Dynamical changes in neurological diseases and anesthesia

Dynamics of neuronal networks can be altered in at least two ways: by changes in connectivity, that is, the physical architecture of the network, or changes in the amplitudes and kinetics of the intrinsic and synaptic currents within and between the elements making up a network. We argue that the latter changes are often overlooked as sources of alterations in network behavior when there are also structural (connectivity) abnormalities present; indeed, they may even give rise to the structural changes observed in these states. Here we look at two clinically relevant states (Parkinson's disease and schizophrenia) and argue that non-structural changes are important in the development of abnormal dynamics within the networks known to be relevant to each disorder. We also discuss anesthesia, since it is entirely acute, thus illustrating the potent effects of changes in synaptic and intrinsic membrane currents in the absence of structural alteration. In each of these, we focus on the role of changes in GABAergic function within microcircuits, stressing literature within the last few years.     

Oxidative stress in zebrafish (Danio rerio) sperm

Laboratories around the world have produced tens of thousands of mutant and transgenic zebrafish lines. As with mice, maintaining all of these valuable zebrafish genotypes is expensive, risky, and beyond the capacity of even the largest stock centers. Because reducing oxidative stress has become an important aspect of reducing the variability in mouse sperm cryopreservation, we examined whether antioxidants might improve cryopreservation of zebrafish sperm. Four experiments were conducted in this study. First, we used the xanthine-xanthine oxidase (X-XO) system to generate reactive oxygen species (ROS). The X-XO system was capable of producing a stress reaction in zebrafish sperm reducing its sperm motility in a concentration dependent manner (P<0.05). Second, we examined X-XO and the impact of antioxidants on sperm viability, ROS and motility. Catalase (CAT) mitigated stress and maintained viability and sperm motility (P>0.05), whereas superoxide dismutase (SOD) and vitamin E did not (P<0.05). Third, we evaluated ROS in zebrafish spermatozoa during cryopreservation and its effect on viability and motility. Methanol (8%) reduced viability and sperm motility (P<0.05), but the addition of CAT mitigated these effects (P>0.05), producing a mean 2.0 to 2.9-fold increase in post-thaw motility. Fourth, we examined the effect of additional cryoprotectants and CAT on fresh sperm motility. Cryoprotectants, 8% methanol and 10% dimethylacetamide (DMA), reduced the motility over the control value (P<0.5), whereas 10% dimethylformamide (DMF) with or without CAT did not (P>0.05). Zebrafish sperm protocols should be modified to improve the reliability of the cryopreservation process, perhaps using a different cryoprotectant. Regardless, the simple addition of CAT to present-day procedures will significantly improve this process, assuring increased and less variable fertilization success and allowing resource managers to dependably plan how many straws are needed to safely cryopreserve a genetic line.     

Associations of infant nutrition with insulin resistance measures in early adulthood: evidence from the Barry-Caerphilly Growth (BCG) study

Background

Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance.

Objective

To assess the association of breast milk and quantity of infant formula and cows'' milk intake during infancy with insulin resistance measures in early adulthood.

Design

Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows'' milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI₀) and insulin secretion (CIR₃₀).

Results

573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows'' milk feeding or of increasing quartiles of formula/cows'' milk consumption during infancy (<3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows'' milk feeding at 3 months were: fasting glucose (−0.07 mmol/l; 95% CI: −0.19, 0.05); fasting insulin (8.0%; −8.7, 27.6); ISI₀ (−6.1%; −11.3, 12.1) and CIR₃₀ (3.8%; −19.0, 32.8). There was also little evidence that increasing intakes of formula/cows'' milk at 3 months were associated with fasting glucose (increase per quartile of formula/cows'' milk intake = 0.00 mmol/l; −0.03, 0.03); fasting insulin (0.8%; −3.2, 5.1); ISI ₀ (−0.9%; −5.1, 3.5) and CIR₃₀ (−2.6%; −8.4, 3.6).

Conclusions

We found no evidence that increasing consumption of formula/cows'' milk in early infancy was associated with insulin resistance in young adulthood.     

Susceptibility to acute mouse adenovirus type 1 respiratory infection and establishment of protective immunity in neonatal mice

There is an incomplete understanding of the differences between neonatal immune responses that contribute to the increased susceptibility of neonates to some viral infections. We tested the hypothesis that neonates are more susceptible than adults to mouse adenovirus type 1 (MAV-1) respiratory infection and are impaired in the ability to generate a protective immune response against a second infection. Following intranasal infection, lung viral loads were greater in neonates than in adults during the acute phase but the virus was cleared from the lungs of neonates as efficiently as it was from adult lungs. Lung gamma interferon (IFN-γ) responses were blunted and delayed in neonates, and lung viral loads were higher in adult IFN-γ(-/-) mice than in IFN-γ(+/+) controls. However, administration of recombinant IFN-γ to neonates had no effect on lung viral loads. Recruitment of inflammatory cells to the airways was impaired in neonates. CD4 and CD8 T cell responses were similar in the lungs of neonates and adults, although a transient increase in regulatory T cells occurred only in the lungs of infected neonates. Infection of neonates led to protection against reinfection later in life that was associated with increased effector memory CD8 T cells in the lungs. We conclude that neonates are more susceptible than adults to acute MAV-1 respiratory infection but are capable of generating protective immune responses.     

Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population

Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.     

Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in drosophila

Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral-ventral pacemaker neurons (LN(v)s) that secrete the neuropeptide PDF (pigment dispersing factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity. Although LN(v)s also express functional PDFR, the role of these autoreceptors has remained enigmatic. Here, we show that (1) PDFR activation in LN(v)s shifts the balance of circadian activity from evening to morning, similar to behavioral responses to summer-like environmental conditions, and (2) this shift is mediated by stimulation of the Gα,s-cAMP pathway and a consequent change in PDF/neurotransmitter corelease from the LN(v)s. These results suggest another mechanism for environmental control of the allocation of circadian activity and provide new general insight into the role of neuropeptide autoreceptors in behavioral control circuits.     

Potentiation of concentric force and acceleration only occurs early during the stretch-shortening cycle

ABSTRACT: McCarthy, JP, Wood, DS, Bolding, MS, Roy, JLP, and Hunter, GR. Potentiation of concentric force and acceleration only occurs early during the stretch-shortening cycle. J Strength Cond Res 26(9): 2345-2355, 2012-The purpose of this study was to determine where stretch-shortening cycle (SSC) potentiation of force, power, velocity, and acceleration occurs across the concentric phase of ballistic leg presses. Second, we examined the influence of late eccentric phase force and length of the amortization phase on potentiated concentric phase performance variables. Twenty-one male runners (age: 31.9 ± 4.7 years) performed SSC and concentric-only (CO) ballistic leg press throws. Potentiations of concentric actions were calculated as the difference between SSC and CO contractions. An analysis splitting the concentric range of motion (ROM) into 6 equal time intervals determined force and acceleration were potentiated (p < 0.05) only during the first one-sixth time interval of concentric motion, whereas velocity and power were potentiated (p < 0.05) at all time intervals over the entire concentric motion with the exception of power over the last one-sixth time interval. A more precise analysis examining 20-millisecond time intervals across the first 200 milliseconds of concentric motion determined force was potentiated only over the first 140 milliseconds and acceleration only over the first 160 milliseconds. Eccentric force measured during the last 100 milliseconds of eccentric motion was related to potentiated force during the initial 200 milliseconds of concentric motion (r = 0.44, p < 0.05) and potentiated mean power across the full concentric ROM (r = 0.62, p < 0.01). Results indicate that in contrast to power and velocity, potentiation of force and acceleration occurs only early during the concentric phase of SSC ballistic leg presses. Correlational findings imply late eccentric phase force is important for generating force and power during the concentric phase of the SSC and thus training focusing on enhancing late phase eccentric force appears important for developing explosive force and power during SSC movements.     

The rapid spread of rusty crayfish (Orconectes rusticus) with observations on native crayfish declines in Wisconsin (U.S.A.) over the past 130 years

The rusty crayfish, Orconectes rusticus, is one of America’s best-known non-indigenous crayfishes, having been identified as extirpating native crayfishes and disrupting local aquatic ecosystems. Over the past 40–50 years, rusty crayfish have spread from its historical range in the Ohio River drainage (U.S.A.), to waters throughout much of Illinois, Michigan, Wisconsin, and Minnesota and parts of 11 other states, Ontario (Canada) and the Laurentian Great Lakes. Using a comprehensive dataset based on all known historical records and extensive present-day surveys (n = 2775) this study reports on the invasion history of rusty crayfish, with observations on concomitant declines of native crayfishes in Wisconsin over the past 130 years (1870–2004). We found that rusty crayfish occurrences have increased from 7% of all crayfish records collected during the first 20 years of their invasion (1965–1984) to 36% of all records during the last 20 years, and that rusty crayfish have replaced the northern clearwater crayfish (O. propinquus) and virile crayfish (O. virilis) as the most dominant member of the contemporary crayfish fauna. In light of our results we discuss the introduction, establishment and integration phases of the rusty crayfish invasion and provide preliminary predictions of the potential distribution of rusty crayfish in Wisconsin lakes based on critical environmental requirements.