on telehealth-based monitoring system.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have considerably high mortality and re-hospitalisation rate. Diaphragmatic dysfunction (DD) is common in COPD patients. However, whether diaphragmatic dysfunction is related to acute exacerbation is yet to be elucidated. This study aimed to evaluate the diaphragm function by magnetic resonance imaging (MRI) in COPD patients and assess whether the impact of DD may help predict AECOPD. METHODS: 20 healthy adult volunteers and 80 COPD patients were enrolled. The diaphragms function parameters were accessed by MRI. Patients were guided to start self-management by the Telehealth-based monitoring system following the enrolment. Events of acute exacerbation of COPD were recorded by the system and confirmed by healthcare providers. Binary univariate and multivariate logistic regression analyses were performed to investigate the factors associated with the frequency of AECOPD. Receiver operating characteristic (ROC) curves were further used to assess the value of prediction indexes. RESULTS: Fifty-nine COPD patients completed a one-year follow-up based on the Telehealth-based monitoring system. The clinical outcomes showed that the diaphragm function parameters at the end of maximal breathing were lower in the COPD group than in the healthy control group (P < 0.05). ANOVA showed significant differences among Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages for diaphragm function parameters, including chest wall motion, lung area, upper-lower diameter, and the diaphragm thickening fraction at the end of maximal breathing (P < 0.05). Moreover, significant differences in diaphragm function parameters were observed between patients with infrequent AECOPD (n = 28) and frequent AECOPD (n = 31) based on the frequency of AECOPD (P < 0.05). The diaphragm thickening fraction and the chest wall motion were associated with AECOPD after adjusting for age, sex, BMI, and lung functions, and the combination of predictions showed better accuracy in predicting the frequency of AECOPD. CONCLUSIONS: In COPD patients, diaphragm function parameters correlate with the severity of airflow limitation. The diaphragm thickening fraction and the chest wall motion were associated with the frequency of AECOPD and can predict it.

Organic-mineral interfacial chemistry drives heterogeneous nucleation of Sr-rich (Ba x , Sr1-x )SO4 from undersaturated solution.

Sr-bearing marine barite [(Ba x , Sr1-x )SO4] cycling has been widely used to reconstruct geochemical evolutions of paleoenvironments. However, an understanding of barite precipitation in the ocean, which is globally undersaturated with respect to barite, is missing. Moreover, the reason for the occurrence of higher Sr content in marine barites than expected for classical crystal growth processes remains unknown. Field data analyses suggested that organic molecules may regulate the formation and composition of marine barites; however, the specific organic-mineral interactions are unclear. Using in situ grazing incidence small-angle X-ray scattering (GISAXS), size and total volume evolutions of barite precipitates on organic films were characterized. The results show that barite forms on organic films from undersaturated solutions. Moreover, from a single supersaturated solution with respect to barite, Sr-rich barite nanoparticles formed on organics, while micrometer-size Sr-poor barites formed in bulk solutions. Ion adsorption experiments showed that organic films can enrich cation concentrations in the adjacent solution, thus increasing the local supersaturation and promoting barite nucleation on organic films, even when the bulk solution was undersaturated. The Sr enrichment in barites formed on organic films was found to be controlled by solid-solution nucleation rates; instead, the Sr-poor barite formation in bulk solution was found to be controlled by solid-solution growth rates. This study provides a mechanistic explanation for Sr-rich marine barite formation and offers insights for understanding and controlling the compositions of solid solutions by separately tuning their nucleation and growth rates via the unique chemistry of solution-organic interfaces.

Deltamethrin induces apoptosis in cerebrum neurons of quail via promoting endoplasmic reticulum stress and mitochondrial dysfunction.

Deltamethrin (DLM) is a widely used and highly effective insecticide. DLM exposure is harmful to animal and human. Quail, as a bird model, has been widely used in the field of toxicology. However, there is little information available in the literature about quail cerebrum damage caused by DLM. Here, we investigated the effect of DLM on quail cerebrum neurons. Four groups of healthy quails were assigned (10 quails in each group), respectively given 0, 15, 30, and 45 mg/kg DLM by gavage for 12 weeks. Through the measurements of quail cerebrum, it was found that DLM exposure induced obvious histological changes, oxidative stress, and neurons apoptosis. To further explore the possible molecular mechanisms, we performed real-time quantitative PCR to detect the expression of endoplasmic reticulum (ER) stress-related mRNA such as glucose regulated protein 78 kD, activating transcription factor 6, inositol requiring enzyme, and protein kinase RNA (PKR)-like ER kinase. In addition, we detected ATP content in quail cerebrum to evaluate the functional status of mitochondria. The study showed that DLM exposure significantly increased the expression of ER stress-related mRNA and decreased ATP content in quail cerebrum tissues. These results suggest that chronic exposure to DLM induces apoptosis of quail cerebrum neurons via promoting ER stress and mitochondrial dysfunction. Furthermore, our results provide a novel explanation for DLM-induced apoptosis of avian cerebrum neurons.

Inhibition of the Nrf2 signaling pathway involved in imidacloprid-induced liver fibrosis in Coturnix japonica.

Imidacloprid (IMI) is a kind of widely used neonicotinoid insecticide. However, the toxicity of IMI is not only applied to target pests but also causes serious negative effects on birds and other creatures. Our previous studies have shown that long-term exposure to IMI can induce liver fibrosis in quails. However, the specific mechanism of quail liver fibrosis induced by IMI is not completely clear. Accordingly, the purpose of this study is to further clarify the potential molecular mechanism of IMI-induced liver fibrosis in quails. Japanese quails (Coturnix japonica) were treated with/without IMI (intragastric administration with 6 mg/kg body weight) in the presence/absence of luteolin (Lut) (fed with 800 mg/kg) for 90 days. The results reveal that IMI can induce hepatic fibrosis, oxidative stress, fatty degeneration, inflammation, and the down-expression of nuclear factor-E2-related factor-2 (Nrf2). Furthermore, the treatment of Lut, a kind of Nrf2 activator, increased the expression of Nrf2 in livers and alleviated liver fibrosis in quails. Altogether, our study demonstrates that inhibition of the Nrf2 pathway is the key to liver fibrosis induced by IMI in quails. These results provide a new understanding for the study of the toxicity of IMI and a practical basis for the treatment of liver fibrosis caused by IMI.

Effect of inorganic mercury exposure on reproductive system of male mice: Immunosuppression and fibrosis in testis.

Mercury as a toxic heavy metal will accumulate in the body and induce various diseases through the food chain. However, it is unknown that the detailed mechanism of reproductive disorder induced by inorganic mercury in male mice to date. This study investigated the toxicological effect of mercuric chloride (HgCl2 ) exposure on reproductive system in male mice. Male Kunming mice received normal saline daily or HgCl2 (3 mg/kg bodyweight) by intraperitoneal injection for a week. The reproductive function was evaluated, and the HgCl2 exposure induced the decline of sperm quality, pregnancy rate, mean litter size, and survival rate. Notably, we firstly found the HgCl2 -induced immunosuppression and fibrosis in mice testis according to the results of RNA sequencing. Collectively, these findings demonstrate that HgCl2 exposure disrupts the reproductive system and induces testicular immunosuppression and fibrosis via inhibition of the CD74 signaling pathway in male mice.

Coprecipitation of Fe/Cr Hydroxides with Organics: Roles of Organic Properties in Composition and Stability of the Coprecipitates.

Iron hydroxides are important scavengers for dissolved chromium (Cr) via coprecipitation processes; however, the influences of organic matter (OM) on Cr sequestration in Fe/Cr-OM ternary systems and the stability of the coprecipitates are not well understood. Here, Fe/Cr-OM coprecipitation was conducted at pH 3, and Cr hydroxide was undersaturated. Acetic acid (HAc), poly(acrylic acid) (PAA), and Suwannee River natural organic matter (SRNOM) were selected as model OMs, which showed different complexation capabilities with Fe/Cr ions and Fe/Cr hydroxide particles. HAc had no significant effect on the coprecipitation, as the monodentate carboxyl ligand in HAc did not favor complexation with dissolved Fe/Cr ions or Fe/Cr hydroxide nanoparticles. Contrarily, PAA and SRNOM with polydentate carboxyl ligand had strong complexation with Fe/Cr ions and Fe/Cr hydroxide nanoparticles, leading to significant amounts of PAA/SRNOM sequestered in the coprecipitates, which caused the structural disorder and fast aggregation of the coprecipitates. In comparison with that of PAA, preferential complexation of Cr ions with SRNOM resulted in higher Cr/Fe ratios in the coprecipitates. This study advances the fundamental understanding of Fe/Cr-OM coprecipitation and mechanisms controlling the composition and stability of the coprecipitates, which is essential for successful Cr remediation and removal in both natural and engineered settings.

Measuring Success of Patients' Continuous Use of Mobile Health Services for Self-management of Chronic Conditions: Model Development and Validation.

BACKGROUND: Mobile health services are gradually being introduced to support patients' self-management of chronic conditions. The success of these services is contingent upon patients' continuous use of them. OBJECTIVE: This study aims to develop a model to measure the success of patients' continuous use of mobile health services for the self-management of chronic conditions. METHODS: The proposed model was derived from the information systems continuance model and the information systems success model. This model contains 7 theoretical constructs: information quality, system quality, service quality, perceived usefulness, user satisfaction, perceived health status, and continuous use intention. A web-based questionnaire survey instrument was developed to test the model. The survey was conducted to collect data from 129 patients who used a mobile health app for hypertension management from 2017 to 2019. The questionnaire items were derived from validated instruments and were measured using a 5-point Likert scale. The partial least squares modelling method was used to test the theoretical model. RESULTS: The model accounted for 58.5% of the variance in perceived usefulness (R2=0.585), 52.3% of the variance in user satisfaction (R2=0.523), and 41.4% of the variance in patients' intention to make continuous use of mobile health services (R2=0.414). The continuous use intention was significantly influenced by their perceived health status (ß=.195, P=.03), perceived usefulness (ß=.307, P=.004), and user satisfaction (ß=.254, P=.04) with the mobile health service. Information quality (ß=.235, P=.005), system quality (ß=.192, P=.02), and service quality (ß=.494, P<.001) had a significantly positive influence on perceived usefulness but not on user satisfaction. Perceived usefulness had a significantly positive influence on user satisfaction (ß=.664, P<.001). In a result opposite to the original hypothesis, perceived health status did not negatively influence patients' intention to continue using the mobile health service but showed a significantly positive correlation. CONCLUSIONS: This study developed a theoretical model to predict and explain patients' continuous use of mobile health services for self-management of chronic conditions and empirically tested the model. Perceived usefulness, user satisfaction, and health status contributed to patients' intention to make continuous use of mobile health services for self-managing their chronic conditions.

Patterns for Patient Engagement with the Hypertension Management and Effects of Electronic Health Care Provider Follow-up on These Patterns: Cluster Analysis.

BACKGROUND: Hypertension is a long-term medical condition. Electronic and mobile health care services can help patients to self-manage this condition. However, not all management is effective, possibly due to different levels of patient engagement (PE) with health care services. Health care provider follow-up is an intervention to promote PE and blood pressure (BP) control. OBJECTIVE: This study aimed to discover and characterize patterns of PE with a hypertension self-management app, investigate the effects of health care provider follow-up on PE, and identify the follow-up effects on BP in each PE pattern. METHODS: PE was represented as the number of days that a patient recorded self-measured BP per week. The study period was the first 4 weeks for a patient to engage in the hypertension management service. K-means algorithm was used to group patients by PE. There was compliance follow-up, regular follow-up, and abnormal follow-up in management. The follow-up effect was calculated by the change in PE (CPE) and the change in systolic blood pressure (CSBP, SBP) before and after each follow-up. Chi-square tests and z scores were used to ascertain the distribution of gender, age, education level, SBP, and the number of follow-ups in each cluster. The follow-up effect was identified by analysis of variances. Once a significant effect was detected, Bonferroni multiple comparisons were further conducted to identify the difference between 2 clusters. RESULTS: Patients were grouped into 4 clusters according to PE: (1) PE started low and dropped even lower (PELL), (2) PE started high and remained high (PEHH), (3) PE started high and dropped to low (PEHL), and (4) PE started low and rose to high (PELH). Significantly more patients over 60 years old were found in the PEHH cluster (P≤.05). Abnormal follow-up was significantly less frequent (P≤.05) in the PELL cluster. Compliance follow-up and regular follow-up can improve PE. In the clusters of PEHH and PELH, the improvement in PE in the first 3 weeks and the decrease in SBP in all 4 weeks were significant after follow-up. The SBP of the clusters of PELL and PELH decreased more (-6.1 mmHg and -8.4 mmHg) after follow-up in the first week. CONCLUSIONS: Four distinct PE patterns were identified for patients engaging in the hypertension self-management app. Patients aged over 60 years had higher PE in terms of recording self-measured BP using the app. Once SBP reduced, patients with low PE tended to stop using the app, and a continued decline in PE occurred simultaneously with the increase in SBP. The duration and depth of the effect of health care provider follow-up were more significant in patients with high or increased engagement after follow-up.