New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Clinical significance of serological biomarkers and neuropsychological performances in patients with temporal lobe epilepsy

<p>Abstract</p> <p>Background</p> <p>Temporal lobe epilepsy (TLE) is a common form of focal epilepsy. Serum biomarkers to predict cognitive performance in TLE patients without psychiatric comorbidities and the link with gray matter (GM) atrophy have not been fully explored.</p> <p>Methods</p> <p>Thirty-four patients with TLE and 34 sex - and age-matched controls were enrolled for standardized cognitive tests, neuroimaging studies as well as measurements of serum levels of heat shock protein 70 (HSP70), S100ß protein (S100ßP), neuronal specific enolase (NSE), plasma nuclear and mitochondrial DNA levels.</p> <p>Results</p> <p>Compared with the controls, the patients with TLE had poorer cognitive performances and higher HSP70 and S100ßP levels (<it>p </it>< 0.01). The patients with higher frequencies of seizures had higher levels of HSP70, NSE and S100ßP (<it>p </it>< 0.01). Serum HSP70 level correlated positively with duration of epilepsy (σ = 0.413, <it>p </it>< 0.01), and inversely with memory scores in the late registration (σ = −0.276, <it>p </it>= 0.01) and early recall score (σ = −0.304, <it>p </it>= 0.007). Compared with the controls, gray matter atrophy in the hippocampal and parahippocampal areas, putamen, thalamus and supplementary motor areas were found in the patient group. The HSP70 levels showed an inverse correlation with hippocampal volume (R square = 0.22, <it>p </it>= 0.007) after controlling for the effect of age.</p> <p>Conclusions</p> <p>Our results suggest that serum biomarkers were predictive of higher frequencies of seizures in the TLE group. HSP70 may be considered to be a stress biomarker in patients with TLE in that it correlated inversely with memory scores and hippocampal volume. In addition, the symmetric extratemporal atrophic patterns may be related to damage of neuronal networks and epileptogenesis in TLE.</p

Comparison of Antibody Repertoires Produced by HIV-1 Infection, Other Chronic and Acute Infections, and Systemic Autoimmune Disease

Background Antibodies (Abs) produced during HIV-1 infection rarely neutralize a broad range of viral isolates; only eight broadly-neutralizing (bNt) monoclonal (M)Abs have been isolated. Yet, to be effective, an HIV-1 vaccine may have to elicit the essential features of these MAbs. The V genes of all of these bNt MAbs are highly somatically mutated, and the VH genes of five of them encode a long (≥20 aa) third complementarity-determining region (CDR-H3). This led us to question whether long CDR-H3s and high levels of somatic mutation (SM) are a preferred feature of anti-HIV bNt MAbs, or if other adaptive immune responses elicit them in general. Methodology and Principal Findings We assembled a VH-gene sequence database from over 700 human MAbs of known antigen specificity isolated from chronic (viral) infections (ChI), acute (bacterial and viral) infections (AcI), and systemic autoimmune diseases (SAD), and compared their CDR-H3 length, number of SMs and germline VH-gene usage. We found that anti-HIV Abs, regardless of their neutralization breadth, tended to have long CDR-H3s and high numbers of SMs. However, these features were also common among Abs associated with other chronic viral infections. In contrast, Abs from acute viral infections (but not bacterial infections) tended to have relatively short CDR-H3s and a low number of SMs, whereas SAD Abs were generally intermediate in CDR-H3 length and number of SMs. Analysis of VH gene usage showed that ChI Abs also tended to favor distal germline VH-genes (particularly VH1-69), especially in Abs bearing long CDR-H3s. Conclusions and Significance The striking difference between the Abs produced during chronic vs. acute viral infection suggests that Abs bearing long CDR-H3s, high levels of SM and VH1-69 gene usage may be preferentially selected during persistent infection

Regulation of mammalian sperm capacitation by endogenous molecules

Capacitation in vitro in mammalian spermatozoa can be regulated by a number of first messengers, including fertilization promoting peptide, adenosine, calcitonin and angiotensin II, all of which are found in seminal plasma. The responses appear to involve several separate signal transduction pathways that have a common end point. These seminal-plasma derived first messengers can bind to specific receptors and directly or indirectly modulate the activity of membrane-associated adenylyl cyclase isoforms and production of the second messenger cAMP. Responses to all of these except angiotensin II involve initial acceleration of cAMP production and capacitation followed by inhibition of both cAMP production and spontaneous acrosome loss, resulting in maintenance of fertilizing potential. Appropriate G proteins and various phosphodiesterase isoforms also appear to be involved. The transition from stimulatory to inhibitory responses involves loss of decapacitation factors (DF) from receptors (DF-R) on the external surface; a DF-R present on both mouse and human spermatozoa has recently been identified as phosphatidylethanolamine-binding protein 1. The presence/ absence of DF appears to cause changes in the plasma membrane that then alter the functionality of various membrane-associated proteins, including receptors. Since spermatozoa contact these first messengers at ejaculation, it is plausible that their actions observed in vitro also occur in vivo, allowing these molecules to play a pivotal role in enhancing the chances of successful fertilization