Wakefulness affects synaptic and network activity by increasing extracellular astrocyte-derived adenosine

Loss of sleep causes an increase in sleep drive and deficits in hippocampal-dependent memory. Both of these responses are thought to require activation of adenosine A1 receptors (adorA1Rs) and release of transmitter molecules including ATP, which is rapidly converted to adenosine in the extracellular space, from astrocytes in a process termed gliotransmission. Although it is increasingly clear that astrocyte-derived adenosine plays an important role in driving the homeostatic sleep response and the effects of sleep loss on memory (Halassa et al., 2009; Florian et al., 2011), previous studies have not determined whether the concentration of this signaling molecule increases in response to wakefulness. Here, we show that the level of adorA1R activation increases in response to wakefulness in mice (Mus musculus). We found that this increase affected synaptic transmission in the hippocampus and modulated network activity in the cortex. Direct biosensor-based measurement of adenosine showed that the net extracellular concentration of this transmitter increased in response to normal wakefulness and sleep deprivation. Genetic inhibition of gliotransmission prevented this increase and attenuated the wakefulness-dependent changes in synaptic and network regulation by adorA1R. Consequently, we conclude that wakefulness increases the level of extracellular adenosine in the hippocampus and that this increase requires the release of transmitters from astroctyes

The sexual health needs of looked after young people; findings from qualitative interviews led through public health and health psychology.

Background - Looked after young people (LAYP) have poorer sexual health outcomes than their peers. However, research seldom examines the health needs of, or intervenes with, this group. The aim of the current study was to identify LAYP's perceived sexual health needs and explore sources of sexual health information, knowledge levels, concerns and service preferences. Methods - Looked after young people within Fife, Scotland, were recruited through their workers and carers to participate in qualitative semi-structured interviews. Those aged 12–19 years were targeted for recruitment. National Health Services ethics approval was granted. Thematic analysis was conducted using NVivo. Results - Interviews were conducted with 10 LAYP. Key themes included gaps in knowledge, and gaps between knowledge and behaviour. Being ‘looked after’ may have negative consequences on knowledge, sources of support and safer sex. A flexible, one-to-one service, aimed at several lifestyle issues, not solely sexual health, was preferred by respondents. Conclusion - Looked after young people require support to bridge the gap between knowledge and behaviour and several theories relevant to the findings have been identified. Participants desired more support around a range of health issues, which may come from school, workers and carers, as well as health professionals. Further research examining effective interventions with this group is crucial to improve outcomes

COMPARISON OF HERITABILITY ESTIMATES FROM DAUGHTER-DAM REGRESSION AND PATERNAL HALF-SIB CORRELATION

Analysis of 60,000 pairs of daughter and dam first-lactation records expressed as deviations from herd-mate averages for five breeds yielded markedly different heritability estimates from daughter-dam regression than from paternal half-sib correlation. These results suggest that 18% of the within-herd variation is due to genetic maternal effects. The same records analyzed as mature equivalent records and not as deviations but by a sire by herd model did not show this difference. Confounding between year and sire effects probably biased the intraclass correlation estimates upward in the latter analysis, since year effects were not included in the statistical model

Genetic and Maternal Influence on the First Three Lactations of Holstein Cows

Milk records of up to the first three lactations of artificially sired Holstein daughters and their dams were used to estimate heritability from both daughter-dam regression and paternal half-sib correlation. The within-herd estimates from records expressed as deviations from herd-mate averages were .37, .30, and .24 from daughter-dam regression for the first three lactations ; and the corresponding estimates from half-sib correlation were .24, .21, and .23. These results suggest a large maternal effect in the first lactation, a small amount in the second, and little in the third lactation. Analysis of the records not as deviations gave the same pattern for the daughter-dam regressions, but confounding of sires with year-seasons apparently biased the half-sib correlations upward. The consequences of considering unequal heritability for different lactations if the apparent difference is due to maternal effects is illustrated for selection for first-lactation breeding value from up to three records on the cow herself and on her dam

Sire Effects in Different Housing Systems

Over 1,000 Holstein herds in New York\u27s Dairy Herd Improvement Cooperative were classified as to housing system. The two housing systems considered were stanchions and free stalls. First-lactation records (21,285) produced in these herds by daughters sired through artificial insemination were analyzed to determine if housing system would affect sire ranking. The study covered records started in 1964 through 1967. The sire component of variance was estimated for each housing system for deviations of these records from their adjusted herdmate averages. The covariance between the means of daughters in each housing system was computed. The genetic correlation between sire effects in the two systems was determined by dividing this covariance by the geometric mean of the sire components of variance for the two housing systems. The estimated correlation was near unity for each year of the study, indicating essentially complete agreement between sire rankings in the two housing systems

Estimates of genetic parameters and selection strategies to improve the economic efficiency of postweaning growth in lambs

The objectives of this study were to estimate (co)variance components for growth and feed efficiency measures, and to compare selection strategies to improve economic efficiency of gain. Variance components for pre- and postweaning growth, body weight, and measures of feed efficiency were estimated from data collected on 1,047 Targhee lambs over 7 yr. Approximately 21 d after weaning, lambs were group-fed for 4 wk, with ad libitum access to a diet of 37% whole barley grain and 63% pelleted alfalfa hay. Lambs were then individually fed for 6 wk. Lambs were then returned to group feeding for another 4-wk period. The mean feed conversion ratio (gain/intake) for the individual feeding period was 0.11. Mean postweaning ADG for the total 14-wk feeding period was 0.26 kg. (Co)variance components were estimated from single- and two-trait animal models using REML. The selection strategies compared included direct selection, index selection, and restricted index selection. Estimates of (co)variances derived from single- and two-trait models were similar, except for mid-test body weight. Preweaning growth had a low heritability estimate (0.03 ± 0.04) compared with postweaning growth measures (0.25 to 0.39), but all measures of growth were highly correlated (r2 \u3e 0.98). Heritability estimates of measures of gain efficiency were variable (total feed intake = &#;0.39; feed conversion ratio = &#;0.26; residual feed intake = &#;0.26). Total feed intake was strongly correlated genetically with feed conversion ratio (0.79) and residual feed intake (0.77). The estimate of genetic correlation between feed conversion ratio and residual feed intake was low (0.23). Comparison of selection strategies showed the superiority of index selection (ADG, total feed, body weight) for economic improvement compared with other strategies. Economic response to direct selection for ADG was at least twice that for direct selection for feed conversion ratio or against total feed intake, and that for restricted indices (selecting against residual feed, while holding body weight and/or gain constant). Selection for ADG may be a practical approach for indirectly improving efficiency of gain in lambs

Estimates of genetic parameters and selection strategies to improve the economic efficiency of postweaning growth in lambs

The objectives of this study were to estimate (co)variance components for growth and feed efficiency measures, and to compare selection strategies to improve economic efficiency of gain. Variance components for pre- and postweaning growth, body weight, and measures of feed efficiency were estimated from data collected on 1,047 Targhee lambs over 7 yr. Approximately 21 d after weaning, lambs were group-fed for 4 wk, with ad libitum access to a diet of 37% whole barley grain and 63% pelleted alfalfa hay. Lambs were then individually fed for 6 wk. Lambs were then returned to group feeding for another 4-wk period. The mean feed conversion ratio (gain/intake) for the individual feeding period was 0.11. Mean postweaning ADG for the total 14-wk feeding period was 0.26 kg. (Co)variance components were estimated from single- and two-trait animal models using REML. The selection strategies compared included direct selection, index selection, and restricted index selection. Estimates of (co)variances derived from single- and two-trait models were similar, except for mid-test body weight. Preweaning growth had a low heritability estimate (0.03 ± 0.04) compared with postweaning growth measures (0.25 to 0.39), but all measures of growth were highly correlated (r2 \u3e 0.98). Heritability estimates of measures of gain efficiency were variable (total feed intake = &#;0.39; feed conversion ratio = &#;0.26; residual feed intake = &#;0.26). Total feed intake was strongly correlated genetically with feed conversion ratio (0.79) and residual feed intake (0.77). The estimate of genetic correlation between feed conversion ratio and residual feed intake was low (0.23). Comparison of selection strategies showed the superiority of index selection (ADG, total feed, body weight) for economic improvement compared with other strategies. Economic response to direct selection for ADG was at least twice that for direct selection for feed conversion ratio or against total feed intake, and that for restricted indices (selecting against residual feed, while holding body weight and/or gain constant). Selection for ADG may be a practical approach for indirectly improving efficiency of gain in lambs

Sequential Transformation for Multiple Traits for Estimation of (Co)variance Components with a Derivative-Free Algorithm for Restricted Maximum Likelihood

Transformation of multiple-trait records that undergo sequential selection can be used with derivative-free algorithms to maximize the restricted likelihood in estimation of covariance matrices as with derivative methods. Data transformation with appropriate parts of the Choleski decomposition of the current estimate of the residual covariance matrix results in mixed-model equations that are easily modified from round to round for calculation of the logarithm of the likelihood. The residual sum of squares is the same for transformed and untransformed analyses. Most importantly, the logarithm of the determinant of the untransformed coefficient matrix is an easily determined function of the Choleski decomposition of the residual covariance matrix and the determinant of the transformed coefficient matrix. Thus, the logarithm of the likelihood for any combination of covariance matrices can be determined from the transformed equations. Advantages of transformation are 1) the multiple-trait mixed-model equations are easy to set up, 2) the least squares part of the equations does not change from round to round, 3) right-hand sides change from round to round by constant multipliers, and 4) less memory is required. An example showed only a slight advantage of the transformation compared with no transformation in terms of solution time for each round (1 to 5%)

Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice

Experimental allergic encephalomyelitis (EAE)' is an autoimmune inflammatory demyelinating disease in the central nervous system (CNS) of animals immunized with myelin basic protein (MBP). The disease is directly mediated by Thelper cells that recognize MBP in the context ofclass II antigens of the MHC (1-3). In nude mice, a single clone of adoptively transferred MBP-reactive T helper cells can cause EAE (4), suggesting that these are the only T cells required for disease induction. As a prototypic model of T helper cell-mediated autoimmune disease, observations in EAE could likely be applicable to other T helper cell-mediated diseases such as murine lupus (5), thyroiditis (6), collagen arthritis (7), and adjuvant arthritis (8), as well as human autoimmune diseases. The MBP epitope is determined in part by the MHC. Using proteolytic peptide fragments of MBP, SJL/J (H-2s) and BIO.T(6R) (H-2q) mice were found to develop EAE to the COOH-terminal peptide of MBP, whereas PL/J (H-2u) and A/J (H-2k) mice developed EAE to the NH2-terminal peptide of MBP (9). Recently, by using synthetic peptides that overcome the difficulties of obtaining pure uncontaminated proteolytic peptides, a single T cell encephalitogenic epitope for PL/J mice has been identified . This epitope consists of the first nine NH2-terminal amino acid residues of MBP which must be acetylated at the a amino group to induce disease (10). Similar fine mapping of the encephalitogenic T cell epitope(s) for SJL/J mice has not been done, in part because of the large size of the COOH-terminal peptic fragment of MBP (residues 89-169 of rat MBP, reference 9). MouseMBP consists offour major forms due to differential RNA splicing of exons II and VI (11), resulting in molecular masses of 21, 18.5, 17.5, and 14 kD, in the relative amounts of 1 :10:3.5:35 . Since EAE can also be induced with the small form of rat MBP (14 kD), which has exons II and VI of the MBP gene deleted (12), the COOH-terminal encephalitogenic determinant for SJL/J mice must be present within a segment ofonly 42 amino acid residues . Consistent withthis notion is the observation that this peptide sequence is identical among the MBPs of several mammalian species, including mouse, rat, bovine, guinea pig, and porcine, all of which can induce EAE in SJL/mice (13, 14). To identify the SJL/J encephalitogenic T cell epitope(s), overlapping peptides to the COOH-terminal region ofthe small form of mouse MBP were synthesized. Two overlapping peptides encompassing an 18-amino acid region were found to elicit EAE in SJL/J mice. The finding of a single peptide region of MBP that is responsible for encephalitogenic T cell epitopes in SJL/J mice is analogous to that of the PL/J mice and has implications for the development of specific therapy for T cell-mediated autoimmune diseases