NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation

The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.Subject terms: Gastric cancer, Post-translational modifications     

Influence of fibrillin-1 genotype on the aortic stiffness in men.

Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28-81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 G>T polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease.     

SHAPE analysis of the FIV Leader RNA reveals a structural switch potentially controlling viral packaging and genome dimerization

Feline immunodeficiency virus (FIV) infects many species of cat, and is related to HIV, causing a similar pathology. High-throughput selective 2' hydroxyl acylation analysed by primer extension (SHAPE), a technique that allows structural interrogation at each nucleotide, was used to map the secondary structure of the FIV packaging signal RNA. Previous studies of this RNA showed four conserved stem-loops, extensive long-range interactions (LRIs) and a small, palindromic stem-loop (SL5) within the gag open reading frame (ORF) that may act as a dimerization initiation site (DIS), enabling the virus to package two copies of its genome. Our analyses of wild-type (wt) and mutant RNAs suggest that although the four conserved stem-loops are static structures, the 5' and 3' regions previously shown to form LRI also adopt an alternative, yet similarly conserved conformation, in which the putative DIS is occluded, and which may thus favour translational and splicing functions over encapsidation. SHAPE and in vitro dimerization assays were used to examine SL5 mutants. Dimerization contacts appear to be made between palindromic loop sequences in SL5. As this stem-loop is located within the gag ORF, recognition of a dimeric RNA provides a possible mechanism for the specific packaging of genomic over spliced viral RNAs.     

Discovery of a novel site regulating glucokinase activity following characterization of a new mutation causing hyperinsulinemic hypoglycemia in humans

Type 2 diabetes is a global problem, and current ineffective therapeutic strategies pave the way for novel treatments like small molecular activators targeting glucokinase (GCK). GCK activity is fundamental to beta cell and hepatocyte glucose metabolism, and heterozygous activating and inactivating GCK mutations cause hyperinsulinemic hypoglycemia (HH) and maturity onset diabetes of the young (MODY) respectively. Over 600 naturally occurring inactivating mutations have been reported, whereas only 13 activating mutations are documented to date. We report two novel GCK HH mutations (V389L and T103S) at residues where MODY mutations also occur (V389D and T103I). Using recombinant proteins with in vitro assays, we demonstrated that both HH mutants had a greater relative activity index than wild type (6.0 for V389L, 8.4 for T103S, and 1.0 for wild type). This was driven by an increased affinity for glucose (S(0.5), 3.3 ± 0.1 and 3.5 ± 0.1 mm, respectively) versus wild type (7.5 ± 0.1 mm). Correspondingly, the V389D and T103I MODY mutants had markedly reduced relative activity indexes (<0.1). T103I had an altered affinity for glucose (S(0.5), 24.9 ± 0.6 mm), whereas V389D also exhibited a reduced affinity for ATP and decreased catalysis rate (S(0.5), 78.6 ± 4.5 mm; ATP(K(m)), 1.5 ± 0.1 mm; K(cat), 10.3 ± 1.1s(-1)) compared with wild type (ATP(K(m)), 0.4 ± <0.1; K(cat), 62.9 ± 1.2). Both Thr-103 mutants showed reduced inhibition by the endogenous hepatic inhibitor glucokinase regulatory protein. Molecular modeling demonstrated that Thr-103 maps to the allosteric activator site, whereas Val-389 is located remotely to this position and all other previously reported activating mutations, highlighting α-helix 11 as a novel region regulating GCK activity. Our data suggest that pharmacological manipulation of GCK activity at locations distal from the allosteric activator site is possible.     

A mathematical model of avian influenza with half-saturated incidence

The widespread impact of avian influenza viruses not only poses risks to birds, but also to humans. The viruses spread from birds to humans and from human to human In addition, mutation in the primary strain will increase the infectiousness of avian influenza. We developed a mathematical model of avian influenza for both bird and human populations. The effect of half-saturated incidence on transmission dynamics of the disease is investigated. The half-saturation constants determine the levels at which birds and humans contract avian influenza. To prevent the spread of avian influenza, the associated half-saturation constants must be increased, especially the half-saturation constant H _m for humans with mutant strain. The quantity H _m plays an essential role in determining the basic reproduction number of this model. Furthermore, by decreasing the rate β _m at which human-to-human mutant influenza is contracted, an outbreak can be controlled more effectively. To combat the outbreak, we propose both pharmaceutical (vaccination) and non-pharmaceutical (personal protection and isolation) control methods to reduce the transmission of avian influenza. Vaccination and personal protection will decrease β _m, while isolation will increase H _m. Numerical simulations demonstrate that all proposed control strategies will lead to disease eradication; however, if we only employ vaccination, it will require slightly longer to eradicate the disease than only applying non-pharmaceutical or a combination of pharmaceutical and non-pharmaceutical control methods. In conclusion, it is important to adopt a combination of control methods to fight an avian influenza outbreak.     

Visual Dependency and Dizziness after Vestibular Neuritis

Symptomatic recovery after acute vestibular neuritis (VN) is variable, with around 50% of patients reporting long term vestibular symptoms; hence, it is essential to identify factors related to poor clinical outcome. Here we investigated whether excessive reliance on visual input for spatial orientation (visual dependence) was associated with long term vestibular symptoms following acute VN. Twenty-eight patients with VN and 25 normal control subjects were included. Patients were enrolled at least 6 months after acute illness. Recovery status was not a criterion for study entry, allowing recruitment of patients with a full range of persistent symptoms. We measured visual dependence with a laptop-based Rod-and-Disk Test and severity of symptoms with the Dizziness Handicap Inventory (DHI). The third of patients showing the worst clinical outcomes (mean DHI score 36–80) had significantly greater visual dependence than normal subjects (6.35° error vs. 3.39° respectively, p = 0.03). Asymptomatic patients and those with minor residual symptoms did not differ from controls. Visual dependence was associated with high levels of persistent vestibular symptoms after acute VN. Over-reliance on visual information for spatial orientation is one characteristic of poorly recovered vestibular neuritis patients. The finding may be clinically useful given that visual dependence may be modified through rehabilitation desensitization techniques.     

A ‘kinship anthropology of politics’? Interest,the collective self,and kinship in Argentine unions★

In this article I argue for a kinship anthropology of politics, understood as a focus on the day‐to‐day imbrications of kinship and politics in a given political space, and the implications of that for the construction of political subjects. I describe kinship within shop‐floor‐level trade union delegations of state employees in Argentina in three different ways: first, languages of kinship mobilized to describe political allegiance and dispositions, especially inheritance; second, family connections in recruitment and activism; and, third, practices of kinning as relatedness. The combination of these three kinship modes creates the union as kin group, and enables it to act on the world politically in order to transform it.