We propose a new method for determining the target genes of transcriptional enhancers in specific cells and tissues. It combines global trends across many samples and sample-specific information, and considers the joint effect of multiple enhancers. Our method outperforms existing methods when predicting the target genes of enhancers in unseen samples, as evaluated by independent experimental data. Requiring few types of input data, we are able to apply our method to reconstruct the enhancer-target networks in 935 samples of human primary cells, tissues and cell lines, which constitute by far the largest set of enhancer-target networks. The similarity of these networks from different samples closely follows their cell and tissue lineages. We discover three major co-regulation modes of enhancers and find defense-related genes often simultaneously regulated by multiple enhancers bound by different transcription factors. We also identify differentially methylated enhancers in hepatocellular carcinoma (HCC) and experimentally confirm their altered regulation of HCC-related genes.

ObjectiveFaecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI.DesignUltra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response.ResultsSubjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria, Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone.ConclusionsIn a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI.Trial registration numberNCT02570477

Background: The restoration of normal axial alignment of the lower extremity is important to surgeons who perform reconstructive surgery of the knee. However, data on the normal alignment of the lower extremity in Chinese adults are not available. Methods: The axial alignment of the lower extremity in twenty-five adult male and twenty-five adult female volunteers of southern Chinese origin was measured on weight-bearing radiographs of the entire lower limb. The mean age was twenty-four years for the male volunteers and twenty-three years for the female volunteers. The results were compared with those of two similar studies of white volunteers in the United States. Results: The medial inclination of the tibial plateau in the Chinese subjects (mean and standard deviation, 5.4 ± 2.5 degrees for women and 4.9 ± 2.3 degrees for men) was greater than the commonly reported 3 degrees. The extremities of the Chinese women were found to have a mean of 2.2 ± 2.5 degrees of varus alignment, and those of the Chinese men had a mean of 2.2 ± 2.7 degrees of varus alignment. Conclusions: Compared with the white subjects described in the studies by Moreland et al. and Hsu et al., the Chinese subjects had significantly larger medial inclination of the knee joint (knee-joint obliquity) (p < 0.005) and the female Chinese subjects had significantly more varus alignment of the lower extremity (p < 0.025). Clinical Relevance: Five degrees of external rotation of the femoral component, instead of the commonly reported 3 degrees, may be required to obtain a rectangular flexion gap in total knee arthroplasty in Chinese patients. The racial difference in the knee-joint obliquity may contribute to the racial difference in the ratio of knee osteoarthritis to hip osteoarthritis. Additional studies are necessary to confirm this relationship.

The incidence of femoral or tibial bowing in the coronal plane was high in a Chinese population with end-stage osteoarthritis of the knee. This phenomenon may increase bone cut errors in total knee replacement if an intramedullary alignment system is used and the extent of bowing is not recognised.

Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI). Bacterial colonization in recipients after FMT has been studied, but little is known about the role of the gut fungal community, or mycobiota. Here, we show evidence of gut fungal dysbiosis in CDI, and that donor-derived fungal colonization in recipients is associated with FMT response. CDI is accompanied by over-representation of Candida albicans and decreased fungal diversity, richness, and evenness. Cure after FMT is associated with increased colonization of donor-derived fungal taxa in recipients. Recipients of successful FMT (“responders”) display, after FMT, a high relative abundance of Saccharomyces and Aspergillus, whereas “nonresponders” and individuals treated with antibiotics display a dominant presence of Candida. High abundance of C. albicans in donor stool also correlates with reduced FMT efficacy. Furthermore, C. albicans reduces FMT efficacy in a mouse model of CDI, while antifungal treatment reestablishes its efficacy, supporting a potential causal relationship between gut fungal dysbiosis and FMT outcome.