Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite–Protein Physical Interaction Subnetworks Altered in Cancer

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.     

Subcellular origin of the oxalate- or inorganic phosphate-stimulated Ca2+ transport by smooth muscle microsomes: revisitation of the old problem by a new approach using saponin

Saponin, a cell-skinning reagent which perforates the cell membrane via its specific interaction with plasmalemmal cholesterol, was used to identify the subcellular origin of ATP-dependent Ca2+ accumulation in the presence and absence of inorganic phosphate and oxalate by microsomal fractions isolated from rat vas deferens and dog aorta. The purified plasma membranes from rat gastric fundus muscle, which elicit the stimulation of ATP-dependent Ca2+ accumulation by inorganic phosphate but not by oxalate, were used as a control reference. Saponin at concentrations effective for skinning smooth muscle fibres (10-50 micrograms/ml) inhibited Ca2+ binding in the absence of ATP to a similar extent in all fractions, but the inhibition of ATP-dependent Ca2+ accumulation was more pronounced in dog aorta microsomes and rat gastric fundus muscle plasma membranes than in rat vas deferens microsomes. The resistance of phosphate- and oxalate-stimulated ATP-dependent Ca2+ accumulation to inhibition by saponin was much greater in rat vas deferens than in dog aorta microsomes. Our results suggest that phosphate- and oxalate-stimulated ATP-dependent Ca2+ accumulation also occurs in plasma membrane vesicles isolated from smooth muscle and is by no means an unique property of endoplasmic reticulum.     

The Role of Host Cytoskeleton in Flavivirus Infection

The family of flaviviruses is one of the most medically important groups of emerging arthropod-borne viruses. Host cell cytoskeletons have been reported to have close contact with flaviviruses during virus entry, intracellular transport, replication, and egress process, although many detailed mechanisms are still unclear. This article provides a brief overview of the function of the most prominent flaviviruses-induced or-hijacked cytoskeletal structures including actin, microtubules and intermediate filaments, mainly focus on infection by dengue virus, Zika virus and West Nile virus. We suggest that virus interaction with host cytoskeleton to be an interesting area of future research.     

Spatial analysis of hepatocellular carcinoma and socioeconomic status in China from a Population-based Cancer Registry

Background: Little is known about geographic variations in liver cancer at high incident regions. We aimed to identify spatial variation of hepatocellular carcinoma (HCC) at a high-risk area in China and determine its association with socioeconomic status (SES). Methods: Based on 2299 liver cancer cases diagnosed in Haimen from 2003 to 2006, we calculated age–sex standardized incidence ratios (SIRs) and used two spatial scan statistics to determine the geographic variations in HCC. Bayesian hierarchical model was used to explore the association between HCC incidence and SES. Results: Age and sex SIRs for HCC varied from 0.54 to 1.97 for 24 townships. The eastern region of Haimen was identified to have a significantly increased risk of HCC. Fitting of a Bayesian hierarchical model linking per-capita fiscal revenue with SIRs of HCC indicated that the area with a lower revenue had a significantly higher incidence of HCC [β_log(revenue) = ?0.179, posterior 95% Bayesian credible interval (CI) = (?0.326, ?0.04)]. Conclusions: This study demonstrated substantial geographic variation in the incidence of HCC within a high-risk region, which was associated with SES. HCC control and intervention should focus on disadvantaged areas to reduce the HCC disparities.     

The effects of dispersal limitation and topographic heterogeneity on beta diversity and phylobetadiversity in a subtropical forest

We assessed the effects of topographic heterogeneity and stem density on species composition between grains of different sizes (20 × 20, 50 × 50, and 100 × 100 m), based on partial Mantel tests. Similarity in species composition was measured by the abundance-based Jaccard index (C_J) and by an index that incorporates phylogenetic information into C_J (pC_J). Plants were divided into five groups, arbor, subarbor, and shrub according to life form and two other groups: species that produce dry fruits (PDF) and that produce fleshy fruits (PFF). C_J and pC_J between any two grains at each grain size were calculated separately for these groups and for all species combined. In order to examine what influences C_J and pC_J, we analyzed their correlations with topographic heterogeneity variables and two dispersal limitation-related variables (stem and topographic resistance). Our data indicate that at all three grain sizes, C_J and pC_J decrease with increasing distance for all plant groups. Dispersal limitation and topographic heterogeneity were both important at 20 × 20 and 50 × 50 m grain sizes for C_J and pC_J of all plant groups; and at 100 × 100 m grain size, topographic heterogeneity dominates over dispersal limitation for some plant groups. C_J and pC_J of PDFs are less negatively correlated with stem resistance than those of PFFs. We conclude that both beta diversity and phylobetadiversity are dependent on plant groups and grain sizes.     

Developing a Novel Gene-Delivery Vector System Using the Recombinant Fusion Protein of Pseudomonas Exotoxin A and Hyperthermophilic Archaeal Histone HPhA

Non-viral gene delivery system with many advantages has a great potential for the future of gene therapy. One inherent obstacle of such approach is the uptake by endocytosis into vesicular compartments. Receptor-mediated gene delivery method holds promise to overcome this obstacle. In this study, we developed a receptor-mediated gene delivery system based on a combination of the Pseudomonas exotoxin A (PE), which has a receptor binding and membrane translocation domain, and the hyperthermophilic archaeal histone (HPhA), which has the DNA binding ability. First, we constructed and expressed the rPE-HPhA fusion protein. We then examined the cytotoxicity and the DNA binding ability of rPE-HPhA. We further assessed the efficiency of transfection of the pEGF-C1 plasmid DNA to CHO cells by the rPE-HPhA system, in comparison to the cationic liposome method. The results showed that the transfection efficiency of rPE-HPhA was higher than that of cationic liposomes. In addition, the rPE-HPhA gene delivery system is non-specific to DNA sequence, topology or targeted cell type. Thus, the rPE-HPhA system can be used for delivering genes of interest into mammalian cells and has great potential to be applied for gene therapy.     

Cognitive Impairment,Depression, Comorbidity of the Two and Associated Factors among the Early Sixties in a Rural Korean Community

This study was conducted to investigate the prevalence of cognitive impairment, depression, and comorbidity of the two conditions and related factors in subjects aged in early 60s. This cross-sectional study included 3,174 inhabitants aged 60–64 years old in a rural area of Korea. Cognitive function was evaluated by the Korean version of the Mini-Mental State Examination (MMSE-K), and depression was measured using the short form of the Geriatric Depression Scale (GDS-15). The overall prevalence of cognitive impairment (MMSE-K≤24) was 17.4%, that of depression was 26.0% (GDS-15≥8), and the co-morbidity was 7.1%. Female gender, living with one housemate, and high GDS-15 score were significantly associated with increased cognitive impairment. Employment status and more years of schooling were associated with a decreased probability of cognitive impairment. Increased depression was significantly associated with bereavement and receiving benefits from the Medical Aid Program. Employed status, more years of schooling, and higher MMSE-K scores were significantly associated with decreased depression. The risk of comorbidity was associated with bereavement and receipt of Medical Aid benefits (odds ratio[OR], 1.85; 95% confidence interval[CI], 1.26–2.71; OR, 5.02; 95% CI, 2.37–10.63; respectively). Employment and more years of schooling were associated with a lower risk of comorbidity (OR, 0.46; 95% CI, 0.34–0.62, P-trend <0.01). The correlated factors for cognitive impairment, depression, and comorbidity of the two conditions were similar, and employment status and years of schooling were associated with all three conditions.     

The Neural Basis of Responsibility Attribution in Decision-Making

Social responsibility links personal behavior with societal expectations and plays a key role in affecting an agent’s emotional state following a decision. However, the neural basis of responsibility attribution remains unclear. In two previous event-related brain potential (ERP) studies we found that personal responsibility modulated outcome evaluation in gambling tasks. Here we conducted a functional magnetic resonance imaging (fMRI) study to identify particular brain regions that mediate responsibility attribution. In a context involving team cooperation, participants completed a task with their teammates and on each trial received feedback about team success and individual success sequentially. We found that brain activity differed between conditions involving team success vs. team failure. Further, different brain regions were associated with reinforcement of behavior by social praise vs. monetary reward. Specifically, right temporoparietal junction (RTPJ) was associated with social pride whereas dorsal striatum and dorsal anterior cingulate cortex (ACC) were related to reinforcement of behaviors leading to personal gain. The present study provides evidence that the RTPJ is an important region for determining whether self-generated behaviors are deserving of praise in a social context.     

Confirmation of the single-step membrane filtration procedure for estimating Pseudomonas aeruginosa densities in water.

The efficiency of two procedures, membrane filtration and most probable number, to resuscitate and enumerate Pseudomonas aeruginosa have been compared at two temperatures and varying incubation periods. Data indicate that the membrane filtration procedure using mPA or mPA medium B is more efficient than the most-probable-number procedure in estimating P. aeruginosa populations. It was also found that the specificity of the membrane filtration procedure was such that 92 to 99% of the colonies counted as P. aeruginosa were confirmed, whereas only 2.7 to 10% of the nontypical colonies were confirmed as P. aeruginosa. Furthermore, the data indicate that mPA medium B combined with a 3- to 4-day incubation period at 4.15 degrees C is slightly more specific than mPA medium and is a valid single-step procedure for the resuscitation and enumeration of P. aeruginosa from water or sewage effluent.     

Target size analysis of neurotensin receptors

The neurotensin receptors from rat brain synaptosomal membranes differed in subunit structure from those in rat gastric fundus smooth muscle plasma membranes when studied following photoaffinity labelling or after exposure to cross-linking reagents. However, these two receptors were similar in their recognition properties. In this study we compared the target size of the two receptors by radiation inactivation and observed that the receptors in both tissues had similar target sizes (mean values 103,000 and 108,000 daltons). This suggests that the differences in size observed in biochemical studies may reflect changes occurring during the isolation procedures, or, on the other hand, there might be inherent difference in the subunit structure of these receptors.