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Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity. Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts 1 , 2 , 3 , 4 . Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene ( AMY1 ) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression ( P = 2.31 × 10 −14 ) and serum enzyme levels ( P < 2.20 × 10 −16 ), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m 2 ; P = 6.93 × 10 −10 ) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10 −10 ). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

Short-chain fatty acids (SCFAs) inhibit human colorectal cancer cell growth and tumorigenicity. We investigated the mechanism of the anti-proliferative effects of SCFAs on human colorectal cancer cells by examining their effects on gene expression. The DLD-1 cell line was cultured with different SCFAs. Gene groups whose expression levels decreased to <50% or increased >50% compared to untreated cells and the signalling pathways responsible for DLD-1 cell growth inhibition were identified and analyzed. Genes whose expression levels decreased to ≤50% (791 genes) showed remarkable changes in gene function compared to genes whose expression levels increased ≥50%. These genes encode proteins involved in DNA replication and cell cycle/proliferation that contribute to major pathways responsible for suppression of colorectal carcinogenesis pathways. SCFAs inhibited the expression of genes encoding proteins involved in DNA replication and cell cycle/proliferation of human colorectal cancer cells and exerted antiproliferative activity via different pathways.

Rotavirus (RV) is the major causes of severe diarrhea in infants and young children under five years of age. There are no effective drugs for the treatment of rotavirus in addition to preventive live attenuated vaccine. Recent evidence demonstrates that microRNAs (miRNAs) can affect RNA virus replication. However, the antiviral effect of miRNAs during rotavirus replication are largely unknown. Here, we determined that miR-7 is upregulated during RV replication and that it targets the RV NSP5 (Nonstructural protein 5). Results suggested that miR-7 affected viroplasm formation and inhibited RV replication by down-regulating RV NSP5 expression. Up-regulation of miR-7 expression is a common regulation method of different G-type RV-infected host cells. Then, we further revealed the antiviral effect of miR-7 in diarrhea suckling mice model. MiR-7 is able to inhibit rotavirus replication in vitro and in vivo. These data provide that understanding the role of cellular miR-7 during rotaviral replication may help in the identification of novel therapeutic small RNA molecule drug for anti-rotavirus.

The spread of the African swine fever virus (ASF virus) genotype ii in the Eurasian region has been very successful and often inexplicable. The virus spreads rapidly and persists in areas with wild boar populations, but areas without feral pig populations are also affected. The virus has shown the ability to survive for a long time in the environment without a population of susceptible hosts, both pigs and Ornithodoros soft ticks. Published data indicated that ASF viruses persist significantly longer in an environment with some freshwater snails (especially Pomacea bridgesii , Tarebia granifera , Asolene spixii , Melanoides tuberculate , and Physa fontinalis ), compared to freshwater without snails. Data obtained in this study suggest that gastropods theoretically can be the hosts of the ASF virus. Also, we have proven the possibility of long-term existence of an infectious virus when infected in vitro.

The transcription of herpes simplex virus type 1 (HSV-1) genes is regulated by viral and cellular transcription factors and genome replication. One regulatory aspect is accessibility of viral genes to the host transcription machinery. In this study, we determine how the major HSV-1 transcriptional regulatory protein, ICP4, and viral DNA replication affect accessibility, and how this relates to viral gene transcription. We also assessed viral genome accessibility in a sensory neuronal model that has the potential for viral gene silencing and establishment of quiescent or latent infection. We conclude that the accessibility of the viral genome to the cellular machinery responsible for viral gene expression is an important determinant to infection outcome.

Epstein-Barr virus (EBV) persists in infected cells by maintaining its episome through the viral protein EBNA1. We discovered that PIAS1 SUMOylates EBNA1 at specific sites, a process essential for EBNA1 to retain the viral episome and suppress reactivation. When SUMOylation is disrupted, the EBV-based replicon becomes less stable, and EBV is more likely to reactivate. These findings reveal a new layer of host control of EBV latency and reactivation and highlight PIAS1-mediated EBNA1 SUMOylation as a key mechanism regulating viral persistence.

Herpes simplex virus type 1 remains a major clinical burden, and resistance to existing therapies underscores the need for alternative strategies. This study reveals a mechanism by which HSV-1 regulates host cell cycle and translation control through cyclin-dependent kinase signaling and the 4E-binding protein 1 pathway. By revealing that pharmacological inhibition of this pathway suppresses viral replication, we identify a host-directed therapeutic approach that circumvents challenges associated with viral resistance to the current drugs. The demonstration of potent antiviral activity by GW8510, a small-molecule cyclin-dependent kinase inhibitor, establishes a promising foundation for translational development and highlights the potential of targeting host regulatory networks to combat viral infection.

The long-lasting persistence of hepatitis B virus (HBV) genomes in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for the HBV surface antigen (HBsAg) is termed occult HBV infection (OBI). Although in a minority of cases the lack of HBsAg detection is due to infection with variant viruses unrecognized by available assays (S-escape mutants), the typical OBI is related to replication-competent HBVs strongly suppressed in their replication activity. The causes of HBV suppression are not yet well clarified, although the host’s immune surveillance and epigenetic mechanisms are likely involved. OBI is a worldwide diffused entity, but the available data of prevalence in various categories of individuals are often contrasting because of the different sensitivity and specificity of the methods used for its detection in many studies. OBI may have an impact in several different clinical contexts. In fact, it can be transmitted (i.e., through blood transfusion and liver transplantation) causing classic forms of hepatitis B in newly infected individuals. The development of an immunosuppressive status (mainly by immunotherapy or chemotherapy) may induce OBI reactivation and development of acute and often severe hepatitis. Finally, evidence suggests that OBI can favor the progression of liver fibrosis, in particular in HCV-infected patients. The possible contribution of OBI to the establishment of cirrhosis also implies its possible indirect role in the development of hepatocellular carcinoma. On the other hand, OBI may maintain most of the direct transforming properties of the overt HBV infection, such as the capacity to integrate in the host’s genome and to synthesize pro-oncogenic proteins.

Background The evolution of mycoplasmas from a common ancestor with Firmicutes has been characterized not only by genome down-sizing but also by horizontal gene transfer between mycoplasma species sharing a common host. The mechanisms of these gene transfers remain unclear because our knowledge of the mycoplasma mobile genetic elements is limited. In particular, only a few plasmids have been described within the Mycoplasma genus. Results We have shown that several species of ruminant mycoplasmas carry plasmids that are members of a large family of elements and replicate via a rolling-circle mechanism. All plasmids were isolated from species that either belonged or were closely related to the Mycoplasma mycoides cluster; none was from the Mycoplasma bovis-Mycoplasma agalactiae group. Twenty one plasmids were completely sequenced, named and compared with each other and with the five mycoplasma plasmids previously reported. All plasmids share similar size and genetic organization, and present a mosaic structure. A peculiar case is that of the plasmid pMyBK1 from M. yeatsii; it is larger in size and is predicted to be mobilizable. Its origin of replication and replication protein were identified. In addition, pMyBK1 derivatives were shown to replicate in various species of the M . mycoides cluster, and therefore hold considerable promise for developing gene vectors. The phylogenetic analysis of these plasmids confirms the uniqueness of pMyBK1 and indicates that the other mycoplasma plasmids cluster together, apart from the related replicons found in phytoplasmas and in species of the clade Firmicutes. Conclusions Our results unraveled a totally new picture of mycoplasma plasmids. Although they probably play a limited role in the gene exchanges that participate in mycoplasma evolution, they are abundant in some species. Evidence for the occurrence of frequent genetic recombination strongly suggests they are transmitted between species sharing a common host or niche.

Genomic instability is a hallmark of cancer. EBV contributes to host genomic instability after primary infection. This study maps the EBV-induced genomic variations using deep whole genome sequencing and identifies the critical factor MUC19, which is one of the most understudied genes, with a genomic sequence exceeding 177 kbp that encodes a protein over 800 kD. In this study, we revealed that EBV induced the duplicated copy number variants of the MUC19 gene and enhanced its expression, which further promotes cell survival and cell cycle via mTOR signaling. Overall, this study maps the genomic perturbations induced by EBV primary infection and offers new insights into the critical role of MUC19 in EBV latency.