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Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disorder caused by variants in the ABCB11 gene encoding the bile salt export pump (BSEP). We investigated the molecular defect in a PFIC2 infant and rescued the splicing defect with antisense oligonucleotides (ASOs).Whole-exome sequencing (WES) revealed compound heterozygous variants in the ABCB11 gene in a PFIC2 patient. Liver biopsy was immunostained for BSEP. The splicing effect of the candidate variants was investigated by minigene assay. ASOs were designed to rescue aberrant splicing.A Chinese girl of two nonconsanguineous healthy parents suffered from low glutamyl transpeptidase cholestasis and showed no response to the ursodeoxycholic acid. WES revealed that the patient was compound heterozygous for two novel variants in the ABCB11 gene: c.76+29TG and c.390-2AG. Liver immunohistochemistry showed the absence of BSEP. The variant c.76+29TG was confirmed to retain 42 bp in the mature mRNA. The variant c.390-2AG was confirmed to cause exon 6 skipping. We designed two ASOs and identified one of them that efficiently induced pseudoexon exclusion.We reported two novel variants of the ABCB11 gene, c.76+29TG and c.390-2AG, in a PFIC2 infant, thereby expanding the genotype of PFIC2. Our findings provide evidence for ASOs as a therapeutic approach for PFIC2 patients carrying intronic variants.

Background & Aims: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first months of life. Methods: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis，and re-analyzed phenotype and WES data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Results: Overall, we identified disease causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) were metabolic liver diseases, 9 (17%) were syndromic cholestasis, 9 (17%) were progressive familial intrahepatic cholestasis, 3 (6%) were bile acid synthesis defects, 3(6%) were infantile liver failure and 10 (19%) were phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G>A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By reanalyzing WES data, two patients were newly solved, which had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved trio families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice model. Conclusions: In a single center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Rigorous analysis of WES data of well-phenotyped patients with intrahepatic cholestasis leads to a broader understanding of gene-specific phenotypic spectra as well as monogenic candidate gene identification.

The timing of phenological events is highly sensitive to climate change, and may influence ecosystem structure and function. Although changes in flowering phenology among species under climate change have been reported widely, how species-specific shifts will affect phenological synchrony and community-level phenology patterns remains unclear. We conducted a manipulative experiment of warming and precipitation addition and reduction to explore how climate change affected flowering phenology at the species and community levels in an alpine meadow on the eastern Tibetan Plateau. We found that warming advanced the first and last flowering times differently and with no consistent shifts in flowering duration among species, resulting in the entire flowering period of species emerging earlier in the growing season. Early-flowering species were more sensitive to warming than mid- and late-flowering species, thereby reducing flowering synchrony among species and extending the community-level flowering season. However, precipitation and its interactions with warming had no significant effects on flowering phenology. Our results suggest that temperature regulates flowering phenology from the species to community levels in this alpine meadow community, yet how species shifted their flowering timing and duration in response to warming varied. This species-level divergence may reshape flowering phenology in this alpine plant community. Decreasing flowering synchrony among species and the extension of community-level flowering seasons under warming may alter future trophic interactions, with cascading consequences to community and ecosystem function.

To explore the clinical features and genetic basis of a patient with glycogen storage disease type VI (GSD-VI).Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the proband and his parents. Genetic variants were detected by using whole exome sequencing. Candidate variants were verified by Sanger sequencing followed by bioinformatics analysis.The proband presented fasting hypoglycemia, hepatomegaly, growth retardation, transaminitis, metabolic acidosis and hyperlactatemia. Liver biopsy indicated GSD. Novel compound heterozygous PYGL gene variants (c.2089AG/c.158_160delACT) were detected in the proband. Compound heterozygosity was confirmed by Sanger sequencing of the patient's genomic DNA. Provean and MutationTaster predicted the two variants as deleterious and the variant sites are highly conserved.The compound heterozygous variants (c.2089AG/c.158_160delACT) of PYGL gene probably underlay the GSD in the patient. The two novel variants have expanded the spectrum of PYGL gene variants and provided the basis for genetic counseling of the family.

To explore whether radiomic features of perihematomal tissue can improve the forecasting accuracy for the prognosis of patients with an intracerebral hemorrhage (ICH).In total, 118 ICH patients were retrospectively studied that had a clinical and radiological diagnosis of spontaneous ICH. The functional outcome 3 months after ictus was measured using the modified Rankin Scale (mRS), which was divided into good (mRS ≤ 2) and poor outcomes (mRS 2). A total of 2260 radiomics features were obtained from non-contrast computer tomography (NCCT) images, with 1130 features extracted from the hematoma and the hematoma plus perihematoma. The high-dimensional data was modeled by a logistic regression algorithm and the accuracy of the model was verified by five-fold cross-validation. The predictive performance of radiomics models was assessed by the area under the receiver operating characteristic (ROC) curve.In the test set, the mean ROC area under the curve (AUC) of the hematoma set to predict the prognosis of ICH was 0.83, and the specificity and sensitivity were 78% and 81%, respectively. When the hematoma and perihematomal tissue were combined, the mean AUC increased to 0.88, and the specificity and sensitivity reached 85% and 84%, respectively. The hematoma plus perihematoma model showed a significantly higher AUC and specificity.Analysis of the hematoma and perihematomal tissue NCCT-based radiomics could potentially identify the progression of a hematoma more accurately and could be a valuable clinical target to enhance the prediction of outcomes in patients with ICH.

This paper proposes a distributed power supply consumption metering assessment index system and method for rural energy internet, which can be used in the dispatch and design departments of power companies. The method can solve the problems that exist in the existing distribution system, such as the lack of basis for siting and capacity determination and access of large-scale distributed power units, and the single and one-sided assessment index of distributed power consumption capacity. Firstly, analysing the characteristics of the new rural power grid, considering the impact of the uncertainty of distributed power supply output, organically combine the influencing factors of power quality, power supply reliability and operational safety and establish a multi-dimensional index evaluation system to measure the ability of distributed power sources to consume. Finally, the improved fuzzy estimation is used to determine the consumption capacity of the rural grid. The data of a rural grid operation is analysed by case study to accurately assess the consumption capacity of distributed power sources in the area.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder characterized by a wide range of clinical features, including muscle weakness, hypoglycemia, metabolic acidosis, and multisystem dysfunctions. Loss-of-function mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene are associated with MADD. Disease-causing synonymous variants in the ETFDH gene have not been reported so far.Methods: We reported the clinical course of a Chinese girl who was diagnosed with late-onset MADD by the whole exome sequencing. The effects of variants on mRNA splicing were analyzed through transcript analysis in vivo and minigene splice assay in vitro.Results: The 6-month-old girl initially showed muscle weakness, muscular hypotonia, mild myogenic damage, and fatty liver. The blood and urine metabolic screening by tandem mass spectrometry suggested MADD. Molecular analysis of ETFDH gene revealed two novel heterozygous variants, a frameshift mutation c.1812delG (p.V605Yfs*34) in exon 13 and a synonymous variant c.579A>G (p.E193E) in exon 5. The transcript analysis in vivo exhibited that the synonymous variant c.579A>G caused exon 5 skipping. The minigene splice assay in vitro confirmed the alteration of ETFDH mRNA splicing which could lead to the production of a truncated protein. Supplementation of riboflavin, carnitine and low-fat diet improved the clinical symptoms.Conclusion: We firstly report a rare case of MADD with a pathogenic synonymous variant in the ETFDH gene which highlights the importance and necessity of bioinformatic analysis and functional testing for synonymous variants when searching for causative gene mutations. The results expand the spectrum of pathogenic variants in MADD.

Background/Aims: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. Methods: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. Results: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson’s χ2 test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. Conclusion: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm.

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA. Heterozygous MARS mutations have been reported to cause Charcot-Marie-Tooth disease, axonal, type 2U (CMT2U). Homozygous or compound heterozygous mutations in MARS gene would cause interstitial lung and liver disease (ILLD), a severe disease onset in infancy or early childhood. Here we report a Chinese ILLD family with two affected boys diagnosed by exome sequencing. They carry novel compound heterozygous MARS mutations (p.Asp145Asn and p.Phe802Ser). Their phenotype is concordant with ILLD description. As ILLD patients were only reported by two studies, we summarized all the reported patients and characterized the principle clinical features as interstitial lung disease, developmental delay, postnatal growth failure, non-life-threatening liver dysfunction and anemia. Genotype-phenotype correlation analysis suggests most of the ILLD mutations locate in the catalytic domain of MARS. ILLD and CMT2U might have different disease mechanism.

Background X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease characterized by haemophagocytic lymphohistiocytosis, recurrent splenomegaly and inflammatory bowel disease (IBD). The only curative treatment is haematopoietic stem cell transplant (HSCT). Case presentation Here, we report the case of a 22-month-old male with a long history of abdominal distension and anaemia. Clinical and laboratory findings were consistent with eosinophilic colitis. To identify the underlying disease, we performed exome sequencing, which showed an unreported frameshift mutation in the XIAP gene. Conclusion We present eosinophilic colitis as the initial manifestation of XIAP deficiency for the first time in this article, which expands the mutation spectrum and phenotype of this disease.

Haploinsufficiency of ARID1B (AT-rich interaction domain 1B) has been involved in autism spectrum disorder, nonsyndromic and syndromic intellectual disability, and corpus callosum agenesis. Growth impairment is a major clinical feature caused by ARID1B mutations; however, the mechanistic link has not been elucidated. Here, we confirm that growth delay is a common characteristic of patients with ARID1B mutations, which may be associated with dysregulation of the Wnt/β-catenin signaling pathway. An analysis of patients harboring pathogenic variants of ARID1B revealed that nearly half had short stature and nearly all had below-average height. Moreover, the percentage of patients with short stature increased with age. Knockdown of arid1b in zebrafish embryos markedly reduced body length and perturbed the expression of both chondrogenic and osteogenic genes including sox9a, col2a1a, runx2b, and col10a1. Knockout of Arid1b in chondrogenic ATDC5 cells inhibited chondrocyte proliferation and differentiation. Finally, Wnt/β-catenin signaling was perturbed in Arid1b-depleted zebrafish embryos and Arid1b knockout ATDC5 cells. These data indicate that ARID1B modulates bone growth possibly via regulation of the Wnt/β-catenin pathway, and may be an appropriate target for gene therapy in disorders of growth and development.

Curcumin is known to possess anti‑inflammatory properties. Despite the fact that curcumin is known to be a strong inhibitor of H+, K+‑ATPase activity, the mechanism underlying the curcumin‑induced inhibition of the transcription of the H+, K+‑ATPase α subunit in gastric mucosal parietal cells remains unclear. The present study investigated the possible mechanism by which curcumin inhibits stomach H+, K+‑ATPase activity during the acute phase of gastric ulcer disease. A rat model of stress‑induced gastric ulcers was produced, in which the anti‑ulcer effects of curcumin were examined. Curcumin‑induced inhibition of the H+, K+‑ATPase promoter via histone acetylation, was verified using a chromatin immunoprecipitation assay. The results showed that curcumin improved stress‑induced gastric ulcer disease in rats, as demonstrated by increased pH values and reduced gastric mucosal hemorrhage and ulcer index. These effects were accompanied by a significant reduction in the level of histone H3 acetylation at the site of the H+, K+‑ATPase promoter and in the expression of the gastric H+,K+‑ATPase α subunit gene and protein. In conclusion, curcumin downregulated the acetylation of histone H3 at the site of the H+, K+‑ATPase promoter gene, thereby inhibiting the transcription and expression of the H+, K+‑ATPase gene. Curcumin was shown to have a preventive and therapeutic effect in gastric ulcer disease.

KMT2A mutations cause Wiedemann-Steiner syndrome (WDSTS), which is characterized by hypertrichosis cubiti, short stature, and distinct facial features in general. Here, we report two Chinese boys with novel nonsense KMT2A mutations. Most of their phenotypes are concordant with WDSTS. They, however, lack the key WDSTS feature-hypertrichosis cubiti. Additionally, their transverse palmar creases are absent. We further summarized the genotypes and phenotypes of the KMT2A mutation carriers. The consensus phenotypes include postnatal growth retardation, developmental delay, short stature, and intellectual disability. The common facial features include thick eyebrows, long eyelashes, downslanting, and narrow palpebral fissures, wide nasal bridge, and broad nasal tip. They have generalized hypertrichosis. A hairy back can be observed as frequently as hairy elbows in patients with KMT2A mutations. Absent palmar proximal transverse creases are only observed in these two Chinese boys. This might be due to the difference in ethnic background. Thus far, all mutations in KMT2A are located before the FYRC domain. They would truncate KMT2A mRNA transcripts. Haploinsufficiency of the histone methyltransferase activity would therefore influence transcriptional regulation. © 2016 Wiley Periodicals, Inc.

Background Idiopathic short stature (ISS) refers to short stature with no evident etiologies. The custom genome-wide microarray specifically designed to cover height-related genes may be helpful to detect copy number variations (CNVs) in ISS patients, which may be missed by the general microarray. The aim of the study was to validate the applicability of the custom microarray and to analyze CNVs in Chinese ISS children. Results Sixty non-polymorphic CNVs were identified in 119 ISS patients. There were 13 small CNVs with a size below 50 kb, accounting for 21.7 % of all the CNVs (13/60). Five pathogenic or possibly pathogenic CNVs were detected in five patients, including deletions at 22q11.21, duplications at 4q11-q13.1, 4q12 and Yp11.32-p11.2. Taking only the pathogenic variants into account, the diagnostic yield was 2.5 % (3/119). The TMEM165, POLR2B and PDGFRA genes were analyzed as candidate genes. A 15 kb deletion in the RASA2 gene was of interest for further investigation. Conclusions This study showed that the custom microarray is applicable to detect CNVs in patients with short stature. Candidate genes and CNVs detected in ISS patients may be helpful for CNV analysis of short stature, especially in East Asian population. Electronic supplementary material The online version of this article (doi:10.1186/s13039-016-0225-0) contains supplementary material, which is available to authorized users.

List of 1469 height-associated candidate genes analyzed by genome-wide association studies. Table S2. Summary of type III and IV CNVs. Table S3. Primers of qPCR. Figure S1. Screenshots of chromosome microarray and qPCR. (DOC 7216Â kb)

Charge-discharge experiments of lithium iron phosphate (LiFePO4) battery packs have been performed on an experimental platform, and electrochemical properties and damage mechanism of LiFePO4 batteries are also analyzed in extreme cases. Our results indicate that overcharge has little impact on utilizable capacity of the battery in the short term. Over-discharge has a huge impact on utilizable capacity of the battery. Based on these results, a management method of battery pack for reducing battery damage is proposed. At the same time, this method can also slow the rate of battery pack capacity attenuation and extend cycle life of battery pack.

Background The UGT1A1 gene encodes a responsible enzyme, UDP-glucuronosyltransferase1A1 (UGT1A1), for bilirubin metabolism. Many mutations have already been identified in patients with inherited disorders with unconjugated hyperbilirubinemia, such as Crigler-Najjar syndromes and Gilbert’s syndrome. Case presentation In this report, we presented a boy with intermittent unconjugated hyperbilirubinemia, whose genetic analysis showed a new compound heterozygote determined by three mutations, c.211G > A (p.G71R), c.508_510delTTC (p.F170-) and c.1456 T > G (p.Y486D) in the hotspot regions of the UGT1A1 gene (exons 1 and 5) in Asian populations, presenting a genotype compatible with clinical picture of CNS-II. The family genetic analysis confirmed the origin of these mutations. Conclusion UGT1A1 gene analysis should be performed in all cases with unexplained unconjugated hyperbilirubinemia. The description of patients with peculiar genotypes especially including family analysis could help explain the relationship between the genotype and phenotype,it is helpful for clinicians to predict the outcome of the patients.