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Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.

Groundwater nitrate (NO 3 - ) contamination in China has become a serious environmental problem, especially in agricultural production areas, which greatly affects the safety of drinking groundwater and requires urgent attention. In this study, the main sources of groundwater nitrate in China were reviewed, including atmospheric deposition, soil nitrogen, agricultural fertilization, and fecal sewage, among which fecal sewage and agricultural fertilization were the main reasons for the excessive groundwater nitrate. The application of hydrochemical analysis, multivariate statistical analysis, stable isotope tracer method, and microbial source tracking in the source apportionment of groundwater nitrate was summarized. All types of source apportionment methods had certain limitations. It is suggested that a variety of methods should be used to identify the source of groundwater nitrate, and the contribution rate of different pollution sources should be calculated using multivariate statistical analysis and isotope quantitative analysis models. The source apportionment of nitrate pollution has undergone a process from qualitative to quantitative research. At present, the SIAR and MixSIAR models based on δ 15 N-NO 3 - and δ 18 O-NO 3 - have been used widely to analyze the source of nitrate. However, due to the overlap of isotope characteristic values of different input end-members, the difference in δ 15 N-NO 3 - and δ 18 O-NO 3 - values under different spatial and temporal changes, and the influence of isotope fractionation in the process of nitrogen migration and transformation, the results calculated by the model remain uncertain. It is necessary to further optimize the analytical method of the model to obtain the source of nitrate pollution and its contribution rate more accurately to further aid in the scientific management of groundwater resources.

Background: Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density. The mechanism by which LNA impairs the skeleton is unclear, and there is a paucity of research on the effects of LNA on bone-forming osteoblasts., Methods: The effect of LNA on osteoblast differentiation, cellular bioenergetics, and production of oxidized PUFA metabolites in vitro, was studied using primary mouse bone marrow stromal cells (BMSC) and MC3T3-E1 osteoblast precursors., Results: LNA treatment decreased alkaline phosphatase activity, an early marker of osteoblast differentiation, but had no effect on committed osteoblasts or on mineralization by differentiated osteoblasts. LNA suppressed osteoblast commitment by blunting the expression of Runx2 and Osterix, key transcription factors involved in osteoblast differentiation, and other key osteoblast-related factors involved in bone formation. LNA treatment was associated with increased production of oxidized LNA- and arachidonic acid-derived metabolites and blunted oxidative phosphorylation, resulting in decreased ATP production., Conclusion: Our results show that LNA inhibited early differentiation of osteoblasts and this inhibitory effect was associated with increased production of oxidized PUFA metabolites that likely impaired energy production via oxidative phosphorylation., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Urease-producing bacteria (UPB) are widely present in soil and play an important role in soil ecosystems. In this study, 65 UPB strains were isolated from cadmium (Cd)-polluted soil around a lead-zinc mine in Yunnan Province, China. The Cd tolerance, removal of Cd from aqueous solution, production of indoleacetic acid (IAA) and plant growth-promoting effects of these materials were investigated. The results indicate that among the 65 UPB strains, four strains with IAA-producing ability were screened and identified as Bacillus thuringiensis W6-11, B. cereus C7-4, Serratia marcescens W11-10, and S. marcescens C5-6. Among the four strains, B. cereus C7-4 had the highest Cd tolerance, median effect concentration (EC 50 ) of 59.94 mg/L. Under Cd 5 mg/L, S. marcescens C5-6 had the highest Cd removal from aqueous solution, up to 69.83%. Under Cd 25 mg/kg, inoculation with B. cereus C7-4 significantly promoted maize growth in a sand pot by increasing the root volume, root surface area, and number of root branches by 22%, 29%, and 20%, respectively, and plant height and biomass by 16% and 36%, respectively, and significantly increasing Cd uptake in the maize roots. Therefore, UPB is a potential resource for enhancing plant adaptability to Cd stress in plants with Cd-polluted habitats.

The Kuaize River is a small typical karst watershed in the source area of the Pearl River as well as an important coal mining area in Eastern Yunnan with a fragile ecological environment. Strengthening the research on the water environment in the region plays an important role in supporting the comprehensive management of the ecological environment and water resources in the source region of the Pearl River. Through the systematic collection of surface water, karst groundwater, and mine water samples, mathematical statistics analysis, correlation analysis, ion ratio analysis, absolute principal component scores multiple linear regression(APCS-MLR), and other methods were used to study the characteristics of hydrochemical evolution and control factors in Kuaize River Basin. The results showed that the average pH value of surface water in Kuaize River Basin was 7.8, which was weakly alkaline. The main cations were Ca 2+ and Na + , showing the characteristics of Ca 2+ >Na + >Mg 2+ >K + . The main anions were HCO 3 - and SO 4 2- , showing the characteristics of HCO 3 >Cl - >SO 4 2- >NO 3 - >Cl - . The variation coefficients of Na + , SO 4 2- , and NO 3 - in surface water were high, showing strong spatial variability. The water chemical type of the trunk stream was mainly HCO 3 -Ca, whereas the water chemical type of the tributary was relatively complex, mainly HCO 3 -Ca, HCO 3 -Ca·Na, and HCO 3 , Cl 4 -Ca·Na. The chemical composition of surface water was mainly affected by rock weathering, cation exchange, and human activities. Ca 2+ , Mg 2+ , Na + , and HCO 3 - in surface water mainly came from the weathering of carbonate rock and silicate rock; SO 4 2- mainly came from the oxidation of sulfide, such as pyrite in coal seams; K + , Cl - , and NO 3 - mainly came from domestic sewage and agricultural activities. The APCS-MLR receptor model analysis results showed that the surface water in the Kuaize River Basin was mainly affected by sulfide oxidation, carbonate weathering, weathering of silicate rock in mine water, domestic sewage, agricultural activities, and unknown sources. In general, the contribution rate of human activities such as mining, domestic sewage, and agricultural activities to the surface water reached 47.17%, indicating that human activities were the key driving factor of surface water chemistry in the Kuaize River Basin.

TheWudu River is a typical mining-type watershed in the karst mountainous area of western Guizhou Province. Based on the collection of the main stream, tributaries, spring water, and mine water samples in Wudu River Basin, the hydrochemical characteristics and control factors of Wudu River Basin were studied using Gibbs diagram, Piper diagram, and mathematical statistics analysis, and the solute contribution rate of different sources was calculated. The results revealed that the pH value of the water in the Wudu River Basin ranged from 7.87 to 8.52, with an average of 8.14. The TDS values ranged from 135 to 243 mg·L -1 , with an average of 191.7 mg·L -1 . The major cations in natural river and spring water were Ca 2+ and Mg 2+ , the major anion was HCO 3 - , and the hydrochemical type was HCO 3 -Ca. However, owing to the influence of mining activities, the major cations in some tributaries were Ca 2+ and Na + , and the hydrochemical types transitioned to HCO 3 ·SO 4 -Ca and HCO 3 ·SO 4 -Ca·Na. The ion components of river water in Wudu River Basin were affected by mine water discharge and cation exchange, carbonate rock weathering, silicate rock weathering, and agricultural fertilization. The high concentration of SO 4 2- and Na + in mine water was the primary source of SO 4 2- and Na + in the tributaries of the Wudu River. The method for calculating chemical material balance showed that the contribution rate of carbonate rock weathering ranged from 44.12% to 86.92%, with an average of 74.32%. The contribution rate of mining activities ranged from 3.28% to 37.07%, with an average of 11.61%. Carbonate rock weathering was the main controlling factor of hydrochemical components in the Wudu River Basin; meanwhile, mining activities also had a certain impact on river water chemistry but they showed spatial heterogeneity. The average contribution rates of atmospheric precipitation, silicate rock weathering, agricultural activities, and domestic sewage were 3.75%, 4.67%, 2.85%, and 2.81%, respectively, which had a limited impact on the hydrochemical components of the basin.

In this study, we propose a radiomics clinical probability-weighted model for the prediction of prognosis for non-small cell lung cancer (NSCLC). The model combines radiomics features extracted from radiotherapy (RT) planning images with clinical factors such as age, gender, histology, and tumor stage. CT images with radiotherapy structures of 422 NSCLC patients were retrieved from The Cancer Imaging Archive (TCIA). Radiomic features were extracted from gross tumor volumes (GTVs). Five machine learning algorithms, namely decision trees (DT), random forests (RF), extreme boost (EB), support vector machine (SVM) and generalized linear model (GLM) were optimized by a voted ensemble machine learning (VEML) model. A probabilistic weighted approach is used to incorporate the uncertainty associated with both radiomic and clinical features and to generate a probabilistic risk score for each patient. The performance of the model is evaluated using a receiver operating characteristic (ROC). The Radiomic model, clinical factor model, and combined radiomic clinical probability-weighted model demonstrated good performance in predicting NSCLC survival with AUC of 0.941, 0.856 and 0.949, respectively. The combined radiomics clinical probability-weighted enhanced model achieved significantly better performance than the radiomic model in 1-year survival prediction (chi-square test, p < 0.05). The proposed model has the potential to improve NSCLC prognosis and facilitate personalized treatment decisions.

Objective: To investigate the spatial distribution characteristics and correlation between the prevalence of dental fluorosis and the chemical elemental composition of drinking water sources in coal-fired fluorosis areas. Methods: Based on the survey data on the prevalence of dental fluorosis at CDC in Guizhou Province in 2022, 274 original surface drinking water sources were collected in typical coal-fired fluorosis areas, and fluoride (F), calcium (Ca), magnesium (Mg), aluminum (Al), titanium (Ti), chromium (Cr), manganese (Mn), iron (Fe), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), molybdenum (Mo), cadmium (Cd), barium (Ba), lead (Pb) 17 elements; apply Moran's I index, Getis-Ord Gi * hotspot analysis of the global spatial autocorrelation of chemical elements in drinking water and the degree of aggregation of each element on the local area, and correlation analysis with the prevalence of dental fluorosis in the region. Results: Except for Cu, Zn, and Cd, global spatial autocorrelation Moran's I was negative, and all other elements were positive. F, Ca, Al, Ti, As, Mo, Cd, and Cu elements showed high values of aggregation in the southeastern low-altitude area; Mg, Ba, Pb, Cr, Mn, and Fe elements were mainly aggregated in the central altitude terrain transition area, Zn and Se elements in water sources are significantly positively correlated with the prevalence of dental fluorosis ( P <0.05). In contrast, F, Mg, Al, Ti, As, Mo, Cd, Ba, and Pb elements negatively correlate ( P <0.05). Elements in the central region were high-high aggregation, as a hot spot aggregation area with high disease incidence, while F, Al, Mn, Mo, Cd, and Ba elements in the western region were low-low aggregation, as a cold spot aggregation area with a low incidence of fluorosis. Conclusions: The risk of population fluoride exposure in surface drinking water sources is shallow. However, the chemical element content of drinking water sources in coal-fired polluted endemic fluorosis areas has prominent spatial geographical distribution characteristics. There is a significant spatial aggregation effect with the prevalence of dental fluorosis, which may play a synergistic or antagonistic effect on the occurrence and prevalence of dental fluorosis.

Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population (1-3), but the basis for this association remains unclear. We employed a spatially defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from vitamin D-deficient or vitamin D-replete PHPT patients. A cross-sectional panel of eucalcemic cadaveric donor parathyroid glands was examined in parallel as normal tissue controls. Here, we report that parathyroid tumors from vitamin D-deficient PHPT patients (Def-Ts) are intrinsically different from those of vitamin D-replete patients (Rep-Ts) of similar age and preoperative clinical presentation. The parathyroid oxyphil cell content is markedly higher in Def-Ts (47.8%) relative to Rep-Ts (17.8%) and normal donor glands (7.7%). Vitamin D deficiency is associated with increased expression of electron transport chain and oxidative phosphorylation pathway components. Parathyroid oxyphil cells, while morphologically distinct, are comparable to chief cells at the transcriptional level, and vitamin D deficiency affects the transcriptional profiles of both cell types in a similar manner. These data suggest that oxyphil cells are derived from chief cells and imply that their increased abundance may be induced by low vitamin D status. Gene set enrichment analysis reveals that pathways altered in Def-Ts are distinct from Rep-Ts, suggesting alternative tumor etiologies in these groups. Increased oxyphil content may thus be a morphological indicator of tumor-predisposing cellular stress., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Tuochangjiang River is a typical mining-type watershed in the karst mountainous area of western Guizhou province. The study of its hydrochemical evolution characteristics and driving factors is of great significance to the local economic development and the scientific management of water resources. The samples of river water, spring water, and mine water in the Tuochangjiang River Basin were collected, and the sources of solutes and their contribution to the chemical components of river water were discussed by means of hydrochemical diagrams, mathematical statistics, and the absolute principal component scores-multivariate linear regression model (APCS-MLR). The results showed that the pH of the river water ranged between 7.30 to 8.31, and the TDS value ranged between 40 to 520 mg·L -1 , which was mainly contributed by Ca 2+ , Na + , HCO 3 - , and SO 4 2- . The dominant cations in river water were Ca 2+ and Na + , the dominant anions were HCO 3 - and SO 4 2- , and the main water chemistry transitioned from HCO 3 -Ca to HCO 3 -Ca·Na and HCO 3 ·SO 4 -Ca·Na type, whereas that of the mine water was mainly the HCO 3 -Na and HCO 3 ·SO 4 -Na types. The chemical composition of river water was affected by rock weathering, exchange adsorption of anions, mineral dissolution and precipitation, and human activities, in which Ca 2+ were mainly from the discharge of mining wastewater, and Cl 2+ , and HCO 3 - were mainly derived from the weathering and dissolution of carbonate and silicate rocks, Na + and SO 4 2- were mainly from the discharge of mining wastewater, and Cl - and NO 3 - were affected by domestic sewage and agricultural activities, respectively. APCS-MLR analysis further showed that the river water solutes mainly included five sources:discharge of mining wastewater, dissolution of soil minerals, geological background, agricultural activities, and unknown sources, and their contribution rates to river water were 23.49%, 35.04%, 13.87%, 7.96%, and 20.63%, respectively. Mining factors and soil factors were the most important sources of solutes in the river water, and they were the main driving factors for the hydrochemical evolution of the Tuochangjiang River Basin.

Objective: To develop a Fear of Cancer Scale (FOCS) for non-cancer populations., Methods: FOCS was developed by classical measurement theory. A total of 15 college students were invited to conduct semi-structured interviews. Seven experts were invited for expert consultation. A total of 2012 Chinese college students who had completed the electronic questionnaire on WJX.cn platform was included. The reliability and validity of FOCS were verified. Multiple linear regression analysis was adopted to explore the influencing factors of cancer fear among college students and further verify the validity of FOCS., Results: There were 17 items in the FOCS, including two subscales - direct fear (8 items), and indirect fear (9 items). FOCS had good validity and reliability. Multiple linear regression showed that GAD-7 score, CSDS score, negative coping score, positive coping score, guardian's highest education, gender, life satisfaction, nationality and major were the influencing factors of cancer fear ( p  < .05)., Conclusions: The 17-item FOCS was a reliable and valid measure to examine the level of cancer fear in non-cancer populations.

Objectives: To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction., Methods: In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3 + , CD4 + , and CD8 + T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55)., Results: iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759-0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647-0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206-0.546, p < 0.001), Resec4 (0.199, 0.040-1.000, p < 0.001), and TCIA (0.303, 0.098-0.944, p = 0.001)., Conclusions: iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection., Key Points: • Decoding tumour immune microenvironment enables advanced biomarkers identification. • Immune ecosystem diversity index characterises intratumoural immune status noninvasively. • Immune ecosystem diversity index is prognostic for NSCLC patients., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Immune reconstitution bone loss (IRBL) is a common side-effect of antiretroviral therapy (ART) in people with human immunodeficiency virus (PWH). Immune reconstitution bone loss acts through CD4+ T-cell/immune reconstitution-induced inflammation and is independent of antiviral regimen. Immune reconstitution bone loss may contribute to the high rate of bone fracture in PWH, a cause of significant morbidity and mortality. Although IRBL is transient, it remains unclear whether bone recovers, or whether it is permanently denuded and further compounds bone loss associated with natural aging., Methods: We used a validated IRBL mouse model involving T-cell reconstitution of immunocompromised mice. Mice underwent cross-sectional bone phenotyping of femur and/or vertebrae between 6 and 20 months of age by microcomputed tomography (µCT) and quantitative bone histomorphometry. CD4+ T cells were purified at 20 months to quantify osteoclastogenic/inflammatory cytokine expression., Results: Although cortical IRBL in young animals recovered with time, trabecular bone loss was permanent and exacerbated skeletal decline associated with natural aging. At 20 months of age, reconstituted CD4+ T cells express enhanced osteoclastogenic cytokines including RANKL, interleukin (IL)-1β, IL-17A, and tumor necrosis factor-α, consistent with elevated osteoclast numbers., Conclusions: Immune reconstitution bone loss in the trabecular compartment is permanent and further exacerbates bone loss due to natural aging. If validated in humans, interventions to limit IRBL may be important to prevent fractures in aging PWH., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Background: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR., Methods: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox )., Results: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D 3 ), and parathyroid hormone levels. Renal tubular α -Klotho protein expression was increased in KO mice but vascular α -Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice., Conclusions: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis., (Copyright © 2022 by the American Society of Nephrology.)

In order to serve the water resources management of the Xiaohuangni River basin, this study explored the hydrochemical composition characteristics and ion sources of surface water in the basin. Samples of main stream and tributary river water and mine water were systematically collected. By means of a Piper diagram, Gibbs diagram, ion ratio coefficient, and mathematical statistical analysis, we analyzed the hydrochemical composition, spatial distribution characteristics, and main control factors of the Xiaohuangni River and evaluated the solute contribution rates of different sources. The results showed that the pH of the Xiaohuangni River basin ranged between 7.17 to 9.14, with an average of 8.00, which is generally considered weakly alkaline. Additionally, the total dissolved solids ranged between 154 mg·L -1 to 460 mg·L -1 , with an average of 257.39 mg·L -1 , which was equivalent to that of the main stream of the Xijiang River. The dominant cation was Ca 2+ , accounting for 69% of the total cations; the dominant anions were HCO 3 - and SO 4 2- , accounting for 65% and 30% of the total anions, respectively. The main chemical type of the main stream was HCO 3 -Ca. Affected by mining activities, the tributaries transitioned from HCO 3 -Ca to HCO 3 ·SO 4 -Ca and HCO 3 ·SO 4 -Ca·Na type. River water solute was mainly controlled by the weathering of carbonate rock and silicate rock, with the participation of sulfuric and carbonic acid. The contribution rate of carbonate weathering to river water solute was 63%, and that of silicate weathering was 16.33%. Meanwhile, human activities contributed markedly to the dissolved solutes of the Xiaohuangni River basin, in which the contribution rate of mining activities was 13.4%, and the contribution rate of agricultural activities and domestic sewage was 4%.

Exploring the spatial distribution characteristics and variation law of soil pH and analyzing the impact of environmental factors on the spatial differentiation of soil pH are of great significance to the accurate management of soil pH and the sustainable utilization of soil resources in the complex mountainous environment of Anshun City. Based on 22 851 field sampling points, using the methods of global Moran's I index, cold and hot spot analysis, semi-variance function, and Kriging interpolation, the spatial structure characteristics and distribution law of soil pH in Anshun City were revealed from different angles, and the influence of environmental factors on its spatial differentiation was analyzed with the help of geographic detectors. The results showed that:① the variation range of topsoil pH value in Anshun City was 3.56-8.61, the mean value was 6.28, and the coefficient of variation was 16.33%. ② In the global space, soil pH showed aggregation distribution; in the local space, the west and northwest were hot spots, whereas the east and south were cold spots. The nugget coefficient (40.19%) showed that the spatial variability in soil pH was determined by both structural and random factors, but the role of structural factors was greater. ③ In terms of spatial distribution, soil pH mainly presented a patchy mosaic distribution pattern, in which slightly acidic soil (57.14%) was concentrated in the east, northeast, and south of Anshun City; neutral soil (30.13%) was concentrated in the west, northwest, and southeast; and strongly acidic soil (6.12%) and alkaline soil (6.45%) were embedded in slightly acidic soil and neutral soil, respectively, in a block structure. ④ The geo-detector analysis showed that the explanatory power of various environmental factors to the spatial variation in soil pH was ranked as soil type (9.4%)>soil forming parent rock (7.9%)>altitude (2.1%)>land use (1.8%)>slope (0.1%), in which the q value of the interaction between soil type and parent rock type and other factors was large. Therefore, soil type and parent rock type were the main controlling factors of soil pH spatial variation in Anshun City.

Screening and linkage to care are essential to achieve viral hepatitis elimination before 2030. The accurate identification of endemic areas is important for controlling diseases with geographic aggregation. Viral activity drives prognosis of chronic hepatitis B and hepatitis C virus infection. This screening was conducted in Chiayi County from 2018-2019. All residents aged 30 years or older were invited to participate in quantitative HBsAg (qHBsAg) and HCV Ag screening. Among the 4010 participants (male:female = 1630:2380), the prevalence of qHBsAg and HCV Ag was 9.9% (396/4010) and 4.1% (163/4010), respectively. High-prevalence townships were identified, three for qHBsAg > 15% and two for HCV Ag > 10%. The age-specific prevalence of qHBsAg was distributed in an inverse U-shape with a peak (16.0%, 68/424) for subjects in their 40 s; for HCV, prevalence increased with age. Concentrations of qHBsAg < 200 IU/mL were found in 54% (214/396) of carriers. The rate of oral antiviral treatment for HCV was 75.5% (114/151), with subjects younger than 75 years tending to undergo treatment (85.6% vs. 57.4%, p < 0.001). QHBsAg and HCV Ag core antigens can reflect the concentration of the viral load, which serves as a feasible screening tool. Using quantitative antigen screening for hepatitis B and C in community-based screening, two hyperendemic townships were identified from an endemic county.

The calcium-sensing receptor (CaSR) drives essential calcium ion (Ca 2+ ) and E-cadherin‒mediated processes in the epidermis, including differentiation, cell-to-cell adhesion, and epidermal barrier homeostasis in cells and in young adult mice. We now report that decreased CaSR expression leads to impaired Ca 2+ signal propagation in aged mouse (aged >22 months) epidermis and human (aged >79 years, donor age) keratinocytes. Baseline cytosolic Ca 2+ concentrations were higher, and capacitive Ca 2+ entry was lower in aged than in young keratinocytes. As in Casr-knockout mice ( Epid CaSR -/- ), decreased CaSR expression led to decreased E-cadherin and phospholipase C-γ expression and to a compensatory upregulation of STIM1. Pretreatment with the CaSR agonist N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine normalized Ca 2+ propagation and E-cadherin organization after experimental wounding. These results suggest that age-related defects in CaSR expression dysregulate normal keratinocyte and epidermal Ca 2+ signaling, leading to impaired E-cadherin expression, organization, and function. These findings show an innovative mechanism whereby Ca 2+ - and E-cadherin‒dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function., (Published by Elsevier Inc.)

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a class B G protein–coupled receptor (GPCR) that regulates mineral ion, vitamin D, and bone homeostasis. Activation of the PTHR by PTH induces both transient cell surface and sustained endosomal cAMP production. To address whether the spatial (location) or temporal (duration) dimension of PTHR-induced cAMP encodes distinct biological outcomes, we engineered a biased PTHR ligand (PTH 7d ) that elicits cAMP production at the plasma membrane but not at endosomes. PTH 7d stabilized a unique active PTHR conformation that mediated sustained cAMP signaling at the plasma membrane due to impaired β-arrestin coupling to the receptor. Experiments in cells and mice revealed that sustained cAMP production by cell surface PTHR failed to mimic the pharmacological effects of sustained endosomal cAMP production on the abundance of the rate-limiting hydroxylase catalyzing the formation of active vitamin D, as well as increases in circulating active vitamin D and Ca 2+ and in bone formation in mice. Thus, similar amounts of cAMP generated by PTHR for similar lengths of time in different cellular locations, plasma membrane and endosomes, mediate distinct physiological responses. These results unveil subcellular signaling location as a means to achieve specificity in PTHR-mediated biological outcomes and raise the prospect of rational drug design based upon spatiotemporal manipulation of GPCR signaling.

Aims: Diabetes mellitus is a major cause of death worldwide, including Taiwan. The mortality data of the subsets of patients who suffered from microvascular or macrovascular complications is limited. The aim of this study was to investigate the causes of in-hospital death of patients with type 2 diabetes, especially the patients with microvascular, macrovascular and both micro-macrovascular complications., Methods: A total of 12 159 patients with type 2 diabetes were identified from the Taiwan National Health Insurance Research Database (NHIRD) to analyse the causes of death. Type 2 diabetic subjects with microvascular, macrovascular and both micro-macrovascular complications were further classified and compared to patients without microvascular and macrovascular complications in the logistic regression analysis of the risk of death., Results: Pneumonia increased risk of in-hospital death in patients with microvascular, macrovascular and both micro-macrovascular complications, with adjusted odds ratios (AORs) of 2.13 (95% confidence interval [CI] 1.09-4.18), 3.26 (1.71-6.24) and 3.96 (2.17-7.22), respectively. Septicaemia increased risk of in-hospital death in patients with macrovascular (AOR 2.57 [1.31-5.04]) and both micro-macrovascular complications (AOR 4.69 [2.58-8.50])., Conclusion: Pneumonia increased risk of in-hospital death among the type 2 diabetic patients with microvascular, macrovascular and both micro-macrovascular complications. Therefore, efforts aim at preventing pneumonia or decreasing its severity may increase survival., (© 2021 John Wiley & Sons Ltd.)

Background: Patients with chronic obstructive pulmonary disease (COPD) are more susceptible to Aspergillus colonization or infection. Several studies have demonstrated that invasive pulmonary Aspergillosis (IPA) and Aspergillus hypersensitivity (AH) have a detrimental effect on COPD. However, it remains to be clarified whether Aspergillus colonization is associated with acute exacerbation of COPD (AECOPD). This study aimed to explore the impact of Aspergillus colonization in the lower respiratory tract on AECOPD. Method: Patients with Aspergillus colonization were identified from a retrospective cohort of hospitalized AECOPD from 2011 to 2016 in eight centers in Shanghai, China. The demographic information, conditions of the stable stage, clinical characteristics during hospitalization, and 1-year follow-up information after discharge were collected and compared to participants without fungi colonization. Result: Twenty-six hospitalized AECOPD patients with Aspergillus colonization and 72 controls were included in the final analysis after excluding patients with other fungi isolation and matching. The rates of recurrence of acute exacerbation within 90 days and 180 days after discharge in the patients with Aspergillus colonization were both significantly higher than that in the fungi negative patients (90 days: 19.2 vs. 4.2%, p = 0.029; 180 days: 23.1 vs. 4.2%, p = 0.010), and the all-cause mortality within 1 year was also higher (11.5 vs. 0.0%, p = 0.017). Multivariate logistic regression analysis showed that Aspergillus colonization was an independent risk factor for the recurrence of acute exacerbation within 90 days and 180 days (90 days: OR = 8.661, 95% CI: 1.496-50.159, p = 0.016; 180 days: OR =10.723, 95% CI: 1.936-59.394, p = 0.007). Conclusion: Aspergillus colonization may predict poor prognosis of AECOPD while leading to an increased risk of recurrent AECOPD in a short period., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Zuo, Cheng, Huang, Bao, Jin, Gao, Tu, Hu, Hang, Wang, Zhang and Zhang.)

Background: This study aimed to devise a Cancer symptoms Discrimination Scale (CSDS) suitable for China based on a cross-sectional survey., Methods: The CSDS was developed using the classical measurement theory. A total of 3610 students from Yunnan province, China, participated in the cross-sectional survey. The test version of the scale was modified by the item analysis method, and after the official version of CSDS was developed, its reliability and validity were verified. A univariate analysis of variance and a multiple linear regression model were used to analyze the influencing factors of cancer symptoms discrimination among the university/college students., Results: There were 21 items in total for the CSDS, including 3 subscales --- common clinical manifestations (11 items), physical appearance defects (6 items), and drainage tube(s) wearing (4 items). This CSDS had good validity (GFI = 0.930, AGFI = 0.905, RMR = 0.013, I-CVIs> 0.80, and the Pearson correlation coefficient was satisfactory.) and reliability (Cronbach's alpha = 0.862, spearman-brown coefficient = 0.875). The multiple linear regression showed that certain factors may affect the students' discrimination level against cancer symptoms (P < 0.05), including gender, major, current education degree, guardian's highest record of formal schooling, self-rated health status, history of care for cancer patients, family relationship, ways of cancer knowledge acquisition, good/poor understanding of cancer-related information, degree of cancer fear, and their perception of cancer infectiousness., Conclusion: This CSDS, with good reliability and validity, can be used for the evaluation of the discrimination risk and levels against cancer symptoms among healthy students.

Background: The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19., Methods: We did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19., Findings: We enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53 617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74-6·33; p<0·0001), fatigue (OR 1·56, 1·01-2·41; p=0·043), white blood cell count less than 4 × 10 9 per L (OR 2·44, 1·28-4·64; p=0·0066), lymphocyte count less than 0·8 × 10 9 per L (OR 1·82, 1·00-3·31; p=0·049), ground glass opacity (OR 1·95, 1·32-2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04-2·28; p=0·032) were independent risk factors for confirmed COVID-19., Interpretation: The screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease., Funding: National Natural Science Foundation of China., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Group-III monochalcogenides of two-dimensional (2D) layered materials have attracted widespread attention among scientists due to their unique electronic performance and interesting chemical and physical properties. Indium sulfide (InS) is attracting increasing interest from scientists because it has two distinct crystal structures. However, studies on the synthesis of highly crystalline, large-area, and atomically thin-film InS have not been reported thus far. Here, the chemical vapor deposition (CVD) synthesis method of atomic InS crystals has been reported in this paper. The direct chemical vapour phase reaction of metal oxides with chalcogen precursors produces a large-sized hexagonal crystal structure and atomic-thickness InS flakes or films. The InS atomic films are merged with a plurality of triangular InS crystals that are uniform and entire and have surface areas of 1 cm2 and controllable thicknesses in bilayers or trilayers. The properties of the as-grown highly crystalline samples were characterized by spectroscopic and microscopic measurements. The ion-gel gated InS field-effect transistors (FETs) reveal n-type transport behavior, and have an on-off current ratio of >103 and a room-temperature electron mobility of ∼2 cm2 V-1 s-1. Moreover, our CVD InS can be transferred from mica to any substrates, so various 2D materials can be reassembled into vertically stacked heterostructures, thus facilitating the development of heterojunctions and exploration of the properties and applications of their interactions.

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B 1 receptor (GABA B1 R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABA B1 R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABA B1 R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABA B1 R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABA B1 R heteromer to HPT.

Calcium and its putative receptor (CaSR) control skeletal development by pacing chondrocyte differentiation and mediating osteoblast (OB) function during endochondral bone formation-an essential process recapitulated during fracture repair. Here, we delineated the role of the CaSR in mediating transition of callus chondrocytes into the OB lineage and subsequent bone formation at fracture sites and explored targeting CaSRs pharmacologically to enhance fracture repair. In chondrocytes cultured from soft calluses at a closed, unfixed fracture site, extracellular [Ca 2+ ] and the allosteric CaSR agonist (NPS-R568) promoted terminal differentiation of resident cells and the attainment of an osteoblastic phenotype. Knockout (KO) of the Casr gene in chondrocytes lengthened the chondrogenic phase of fracture repair by increasing cell proliferation in soft calluses but retarded subsequent osteogenic activity in hard calluses. Tracing growth plate (GP) and callus chondrocytes that express Rosa26-tdTomato showed reduced chondrocyte transition into OBs (by >80%) in the spongiosa of the metaphysis and in hard calluses. In addition, KO of the Casr gene specifically in mature OBs suppressed osteogenic activity and mineralizing function in bony calluses. Importantly, in experiments using PTH (1-34) to enhance fracture healing, co-injection of NPS-R568 not only normalized the hypercalcemic side effects of intermittent PTH (1-34) treatment in mice but also produced synergistic osteoanabolic effects in calluses. These data indicate a functional role of CaSR in mediating chondrogenesis and osteogenesis in the fracture callus and the potential of CaSR agonism to facilitate fracture repair. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Calcium-sensing receptor (CaSR) is the molecular sensor by which cells respond to small changes in extracellular Ca 2+ concentrations. CaSR has been reported to play a role in glandular and fluid secretion in the gastrointestinal tract and to regulate differentiation and proliferation of skin keratinocytes. CaSR is present in the esophageal epithelium, but its role in this tissue has not been defined. We deleted CaSR in the mouse esophagus by generating keratin 5 CreER;CaSR Flox+/+ compound mutants, in which loxP sites flank exon 7 of CaSR gene. Recombination was initiated with multiple tamoxifen injections, and we demonstrated exon 7 deletion by PCR analysis of genomic DNA. Quantitative real-time PCR and Western blot analyses showed a significant reduction in CaSR mRNA and protein expression in the knockout mice ( Eso CaSR -/- ) as compared with control mice. Microscopic examination of Eso CaSR -/- esophageal tissues showed morphological changes including elongation of the rete pegs, abnormal keratinization and stratification, and bacterial buildup on the luminal epithelial surface. Western analysis revealed a significant reduction in levels of adherens junction proteins E-cadherin and β catenin and tight junction protein claudin-1, 4, and 5. Levels of small GTPase proteins Rac/Cdc42, involved in actin remodeling, were also reduced. Ussing chamber experiments showed a significantly lower transepithelial resistance in knockout (KO) tissues. In addition, luminal-to-serosal-fluorescein dextran (4 kDa) flux was higher in KO tissues. Our data indicate that CaSR plays a role in regulating keratinization and cell-cell junctional complexes and is therefore important for the maintenance of the barrier function of the esophagus. NEW & NOTEWORTHY The esophageal stratified squamous epithelium maintains its integrity by continuous proliferation and differentiation of the basal cells. Here, we demonstrate that deletion of the calcium-sensing receptor, a G protein-coupled receptor, from the basal cells disrupts the structure and barrier properties of the epithelium.

Background: Bridging studies are mandatory in the EU and USA if the reference biological product used in the biosimilar comparability exercise is foreign sourced. However, it has been argued that the duplication of bridging studies may limit biosimilar development., Objective: The aim of the study was to explore whether it is necessary to conduct pharmacokinetic (PK)/pharmacodynamic (PD) bridging studies for biosimilars. This study examines similarities and differences between EU- and US-licensed reference biological products, based on literature-reported PK and/or PD data., Methods: We searched PubMed, Drugs@FDA, and European Medicines Agency (EMA) databases to identify biosimilar bridging studies designed to evaluate similarities between EU- and US-licensed reference biological products. PK and/or PD parameters were retrieved; the ratio of the parameter value of the EU-licensed product to that of the US-licensed product and its corresponding 90% confidence intervals (CIs) were calculated. Similarity was declared if the 90% CIs for the ratios of the PK or PD parameters were within the range of 80-125%., Results: Thirty-one bridging studies were identified for 11 biosimilars, including adalimumab (n = 10), bevacizumab (n = 4), epoetin alfa (n = 1), etanercept (n = 2), filgrastim (n = 1), infliximab (n = 3), insulin glargine (n = 1), insulin lispro (n = 1), PEGfilgrastim (n = 2), rituximab (n = 2), and trastuzumab (n = 4). Most studies showed PK and/or PD similarities between the EU- and US-licensed reference biological products. However, among the 31 studies, only three studies (accounting for two biologics, PEGfilgrastim and adalimumab) showed dissimilarity between the EU and US reference products. Although one bridging study on PEGfilgrastim (Sandoz) indicated dissimilar PKs (maximum observed plasma concentration [C max ] and area under the concentration-time curve [AUC]) between the reference products, the other study (Mylan) demonstrated similar PK. Moreover, two of ten studies involving adalimumab failed to demonstrate similarities between the reference products. However, for both cases, PK similarities were later confirmed in the follow-up bridging studies with larger sample sizes., Conclusion: Our analysis reveals that, in most cases, the reference biological products originated from the EU and those from the USA are almost indistinguishable in terms of PK/PD properties. Additional in vivo bridging studies between reference products from different global regions may not be required if similar physicochemical and structural properties are evident in vitro.

Background: Natural compounds from plants are known to provide a source of anthelmintic molecules. In previous studies, we have shown that plant extracts from the plant Picria fel-terrae Lour. and particular fractions thereof have activity against the free-living nematode Caenorhabditis elegans, causing quite pronounced stress responses in this nematode. We have also shown that a fraction, designated Pf-fraction 5, derived from this plant has a substantial adverse effect on this worm; however, nothing is known about the molecular processes affected in the worm. In the present study, we explored this aspect., Results: Key biological processes linked to upregulated genes (n = 214) included 'response to endoplasmic reticulum stress' and 'lipid metabolism', and processes representing downregulated genes (n = 357) included 'DNA-conformation change' and 'cellular lipid metabolism'., Conclusions: Exposure of C. elegans to Pf-fraction 5 induces significant changes in the transcriptome. Gene ontology analysis suggests that Pf-fraction 5 induces endoplasmic reticulum and mitochondrial stress, and the changes in gene expression are either a direct or indirect consequence of this. Further work is required to assess specific responses to sub-fractions of Pf-fraction 5 in time-course experiments in C. elegans, to define the chemical(s) with potent anthelmintic properties, to attempt to unravel their mode(s) of action and to assess their selectivity against nematodes.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Extracellular Ca 2+ (Ca 2+ o ) is a crucial regulator of epidermal homeostasis and its receptor, the Ca 2+ -sensing receptor (CaSR), conveys the Ca 2+ o signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca 2+ (Ca 2+ i ) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca 2+ i in epidermis. CaSR and E-cadherin were co-expressed at the cell-cell membrane between migratory keratinocytes in the nascent epithelial tongues. Blocking the expression of CaSR or E-cadherin in cultured keratinocytes markedly inhibited the wound-induced Ca 2+ i propagation and their ability to migrate collectively. Depleting CaSR also suppressed keratinocyte proliferation by downregulating the E-cadherin/epidermal growth factor receptor/mitogen-activated protein kinase signaling axis. Blunted epidermal Ca 2+ i response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout ( Epid Casr -/- ) mice, whose shortened neo-epithelia exhibited declined E-cadherin expression and diminished keratinocyte proliferation and differentiation. Conversely, stimulating endogenous CaSR with calcimimetic NPS-R568 accelerated wound re-epithelialization through enhancing the epidermal Ca 2+ i signals and E-cadherin membrane expression. These findings demonstrated a critical role for the CaSR in epidermal regeneration and its therapeutic potential for improving skin wound repair., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic fluoride-arsenic combined poisoning is a global public health problem. While the cause of the disease is clear, the pathogenesis is unknown. Given that there is no specific treatment, early prevention is particularly important. Biological exposure limits are designed to investigate the maximum allowable concentration of harmful effects from exogenous chemicals. To explore the biological exposure limits for mixed exposures of fluoride and arsenic, we compared the contents of fluorine and arsenic in the environmental media of the control and fluoride-arsenic combined exposure areas and analyzed the dose-effect and dose-response relationship between fluoride, arsenic and the key proteins of Wnt signaling pathways. The benchmark dose method was used to estimate the biological exposure limit for fluoride-arsenic combined exposure. The results showed that the content of fluoride in coal, clay, indoor air, outdoor air, chili and rice, as well as arsenic content in coal, clay, outdoor air, chili and rice was higher than that of the control. With the increase of fluoride and arsenic exposure levels, the glycogen synthase kinase 3&beta; (GSK3&beta;), &beta;-catenincontents and the prevalence of Wnt/&beta;-catenin signaling pathway antagonistic protein Dickkopf-1 (DKK1), GSK3&beta;, Beta-catenin (&beta;-catenin) gradually increased, but the content of DKK1 significantly decreased. Based on the Wnt signaling pathway, the biological exposure limit for fluoride-arsenic combined exposure was urinary fluoride of 0.52 mg&middot;g -1 creatinine and urinary arsenic of 6.59 mg&middot;g -1 creatinine. Our results had important guiding significance for early prevention of body damage caused by fluoride-arsenic combined poisoning.

Chronic exposure to fluoride is a public health problem worldwide. We explored the relationship between fluoride exposure, orthopedic injuries and bone formation markers alkaline phosphatase (ALP), bone Gla protein (BGP) in participants with coal-burning fluorosis in Hehua Village (coal-burning fluorosis endemic area) in Zhijin County of Guizhou Province and Zhangguan Village (non-fluoride contaminated area) in Anshun City of Guizhou Province. Environmental samples were collected and fluoride contents were examined using a fluoride ion-selective electrode. Dental fluorosis and skeletal fluorosis of 295 participants from Hehua Village and 85 participants from Zhangguan Village were diagnosed with informed consent. Urinary samples and peripheral blood samples were collected from the participants to determine urinary fluoride (UF), ALP acti-vity, and BGP content. The results showed that fluoride contents in rice, pepper, corn, drinking water, clay, vegetable-grown soil, coal and indoor and outdoor air were significantly higher than those in the control area, but lower than the previously reported values. With the increases of UF concentration, the ALP activity and BGP content significantly increased, the severity of skeletal fluorosis was greater, but with no significant changes in dental fluorosis. There was positive correlation between the severity of skeletal fluorosis and ALP activity, BGP content. These results indicated that low fluoride exposure could cause orthopedic injuries. ALP and BGP could be used to eva-luate the bone turnover in patients with skeletal fluorosis, which would be useful in the auxiliary diagnosis and therapeutic evaluation of skeletal fluorosis.

In past decades, fluorine exposure of plants and human caused by regional geochemical anomalies of fluorine or environmental pollution has received widespread concerns. Many in-depth researches have been conducted on the geochemical behavior of fluorine in different environmental media, but with disputes and uncertainties. We reviewed the research advances on geochemical behaviors of fluorine in the atmosphere, water and soil, including source, quantity, existence form, migration, transformation, and controlling factors. The observation of correlation between geochemical behaviors of fluorine and plant and human fluoride exposure was also reviewed. Moreover, we proposed that the future research on environmental geochemical behaviors of fluorine should give priority to particular directions.

Recently, 2D materials of indium selenide (InSe) layers have attracted much attention from the scientific community due to their high mobility transport and fascinating physical properties. To date, reports on the synthesis of high-quality and scalable InSe atomic films are limited. Here, a synthesis of InSe atomic layers by vapor phase selenization of In 2 O 3 in a chemical vapor deposition (CVD) system, resulting in large-area monolayer flakes or thin films, is reported. The atomic films are continuous and uniform over a large area of 1 × 1 cm 2 , comprising of primarily InSe monolayers. Spectroscopic and microscopic measurements reveal the highly crystalline nature of the synthesized InSe monolayers. The ion-gel-gated field-effect transistors based on CVD InSe monolayers exhibit n-type channel behaviors, where the field effect electron mobility values can be up to ≈30 cm 2 V -1 s -1 along with an on/off current ratio, of >10 4 at room temperature. In addition, the graphene can serve as a protection layer to prevent the oxidation between InSe and the ambient environment. Meanwhile, the synthesized InSe films can be transferred to arbitrary substrates, enabling the possibility of reassembly of various 2D materials into vertically stacked heterostructures, prompting research efforts to probe its characteristics and applications., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, a pseudodouble-chained ion pair amphiphile (IPA), hexadecyltrimethylammoniumdodecylsulfate (HTMA-DS), and dialkyldimethylammonium bromide (DXDAB) with different chain lengths were used as the main materials to fabricate positively charged catanionic vesicles with various mole fractions of cholesterol. The effects of cholesterol and DXDAB alkyl chain length on physical stability of the catanionic vesicles were then investigated by size, zeta potential, and Fourier transform infrared analyses. With the presence of cholesterol in the mixed HTMA-DS/DXDAB vesicles or with increasing the DXDAB content in the presence of a proper amount of cholesterol, the physical stability of the catanionic vesicles could be enhanced. The spacing effect of cholesterol would reduce the counterion binding tendency at the charged vesicle surfaces, resulting in a more pronounced charge character of the catanionic vesicles. Furthermore, cholesterol-induced disordered structure contributed to the flexibility of the vesicular bilayers. Thus the physical stability of the vesicles was improved by adding cholesterol. With increasing the hydrocarbon chain length of DXDAB, cholesterol located toward the middle of the bilayers, enhancing the effects of cholesterol on charge and molecular packing characteristics of the vesicles. This led to a more pronounced stability enhancement effect on the vesicles with a longer alkyl chain length of DXDAB. The results suggested that the presence of cholesterol in the HTMA-DS/DXDAB catanionic vesicles could enhance vesicle stability through adjusting intra-vesicle and/or inter-vesicle interactions. In addition, the stability enhancement effect was more pronounced in the systems with a long DXDAB alkyl chain. The findings will be useful for developing new formulas of catanionic vesicles as drug delivery carriers.

Edge morphology and lattice orientation of single-crystal molybdenum disulfide (MoS 2 ) monolayers, a transition metal dichalcogenide (TMD), possessing a triangular shape with different edges grown by chemical vapor deposition are characterized by atomic force microscopy and transmission electron microscopy. Multiphoton laser scanning microscopy is utilized to study one-dimensional atomic edges of MoS 2 monolayers with localized midgap electronic states, which result in greatly enhanced optical second-harmonic generation (SHG). Microscopic S-zigzag edge and S-Mo Klein edge (bare Mo atoms protruding from a S-zigzag edge) terminations and the edge-atom dependent resonance energies can therefore be deduced based on SHG images. Theoretical calculations based on density functional theory clearly explain the lower energy of the S-zigzag edge states compared to the corresponding S-Mo Klein edge states. Characterization of the atomic-scale variation of edge-enhanced SHG is a step forward in this full-optical and high-yield technique of atomic-layer TMDs.

When the skin is injured, keratinocytes proliferate, migrate, and differentiate to regenerate the epidermis. We recently showed that ablation of the vitamin D receptor (Vdr) in keratinocytes delays wound re-epithelialization in mice also fed a low-calcium diet, implicating a cooperative role of Vdr and calcium signaling in this process. In this study, we examined the role of vitamin D and calcium signaling in wound healing by deleting their receptors, Vdr and the calcium-sensing receptor (Casr). Gene expression profiling of neonatal epidermis lacking both Vdr and Casr [Vdr and Casr double knockout (DKO)] specifically in keratinocytes revealed that DKO affects a number of pathways relevant to wound healing, including Vdr, β-catenin, and adherens junction (AJ) signaling. In adult skin, DKO caused a significant delay in wound closure and re-epithelialization, whereas myofibroblast numbers and matrix deposition were unaffected. The injury-induced proliferation of epidermal keratinocytes was blunted in both epidermis and hair follicles, and expression of β-catenin target genes was reduced in the DKO. Expression of E-cadherin and desmoglein 1 was reduced in the shortened leading edges of the epithelial tongues re-epithelializing the wounds, consistent with the decreased migration rate of DKO keratinocytes in vitro. These results demonstrate that Vdr and Casr are required for β-catenin-regulated cell proliferation and AJ formation essential for re-epithelialization after wounding. We conclude that vitamin D and calcium signaling in keratinocytes are required for a normal regenerative response of the skin to wounding., (Copyright © 2017 Endocrine Society.)

Objective: To study the prevalence of obstructive sleep apnea hypopnea syndrome (OSAHS) and its relationship with traffic accidents in the professional drivers. Methods: Questionnaires of OSAHS were sent to 950 professional drivers who had annual physical examination at the Central Hospital of Jiading District in Shanghai from October 2014 to September 2015. Those with moderate to severe snoring and/or Epworth Sleepiness Scale (ESS)≥9 performed the home sleep testing. All drivers were divided into OSAHS and non-OSAHS according to the survey and monitoring. The following parameters were compared such as driving ages, neck circumference, body mass index (BMI), average night sleep time, ESS, hypertension, diabetes, hypertrophy of tonsil and the incidence of traffic accidents. The risk factors of traffic accidents were analyzed by multivariate Logistic regression. Results: Totally 826 responses were eligible, including 578 (70.0%) with self-reported snoring. There was measurement failure involving 3 of 233 the home sleep testing due to sensor off, 823 subjects were included in the study. The prevalence of OSAHS was 13.5% (111/823). The mild, moderate and severe OSAHS were 47, 38 and 26 cases respectively. There were 712 drives without OSAHS. The neck circumference[(39.8±3.8) vs (39.0±3.0) cm]and BMI[(26.7±4.2) vs (24.4±3.8) kg/m 2 ]were significantly higher in the drivers suffering from OSAHS (all P <0.05). The percentage of ESS≥ 9 (57.7% vs 12.6%), hypertension (27.9% vs 5.9%), diabetes (4.5% vs 1.1%), hypertrophy of tonsil (7.2% vs 2.3%) were higher in the drivers with OSAHS (all P <0.05). There were no significant difference in driving ages and average night sleep time between two groups (all P >0.05). The overall incidence of traffic accidents was 5.8% (48/823) in a year. The percentage was respectively 17.1% (19/111) in OSAHS and 4.1% (29/712) in non-OSAHS ( P <0.001). Multiple logistic regression analysis showed that sleepiness ( OR =30.578, 95% CI: 10.699-87.394; P <0.001), OSAHS ( OR =14.062, 95% CI: 4.791-41.269; P <0.001) and vehicle years ( OR =2.345, 95% CI : 1.183-4.646; P <0.05)were the risk factors, while the average night sleep time ( OR =0.037, 95% CI : 0.014-0.098; P <0.001) was the protective factor. Conclusion: Professional drivers have higher prevalence of OSAHS, which contributes to the increased risk of traffic accidents.

Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Wound healing is essential for survival. This is a multistep process involving a number of different cell types. In the skin wounding triggers an acute inflammatory response, with the innate immune system contributing both to protection against invasive organisms and to triggering the invasion of inflammatory cells into the wounded area. These cells release a variety of cytokines and growth factors that stimulate the proliferation and migration of dermal and epidermal cells to close the wound. In particular, wounding activates stem cells in the interfollicular epidermis (IFE) and hair follicles (HF) to proliferate and send their progeny to re-epithelialize the wound. β-catenin and calcium signaling are important for this activation process. Mice lacking the VDR when placed on a low calcium diet have delayed wound healing. This is associated with reduced β-catenin transcriptional activity and proliferation in the cells at the leading edge of wound closure. These data suggest that vitamin D and calcium signaling are necessary components of the epidermal response to wounding, likely by regulating stem cell activation through increased β-catenin transcriptional activity., (Published by Elsevier Ltd.)

1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis ((epid) Vdr (-∕-) and (epid) Casr (-∕-)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr (-∕-) mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the (epid) Vdr (-∕-) or (epid) Casr (-∕-). But in mice with epidermal specific deletion of both Vdr and Casr ((epid) Vdr (-∕-)/(epid) Casr (-∕-) [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β-catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.