Glycolytic potential (GP) in skeletal muscle is economically important in the pig industry because of its effect on pork processing yield. We have previously mapped a major quantitative trait loci (QTL) for GP on chromosome 3 in a White Duroc × Erhualian F2 intercross. We herein performed a systems genetic analysis to identify the causal variant underlying the phenotype QTL (pQTL). We first conducted genome-wide association analyses in the F2 intercross and an F19 Sutai pig population. The QTL was then refined to an 180-kb interval based on the 2-LOD drop method. We then performed expression QTL (eQTL) mapping using muscle transcriptome data from 497 F2 animals. Within the QTL interval, only one gene (PHKG1) has a cis-eQTL that was colocolizated with pQTL peaked at the same SNP. The PHKG1 gene encodes a catalytic subunit of the phosphorylase kinase (PhK), which functions in the cascade activation of glycogen breakdown. Deep sequencing of PHKG1 revealed a point mutation (C>A) in a splice acceptor site of intron 9, resulting in a 32-bp deletion in the open reading frame and generating a premature stop codon. The aberrant transcript induces nonsense-mediated decay, leading to lower protein level and weaker enzymatic activity in affected animals. The mutation causes an increase of 43% in GP and a decrease of>20% in water-holding capacity of pork. These effects were consistent across the F2 and Sutai populations, as well as Duroc × (Landrace × Yorkshire) hybrid pigs. The unfavorable allele exists predominantly in Duroc-derived pigs. The findings provide new insights into understanding risk factors affecting glucose metabolism, and would greatly contribute to the genetic improvement of meat quality in Duroc related pigs.

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Intrahepatic cholangiocarcinoma (ICC), a type of bile duct cancer, has a high mortality rate. Gut microbiota, bile acid (BA) metabolism, and cytokines have not been characterized in patients with ICC, and better noninvasive diagnostic approaches for ICC are essential to be established. Therefore, in this study we aimed to improve our understanding of changes in gut microbiota, BA metabolism, and cytokines in patients with ICC. We found that the α‐diversities and β‐diversities of ICC were highest and that the abundances of four genera (Lactobacillus, Actinomyces, Peptostreptococcaceae, and Alloscardovia) were increased in patients with ICC compared with those in patients with hepatocellular carcinoma or liver cirrhosis and in healthy individuals. The glycoursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA) plasma‐stool ratios were obviously increased in patients with ICC. Furthermore, the genera Lactobacillus and Alloscardovia that were positively correlated with TUDCA plasma‐stool ratios were combined to discriminate ICC from the other three diseases. Vascular invasion (VI) frequently led to a poor prognosis in patients with ICC. Compared with patients with ICC without VI, patients with VI had a greater abundance of the family Ruminococcaceae, increased levels of plasma interleukin (IL)‐4 and six conjugated BAs, and decreased levels of plasma IL‐6 and chenodeoxycholic acid. A positive correlation between plasma taurocholic acid and IL‐4 was observed in patients with ICC. Plasma TUDCA was negatively correlated with the abundance of the genus Pseudoramibacter and the survival time of patients with ICC, but had no effect on tumor size, as determined in two murine tumor models. Conclusion: In this study, we identified some biomarkers, including gut microbiota, BAs and inflammatory cytokines, for the diagnosis of ICC and prediction of VI in patients with ICC.

BackgroundThe novel coronavirus disease 2019 (COVID-19) pandemic is still spreading across the world. Although the pandemic has an all-round impact on medical work, the degree of its impact on endovascular thrombectomy (EVT) for patients with acute ischemic stroke (AIS) is unclear.MethodsWe continuously included AIS patients with large artery occlusion who underwent EVT in a comprehensive stroke center before and during the Wuhan shutdown. The protected code stroke (PCS) for screening and treating AIS patients was established during the pandemic. The efficacy and safety outcomes including the rate of successful reperfusion (defined as modified Thrombolysis In Cerebral Infarction (mTICI) graded 2b or 3) and time intervals for reperfusion were compared between two groups: pre-pandemic and pandemic.ResultsA total of 55 AIS patients who received EVT were included. The baseline characteristics were comparable between the two groups. The time from hospital arrival to puncture (174 vs 125.5 min; p=0.002) and time from hospital arrival to reperfusion (213 vs 172 min; p=0.047) were significantly prolonged in the pandemic group compared with the pre-pandemic group. The rate of successful reperfusion was not significantly different between the two groups (85.7% (n=18) vs 88.2% (n=30); OR 0.971, 95% CI 0.785 to 1.203; p=1.000).ConclusionThe results of this study suggest a proper PCS algorithm which combines the COVID-19 screening and protection measures could decrease the impact of the disease on the clinical outcomes of EVT for AIS patients to the lowest extent possible during the pandemic.

Migration-proliferation dichotomy is a common mechanism in gliomagenesis; however, an understanding of the exact molecular mechanism of this “go or grow” phenomenon remains largely incomplete. In the present study, we first found that microRNA-9 (miR-9) is highly expressed in glioma cells. MiR-9 inhibited the proliferation and promoted the migration of glioma cells by directly targeting cyclic AMP response element-binding protein (CREB) and neurofibromin 1 (NF1), respectively. Our data also suggested a migration-inhibitory role for CREB through directly regulating the transcription of NF1. Furthermore, we found that the transcription of miR-9-1 is under CREB's control, forming a negative feedback minicircuitry. Taken together, miR-9 inhibits proliferation but promotes migration, whereas CREB plays a pro-proliferative and anti-migratory role, suggesting that the CREB-miR-9 negative feedback minicircuitry plays a critical role in the determination of “go or grow” in glioma cells.

BACKGROUND & AIMS Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). METHODS We searched public databases of mRNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are downregulated in HCCs and reduce expression of genes upregulated in HCCs using a non-parametric, rank-based pattern-matching strategy based on the Kolmogorov–Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In 1 model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated beta catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. RESULTS Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more toxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes downregulated in HCC and reduced expression of 29 genes upregulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt–beta catenin, STAT3, AKT–mTOR, EGFR–Ras–Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 (CDC37) protein and disrupt its interaction with heat shock protein 90 (HSP90). Conclusions In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identif...

A porcine genome linkage map composed of 194 microsatellite markers was constructed with a large-scale White Duroc x Erhualian resource population. The marker order on this linkage map was consistent with the USDA-MARC reference map except for two markers on SSC3, two markers on SSC13 and two markers on SSCX. The length of the sex-averaged map (2344.9 cM) was nearly the same as that of the USDA-MARC and NIAI map. Highly significant heterogeneity in recombination rates between sexes was observed. Except for SSC1 and SSC13, the female autosomes had higher average recombination rates than the male autosomes. Moreover, recombination rates in the pseudoautosomal region were greater in males than in females. These observations are consistent with those of previous reports. The recombination rates on each paternal and maternal chromosome of F(2) animals were calculated. Recombination rates were not significantly affected by the age (in days) or parity of the F(1) animals. However, recombination rates on paternal chromosomes were affected by the mating season of the F(1) animals. This could represent an effect of environmental temperature on spermatogenesis.

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