USP25 contributes to defective neurogenesis and cognitive impairments.

Both Down syndrome (DS) individuals and animal models exhibit hypo-cellularity in hippocampus and neocortex indicated by enhanced neuronal death and compromised neurogenesis. Ubiquitin-specific peptidase 25 (USP25), a human chromosome 21 (HSA21) gene, encodes for a deubiquitinating enzyme overexpressed in DS patients. Dysregulation of USP25 has been associated with Alzheimer's phenotypes in DS, but its role in defective neurogenesis in DS has not been defined. In this study, we found that USP25 upregulation impaired cell cycle regulation during embryonic neurogenesis and cortical development. Overexpression of USP25 in hippocampus promoted the neural stem cells to glial cell fates and suppressed neuronal cell fate by altering the balance between cyclin D1 and cyclin D2, thus reducing neurogenesis in the hippocampus. USP25-Tg mice showed increased anxiety/depression-like behaviors and learning and memory deficits. These results suggested that USP25 overexpression resulted in defective neurogenesis and cognitive impairments, which could contribute to the pathogenesis of DS. USP25 may be a potential pharmaceutical target for DS.

Duplication and Deletion of 22q11 Associated with Anomalous Pulmonary Venous Connection.

Anomalous pulmonary venous connection (APVC) is an uncommon congenital anomaly in which pulmonary venous blood flows directly into the right side of the heart or into the systemic veins. To identify whether there is any association between 22q11 CNVs and APVC, we analyzed the clinical data of 86 APVC patients and then studied the CNVs of 22q11 in 86 sporadic APVC patients by multiplex ligation-dependent probe amplification. The results showed that two patients carried the CNVs of 22q11, one patient had the deletion of 22q11 and the other had the duplication of 22q11. The incidence was significantly higher than that in the normal population (P < 0.01) that suggests a possible etiologic association between the duplication or deletion of 22q11 and the APVC in our patients.

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease.

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

Patients carrying 9q31.1-q32 deletion share common features with Cornelia de Lange Syndrome.

BACKGROUND: Cornelia de Lange Syndrome (CdLS) is a rare but severe clinically heterogeneous developmental disorder characterized by facial dysmorphia, growth and cognitive retardation, and abnormalities of limb development. OBJECTIVES: To determine the pathogenesis of a patient with CdLS. METHODS: We studied a patient with CdLS by whole exome sequencing, karyotyping and Agilent CGH Array. The results were confirmed by quantitative real-time PCR analysis of the patient and her parents. Further comparison of our patient and cases with partially overlapping deletions retrieved from the literature and databases was undertaken. RESULTS: Whole exome sequencing had excluded the mutation of cohesion genes such as NIPBL,SMC1A and SMC3. The result of karyotyping showed a deletion of chromosome 9q31.1-q32 and the result of Agilent CGH Array further displayed a 12.01-Mb region of deletion at chromosome bands 9q31.1-q32. Reported cases with the deletion of 9q31.1-q32 share similar features with our CdLS patient. One of the genes in the deleted region, SMC2, belongs to the Structural Maintenance of Chromosomes (SMC) family and regulates gene expression and DNA repair. CONCLUSIONS: Patients carrying the deletion of 9q31.1-q32 showed similar phenotypes with CdLS.

[Screening for Lynch syndrome in colorectal cancer].

OBJECTIVE: To evaluate the application of mismatch repair (MMR) genes proteins expression to screen for Lynch syndrome in colorectal cancer patients. METHODS: One hundred consecutive colorectal cancers cases collected from 2012 to 2013 were tested immunohistochemically for the protein expression of MLH1, MSH2, MSH6 and PMS2, and also by the ARMS method for the mutation status of BRAF genes in those cases lacking protein expression for MLH1. RESULTS: The result of MMR immunocytochemistry showed that nine of 100 cases lacked MMR protein expression, including three cases each that were MLH1-/PMS2- and MSH2-/MSH6- respectively, two cases were MLH6- and one case was PMS2-; overall, the majority of these cases lacked protein expression of MLH1 and MSH2. The BRAF genes mutation test showed one case of mutation, indicating that the patient might have MLH1 gene methylation as a result of the mutation of BRAF genes, and that was a sporadic case. The age of onset for patients lacking MMR protein expression was lower than patients with sporadic colorectal cancer (P = 0.011). Colorectal cancers associated with the lack of MMR protein expression mostly occurred in the right colon (P = 0.001), and histomorphologically were often accompanied by mucinous adenocarcinoma (P = 0.010) and tumor lymphocytic infiltration. CONCLUSION: Immunohistochemical staining for MMR proteins in patients with colorectal cancer, accompanied by testing for BRAF genes mutation, may be an effective approach to screen for Lynch syndrome.

Dynamic influence of maternal education on height among Chinese children aged 0-18 years.

Background: Maternal education is one of key factors affecting nurturing environment which significantly impacts children's height levels throughout their developmental stages. However, the influence of maternal education on children's height is less studied. This study aims to investigate the dynamic influence of maternal education on children's height among Chinese children aged 0-18 years. Methods: Children undergoing health examinations from January 2021 to September 2023 were included in this study. Clinical information including height, weight, maternal pregnancy history, blood specimens for bone metabolism-related indicators and maternal education level was collected. Children's height was categorized into 14 groups based on age and gender percentiles, following WHO 2006 growth standards. One-way analysis of variance (ANOVA), linear regression, chi-square test and Fisher's exact test were applied for data analysis. Results: A total of 6269 samples were collected, including 3654 males and 2615 females, with an average age of 8.38 (3.97) for males and 7.89 (3.55) for females. Significant correlations between maternal education level, birth weight, birth order, weight percentile, vitamin D, serum phosphorus, alkaline phosphatase levels, and children's height were identified. Birth weight's influence on height varied across age groups. Compared with normal birth weight children, low birth weight children exhibited catch-up growth within the first 6 years and a subsequent gradual widening of the height gap from 6 to 18 years old. Remarkably, the impact of maternal education on height became more pronounced among children above 3-6 years old, which can mitigate the effect of low birth weight on height. Conclusion: We found that weight percentile, birth weight, birth order, bone marker levels, and maternal education level have significant effect on height. Maternal education attenuates the impact of low birth weight on height. The findings indicated that maternal education plays a consistent and critical role in promoting robust and healthy growth.

Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Effects of Lactobacillus on hyperlipidemia in high-fat diet-induced mouse model.

Introduction: Hyperlipidemia refers to a group of lipid metabolism disorders characterized by increased levels of total cholesterol, triglyceride, and/or low-density lipoprotein cholesterol and/or decreased levels of high-density lipoprotein cholesterol. This study aims to investigate the effects of Lactobacillus on lipid metabolism and hepatic steatosis in male mice fed with a high-fat diet by measuring blood lipid, hepatic function and hepatocyte morphology. Material and methods: Eighty male Institute of Cancer Research (ICR) mice were fed with a high-fat diet for 6 weeks to establish hyperlipidemic models. Then, mice were treated with a high or low concentration of Lactobacillus of human source, mouse source, or plant source, respectively. Results: After 3 weeks of therapy, except for the human Lactobacillus treatment group, the blood cholesterol, triglyceride and low-density lipoprotein cholesterol in mice treated with Lactobacillus of mouse and plant source were lower than those in the hyperlipidemic model group. After 4 weeks of treatment, the levels of blood biochemical indexes in mice in all treatment groups were significantly different, when compared to those in the hyperlipidemic model group. Conclusions: Lactobacillus may regulate blood lipid in mice fed with a high-fat diet. Lactobacillus can improve the high cholesterol, high blood lipid, and injury of hepatic function, and prevent further development of atherosclerosis caused by a high-fat diet to some extent. Correct dietary structure is the basis for the treatment of dietary hyperlipidemia and its complications.

Gallic acid inhibits neuroinflammation and reduces neonatal hypoxic-ischemic brain damages.

Neuroinflammation is a leading cause of secondary neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE). Regulation of neuroinflammation may be beneficial for treatment of HIE and its secondary complications. Gallic acid (GA) has been shown to have anti-inflammatory and antioxidant effects. In this report we found that oxygen-glucose deprivation and/reoxygenation (OGD/R)-induced cell death, and the generation of excessive reactive oxygen species (ROS) and inflammatory cytokines by microglia were inhibited by GA treatment. Furthermore, GA treatment reduced neuroinflammation and neuronal loss, and alleviated motor and cognitive impairments in rats with hypoxic-ischemic brain damage (HIBD). Together, our results reveal that GA is an effective regulator of neuroinflammation and has potential as a pharmaceutical intervention for HIE therapy.

The Diagnostic Utility of the Basal Luteinizing Hormone Level and Single 60-Minute Post GnRH Agonist Stimulation Test for Idiopathic Central Precocious Puberty in Girls.

Objective: The present study aimed to assess the diagnostic utility of the Luteinizing hormone (LH) levels and single 60-minute post gonadotropin-releasing hormone (GnRH) agonist stimulation test for idiopathic central precocious puberty (CPP) in girls. Methods: Data from 1,492 girls diagnosed with precocious puberty who underwent GnRH agonist stimulation testing between January 1, 2016, and October 8, 2020, were retrospectively reviewed. LH levels and LH/follicle-stimulating hormone (FSH) ratios were measured by immuno-chemiluminescence assay before and at several timepoints after GnRH analogue stimulation testing. Mann-Whitney U test, Spearman's correlation, χ2 test, and receiver operating characteristic (ROC) analyses were performed to determine the diagnostic utility of these hormone levels. Results: The 1,492 subjects were split into two groups: an idiopathic CPP group (n = 518) and a non-CPP group (n = 974). Basal LH levels and LH/FSH ratios were significantly different between the two groups at 30, 60, 90, and 120 minutes after GnRH analogue stimulation testing. Spearman's correlation analysis showed the strongest correlation between peak LH and LH levels at 60 minutes after GnRH agonist stimulation (r = 0.986, P < 0.001). ROC curve analysis revealed that the 60-minute LH/FSH ratio yielded the highest consistency, with an area under the ROC curve (AUC) of 0.988 (95% confidence interval [CI], 0.982-0.993) and a cut-off point of 0.603 mIU/L (sensitivity 97.3%, specificity 93.0%). The cut-off points of basal LH and LH/FSH were 0.255 mIU/L (sensitivity 68.9%, specificity 86.0%) and 0.07 (sensitivity 73.2%, specificity 89.5%), respectively, with AUCs of 0.823 (95% CI, 0.799-0.847) and 0.843 (95% CI, 0.819-0.867), respectively. Conclusions: A basal LH value greater than 0.535 mIU/L can be used to diagnose CPP without a GnRH agonist stimulation test. A single 60-minute post-stimulus gonadotropin result of LH and LH/FSH can be used instead of a GnRH agonist stimulation test, or samples can be taken only at 0, 30, and 60 minutes after a GnRH agonist stimulation test. This reduces the number of blood draws required compared with the traditional stimulation test, while still achieving a high level of diagnostic accuracy.

Comparison of Induction Chemotherapy Plus Concurrent Chemoradiotherapy and Concurrent Chemoradiotherapy Alone in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Induction chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy alone are both standard treatment regimens for managing locally advanced nasopharyngeal carcinoma. However, the results of comparisons between them in clinical trials vary. Therefore, we designed this meta-analysis to illustrate their advantages and disadvantages in patients with locally advanced nasopharyngeal carcinoma. METHODS: We thoroughly searched the PubMed, EMBASE, and Cochrane Library databases and then merged the effect indicators of hazard ratios and risk ratios using RevMan 5.1. RESULTS: Seven randomized controlled trials totaling 2,319 patients were included in our research. The synthesized results showed that induction chemotherapy plus concurrent chemoradiotherapy improved overall survival (HR = 0.75, 95% CI: 0.63-0.89, P = 0.001), progression-free survival (HR = 0.69, 95% CI: 0.60-0.80, P < 0.001), distant metastasis-free survival (HR = 0.65, 95% CI: 0.53-0.80, P < 0.001) and locoregional recurrence-free survival (HR = 0.68 95%, CI: 0.54-0.86, P = 0.001) versus concurrent chemoradiotherapy alone. It also increased the risk of anemia, thrombocytopenia, and neutropenia during concurrent chemoradiotherapy. However, the incidence of leukopenia and mucositis was similar in induction chemotherapy and induction chemotherapy plus concurrent chemoradiotherapy. Furthermore, the subgroup analysis showed better survival outcomes with induction chemotherapy plus concurrent chemoradiotherapy than with concurrent chemoradiotherapy alone in the triweekly cisplatin subgroup (all P < 0.01), whereas induction chemotherapy plus concurrent chemoradiotherapy could only improve progression-free survival and locoregional recurrence-free survival in the weekly cisplatin subgroup (HR = 0.78, P = 0.02; and HR = 0.66, P = 0.03, respectively). CONCLUSIONS: Induction chemotherapy plus concurrent chemoradiotherapy improved survival outcomes in patients with locally advanced nasopharyngeal carcinoma versus concurrent chemoradiotherapy. For the weekly cisplatin regimen subgroup, it did not improve remote control or overall survival versus concurrent chemoradiotherapy alone, warranting further clarification.

A Novel Prognostic Prediction Model for Colorectal Cancer Based on Nine Autophagy-Related Long Noncoding RNAs.

INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal cancer and has a low overall survival rate. Tumor-node-metastasis staging alone is insufficient to predict patient prognosis. Autophagy and long noncoding RNAs play important roles in regulating the biological behavior of CRC. Therefore, establishing an autophagy-related lncRNA (ARlncRNA)-based bioinformatics model is important for predicting survival and facilitating clinical treatment. METHODS: CRC data were retrieved from The Cancer Genome Atlas. The database was randomly divided into train set and validation set; then, univariate and multivariate Cox regression analyses were performed to screen prognosis-related ARlncRNAs for prediction model construction. Interactive network and Sankey diagrams of ARlncRNAs and messenger RNAs were plotted. We analyzed the survival rate of high- and low-risk patients and plotted survival curves and determined whether the risk score was an independent predictor of CRC. Receiver operating characteristic curves were used to evaluate model sensitivity and specificity. Then, the expression level of lncRNA was detected by quantitative real-time polymerase chain reaction, and the location of lncRNA was observed by fluorescence in situ hybridization. Additionally, the protein expression was detected by Western blot. RESULTS: A prognostic prediction model of CRC was built based on nine ARlncRNAs (NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503, LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly lower in the high-risk group than in the low-risk group among train set, validation set, and all patients (all p < 0.001). The model had high sensitivity and accuracy in predicting the 1-year overall survival rate (area under the curve = 0.717). The prediction model risk score was an independent predictor of CRC. LINC00174 and NKILA were expressed in the nucleus and cytoplasm of normal colonic epithelial cell line NCM460 and colorectal cancer cell lines HT29. Additionally, LINC00174 and NKILA were overexpressed in HT29 compared with NCM460. After autophagy activation, LINCC00174 expression was significantly downregulated both in NCM460 and HT29, while NKILA expression was significantly increased. CONCLUSION: The new ARlncRNA-based model predicts CRC patient prognosis and provides new research ideas regarding potential mechanisms regulating the biological behavior of CRC. ARlncRNAs may play important roles in personalized cancer treatment.

Comparison of Dosimetric Benefits of Three Precise Radiotherapy Techniques in Nasopharyngeal Carcinoma Patients Using a Priority-Classified Plan Optimization Model.

INTRODUCTION: Although intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy (TOMO) are broadly applied for nasopharyngeal carcinoma (NPC), the best technique remains unclear. Therefore, this study was conducted to address this issue. METHODS: The priority-classified plan optimization model was applied to IMRT, VMAT and TOMO plans in forty NPC patients according to the latest international guidelines. And the dosimetric parameters of planning target volumes (PTVs) and organs at risk (OARs) were compared among these three techniques. The Friedman M test in SPSS software was applied to assess significant differences. RESULTS: The median PGTVnx coverage of IMRT was the lowest (93.5%, P < 0.001) for all T categories. VMAT was comparable to TOMO in OARs clarified as priority I and II, and both satisfied the prescribed requirement. IMRT resulted in a relatively high dose for V25 and V30. Interestingly, subgroup analysis showed that the median PTV coverage of the three techniques was no less than 95% in the early T stage. The heterogeneity index (HI) of PGTVnx in VMAT was better than that in IMRT (P = 0.028). Compared to TOMO, VMAT showed a strong ability to protect eyesight and decrease low-dose radiation volumes. In the advanced T stage subgroup, TOMO numerically achieved the highest median PGTVnx coverage volume compared with VMAT and IMRT (93.61%, 91% and 90%, respectively). The best CI and HI of PCTV-1 were observed in TOMO. Furthermore, TOMO was better than VMAT for sparing the brain stem, spinal cord and temporal lobes (all P < 0.05). However, the median V5, V10, V15, V20 and V25 were significantly higher with TOMO than with VMAT (all P < 0.05). CONCLUSION: In the early T stage, VMAT provides a similar dose coverage and protection of OARs to IMRT, and there are no obvious advantages to choosing TOMO for NPC patients in the early T stage. TOMO may be recommended for patients in the advanced T stage due as it provides the largest dose coverage of PGTVnx and the best protection of the brain stem, spinal cord and temporal lobes. Additionally, more randomized clinical trials are needed for further clarification.

Polydactyly Patient Carried a Mutation of PTCH1 Which Has Been Identified in Nevoid Basal Cell Nevus Syndrome.

Polydactyly frequently exhibits autosomal dominant inheritance, which is characterized by supernumerary fingers or toes. The growth of the limb was controlled by three signaling pathways in three-dimensional axis. Sonic Hedgehog signaling, which controls the anterior to posterior (radial to ulnar) orientation has been suspected to be a main cause for polydactyly. To determine the pathogenesis of the patients with polydactyly, we recruited a polydactyly family with two patients. Taking advantage of next-generation sequencing technology, we applied whole-exome sequencing and Sanger sequencing to the proband and her daughter. The analysis of the whole-exome sequencing showed a heterozygous missense mutation c.3617G>A (p.R1206H) in the PTCH1 gene. The results of Sanger sequencing also verified this mutation. Our research discovered a candidate gene of polydactyly-PTCH1. We are the first to point out the relationship between polydactyly and PTCH1 mutation in human. As the PTCH1 gene mutations have been identified in nevoid basal cell nevus syndrome (NBCCS), and polydactyly is one phenotype of NBCCS, it may provide a new clue to the study of the genotype-phenotype correlations between the PTCH1 gene mutations and NBCCS.

Typhoon Merbok induced upwelling impact on material transport in the coastal northern South China Sea.

Typhoons frequently affect the South China Sea (SCS), playing an important role in changing the coastal marine system. To determine which process has the greatest impact on material transport in the coastal marine area during a typhoon, the sea temperature, salinity, concentration of nutrients, chlorophyll-a, total suspended matter, and δ13C of particulate organic carbon (δ13C-POC) in the water column of coastal Northern SCS (NSCS) were measured during two cruises in June 2017, in the pre- and post-typhoon Merbok periods. The results show that all parameters changed significantly between the two periods. During the pre-typhoon period, stratification of nutrients and physicochemical parameters, combined to high nutrient concentrations, high temperature, and low salinity in the water column of the nearshore area, suggests that the nearshore area is influenced by the river diluted water originated in the coastal cities adjacent to our study area. In the offshore area, mineralization may be responsible for the high nutrient concentration in the bottom water. However, during the post-typhoon, the stratification of nutrients is less significant and their distribution more homogenous in the whole water column of the nearshore area. In the upper water, the nutrient concentration increased and the temperature decreased significantly. These results suggest that the enhanced vertical mixing induced by the typhoon was the dominant process in changing the nutrient distribution pattern in the coastal NSCS.

Comparison of induction chemotherapy plus concurrent chemoradiotherapy and induction chemotherapy plus radiotherapy in locally advanced nasopharyngeal carcinoma.

BACKGROUND: Induction chemotherapy plus concurrent chemoradiotherapy (IC + CCRT) is a standard treatment regimen for locally advanced nasopharyngeal carcinoma (LA-NPC). However, the increased acute toxicity of this intensified chemotherapy may counteract its efficacy. The results of studies focusing on the omission of concurrent chemotherapy (CC) regimens are controversial. Therefore, we carried out a meta-analysis to elucidate the efficacy and toxicity of IC + CCRT versus IC plus radiotherapy alone (IC + RT) for LA-NPC. METHODS: Studies available on PubMed, Embase, Cochrane Library and ClinicalTrails.gov were independently searched by two investigators from inception to March 1, 2020. Review Manager software 5.3 (RevMan 5.3) was employed to calculate pooled hazard ratios (HRs), risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Eight studies with a total of 2605 patients were analysed. The results showed that no significant difference between IC + RT and IC + CCRT for disease-free survival (HR = 1.09, 95% CI: 0,85-1.39, P = 0.50), overall survival (HR = 0.92, 95% CI: 0.78-1.09, P = 0.34), local recurrence-free survival (HR = 1.26, 95% CI: 0.95-1.67; P = 0.10), or distant metastasis-free survival (HR = 1.03, 95% CI: 0.84-1.26, P = 0.79). Notably, the incidence of treatment-related grade 3/4 acute haematological toxicity during radiation was higher in the IC + CCRT group. Subgroup analysis showed similar survival outcomes for IC + CCRT and IC + RT with and without the two-dimensional RT technique. CONCLUSIONS: IC + RT was as effective as IC + CCRT for the management of LA-NPC. The IC + RT regimen has the possibility of replacing the IC + CCRT regimen for LA-NPC in the future due to the lower toxicity, although more high-level evidence is urgently needed for verification.

Assessing Seasonal Nitrate Contamination by Nitrate Dual Isotopes in a Monsoon-Controlled Bay with Intensive Human Activities in South China.

Nitrate (NO3-) dual isotope analysis was performed in Zhanjiang Bay, which is a closed bay with intensive human activities in South China, to investigate seasonal changes in the main NO3- sources and their biogeochemical processes in the monsoon-controlled climate. The relatively low N/P ratios in Zhanjiang Bay suggests that nitrogen (N) is a limiting nutrient, which indicates that the increase of N is favorable for phytoplankton proliferation. However, a sufficient amount of ammonium was found in our study area owing to intensive human activities, which can support biological processes. Thus, less NO3- biological processes were found, indicating that NO3- isotopic characteristics may reveal details of the mixing from various sources. The Bayesian mixing model showed that NO3- in the upper bay originated from manure (43%), soil N (30%), N fertilizer (17%), and N precipitation (10%) during winter, which reflects the local human activities; while NO3- sources during summer were mainly N fertilizer (36%), soil N (32%), and manure (31%), indicating the source as the runoff from the upper river basin. Our results suggest that nitrate dual-isotope was very useful for tracing the main NO3- sources in the condition of the sufficient ammonium, and runoff exerted an important impact on the shift in NO3- sources between both the local source and the source from the upper river basin during the two seasons in this monsoon-controlled bay.

Deep soil water storage varies with vegetation type and rainfall amount in the Loess Plateau of China.

Soil-water storage in a deep soil layer (SWSD), defined as the layer where soil water is not sensitive to daily evapotranspiration and regular rainfall events, functions as a soil reservoir in China's Loess Plateau (LP). We investigated spatial variations and factors that influence the SWSD in the 100-500 cm layers across the entire plateau. SWSD generally decreased from southeast to northwest following precipitation gradient, with a mean value of 587 mm. The spatial variation in the SWSD in grassland was the highest, followed by protection forests, production forests and cropland. Variation in the >550 mm rainfall zone was much lower than that in the <550 mm zone. The significant influencing variables explained 22.3-65.2% of the spatial variation in SWSD. The joint effect of local and climatic variables accounted for most of the explained spatial variation of SWSD for each vegetation type and the <450 mm rainfall zone. Spatial variation of SWSD, however, was dominantly controlled by the local variables in the 450-550 and the >550 mm rainfall zones. Therefore, regional models of SWSD for a specific vegetation need to incorporate climatic, soil and topographic variables, while for a rainfall zone, land use should not be ignored.

Rare copy number variants analysis identifies novel candidate genes in heterotaxy syndrome patients with congenital heart defects.

BACKGROUND: Heterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx. METHODS: We collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models. RESULTS: Nineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning. CONCLUSIONS: Our findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.