Exploring China's water scarcity incorporating surface water quality and multiple existing solutions.

Water scarcity has threatened the sustainability of human life, ecosystem evolution, and socio-economic development. However, previous studies have often lacked a comprehensive consideration of the impact of water quality and existing solutions, such as inter-basin water transfer and unconventional water resources, on water scarcity. In this paper, an improved approach was proposed to quantify water scarcity levels by comprehensively considering surface water quality and multiple solutions. China's water scarcity was first assessed at a high spatial resolution on a monthly basis over the 5-year period from 2014 to 2018. Then, the driving factors including water quality and solutions were identified by a geographic detector model. Finally, an in-depth investigation was conducted to unravel the effects of water quantity solutions (i.e., inter-basin water transfer and unconventional water use), and water quality solutions (i.e., improving surface water quality) on alleviating water scarcity. Based on monthly assessments considering water quality and multiple existing solutions, the results showed that over half of the national population (∼777 million) faced water scarcity for at least one month of the year. Agricultural water use and inadequate water quality were the main driving factors responsible for China's water scarcity. Over four-fifths of the national population (∼1.10 billion) could benefit from alleviated water scarcity through a combination of water quantity and quality solutions. However, the existing solutions considered were insufficient to completely resolve water scarcity in China, especially in Northern China, persisting as a challenging issue. The results obtained from this study provided a better understanding of China's water scarcity, which could contribute to guiding future efforts aimed at alleviating water scarcity and ensuring water security in China.

Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice.

Although neuronal Toll-like receptors (TLRs) (e.g., TLR2, TLR3, and TLR7) have been implicated in itch sensation, the roles of keratinocyte TLRs in chronic itch are elusive. Herein, we evaluated the roles of keratinocyte TLR2 and TLR7 in chronic itch under dry skin and psoriasis conditions, which was induced by either acetone-ether-water treatment or 5% imiquimod cream in mice, respectively. We found that TLR2 and TLR7 signaling were significantly upregulated in dry skin and psoriatic skin in mice. Chronic itch and epidermal hyperplasia induced by dry skin or psoriasis were comparably reduced in TLR2 and TLR7 knockout mice. In the dry skin model, the enhanced messenger RNA (mRNA) expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, TNF-α, and IFN-γ were inhibited in TLR2-/- mice, while CXCL2, IL-31, and IL-6 were inhibited in TLR7-/- mice. In psoriasis model, the enhanced mRNA expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, and TNF-α were inhibited in TLR2-/- mice, while CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, and TNF-α were inhibited in TLR7-/- mice. Incubation with Staphylococcus aureus (S. aureus) peptidoglycan (PGN-SA) (a TLR2 agonist), imiquimod (a TLR7 agonist), and miR142-3p (a putative TLR7 agonist) were sufficient to upregulate the expression of pruritic cytokines or chemokines in cultured keratinocyte HaCaT cells. Finally, pharmacological blockade of C-X-C Motif Chemokine Receptor 1/2 and high mobility group box protein 1 dose-dependently attenuated acute and chronic itch in mice. Together, these results indicate that keratinocyte TLR2 and TLR7 signaling pathways are distinctly involved in the pathogenesis of chronic itch.

ABCA3-related interstitial lung disease beyond infancy.

BACKGROUND: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. METHOD: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. RESULTS: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. CONCLUSION: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

OBJECTIVE: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC). METHODS: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. RESULTS: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS. CONCLUSIONS: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

Role of mitochondrial fusion proteins MFN2 and OPA1 on lung cellular senescence in chronic obstructive pulmonary disease.

BACKGROUND: Mitochondrial dysfunction and lung cellular senescence are significant features involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) stands as the primary contributing factor to COPD. This study examined mitochondrial dynamics, mitophagy and lung cellular senescence in COPD patients and investigated the effects of modulation of mitochondrial fusion [mitofusin2 (MFN2) and Optic atrophy 1 (OPA1)] on CS extract (CSE)-induced lung cellular senescence. METHODS: Senescence-associated secretory phenotype (SASP) component mRNAs (IL-1ß, IL-6, CXCL1 and CXCL8), mitochondrial morphology, mitophagy and mitochondria-related proteins (including phosphorylated-DRP1(p-DRP1), DRP1, MFF, MNF2, OPA1, PINK1, PARK2, SQSTM1/p62 and LC3b) and senescence-related proteins (including P16, H2A.X and Klotho) were measured in lung tissues or primary alveolar type II (ATII) cells of non-smokers, smokers and COPD patients. Alveolar epithelial (A549) cells were exposed to CSE with either pharmacologic inducer (leflunomide and BGP15) or genetic induction of MFN2 and OPA1 respectively. RESULTS: There were increases in mitochondrial number, and decreases in mitochondrial size and activity in lung tissues from COPD patients. SASP-related mRNAs, DRP1 phosphorylation, DRP1, MFF, PARK2, SQSTM1/p62, LC3B II/LC3B I, P16 and H2A.X protein levels were increased, while MFN2, OPA1, PINK1 and Klotho protein levels were decreased in lung tissues from COPD patients. Some similar results were identified in primary ATII cells of COPD patients. CSE induced increases in oxidative stress, SASP-related mRNAs, mitochondrial damage and dysfunction, mitophagy and cellular senescence in A549 cells, which were ameliorated by both pharmacological inducers and genetic overexpression of MFN2 and OPA1. CONCLUSIONS: Impaired mitochondrial fusion, enhanced mitophagy and lung cellular senescence are observed in the lung of COPD patients. Up-regulation of MFN2 and OPA1 attenuates oxidative stress, mitophagy and lung cellular senescence, offering potential innovative therapeutic targets for COPD therapy.

Down-regulation of HuR inhibits pathological angiogenesis in oxygen-induced retinopathy.

HuR (also known as ELAV1), a ubiquitous RNA-binding protein, is implicated in the pathogenesis of diverse diseases via the mechanism of post-transcriptional regulation. Whether it is involved in pathological angiogenesis in oxygen-induced retinopathy is not clear. In this study, we detected HuR expression was increased in the retina of mouse model of oxygen-induced retinopathy (OIR) as well as in vascular endothelial cells exposed to hypoxia. With gain-of-function and loss-of-function studies using adenovirus infection, we found HuR over-expression promoted while HuR knockdown inhibited the migration, proliferation and tube formation of vascular endothelial cells. Moreover, HuR regulated the expression of VEGFA in vascular endothelial cells. We also found the retinal pathological angiogenesis in mouse OIR model was greatly reduced with HuR knockdown using recombinant AAV expressing HuR specific shRNA which was administered by intravitreal injection. The results of this study suggest HuR is involved in pathological angiogenesis via regulating angiogenic behaviors of endothelial cells, providing a potential target for the treatment of retinopathy of prematurity.

The merging of dual umbilical port-incisions for contained morcellation in laparoscopic myomectomy.

Uncontained power morcellation during laparoscopic myomectomy may spread tissue fragments or malignant cells into the abdominal cavity. Recently, various approaches to contained morcellation, have been adopted to retrieve the specimen. However, each of these methods has its own drawbacks. Intraabdominal bag-contained power morcellation adopts a complex isolation system, which prolongs the operation and increases medical costs. Contained manual morcellation via colpotomy or mini-laparotomy increases the trauma and the risk of infection. Contained manual morcellation via umbilical incision during single-port laparoscopic myomectomy may be the most minimally invasive and cosmetic approach. But the popularization of single-port laparoscopy is challenging because of technical difficulties and high costs. We have therefore, developed a surgical technique using 2 umbilical port-incisions (5 mm and 10 mm), which are merged into 1 large umbilical incision (25-30mm) for contained manual morcellation during specimen retrieval, and one 5mm incision in the lower left abdomen for an ancillary instrument. As demonstrated in the video, this technique significantly facilitates surgical manipulation using conventional laparoscopic instruments while still keeping the incisions minimal. It is also economical because the use of an expensive single-port platform and special surgical instruments is avoided. In conclusion, the merging of dual umbilical port-incisions for contained morcellation adds a minimally invasive, cosmetic, and economical option to laparoscopic specimen retrieval that would enrich a gynecologist's skill set, which is particularly relevant in a low-resource settings.

Analysis of the spatiotemporal patterns and decoupling effects of China's water resource spatial equilibrium.

The significance of water resource spatial equilibrium (WRSE) research is to maximally remove the spatial restrictions of water on regional development, including social development, economic development and eco-environmental maintenance. Although great achievements have been made, national-scale WRSE research is rare; besides, the spatiotemporal patterns and decoupling effects of WRSE have been poorly studied in current research. Thus, the aim of this research is to measure the WRSE in China for the period 2008-2019 by using an improved coupling coordination model and to empirically analyse its distribution dynamics and decoupling effects. The results show that the WRSE status of China's 31 provincial administrative regions from 2008 to 2019 is at a moderate level. Based on the spatiotemporal patterns and decoupling effects analysis, areas in urgent need of improving WRSE status are identified, and tailored countermeasures are provided for each area. To our knowledge, this paper is the first nationwide study of the spatiotemporal patterns and decoupling effects of WRSE.

Rapid Determination of Dapagliflozin in Rat Plasma by UHPLC-Q-Orbitrap MS and Its Application to a Pharmacokinetic Study.

Dapagliflozin (DAPA), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is used to treat Type 2 diabetes. In this study, a highly sensitive and selective analytical method based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was established and validated for the determination of DAPA in rat plasma. The separation of DAPA and internal standard (DAPA-d5) were performed on a reversed-phase ACQUITY UPLC® BEH C18 column (100 × 3.0 mm, 1.7 µm). The mobile phase is composed of 0.1% formic acid in water (solvent A) and methanol (solvent B) in gradient elution. Under the negative ion mode, full MS/dd-MS2 was adopted to collect data via Q-Orbitrap. DAPA was effectively separated from matrix backgrounds within 10 min, and DAPA in plasma showed a good linear relationship in the range of 10-10000 µg/L. The determination coefficient (R2) was 0.9987, and the lower limit of quantification (LLOQ) was 10 µg/L. The precision and accuracy were all less than 10%, and the extraction recovery of DAPA was 86.16-96.06% from plasma. This study offered an efficient separation and quantification method for DAPA. The improved and validated method succeeded in evaluating the pharmacokinetics of DAPA in rat plasma samples after a single oral administration of 1 mg/kg.

Development and validation of a multivariate model for predicting heart failure hospitalization and mortality in patients receiving maintenance hemodialysis.

BACKGROUND: Heart failure (HF) in patients undergoing maintenance hemodialysis (MHD) increases their hospitalization rates, mortality, and economic burden significantly. We aimed to develop and validate a predictive model utilizing contemporary deep phenotyping for individual risk assessment of all-cause mortality or HF hospitalization in patients on MHD. MATERIALS AND METHODS: A retrospective review was conducted from January 2017 to October 2022, including 348 patients receiving MHD from four centers. The variables were adjusted by Cox regression analysis, and the clinical prediction model was constructed and verified. RESULTS: The median follow-up durations were 14 months (interquartile range [IQR] 9-21) for the modeling set and 14 months (9-20) for the validation set. The composite outcome occurred in 72 (29.63%) of 243 patients in the modeling set and 39 (37.14%) of 105 patients in the validation set. The model predictors included age, albumin, history of cerebral hemorrhage, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/"sacubitril/valsartan", left ventricular ejection fraction, urea reduction ratio, N-terminal prohormone of brain natriuretic peptide, and right atrial size. The C-index was 0.834 (95% CI 0.784-0.883) for the modeling set and 0.853 (0.798, 0.908) for the validation set. The model exhibited excellent calibration across the complete risk profile, and the decision curve analysis (DCA) suggested its ability to maximize patient benefits. CONCLUSION: The developed prediction model offered an accurate and personalized assessment of HF hospitalization risk and all-cause mortality in patients with MHD. It can be employed to identify high-risk patients and guide treatment and follow-up.

Quantifying Functional Impairment of ABCA3 Variants Associated with Interstitial Lung Disease.

ATP-binding cassette subfamily A member 3 (ABCA3) is a lipid transporter within alveolar type II cells. Patients with bi-allelic variants in ABCA3 may suffer from a variable severity of interstitial lung disease. We characterized and quantified ABCA3 variants' overall lipid transport function by assessing the in vitro impairment of its intracellular trafficking and pumping activity. We expressed the results relative to the wild type, integrated the quantitative readouts from eight different assays and used newly generated data combined with previous results to correlate the variants' function and clinical phenotype. We differentiated normal (within 1 normalized standard deviation (nSD) of the wild-type mean), impaired (within 1 to 3 nSD) and defective (beyond 3 nSD) variants. The transport of phosphatidylcholine from the recycling pathway into ABCA3+ vesicles proved sensitive to the variants' dysfunction. The sum of the quantitated trafficking and pumping predicted a clinical outcome. More than an approximately 50% loss of function was associated with considerable morbidity and mortality. The in vitro quantification of ABCA3 function enables detailed variant characterization, substantially improves the phenotype prediction of genetic variants and possibly supports future treatment decisions.

ABCA3 Deficiency-Variant-Specific Response to Hydroxychloroquine.

Biallelic variants in ABCA3, the gene encoding the lipid transporter ATP-binding cassette subfamily A member 3 (ABCA3) that is predominantly expressed in alveolar type II cells, may cause interstitial lung diseases in children (chILD) and adults. Currently, there is no proven therapy, but, frequently, hydroxychloroquine (HCQ) is used empirically. We hypothesized that the in vitro responsiveness to HCQ might correlate to patients' clinical outcomes from receiving HCQ therapy. The clinical data of the subjects with chILD due to ABCA3 deficiency and treated with HCQ were retrieved from the literature and the Kids Lung Register data base. The in vitro experiments were conducted on wild type (WT) and 16 mutant ABCA3-HA-transfected A549 cells. The responses of the functional read out were assessed as the extent of deviation from the untreated WT. With HCQ treatment, 19 patients had improved or unchanged respiratory conditions, and 20 had respiratory deteriorations, 5 of whom transiently improved then deteriorated. The in vitro ABCA3 functional assays identified two variants with complete response, five with partial response, and nine with no response to HCQ. The variant-specific HCQ effects in vivo closely correlated to the in vitro data. An ABCA3+ vesicle volume above 60% of the WT volume was linked to responsiveness to HCQ; the HCQ treatment response was concentration dependent and differed for variants in vitro. We generated evidence for an ABCA3 variant-dependent impact of the HCQ in vitro. This may also apply for HCQ treatment in vivo, as supported by the retrospective and uncontrolled data from the treatment of chILD due to ABCA3 deficiency.

Browning of Mammary Fat Suppresses Pubertal Mammary Gland Development of Mice via Elevation of Serum Phosphatidylcholine and Inhibition of PI3K/Akt Pathway.

Mammary fat plays a profound role in the postnatal development of mammary glands. However, the specific types (white, brown, or beige) of adipocytes in mammary fat and their potential regulatory effects on modulating mammary gland development remain poorly understood. This study aimed to investigate the role of the browning of mammary fat on pubertal mammary gland development and explore the underlying mechanisms. Thus, the mammary gland development and the serum lipid profile were evaluated in mice treated with CL316243, a ß3-adrenoceptor agonist, to induce mammary fat browning. In addition, the proliferation of HC11 cells co-cultured with brown adipocytes or treated with the altered serum lipid metabolite was determined. Our results showed that the browning of mammary fat by injection of CL316243 suppressed the pubertal development of mice mammary glands, accompanied by the significant elevation of serum dioleoylphosphocholine (DOPC). In addition, the proliferation of HC11 was repressed when co-cultured with brown adipocytes or treated with DOPC. Furthermore, DOPC suppressed the activation of the PI3K/Akt pathway, while the DOPC-inhibited HC11 proliferation was reversed by SC79, an Akt activator, suggesting the involvement of the PI3K/Akt pathway in the DOPC-inhibited proliferation of HC11. Together, the browning of mammary fat suppressed the development of the pubertal mammary gland, which was associated with the elevated serum DOPC and the inhibition of the PI3K/Akt pathway.

Evaluation and prediction of water-energy-carbon nexus efficiency in China based on a new multiregional input-output perspective.

Water, energy and carbon are three basic environmental factors that affect countries. An in-depth study of the water-energy-carbon (WEC) nexus is of great significance for realizing regional sustainable development. However, at present, research on the evaluation and prediction of large-scale WEC nexus based on multiple perspectives is not sufficiently mature, especially the prediction of WEC nexus efficiency. This study evaluates and predicts the WEC nexus efficiency in 30 regions of China based on a new comprehensive perspective. The WEC efficiency and the slack variables of 30 regions from 2006 to 2020 were calculated by using the slack-based measure model. The 30 regions were divided into 4 efficiency groups using hierarchical cluster analysis. Efficiency trends in 2006-2020 were analyzed for specific regions. The coupling interaction between the WEC nexus is studied based on the perspective of the coupling degree and coupling coordination degree. More importantly, this study is the first to quantitatively predict the WEC efficiency of 30 regions in China from 2021 to 2030, using the rank set pair analysis model. The following results were obtained in this paper. The WEC efficiency has a slow decreasing trend in 2006-2020. A total of 16.7% and 33.3% of the regions are in the extreme and high coupling coordination stages, respectively, and are mainly concentrated in the northern and southeastern parts of China. Fifty percent of the regions have moderate coupling coordination, mainly concentrated in the central and southern regions. From 2021 to 2030, the WEC efficiency of Beijing, Tianjin and Qinghai will remain at a high level; the WEC efficiency of Shandong and other regions will remain at a low level; and 70% of the regions' water efficiency will remain low. This paper has important guiding significance for promoting the regional WEC nexus balance and sustainable development of the economy, society and environment. According to the characteristics of the four efficiency groups, some valuable suggestions on regional sustainable development are proposed.

Modeling water inequality and water security: The role of water governance.

Water Inequality, Water Security and Water Governance are fundamental parameters that affect the sustainable use of water resources. Through policy formulation and decision-making, Water Governance determines both Water Security and Water Inequality. Largely, where Water Inequality exists, Water Security is undermined through unsustainable water use practices that lead to pollution of water resources, conflicts, hoarding of water, and poor sanitation. Incidentally, the interconnectedness of Water Governance, Water Inequality and Water Security has not been investigated previously. This study modified the Gini coefficient and used a Logistics Growth of Water Resources Model (LGWR Model) to access Water Inequality and Water Security mathematically, and discussed the connected role of Water Governance. We tested the validity of both models by calculating the actual Water Inequality and Water Security of Ghana. We also discussed the implications of Water Inequality on Water Security and the overarching role of Water Governance. The results show that regional Water Inequality is widespread in some parts. The Volta region showed the highest Water Inequality (Gini index of 0.58), while the Central region showed the lowest (Gini index of 0.15). Water Security is moderately sustainable. The use of water resources is currently stress-free. It was estimated to maintain such status until 2132 ± 18 when Ghana will consume half of the current total water resources of 53.2 billion cubic meters. Effectively, Water Inequality is a threat to Water Security, results in poverty, under-development heightens tensions in water use, and causes instability. With proper Water Governance, Water Inequality can be eliminated through formulating and implementing approaches that engender equal allocation and sustainable use of water resources.

Transcriptome analysis reveals genes related to the synthesis and metabolism of cell wall polysaccharides in goji berry (Lycium barbarum L.) from various regions.

BACKGROUND: In goji berries (Lycium barbarum L.), the cell wall properties and ripening environment affect fruit quality and their economic benefits. However, the mechanism underlying the cell wall remains to be fully elucidated. RESULTS: The results showed that total sugar content was higher in Qinghai berries (13.87%, P < 0.01), whereas cellulose content peaked in Zhongning berries (28%, P < 0.05). Arabinose, galactose, and galacturonic acid were the principal components of the cell wall polysaccharides in goji berries. Among them, the content of galactose in Zhongning was significantly the highest (P < 0.05). Interestingly, we found that highly expressed ß-glucosidase and lowly expressed endoglucanase led to cellulose accumulation by RNA-sequencing analysis. The expression analysis results suggested that pectate lyase and pectinesterase enzymes could be major factors related to higher galactose and galacturonic acid contents in Zhongning compared to in Qinghai and Gansu. The starch and sucrose metabolism pathway, pentose and glucuronate interconversions pathway, and galactose metabolism pathway played a significant role in cell wall polysaccharide synthesis and metabolism. CONCLUSION: In the present study, we aimed to provide some insights into the cell wall on polysaccharide composition, structural features, and gene analysis in goji berries from Zhongning, Qinghai, and Gansu in China. These results might help to clarify the molecular function of the major genes in the cell wall polysaccharides of goji berries and provide a solid foundation for further study. © 2023 Society of Chemical Industry.

High-Content Screening Identifies Cyclosporin A as a Novel ABCA3-Specific Molecular Corrector.

ABCA3 (ATP-binding cassette subfamily A member 3) is a lipid transporter expressed in alveolar type II cells and localized in the limiting membrane of lamellar bodies. It is crucial for pulmonary surfactant storage and homeostasis. Mutations in the ABCA3 gene are the most common genetic cause of respiratory distress syndrome in mature newborns and of interstitial lung disease in children. Apart from lung transplant, there is no cure available. To address the lack of causal therapeutic options for ABCA3 deficiency, a rapid and reliable approach is needed to investigate variant-specific molecular mechanisms and to identify pharmacologic modulators for monotherapies or combination therapies. To this end, we developed a phenotypic cell-based assay to autonomously identify ABCA3 wild-type-like or mutant-like cells by using machine learning algorithms aimed at identifying morphologic differences in wild-type and mutant cells. The assay was subsequently used to identify new drug candidates for ABCA3-specific molecular correction by using high-content screening of 1,280 Food and Drug Administration-approved small molecules. Cyclosporin A was identified as a potent corrector, specific for some but not all ABCA3 variants. Results were validated by using our previously established functional small-format assays. Hence, cyclosporin A may be selected for orphan drug evaluation in controlled repurposing trials in patients.

In-Situ Silica Xerogel Assisted Facile Synthesis of Fe-N-C Catalysts with Dense Fe-Nx Active Sites for Efficient Oxygen Reduction.

In the past decade, atomically dispersed Fe active sites (coordinated with nitrogen) on carbon materials (FeNC) have emerged rapidly as promising single-atom catalysts (SACs) for the oxygen reduction reaction (ORR) to substitute precious group metal (PGM) catalysts, owing to their earth abundance and low cost. Nonetheless, the production of highly active FeNC SACs is largely restricted by material cost, low product yield and difficulty of microstructure design. Herein, the authors demonstrate a facile in-situ xerogel (ISG) assisted synthetic strategy, using cheap materials, to construct FeNC SACs (ISG FeNC). The porous silica xerogel, formed in-situ with the FeNC precursors, encourages the emergence of enormous micropores/mesopores and homogeneous confinement/protection to the precursors during pyrolysis, benefiting to the formation of abundant accessible active sites (27.6 × 1019 sites g-1 ). Correspondingly, the ISG FeNC exhibits excellent ORR activity with a half-wave potential (E1/2  = 0.91 V) in alkaline medium. The Zn-air battery assembled using the ISG FeNC SACs as the bifunctional catalyst of air cathode, demonstrates commendable performance with high peak power density of 249.1 mW cm-2 and superior long-term stability (660 cycles with 220 h). This work offers an economic and efficient way to fabricate PGM-free SACs for diverse applications.

Facile Synthesis of Carbon Dots from Biomass Material and Multi-Purpose Applications.

Selective and sensitive water content measurement in organic solvents is extremely significant for both industrial use and laboratory preparation. Carbon nanodots are promising carbon nanomaterials with unique and novel properties and thus have drawn growing attention. However, the hydrothermal approach for the preparation of carbon dots always uses water as solvent, and consequently, the development of carbon dots from biomass materials for fluorescence detection of water content remains unexplored. Here, carbon dots were prepared from gallic acid via a cheap and facile one-step method. The as-prepared carbon dots present excellent sensitivity and selectivity toward water content and exhibits good linear relationships with water content in range of 0-10%. The carbon dots demonstrated a strong antioxidation capacity and colour-reaction of Fe3+ like gallic acid. The carbon dots also showed solid-state lighting.

Polygenic association of glomerular filtration rate decline in world trade center responders.

BACKGROUND: The factors associated with estimated glomerular filtrate rate (eGFR) decline in low risk adults remain relatively unknown. We hypothesized that a polygenic risk score (PRS) will be associated with eGFR decline. METHODS: We analyzed genetic data from 1,601 adult participants with European ancestry in the World Trade Center Health Program (baseline age 49.68 ± 8.79 years, 93% male, 23% hypertensive, 7% diabetic and 1% with cardiovascular disease) with ≥ three serial measures of serum creatinine. PRSs were calculated from an aggregation of single nucleotide polymorphisms (SNPs) from a recent, large-scale genome-wide association study (GWAS) of rapid eGFR decline. Generalized linear models were used to evaluate the association of PRS with renal outcomes: baseline eGFR and CKD stage, rate of change in eGFR, stable versus declining eGFR over a 3-5-year observation period. eGFR decline was defined in separate analyses as "clinical" (> -1.0 ml/min/1.73 m2/year) or "empirical" (lower most quartile of eGFR slopes). RESULTS: The mean baseline eGFR was ~ 86 ml/min/1.73 m2. Subjects with decline in eGFR were more likely to be diabetic. PRS was significantly associated with lower baseline eGFR (B = -0.96, p = 0.002), higher CKD stage (OR = 1.17, p = 0.010), decline in eGFR (OR = 1.14, p = 0.036) relative to stable eGFR, and the lower quartile of eGFR slopes (OR = 1.21, p = 0.008), after adjusting for established risk factors for CKD. CONCLUSION: Common genetic variants are associated with eGFR decline in middle-aged adults with relatively low comorbidity burdens.