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DNA methylation and mRNA expression correlations are often presented with inconsistent evidence supporting causal regulation. We hypothesized that causal regulatory methylation elements would exhibit heightened demethylation sensitivity. To investigate, we analyzed 20 whole-genomic bisulfite sequenced samples before and after demethylation and identified narrow-width (45-294 bp) elements within a short plateau, termed Methylation Mesa (MM). The Mesa signature was conserved across species and was independent of CpG islands. Mesa also demonstrate high concordance with primed and active histone marks. To assess causality, we developed CRISPR-DiR, a highly precise targeted demethylation technology. Targeted demethylation of a Mesa triggers locus and distal chromatin rewiring events that initiate mRNA expression significantly greater than promoter-CpG island targeting. Thus, Mesa are self-sustaining epigenetic regulatory elements that maintain long-term gene activation through focused demethylation only within the Mesa core, resulting in subsequent histone modifications and chromatin rewiring events that interact with distal elements also marked as Mesas., Competing Interests: Competing interests The authors declare no competing interests for this project.

Objectives: To explore the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with risk of congenital heart disease (CHD) in offspring., Methods: The parents of children with simple CHD aged 0 to 1 year ( n =683) were recruited as the case group, while the parents of healthy children aged 0 to 1 year ( n =740) served as the control group. A case-control study was conducted, and a questionnaire was used to collect information on perinatal exposures. After controlling for relevant confounding factors using multivariate logistic regression analysis and propensity score matching, the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with CHD were examined, as well as the cumulative effects of smoking and drinking on CHD risk., Results: Maternal active smoking ( OR =2.91, 95% CI : 1.60-5.30), passive smoking ( OR =1.94, 95% CI : 1.56-2.42), and alcohol consumption ( OR =2.59, 95% CI : 1.89-3.54), as well as paternal smoking ( OR =1.52; 95% CI : 1.22-1.90) and drinking ( OR =1.48, 95% CI : 1.19-1.84), were associated with an increased risk of CHD in offspring. There was no interaction between parental smoking and drinking behaviors during the periconceptional period concerning the risk of CHD in offspring ( P >0.05). The more parents' smoking and drinking behaviors during the perinatal pregnancy, the higher the risk of CHD in their offspring ( OR =1.50, 95% CI : 1.36-1.65)., Conclusions: Parental smoking and alcohol consumption during the periconceptional period are associated with the occurrence of CHD in offspring, and there is a cumulative effect on CHD risk, suggesting that reducing tobacco and alcohol exposure during the periconceptional period may lower the incidence of CHD.

A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients., Significance: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: SARS-CoV-2 continues to mutate over time, and reports on children infected with Omicron BA.5 are limited. We aimed to analyze the specific symptoms of Omicron-infected children and to improve patient care., Methods: We selected 315 consecutively hospitalized children with Omicron BA.5 and 16,744 non-Omicron-infected febrile children visiting the fever clinic at our hospital between December 8 and 30, 2022. Specific convulsions and body temperatures were compared between the two cohorts. We analyzed potential associations between convulsions and vaccination, and additionally evaluated the brain damage among severe Omicron-infected children., Results: Convulsion rates (97.5% vs. 4.3%, P < 0.001) and frequencies (median: 2.0 vs. 1.6, P < 0.001) significantly differed between Omicron-infected and non-Omicron-infected febrile children. The body temperatures of Omicron-infected children were significantly higher during convulsions than when they were not convulsing and those of non-Omicron-infected febrile children during convulsions (median: 39.5 vs. 38.2 and 38.6 °C, both P < 0.001). In the three Omicron-subgroups, the temperature during convulsions was proportional to the percentage of patients and significantly differed ( P < 0.001), while not in the three non-Omicron-subgroups ( P = 0.244). The convulsion frequency was lower in the 55 vaccinated children compared to the 260 non-vaccinated children (average: 1.8 vs. 2.1, P < 0.001). The vaccination dose and convulsion frequency in Omicron-infected children were significantly correlated ( P < 0.001). Fifteen of the 112 severe Omicron cases had brain damage., Conclusions: Omicron-infected children experience higher body temperatures and frequencies during convulsions than those of non-Omicron-infected febrile children. We additionally found evidence of brain damage caused by infection with omicron BA.5. Vaccination and prompt fever reduction may relieve symptoms., (© 2024. The Author(s).)

The conversion of woody biomass to H 2 through photocatalysis provides a sustainable strategy to generate renewable hydrogen fuel but was limited by the slow decomposition rate of woody biomass. Here, we fabricate ultrasmall TiO 2 nanoparticles with tunable concentration of oxygen vacancy defects (V O -TiO 2 ) as highly efficient photocatalysts for photocatalytic conversion of woody biomass to H 2 . Owing to the positive role of oxygen vacancy in reducing energy barrier for the generation of • OH which was the critical species to oxidize woody biomass, the obtained V O -TiO 2 achieves rapid photocatalytic conversion of α-cellulose and poplar wood chip to H 2 in the presence of Pt nanoclusters as the cocatalyst. As expected, the highest H 2 generation rate in α-cellulose and poplar wood chip system respectively achieve 1146 and 59 μmol h -1 g -1 , and an apparent quantum yield of 4.89% at 380 nm was obtained in α-cellulose aqueous solution.

Objectives: To investigate how maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation are associated with the incidence of ventricular septal defects (VSD) in offspring., Methods: A case-control study was conducted, recruiting 426 mothers of infants with VSD under one year old and 740 mothers of age-matched healthy infants. A questionnaire survey collected data on maternal exposures, and blood samples were analyzed for genetic polymorphisms. Multivariable logistic regression analysis and inverse probability of treatment weighting were used to analyze the associations between genetic loci and VSD. Crossover analysis and logistic regression were utilized to examine the additive and multiplicative interactions between the loci and folic acid intake., Results: The CT and TT genotypes of the maternal MTR gene at rs6668344 increased the susceptibility of offspring to VSD ( P <0.05). The GC and CC genotypes at rs3768139, AG and GG at rs1050993, AT and TT at rs4659743, GG at rs3768142, and GT and TT at rs3820571 were associated with a decreased risk of VSD ( P <0.05). The variations at rs6668344 demonstrated an antagonistic multiplicative interaction with folic acid supplementation in relation to VSD ( P <0.05)., Conclusions: Maternal MTR gene polymorphisms significantly correlate with the incidence of VSD in offspring. Mothers with variations at rs6668344 can decrease the susceptibility to VSD in their offspring by supplementing with folic acid during the periconceptional period, suggesting the importance of periconceptional folic acid supplementation in genetically at-risk populations to prevent VSD in offspring.

Solar photocatalytic H 2 production from lignocellulosic biomass has attracted great interest, but it suffers from low photocatalytic efficiency owing to the absence of highly efficient photocatalysts. Herein, we designed and constructed ultrathin MoS 2 -modified porous TiO 2 microspheres (MT) with abundant interface Ti-S bonds as photocatalysts for photocatalytic H 2 generation from lignocellulosic biomass. Owing to the accelerated charge transfer related to Ti-S bonds, as well as the abundant active sites for both H 2 and ● OH generation, respectively, related to the high exposed edge of MoS 2 and the large specific surface area of TiO 2 , MT photocatalysts demonstrate good performance in the photocatalytic conversion of α-cellulose and lignocellulosic biomass to H 2 . The highest H 2 generation rate of 849 μmol·g -1 ·h -1 and apparent quantum yield of 4.45% at 380 nm was achieved in α-cellulose aqueous solution for the optimized MT photocatalyst. More importantly, lignocellulosic biomass of corncob, rice hull, bamboo, polar wood chip, and wheat straw were successfully converted to H 2 over MT photocatalysts with H 2 generation rate of 10, 19, 36, 29, and 8 μmol·g -1 ·h -1 , respectively. This work provides a guiding design approach to develop highly active photocatalysts via interface engineering for solar H 2 production from lignocellulosic biomass.

Photocatalytic nitrogen fixation from N 2 provides an alternative strategy for ammonia (NH 3 ) production, but it was limited by the consumption of a sacrificial electron donor for the currently reported half-reaction system. Here, we use naturally abundant and renewable cellulose as the sacrificial reagent for photocatalytic nitrogen fixation over oxygen-vacancy-modified MoO 3 nanosheets as the photocatalyst. In this smartly designed photocatalytic system, the photooxidation of cellulose not only generates value-added chemicals but also provides electrons for the N 2 reduction reaction and results in the production of NH 3 with a maximum rate of 68 μmol·h -1 ·g -1 . Also, the oxygen vacancies provide efficient active sites for both cellulose oxygenolysis and nitrogen fixation reactions. This work represents useful inspiration for realizing nitrogen fixation coupled with the generation of value-added chemicals from N 2 and cellulose through a photocatalysis strategy.

The conversion of lignocellulosic biomass to chemical fuel can achieve the sustainable use of lignocellulosic biomass, but it was limited by the lack of an effective conversion strategy. Here, we reported a unique approach of photothermal catalysis by using MoS 2 -reduced graphene oxide (MoS 2 /RGO) as the catalyst to convert lignocellulosic biomass into H 2 fuel in alkaline solution. The RGO acting as a support for the growth of MoS 2 results in the high exposed Mo edges, which act as efficient Lewis acidic sites for the oxygenolysis of lignocellulosic biomass dissolved in alkaline solution. The broad light absorption capacity and abundant Lewis acidic sites make MoS 2 /RGO to be efficient catalysts for photothermal catalytic H 2 production from lignocellulosic biomass, and the H 2 generation rate with respect to catalyst under 300 W Xe lamp irradiation in cellulose, rice straw, wheat straw, polar wood chip, bamboo, rice hull, and corncob aqueous solution achieve 223, 168, 230, 564, 390, 234, and 55 μmol·h -1 ·g -1 , respectively. It is believed that this photothermal catalysis is a simple and "green" approach for the lignocellulosic biomass-to-H 2 conversion, which would have great potential as a promising approach for solar energy-driven H 2 production from lignocellulosic biomass.

Objective: To explore the clinical characteristics of rheumatic disease (RD) patients who suffered from moderate or severe coronavirus disease 2019 (COVID-19) infection and to evaluate risk factors of COVID-19 infection in RD patients., Methods: A retrospective analysis was conducted on 148 moderate or severe COVID-19 patients admitted to the First People's Hospital of Suqian Affiliated to Nanjing Medical University, including 74 RD patients and 74 non-RD patients. Clinical data were collected including clinical characteristics and laboratory tests., Results: The RD group showed a higher proportion of females with a higher incidence of interstitial lung disease and kidney disease than the non-RD group. Also, the incidence of fatigue, olfactory dysfunction and musculoskeletal pain was higher in the RD group, but the incidence of cough, wheezing, and fever was lower compared with non-RD patients. The hospitalized course of the RD group (12.7 days ± 6.55) was significantly longer than that in the non-RD group (8.07 days ± 3.40). Also, patients in the RD group had higher levels of erythrocyte sedimentation rate, interleukin (IL)-2, and IL-4 than the non-RD group. The logistic regression analysis showed that dizziness and headache, C-reactive protein (CRP) > 8 mg/L and lactate dehydrogenase (LDH) > 248 μ/L were independent risk factors for severe COVID-19 infections of RD patients., Conclusion: RD patients who suffered from moderate or severe COVID-19 infections have a higher risk of comorbidities, higher levels of inflammation, and longer hospitalized course. Dizziness and headache, CRP > 8 mg/L and LDH > 248 μ/L are risk factors for severe COVID-19 infections in RD patients., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: The aim of the study was to investigate the safety and antiviral efficacy of a Chinese multiherb extract-based tincture (GWK) on a population of patients with high-risk human papilloma (hrHPV) infections and hrHPV-caused cervical low-grade squamous intraepithelial lesions (LSILs)., Patients and Methods: Patients with persistent hrHPV infection were enrolled in Group A, including A1 subjects, who received the intervention, and A2 subjects, who received the control. Patients with hrHPV infection causing cervical LSIL were enrolled in Group B, which included B1 subjects, who received the intervention, and B2 subjects, who served as the control. For Groups A1 and B1, hrHPV was tested at 3 months (M3) and 6 months (M6) after the intervention. The side effects were also analyzed., Results: At baseline (D0), a total of 99 patients were enrolled in Group A, with 50 subjects in Group A1 and 49 subjects in Group A2. A total of 91 patients were enrolled in Group B, with 45 subjects in Group B1 and 46 subjects in Group B2. There was no significant difference in the characteristics, including average age, age stratification, and HPV genotype. At M6, both Group A1 and Group B1 had a higher hrHPV clearance rate than the control group (A1/A2: 80.0% vs. 20.4%; B1/B2: 64.4% vs. 15.2%, p<0.001). At M6, the effective rates of Group A1 and Group B1 were 84% (42/50) and 68.9% (31/45), respectively. The side effect rates of Groups A1 and B1 were 11.5% (6/52) and 11.1% (5/45), respectively. Most adverse reactions involved local discomfort, including vulvar erythema, vulvar itch, increased vaginal discharge, cervical bleeding, and mild pain in the lower abdomen. Univariate logistic regression analysis showed that the intervention had an OR of 12 (95% CI 4.431-32.50) for clearing persistent HPV infection (p<0.001). For cervical LSIL, the intervention had an OR of 10.1 for clearing persistent HPV infection (95% CI 3.68-27.7) (p<0.001)., Conclusions: The results of this study suggest that the Chinese multiherb extract-based tincture GWK is safe and well tolerated. Furthermore, this preliminary study showed that this Chinese multiherb extract-based tincture is helpful for promoting HPV clearance in cases of persistent HPV and HPV-induced LSIL.

Background: Although IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking., Methods: We examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation., Results: Within the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034)., Conclusion: IGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.

A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.

A major complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents as aphasia, confusion, weakness, somnolence, seizures, and coma. This is similar to the neurologic manifestations of hypophosphatemia, which can result from sudden increases in metabolic demand for phosphorylated intermediates (e.g., refeeding syndrome and sepsis). Given these similarities, we investigated whether CAR T-cell effector metabolic activity is associated with increased extracellular phosphate consumption and a possible association between hypophosphatemia and ICANS. In vitro 4-1BB and CD28 CD19-targeted CAR T-cell effector activity was found to be associated with increased consumption of media phosphorus, which was temporally associated with increased single-cell effector secretomic activity and increased phosphorus-dependent metabolic demand of the CAR T cells. A clinical cohort of 77 patients treated with CD19-targeted CAR T-cell therapy demonstrated a significant anticorrelation between serum phosphorus and ICANS incidence and severity, with earlier onset of hypophosphatemia after CAR T-cell infusion more likely to result in neurotoxicity. These results imply phosphorous level monitoring could alert to the development of ICANS in clinical scenarios. See related Spotlight by Tobin et al., p. 1422., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: A majority of frequent users of emergency medical services in Singapore present with alcohol-related problems. These patients are known to engage poorly with traditional addiction services and frequently attend Emergency Departments (EDs) instead, resulting in high healthcare burden. Assertive Community Treatment (ACT) is an alternative intervention to traditional addiction management. ACT involves community visits with focus on holistic care and harm-reduction., Materials and Methods: We conducted a prospective before-and-after cohort study at the major tertiary center for addiction disorders in Singapore. The main objective was to evaluate effectiveness of ACT in reducing alcohol-related attendances at EDs nationwide. Socio-demographics, alcohol-related ED attendances, and the Christo Inventory for Substance-misuse Services (CISS) scores were collected for the patients recruited from April 2018 to March 2019. Descriptive analyses and the Wilcoxon Signed-Rank Test were performed., Results: All 14 patients were male with a mean age of 55 years. There was a significant 45.3% reduction in average alcohol-related ED attendances from 6.8 (range 3-22, median 5.5) in the pre-intervention 6-month period, to 3.7 (range 0-28, median 1.5) in the post-intervention 6-month period ( Z = -2.244, p = 0.025). CISS scores showed significant improvement from a pre-intervention median of 13.5 (range 9-16) to a post-intervention median of 6.5 (range 1-10, p = 0.001), corresponding to reduction in alcohol-related problem severity., Conclusion: This pilot study suggests that ACT can be effective in reducing alcohol-related ED attendances and alcohol-related problem severity in patients with AUD who frequently attend ED. A multicenter, prospective study using ACT for such patients across four hospitals in Singapore is currently underway., 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 © 2022 Mak, Mao, Siddiqui, Lim, Davamoni-Thomas, Tang, Bachik, Ng, Kandasami and Lee.)

A girl, aged 11 years, was admitted due to recurrent rash on the whole body and mucosa for 10 years, and typical rash was erythema at the perioral region, hand-foot joints, vulva, and perianal region, with blisters, erosions, and ulcers on the erythema. The girl was improved after zinc supplementation. Her younger brother had similar rash and medical history. The histopathological examination showed epidermal parakeratosis with mild hyperkeratosis, severe spongiform edema of the stratum corneum, significant proliferation of acanthocytes, and vacuolation of keratinocytes. The genetic testing revealed that both the girl and her younger brother had a homozygous mutation of c.1456(exon9)delG in the SLC39A4 gene, and thus the girl was diagnosed with acrodermatitis enteropathica. It is concluded that for children with recurrent rash on the limbs and at the perioral region, genetic testing should be performed as early as possible to make a confirmed diagnosis, and a sufficient dose of zinc supplementation should be given, while the levels of trace elements such as blood zinc should be regularly monitored.

Cu-Modified La 2 Si 2 O 7 /TiO 2 composite materials were prepared by the molten salt method and a solid-phase reduction strategy. Due to the surface plasmon resonance (SPR) of copper, the optical response from the UV to the visible region and near-infrared is increased. In the meantime, it enhances the absorption of visible light by the titanium dioxide and acts as a plasma catalyst. The combination enhances the photothermal properties of the composite. The particle size of Cu/La 2 Si 2 O 7 /TiO 2 is in the range of 100 to 230 nm. Results show that the composite has a good photothermal effect. The 1 mg ml -1 solution can be warmed up to 63.1 °C at 0.5 W cm -2 laser power density with a maximum temperature difference of 45 °C. It has potential applications in solar energy conversion, photothermal catalysis, etc .

β 2 -microglobulin (B 2 M) has been established to impair cognitive function. However, no treatment is currently available for B 2 M-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates B 2 M-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated B 2 M-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of B 2 M-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against B 2 M-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in B 2 M-exposed rats. These findings demonstrated that Itaconate alleviates B 2 M-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond B 2 M-associated neurocognitive disorders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: To deeply explore the experience of front-line nurses who participated in rescuing Wuhan during the early stage of coronavirus disease 2019 (COVID-19) epidemic., Methods: Using a descriptive qualitative design, individual semi-structured interviews were conducted between February 25 and March 5, 2020. A conventional content analysis method was used in data analysis to extract themes and sub-themes., Results: Six themes emerged after data analysis: (a) worries and stress during rescue; (b) difficulties encountered during rescue; (c) experience of team work; (d) experience of interaction with COVID-19 patients; (e) experience of logistic support and widespread concern; and (f) value and significance of the experience., Conclusions: Nurses took on difficult missions in the rescue and played an irreplaceable role. They experienced remarkable psychological changes over the intensive work. It was necessary to understand the feelings and problems of the nurses so as to establish a healthcare system that can protect medical staff effectively in future disasters., (© 2021 Japan Academy of Nursing Science.)

Background: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China., Methods: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world., Results: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million., Conclusions: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Traditional Chinese medicines(TCMs) have certain limitations in the clinical research design in their post-marketing evaluation, so that randomized controlled programs cannot be strictly implemented in some studies, while the objective performance criteria is a reasonable external controlled research method that has been gradually recognized at home and abroad in recent years in addition to randomized controlled trial(RCT) method. It is more mature in medical devices, surgery and other research fields, but there is no relevant report in the field of post-marketing evaluation of Chinese patent medicines. In this paper, the application prospect of the objective performance criteria and the problems were discussed in the field of post-marketing evaluation of TCM. The characteristics of as TCM are more consistent with the scope of the objective performance criteria, the application of the objective performance criteria in post-marketing evaluation of Chinese patent medicines, especially in single arm research, can break through the limitations of existing conventional clinical research methods, and improve the level of evidence, with good feasibility and advantages. However, in the application process, we should pay attention to the key issues such as the selection of index, research population, follow-up period and the reference selection, to ensure the quality of research. This research group has carried out some exploration and practice in the field of post-marketing evaluation of TCM injections by using single arm combined with the objective performance criteria, hoping to establish the key technology in this field, and provide certain research and design reference for the secondary development of Chinese patent medicines.

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4 + T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A girl, aged 22 months, attended the hospital due to recurrent vulvar rashes for more than half a year. Skin biopsy showed Langerhans cell histiocytosis, and evaluation of systemic conditions showed no systemic involvement. Therefore, the girl was diagnosed with Langerhans cell histiocytosis (skin type). In conclusion, for rashes on the vulva alone, if there are no specific clinical manifestations, the possibility of Langerhans cell histiocytosis should be considered after molluscum contagiosum, sexually transmitted diseases, and Fordyce disease are excluded.

Isotopic niches reflect the basic structure and functioning of river food webs; however, their response to riverine environments remains unclear. We used stable isotope analysis and community-wide metrics to quantify how invertebrate niches vary with environmental changes along a large subtropical river in China. Eight niche metrics, which had higher values in the wet than in the dry season, increased from headwaters to the middle river and decreased sharply near the estuarine industrial zones. The δ 13 C value of > - 23.8‰, which indicated consumption of epilithic diatoms, separated the invertebrates between the upper and mid-lower reaches. The δ 15 N values > 9.4‰ identified site-specific nitrogen sources from manure (e.g., animal effluent) and domestic sewage in agricultural area. The output of mixing models showed a downstream shift in carbon utilization by invertebrates from autochthonous periphyton and submerged hydrophytes to allochthonous C3 plants. Principle component (PC) and cluster analysis decomposed and grouped 40 environmental variables into 4 PCs that explained 84.5% of the total variance. Hierarchical partitioning revealed that the second and first PCs, which were driven mainly by biological indicators and habitat characteristics, had the highest explanatory power for niche ranges and areas (e.g., Bayesian ellipse), respectively. Our results suggest that reducing anthropogenic pressures (e.g., habitat loss and water pollution) on river ecosystems through measures, such as protecting diatom-dominated biofilms in riffles and controlling nitrogen loading in rural regions, may produce the greatest impact for river management. Graphical abstract.

Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic T H 17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1 β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Jing Yu et al.)

The Pearl River Delta region is the major economic zone of the Greater Bay Area:it presents a large number of industrial-mining enterprises and is interested by severe heavy metal pollution (mainly caused by Pb and Cd). The research and development of safe and efficient heavy metal remediation materials and technologies is fundamental in order to guarantee regional environmental quality and habitat safety. Goethite-fulvic acid composites were prepared using goethite minerals present in the red soils of the Pearl River Delta region by passivation repair, and were applied to immobilize Pb and Cd in a co-contaminated soil. The results showed that a higher ratio of fulvic acid in the composites enhanced the immobilization effect on Pb and Cd:the immobilization efficiency (IE) of Pb and Cd increased with the passivation time, and then stabilized. Additionally, the exchangeable and carbonate-bound fractions of Pb and Cd in the soil decreased, while the Fe-Mn oxide-bound and residual fractions increased. The cation exchange capacity (CEC), as well as the available K and NH 4 + -N in the soil increased after the application of the composite materials. We conclude that goethite-fulvic acid composites can be effectively applied to the remediation of Pb-Cd contaminated soil.

To study the hydrogeochemical characteristics and formation mechanism of groundwater in a karst development transition zone in southern and northern China, 25 groundwater samples were collected from the Shuangfengya area in the northern part of Bazhong City. Descriptive statistics, coefficients of variation, Schoeller diagrams, Sukalev classification, Piper diagrams, and Gibbs and ion scale coefficients were used to analyze the karst water chemistry and distribution characteristics. The main processes controlling the chemical evolution of the groundwater are also discussed. The research shows that the degree of groundwater mineralization in the study area is generally low, with mostly neutral water and alkaline water. There are some differences in groundwater between the northern and southern regions; the anions and cations in the groundwater in the northern area were mainly HCO 3 - , Ca 2+ , and Mg 2+ , with HCO 3 -Ca·Mg being the main water chemistry type; the anions and cations in the groundwater in the northern area were mainly HCO 3 - , and Ca 2+ , and HCO 3 -Ca was the main water chemistry type. The chemical character of groundwater was controlled by rock weathering and alternate cation adsorption, and evaporation crystallization in the southern region was more significant than in the northern region. Furthermore, rainfall in the northern region had a more significant effect on groundwater geochemistry than in the south. The differences in climate and lithology between the northern and southern region are the dominant factors influencing the differences in hydrochemistry.

Aims: Reactive astrogliosis plays a critical role in neurological deficits after germinal matrix hemorrhage (GMH). It has been reported that interleukin-17A and IL-17A receptor IL-17RA/(C/EBPβ)/SIRT1 signaling pathway enhances reactive astrogliosis after brain injuries. We evaluated the effects of secukinumab on reactive astrogliosis in a rat pup model of GMH., Methods: A total of 146 Sprague Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of collagenase. Secukinumab was administered intranasally 1 hour post-GMH. C/EBPβ CRISPR or SIRT1 antagonist EX527 was administrated intracerebroventricularly (icv) 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, histology, and immunohistochemistry were used to assess treatment regiments in the short term and long term., Results: The endogenous IL-17A, IL-17RA, C/EBPβ, and GFAP and proliferation marker CyclinD1 were increased, while SIRT1 expression was decreased after GMH. Secukinumab treatment improved neurological deficits, reduced ventriculomegaly, and increased cortical thickness. Additionally, treatment increased SIRT1 expression and lowered proliferation proteins PCNA and CyclinD1 as well as GFAP expression. C/EBPβ CRISPR activation plasmid and EX527 reversed the antireactive astrogliosis effects of secukinumab., Conclusion: Secukinumab attenuated reactive astrogliosis and reduced neurological deficits after GMH, partly by regulating IL-17RA/(C/EBPβ)/SIRT1 pathways. Secukinumab may provide a promising therapeutic strategy for GMH patients., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Aim: To determine the effect of osteopontin (OPN) on autophagy and autophagy-apoptosis interactions after SAH., Methods: The endovascular perforation model of SAH or sham surgery was performed in a total of 86 Sprague-Dawley male rats. The temporal expressions of endogenous OPN and autophagy-related proteins (Beclin 1, ATG5, LC3 II to I ratio) were measured in sham and SAH rats at different time points (3, 6, 12, 24, and 72 hours). Rats were randomly divided into three groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), and SAH + rOPN (5 μg/rat recombinant OPN). Neurobehavioral tests were performed 24 hours after SAH, followed by the collection of brain samples for assessment of autophagy and apoptosis proteins. These tests assessed whether an autophagy-apoptosis relationship existed on the histological level in the brain., Results: Endogenous OPN and autophagy-related proteins all increased after SAH. rOPN administration improved neurological dysfunction, increased the expression of autophagy-related proteins (Beclin 1, ATG5, LC3 II to I ratio) and antiapoptotic protein Bcl-2, while decreasing the expression of proapoptotic proteins (cleaved Caspase-3 and Bax). rOPN also regulated autophagy-apoptosis interactions 24 hours after SAH., Conclusion: rOPN attenuates early brain injury and inhibits neuronal apoptosis by activating autophagy and regulating autophagy-apoptosis interactions., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

A girl, aged 15 months, attended the hospital due to recurrent skin erythema, blisters, and desquamation for more than 7 months. Giemsa staining and immunohistochemical staining showed mast cell infiltration and degranulation. Hematoxylin staining showed spinous layer edema and blister formation under the epidermis, with a large amount of serous fluid and a small number of inflammatory cells in the blister. Marked edema was observed in the dermis, with diffused mononuclear cell infiltration. The girl was diagnosed with mastocytosis. Mastocytosis should be considered for children with recurrent skin erythema and blisters.

The Jianjiang alluvial fan is one of the frontal alluvial fan clusters in the Longmen Mountains of the Chengdu Plain. In order to study the groundwater chemical characteristics and controlling factors, we collected 30 groups of groundwater samples on site in May 2018. Descriptive statistical analysis, Piper diagrams, ArcGIS spatial analysis, ion-scale coefficients, and other methods were used to analyze the chemical types and ion spatial distribution characteristics. The main factors controlling the chemical evolution processes of the groundwater and the main sources of ions are discussed. The northeast area of the alluvial fan contains mostly weakly acidic waters, accounting for 13.33%, the rest being weakly alkaline. Groundwater chemical types included HCO 3 ·SO 4 -Ca, HCO 3 -Ca, HCO 3 ·SO 4 -Ca·Mg, and HCO 3 ·SO 4 -Ca·Na, and all groundwater was freshwater. The main ion spatial variation coefficient were between 0.22 and 0.91, and the variability was moderate. The chemical evolution processes of groundwater was mainly controlled by leaching, and human activities have certain influence. The effect of evaporation and concentration, and atmospheric rainfall, and alternating cation adsorption were not obvious.

Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death. mRNA-based therapies are a new class of drugs that work by replacing the missing enzyme. mRNA encoding AGT has the potential to restore normal glyoxylate to glycine metabolism, thus preventing the buildup of calcium oxalate in various organs. Panels of codon-optimized AGT mRNA constructs were screened in vitro and in wild-type mice for the production of a functional AGT enzyme. Two human constructs, wild-type and engineered AGT (RHEAM), were tested in Agxt -/- mice. Repeat dosing in Agxt -/- mice resulted in a 40% reduction in urinary oxalate, suggesting therapeutic benefit. These studies suggest that mRNA encoding AGT led to increased expression and activity of the AGT enzyme in liver that translated into decrease in urinary oxalate levels. Taken together, our data indicate that AGT mRNA may have the potential to be developed into a therapeutic for PH1.

Endocrine disrupting compounds (EDCs) are becoming an increasing concern regarding bioaccumulation in aquatic biota. However, the effects of regional pollution levels and specific feeding habits on the bioaccumulation of EDCs in fish are rarely reported. 4-Nonylphenol (4-NP), bisphenol A (BPA), 4-tert-octylphenol (4-t-OP), triclocarban (TCC) and triclosan (TCS) were determined in abiotic compartments [water, sediment, suspended particulate matter (SPM)] and fish with different feeding habits along the Pearl River, China. EDCs in abiotic compartments exhibited significant (p < 0.05) spatial variations, forming five zones clustered based on site-specific EDC concentrations. 4-NP was the dominant compound, contributing 58-98% of the EDCs in fish, followed by BPA (<41%), 4-t-OP (<13%), and TCC and TCS (<4.7%). The concentrations of 4-NP and 4-t-OP, BPA, and TCC and TCS were the highest in brackish carnivorous, planktivorous, and detritivorous fish, respectively. The bioaccumulation factors (BAFs) showed that 4-NP accumulated (BAF > 5000) in all fish except for suck-feeding detritivores, while 4-t-OP and TCC accumulated in filter-feeding planktivores. The concentration of 4-NP in carnivores was significantly higher than that in detritivores, indicating the potential biomagnification of 4-NP along food chains. EDCs in sediment and SPM and those in water were most positively correlated with those in detritivores and planktivores, respectively, suggesting the potential of fish with these two feeding habits to act as bioindicators of EDC pollutants., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Due to the heterogeneous distribution of resources along large rivers, understanding prey utilization by basin-scale fish assemblages remains a challenge, and thus, recognizing regional fish trophic guilds and indicator species is important. We analyzed the stomach contents of 96 fish species along the subtropical East River in China and identified 8 prey items (29 subcategories). Site-specific differences in fish diet composition (DC) revealed longitudinal shifts in utilized prey taxa, from upstream lotic to downstream semi-lentic items, and these were characterized by a decrease in the proportions of epilithic diatoms and aquatic insect larvae (Ephemeroptera and Chironomidae) accompanied by an increase in bivalves ( Corbicula and Limnoperna ), shrimps and fishes, and organic sediments. The relative prey consumption weighted by fish abundance and biomass indicated that decreasing insect consumption and increasing detritus consumption were two fundamental vectors governing fish-centered feeding pathways. Seventeen prey-oriented fish guilds that were clustered based on DC matrix determined the spatial variation in the fish trophic structure. The cumulative presence of (a) upstream guilds reliant on insects and epiphytes, (b) midstream guilds reliant on hydrophytes, molluscs, and nekton, and (c) downstream guilds reliant on detritus, annelids, and plankton resulted in a longitudinal increase in guild richness, but this continuity was interrupted near the industrialized estuary. The most abundant 28 fish species across the guilds were selected as trophic indicator species; their spatial distribution significantly ( p <  0.05) explained >80% of the environmental and prey variables identified. These species signified the availability of predator-prey links in distinct habitats and the key environmental factors supporting these links. With a high contribution (>51%) of exotic species, an increase in detritivores downstream distinguishes the subtropical East River from temperate rivers. Particularly, in the disturbed lower reaches, the dominance of detritivores prevailed over the predicted increase in other feeding groups (e.g., omnivores and carnivores).

Background: Current models of user participation in mental health services were developed within Western culture and thus may not be applicable to Chinese communities., Aims: To present a new model of user participation, which emerged from research within a Chinese community, for understanding the processes of and factors influencing user participation in a non-Western culture., Method: Multiple qualitative methods, including focus groups, individual in-depth interviews, and photovoice, were applied within the framework of constructivist grounded theory and collaborative research., Results: Diverging from conceptualizations of user participation with emphasis on civil rights and the individual as a central agent, participants in the study highlighted the interpersonal dynamics between service users and different players affecting the participation intensity and outcomes. They valued a reciprocal relationship with their caregivers in making treatment decisions, cooperated with staff to observe power hierarchies and social harmony, identified the importance of peer support in enabling service engagement and delivery, and emphasized professional facilitation in advancing involvement at the policy level., Conclusions: User participation in Chinese culture embeds dynamic interdependence. The proposed model adds this new dimension to the existing frameworks and calls for attention to the complex local ecology and cultural consistency in realizing user participation.

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable., Competing Interests: The authors declare no conflict of interest.

Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first-in-human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11c high MHCII + cells (Cnb1 CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3 + regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11c high MHCII + cells to express IL-2. Deleting IL-2 in CD11c high MHCII + cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin-NFAT-IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.

This study aimed to investigate the occurrence and spatio-temporal distribution of 4- tert -octylphenol (4- t -OP), 4-nonylphenol (4-NP), triclosan (TCS), estrone (E1), 17 β -estradiol (E2), and bisphenol-A (BPA) as endocrine disrupting chemicals (EDCs) in the water of the Liuxi River and to evaluate the risks for estrogenic activity. The results showed that EDCs had been detected at the 14 monitoring sites and the total concentration ranged from 26.07 ng·L -1 to 7109.5 ng·L -1 , with the highest contribution rate coming from 4-NP (78.62%), followed by BPA (11.91%), and the other four EDCs (≤ 4.92%). On a spatial and temporal scale, the EDC contents increased longitudinally from upstream to downstream, especially in the heavily-polluted Baiyun section where the water quality was lower than level Ⅴ. The EDC contents in the tributaries were much higher than those in the main channels. Influenced by the monsoon precipitation, the contents of 4-NP, 4- t -OP, and total EDCs in the rainy season were significantly ( P <0.05) higher than those in the dry season, while the seasonal changes of E1 and E2 followed the opposite tendency. A Pearson correlation analysis showed that DO was significantly negatively correlated with all the EDCs, suggesting that the EDCs and reductive organic pollutants might coexist. As TN, TP, NH 4 + -N, permanganate index, and EC were significantly positively correlated with E1, E2, BPA, and TCS but not obviously correlated with 4-NP ( P >0.05), we presumed that the pollution source of E1, E2, BPA, and TCS might be the same with nitrogen and phosphorus nutrition, originating from the point source emission of the domestic sewage, industrial, and agricultural wastewater. In contrast, 4-NP and 4- t -OP more likely originated from the non-point source pollution from agriculture. RDA results showed that the variation of the EDCs contents by season was more obvious than that in space (RDA1 56.14%>RDA2 14.20%), which was much more influenced by 4-NP in the rainy season and by BPA in the dry season. As E1, E2, and TCS were positively correlated with the Cu, Zn, cyanide, and fecal coliform, these three target compounds could be used to indicate the multiple pollution components for water quality. Compared with the worldwide reported EDC contents in waters, 4-NP, BPA, and TCS contents in the middle and lower reaches of the Liuxi River were at higher levels, while E1, E2, and 4- t -OP were at the middle and lower levels. The risk assessment for estrogenic activity showed that the RQ values in the middle and lower reaches of the Liuxi River were all greater than 1, indicating that the downstream river sections were under high risk for estrogenic activity. As a result, appropriate precautions are needed to improve environmental management.

Across metazoans, cell cycle progression is regulated by E2F family transcription factors that can function as either transcriptional activators or repressors. For decades, the Drosophila E2F family has been viewed as a streamlined RB/E2F network, consisting of one activator (dE2F1) and one repressor (dE2F2). Here, we report that an uncharacterized isoform of dE2F1, hereon called dE2F1b, plays an important function during development and is functionally distinct from the widely-studied dE2F1 isoform, dE2F1a. dE2F1b contains an additional exon that inserts 16 amino acids to the evolutionarily conserved Marked Box domain. Analysis of de2f1b-specific mutants generated via CRISPR/Cas9 indicates that dE2F1b is a critical regulator of the cell cycle during development. This is particularly evident in endocycling salivary glands in which a tight control of dE2F1 activity is required. Interestingly, close examination of mitotic tissues such as eye and wing imaginal discs suggests that dE2F1b plays a repressive function as cells exit from the cell cycle. We also provide evidence demonstrating that dE2F1b differentially interacts with RBF1 and alters the recruitment of RBF1 and dE2F1 to promoters. Collectively, our data suggest that dE2F1b is a novel member of the E2F family, revealing a previously unappreciated complexity in the Drosophila RB/E2F network.