Modulation of Cardiac Performance by Motor Protein Gene Transfer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75444/1/annals.1420.011.pd

UK Housing Market: Time Series Processes with Independent and Identically Distributed Residuals

The paper examines whether a univariate data generating process can be identified which explains the data by having residuals that are independent and identically distributed, as verified by the BDS test. The stationary first differenced natural log quarterly house price index is regressed, initially with a constant variance and then with a conditional variance. The only regression function that produces independent and identically distributed standardised residuals is a mean process based on a pure random walk format with Exponential GARCH in mean for the conditional variance. There is an indication of an asymmetric volatility feedback effect but higher frequency data is required to confirm this. There could be scope for forecasting the index but this is tempered by the reduction in the power of the BDS test if there is a non-linear conditional variance process

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

An exploration of heat tolerance in mice utilizing mRNA and microRNA expression analysis

Background Individuals who rapidly develop hyperthermia during heat exposure (heat-intolerant) are vulnerable to heat associated illness and injury. We recently reported that heat intolerant mice exhibit complex alterations in stress proteins in response to heat exposure. In the present study, we further explored the role of genes and molecular networks associated with heat tolerance in mice. Methodology Heat-induced physiological and biochemical changes were assessed to determine heat tolerance levels in mice. We performed RNA and microRNA expression profiling on mouse gastrocnemius muscle tissue samples to determine novel biological pathways associated with heat tolerance. Principal Findings Mice (n = 18) were assigned to heat-tolerant (TOL) and heat-intolerant (INT) groups based on peak core temperatures during heat exposures. This was followed by biochemical assessments (Hsp40, Hsp72, Hsp90 and Hsf1 protein levels). Microarray analysis identified a total of 3,081 mRNA transcripts that were significantly misregulated in INT compared to TOL mice (p\u3c0.05). Among them, Hspa1a, Dnajb1 and Hspb7 were differentially expressed by more than two-fold under these conditions. Furthermore, we identified 61 distinct microRNA (miRNA) sequences significantly associated with TOL compared to INT mice; eight miRNAs corresponded to target sites in seven genes identified as being associated with heat tolerance pathways (Hspa1a, Dnajb1, Dnajb4, Dnajb6, Hspa2, Hspb3 and Hspb7). Conclusions The combination of mRNA and miRNA data from the skeletal muscle of adult mice following heat stress provides new insights into the pathophysiology of thermoregulatory disturbances of heat intolerance

Individual differences in emotion-cognition interactions: Emotional valence interacts with serotonin transporter genotype to influence brain systems involved in emotional reactivity and cognitive control

The serotonin transporter gene (5-HTTLPR) influences emotional reactivity and attentional bias toward or away from emotional stimuli, and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention toward negatively-valenced emotional information, whereas the long allele is associated with increased reactivity and attention towardpositively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Healthy adult participants were divided into two groups, either homozygous carriers of the 5-HTTLPR long allele or homozygous carriers of the short allele, and underwent functional magnetic resonance imaging (fMRI) while completing an Emotional Stroop-like task that varied in the congruency of task-relevant and task-irrelevant information and the emotional valence of the task-irrelevant information. Behaviorally, participants demonstrated the classic “Stroop effect” (responses were slower for incongruent than congruent trials), which did not differ by 5-HTTLPR genotype. However, fMRI results revealed that genotype influenced the degree to which neural systems were engaged depending on the valence of the conflicting task-irrelevant information. While the “Long” group recruited prefrontal control regions and superior temporal sulcus during conflict when the task-irrelevant information was positively-valenced, the “Short” group recruited these regions during conflict when the task-irrelevant information was negatively-valenced. Thus, participants successfully engaged cognitive control to overcome conflict in an emotional context using similar neural circuitry, but the engagement of this circuitry depended on emotional valence and 5-HTTLPR status. These results suggest that the interplay between emotion and cognition is modulated, in part, by a genetic polymorphism that influences serotonin neurotransmission

Characterization of the ZBTB42 gene in humans and mice

A 12 kb haplotype upstream of the key signaling protein gene, AKT1, has been associated with insulin resistance and metabolic syndrome (Devaney et al. 2010). The region contains the first exon and promoter sequences of AKT1, but also includes the complete transcript unit for a highly conserved yet uncharacterized zinc finger-containing protein (ZBTB42). One of the component SNPs of the 12 kb haplotype metabolic syndrome haplotype changes a conserved amino acid in the predicted ZBTB42 protein, increasing the potential significance of the ZBTB42 transcript unit for contributing to disease risk. Using RT-PCR of human and mouse cells, we verified that the two exon ZBTB42 was expressed and correctly spliced in human skeletal muscle, and murine C2C12 cells. Production of peptide antibodies showed the expected protein in human (47 kD) and mouse (49 kD) immunoblots, and murine tissue distribution showed strongest expression in muscle and ovary. Immunostaining showed nuclear localization of the ZBTB42 protein in human muscle. Confocal imaging analyses of murine muscle showed ZBTB42 distributed in the nucleoplasm, with particular enrichment in nuclei underlying the neuromuscular junctions. The genetic association data of metabolic syndrome, coupled with the molecular characterization of the ZBTB42 transcript unit and encoded protein presented here, suggests that ZBTB42 may be involved in metabolic syndrome phenotypes

Highlights from the Functional Single Nucleotide Polymorphisms Associated with Human Muscle Size and Strength or FAMuSS Study

The purpose of the Functional Single Nucleotide Polymorphisms Associated with Human Muscle Size and Strength study or FAMuSS was to identify genetic factors that dictated the response of health-related fitness phenotypes to resistance exercise training (RT). The phenotypes examined were baseline muscle strength and muscle, fat, and bone volume and their response to RT. FAMuSS participants were 1300 young (24 years), healthy men (42%) and women (58%) that were primarily of European-American descent. They were genotyped for ~500 polymorphisms and completed the Paffenbarger Physical Activity Questionnaire to assess energy expenditure and time spent in light, moderate, and vigorous intensity habitual physical activity and sitting. Subjects then performed a 12-week progressive, unilateral RT program of the nondominant arm with the dominant arm used as a comparison. Before and after RT, muscle strength was measured with the maximum voluntary contraction and one repetition maximum, while MRI measured muscle, fat, and bone volume. We will discuss the history of how FAMuSS originated, provide a brief overview of the FAMuSS methods, and summarize our major findings regarding genotype associations with muscle strength and size, body composition, cardiometabolic biomarkers, and physical activity

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±

Genomics in premature infants: A non-invasive strategy to obtain high-quality DNA

We used a cost-effective, non-invasive method to obtain high-quality DNA from buccal epithelial-cells (BEC) of premature infants for genomic analysis. DNAs from BEC were obtained from premature infants with gestational age ≤ 36 weeks. Short terminal repeats (STRs) were performed simultaneously on DNA obtained from the buccal swabs and blood from the same patient. The STR profiles demonstrated that the samples originated from the same individual and exclude any contamination by external DNAs. Whole exome sequencing was performed on DNAs obtained from BEC on premature infants with and without necrotizing enterocolitis, and successfully provided a total number of reads and variants corroborating with those obtained from healthy blood donors. We provide a proof of concept that BEC is a reliable and preferable source of DNA for high-throughput sequencing in premature infants

Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFβ-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 - 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFβ-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC