The results of this study show a reliable and feasible candidates selection and prognostic criteria of LT in HCC patients.

A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). It had been shown that these families did not have mutations in the WFS1 gene (WFS1) but were mapped to the WFS2 locus at 4q22-25. A G-->C transversion at nucleotide 109 predicts an amino acid change from glutamic acid to glutamine (E37Q). Although the amino acid is conserved and the mutation is nonsynonymous, the pathogenesis for the disorder is because the mutation also causes aberrant splicing. The mutation was found to disrupt messenger RNA splicing by eliminating exon 2, and it results in the introduction of a premature stop codon. Mutations in WFS1 have also been found to cause low-frequency nonsyndromic hearing loss, progressive hearing loss, and isolated optic atrophy associated with hearing loss. Screening of 377 probands with hearing loss did not identify mutations in the WFS2 gene. The WFS1-encoded protein, Wolframin, is known to localize to the endoplasmic reticulum and plays a role in calcium homeostasis. The ZCD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small protein), is also shown to localize to the endoplasmic reticulum but does not interact directly with Wolframin. Lymphoblastoid cells from affected individuals show a significantly greater rise in intracellular calcium when stimulated with thapsigargin, compared with controls, although no difference was observed in resting concentrations of intracellular calcium.

An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of beta cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (betaDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, betaDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. Normoglycemic 2-week-old betaDKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised beta cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in beta cells might protect against type 2 diabetes.

Background Coronavirus disease 2019 (COVID‐19) emerged in Wuhan city and rapidly spread globally outside China. We aimed to investigate the role of peripheral blood eosinophil (EOS) as a marker in the course of the virus infection to improve the efficiency of diagnosis and evaluation of COVID‐19 patients. Methods 227 pneumonia patients who visited the fever clinics in Shanghai General Hospital and 97 hospitalized COVID‐19 patients admitted to Shanghai Public Health Clinical Center were involved in a retrospective research study. Clinical, laboratory, and radiologic data were collected. The trend of EOS level in COVID‐19 patients and comparison among patients with different severity were summarized. Results The majority of COVID‐19 patients (71.7%) had a decrease in circulating EOS counts, which was significantly more frequent than other types of pneumonia patients. EOS counts had good value for COVID‐19 prediction, even higher when combined with neutrophil‐to‐lymphocyte ratio. Patients with low EOS counts at admission were more likely to have fever, fatigue, and shortness of breath, with more lesions in chest CT and radiographic aggravation, and longer length of hospital stay and course of disease than those with normal EOS counts. Circulating EOS level gradually increased over the time, and was synchronous with the improvement in chest CT (12 days vs 13 days, P = .07), later than that of body temperature (12 days vs 10 days, P = .014), but earlier than that of the negative conversion of nucleic acid assays (12 days vs 17 days, P = .001). Conclusion Peripheral blood EOS counts may be an effective and efficient indicator in diagnosis, Evaluation, and prognosis monitoring of COVID‐19 patients.

ObjectiveLiver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively.DesignThis study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria.ResultsCompared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ≤8 cm, or tumour burden >8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001).ConclusionsThe Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma.

Bactrian camels serve as an important means of transportation in the cold desert regions of China and Mongolia. Here we present a 2.01 Gb draft genome sequence from both a wild and a domestic bactrian camel. We estimate the camel genome to be 2.38 Gb, containing 20,821 protein-coding genes. Our phylogenomics analysis reveals that camels shared common ancestors with other even-toed ungulates about 55–60 million years ago. Rapidly evolving genes in the camel lineage are significantly enriched in metabolic pathways, and these changes may underlie the insulin resistance typically observed in these animals. We estimate the genome-wide heterozygosity rates in both wild and domestic camels to be 1.0 × 10−3. However, genomic regions with significantly lower heterozygosity are found in the domestic camel, and olfactory receptors are enriched in these regions. Our comparative genomics analyses may also shed light on the genetic basis of the camel's remarkable salt tolerance and unusual immune system.

SUMMARY Families of alternative splicing regulators often contain multiple paralogs presumed to fulfill different functions. Polypyrimidine tract binding proteins PTBP1 and PTBP2 reprogram developmental pre-mRNA splicing in neurons, but how their regulatory networks differ is not understood. To compare their targeting, we generated a knock-in allele that conditionally expresses PTBP1. Bred to a Ptbp2 knockout, the transgene allowed us to compare the developmental and molecular phenotypes of mice expressing only PTBP1, only PTBP2, or neither protein in the brain. This knock-in Ptbp1 rescued a forebrain-specific but not a pan-neuronal Ptbp2 knockout, demonstrating both redundant and distinct roles for the proteins. Many developmentally-regulated exons exhibited different sensitivities to PTBP1 and PTBP2. Nevertheless, the two paralogs displayed similar RNA binding across the transcriptome indicating that their differential targeting does not derive from their RNA interactions but from possible different cofactor interactions.

BackgroundZymomonas mobilis is a natural ethanologen being developed and deployed as an industrial biofuel producer. To date, eight Z. mobilis strains have been completely sequenced and found to contain 2–8 native plasmids. However, systematic verification of predicted Z. mobilis plasmid genes and their contribution to cell fitness has not been hitherto addressed. Moreover, the precise number and identities of plasmids in Z. mobilis model strain ZM4 have been unclear. The lack of functional information about plasmid genes in ZM4 impedes ongoing studies for this model biofuel-producing strain.ResultsIn this study, we determined the complete chromosome and plasmid sequences of ZM4 and its engineered xylose-utilizing derivatives 2032 and 8b. Compared to previously published and revised ZM4 chromosome sequences, the ZM4 chromosome sequence reported here contains 65 nucleotide sequence variations as well as a 2400-bp insertion. Four plasmids were identified in all three strains, with 150 plasmid genes predicted in strain ZM4 and 2032, and 153 plasmid genes predicted in strain 8b due to the insertion of heterologous DNA for expanded substrate utilization. Plasmid genes were then annotated using Blast2GO, InterProScan, and systems biology data analyses, and most genes were found to have apparent orthologs in other organisms or identifiable conserved domains. To verify plasmid gene prediction, RNA-Seq was used to map transcripts and also compare relative gene expression under various growth conditions, including anaerobic and aerobic conditions, or growth in different concentrations of biomass hydrolysates. Overall, plasmid genes were more responsive to varying hydrolysate concentrations than to oxygen availability. Additionally, our results indicated that although all plasmids were present in low copy number (about 1–2 per cell), the copy number of some plasmids varied under specific growth conditions or due to heterologous gene insertion.ConclusionsThe complete genome of ZM4 and two xylose-utilizing derivatives is reported in this study, with an emphasis on identifying and characterizing plasmid genes. Plasmid gene annotation, validation, expression levels at growth conditions of interest, and contribution to host fitness are reported for the first time.Electronic supplementary materialThe online version of this article (10.1186/s13068-018-1116-x) contains supplementary material, which is available to authorized users.