Accelerated cortical thinning and volume reduction over time in young people at high genetic risk for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk. METHOD: Neuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12-30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions. RESULTS: Compared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval. CONCLUSIONS: This study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.

Structural dysconnectivity of key cognitive and emotional hubs in young people at high genetic risk for bipolar disorder.

Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness. We studied structural connectivity differences between these groups, with a focus on highly connected hubs and networks involving emotional centres. HR participants showed lower structural connectivity in two lateralised sub-networks centred on bilateral inferior frontal gyri and left insular cortex, as well as increased connectivity in a right lateralised limbic sub-network compared with CN subjects. BD was associated with weaker connectivity in a small right-sided sub-network involving connections between fronto-temporal and temporal areas. Although these sub-networks preferentially involved structural hubs, the integrity of the highly connected structural backbone was preserved in both groups. Weaker structural brain networks involving key emotional centres occur in young people at genetic risk of BD and those with established BD. In contrast to other psychiatric disorders such as schizophrenia, the structural core of the brain remains intact, despite the local involvement of network hubs. These results add to our understanding of the neurobiological correlates of BD and provide predictions for outcomes in young people at high genetic risk for BD.

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder.

BACKGROUND: Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12-30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk. METHOD: We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON). RESULTS: The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD. CONCLUSIONS: The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

Interhemispheric white matter integrity in young people with bipolar disorder and at high genetic risk.

BACKGROUND: White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. METHOD: WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. RESULTS: This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. CONCLUSIONS: Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD - a group at particular risk of future hypo/manic episodes - suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Direct imaging of p-n junction in core-shell GaN wires.

While core-shell wire-based devices offer a promising path toward improved optoelectronic applications, their development is hampered by the present uncertainty about essential semiconductor properties along the three-dimensional (3D) buried p-n junction. Thanks to a cross-sectional approach, scanning electron beam probing techniques were employed here to obtain a nanoscale spatially resolved analysis of GaN core-shell wire p-n junctions grown by catalyst-free metal-organic vapor phase epitaxy on GaN and Si substrates. Both electron beam induced current (EBIC) and secondary electron voltage constrast (VC) were demonstrated to delineate the radial and axial junction existing in the 3D structure. The Mg dopant activation process in p-GaN shell was dynamically controlled by the ebeam exposure conditions and visualized thanks to EBIC mapping. EBIC measurements were shown to yield local minority carrier/exciton diffusion lengths on the p-side (∼57 nm) and the n-side (∼15 nm) as well as depletion width in the range 40-50 nm. Under reverse bias conditions, VC imaging provided electrostatic potential maps in the vicinity of the 3D junction from which acceptor Na and donor Nd doping levels were locally determined to be Na = 3 × 10(18) cm(-3) and Nd = 3.5 × 10(18) cm(-3) in both the axial and the radial junction. Results from EBIC and VC are in good agreement. This nanoscale approach provides essential guidance to the further development of core-shell wire devices.

[Etiopathogeny of the delusion of pregnancy using a literature review: Role of hyperprolactinemia and application of the theory of abductive inference]. / Étiopathogénie des délires de grossesse à partir d'une revue de la littérature : rôle de l'hyperprolactinémie et application de la théorie de l'inférence abductive.

INTRODUCTION: Delusions of pregnancy are not well known. The delusion of pregnancy is defined as the belief of being pregnant despite factual evidence to the contrary. The clinical picture is heterogeneous (duration, mechanisms, topics and pre-existing psychiatric disorders). Several causes have been proposed to explain the occurrence of the delusions of pregnancy: cenesthetic theory, hyperprolactinemia, polydipsia and psychodynamic conflicts. Hyperprolactinemia is an interesting hypothesis (physiologic increase during pregnancy and similar manifestations in the course of gestation). The abductive inference theory is a probabilistic model that can clarify the role of hyperprolactinemia in the delusions of pregnancy. The purpose of this paper is to study the role of hyperprolactinemia in the delusions of pregnancy using a literature review. The abductive inference model is used to specify the etiopathogeny of this pathology. METHODS: A research in Medline, Sudoc, BIUM and PSYLINK using the following key words "delusional pregnancy" or "delusion of pregnancy" and "hyperprolactinemia" was conducted. RESULTS: Three articles (case reports) about delusions of pregnancy associated with hyperprolactinemia were found. The cases have some similitudes. First of all, they have similar chronology: delusion appears at the same time as hyperprolactinemia and resolves with biological normalization. Secondly, hyperprolactinemia is always caused by a neuroleptic (haloperidol, olanzapine, risperidone). Concerning pre-existing disorders, a psychiatric pathology for each case was found (schizophrenia, schizo-affective disorder and bipolar disorder). Chronology, reproductivity and reversibility are strong arguments to involve hyperprolactinemia in the delusions of pregnancy (Bradford Hill criteria). Furthermore, this association is biologically plausible: physiologic increase during pregnancy (gestational signal), similar symptoms to those during pregnancy and the role in parental behavior (parental signal). Nevertheless, not everyone with hyperprolactinemia will develop a delusion of pregnancy; the interaction is more complex (non linear); the theory of abductive inference clarifies this relationship. THEORY OF ABDUCTIVE INFERENCE: Abductive inference is a probabilistic model whose goal is to explain the occurrence of delusional beliefs. The first factor is the abnormal data. The second factor is the cognitive process (abductive inference), which uses Bayes' theorem to select the most likely hypothesis to explain the abnormal data. In the delusion of pregnancy, abnormal data is the hyperprolactinemia, signal of gestation without pregnancy. Hypotheses in order to explain this signal are then produced (pregnancy or no pregnancy). In the second part, probabilities associated with each hypothesis, given the hyperprolactinemia, are compared. Since hyperprolactinemia is a gestational signal, the pregnancy hypothesis is most likely. Probabilities associated with each hypothesis without taking hyperprolactinemia into account are compared (prior probability). Since any element of reality indicates a pregnancy, the absence of pregnancy is most likely. In the last step, the posterior probability is calculated using the first two comparisons. The probability associated with the pregnancy hypothesis (taking into account hyperprolactinemia) is relatively higher than the probability associated with the no-pregnancy hypothesis (without taking into account hyperprolactinemia). So, the posterior probability associated with the pregnancy hypothesis is more likely than the posterior probability associated with the no-pregnancy hypothesis. Thus, the subject believes in a pregnancy. CONCLUSION: The research and the treatment of hyperprolactinemia must be conducted when faced with a delusion of pregnancy.

The functional activity of inhibitory G protein (G(i)) is not increased in failing heart ventricle.

Beta-adrenergic receptor (ßAR) inotropic effects are attenuated and muscarinic receptor-mediated inhibition thereof is enhanced in heart failure. We investigated if increased G(i) activity contributes to attenuated ßAR-inotropic effects and potentiates muscarinic accentuated antagonism in failing rat ventricle. Contractility was measured in ventricular strips and adenylyl cyclase (AC) activity in ventricular membranes from rats with post-infarction heart failure (HF) or Sham-operated controls (Sham). The maximal ßAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, ßAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the ßAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit ßAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the ßAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of G(i) did not increase the maximal ßAR inotropic effect or the attenuated basal, ßAR- & forskolin-stimulated AC activity in HF, but increased the potency of isoproterenol only in Sham (~0.5 log unit). In HF ventricle pretreated with PTX, simultaneous inhibition of phosphodiesterases 3,4 (PDE3,4) alone produced a larger inotropic response than isoproterenol in ventricle untreated with PTX (84% and 48% above basal respectively). In the absence of PTX, PDE3,4 inhibition evoked negligible inotropic effects in HF. These data are not consistent with the hypothesis that increased G(i) activity contributes to the reduced ßAR-mediated inotropic response and AC activity in failing ventricle. The data, however, support the hypothesis that G(i), through chronic receptor independent inhibition of AC, together with PDE3,4 activity, is necessary to maintain a low basal level of contractility.

Total fluoride intake and excretion in children up to 4 years of age living in fluoridated and non-fluoridated areas.

Fractional fluoride retention is important during the early years of life when considering the risk of development of dental fluorosis. This study aimed to measure fractional fluoride retention in young children. The objectives were to investigate the relationships between fractional fluoride retention and total daily fluoride intake, age, and body mass index (BMI). Twenty-nine healthy children, up to 4 yr of age, participated; 14 lived in a fluoridated area (0.64 µg ml(-1) of fluoride in drinking water) and 15 lived in a non-fluoridated area (0.04 µg ml(-1) of fluoride in drinking water). The total daily fluoride intake of each child was calculated from the daily dietary fluoride intake and toothpaste ingestion (if fluoride toothpaste was used). Total daily fluoride excretion was measured by collecting voided urine and faeces over a 24-h period, and fractional fluoride retention was calculated by dividing the amount of fluoride retained in the body (total daily fluoride intake minus total daily fluoride excretion) by the total daily fluoride intake. Nine children were excluded from data analysis because of suspected invalid samples. Mean (range) fractional fluoride retention for the remaining 20 children was 0.61 (0.06-0.98). There were no statistically significant correlations between fractional fluoride retention and either age or BMI. However, fractional fluoride retention was correlated with total daily fluoride intake: fractional fluoride retention = 1 - exp (-C × total daily fluoride intake), where C = 28.75 (95% CI = 19.75-37.75). The wide variation in fluoride retention in young children could have important implications when recommendations for fluoride use are being considered.

Superconductivity in doped cubic silicon.

Although the local resistivity of semiconducting silicon in its standard crystalline form can be changed by many orders of magnitude by doping with elements, superconductivity has so far never been achieved. Hybrid devices combining silicon's semiconducting properties and superconductivity have therefore remained largely underdeveloped. Here we report that superconductivity can be induced when boron is locally introduced into silicon at concentrations above its equilibrium solubility. For sufficiently high boron doping (typically 100 p.p.m.) silicon becomes metallic. We find that at a higher boron concentration of several per cent, achieved by gas immersion laser doping, silicon becomes superconducting. Electrical resistivity and magnetic susceptibility measurements show that boron-doped silicon (Si:B) made in this way is a superconductor below a transition temperature T(c) approximately 0.35 K, with a critical field of about 0.4 T. Ab initio calculations, corroborated by Raman measurements, strongly suggest that doping is substitutional. The calculated electron-phonon coupling strength is found to be consistent with a conventional phonon-mediated coupling mechanism. Our findings will facilitate the fabrication of new silicon-based superconducting nanostructures and mesoscopic devices with high-quality interfaces.

[The general practitioner faced with memory problems in the aged patient in Luxembourg: a study of the management employed, the experience of the physicians and the perception of the specific treatment]. / Le médecin généraliste face aux troubles mnésiques du sujet agé au Luxembourg: etude sur la prise en charge réalisée, le vécu des médecins et la perception du traitement spécifique.

Memory impairments are common in elderly. General practitioners are in first line to detect and manage these troubles, for which many countries published recommendations. For Alzheimer disease there are currently four treatments, none of which is healing. Some countries limited the first prescription of those medicines to specialists whereas in Luxembourg, every practitioner is allowed to prescribe them, but has to ask health insurance first. Consequently, it is important that general practitioners know what to do. The aim of our paper is to study the management done by the general practitioners in Luxembourg, the way they feel about it and the way they see the specific medicines for Alzheimer disease. Therefore, we have sent a questionnaire to every general practitioner in Luxembourg. We found that 87% of the practitioners realize at least one cognitive impairment test. More than half of them check for depression and 22.6% also add an autonomy assessment scale, even though all these tests are done by the dependence insurance. The involvement of general practitioners in the diagnosis of dementia is important as more than half of them have a statistically adequate number of demented patients. About two third of the practitioners do systematically start a specific medicine for Alzheimer disease. The management of cognitive impairment is difficult for general practitioners of Luxembourg, particularly the disclosure of diagnosis and management of behavioural and psychological symptoms.

Oxytocin receptors in the nucleus accumbens shell are involved in the consolidation of maternal memory in postpartum rats.

Female rats with maternal experience display a shorter onset of maternal responsiveness compared to those with no prior experience. This phenomenon called 'maternal memory' is critically dependent on the nucleus accumbens (NA) shell. We hypothesized that activation of OT receptors in the NA shell facilitates maternal memory. In Experiment 1, postpartum female rats given 1 hour of maternal experience were infused following the experience with either a high or low dose of an OT antagonist into the NA shell and tested for maternal behavior after a 10-day pup isolation period. Females receiving a high dose of the antagonist showed a significantly longer latency to exhibit full maternal behavior after the pup isolation period compared to females that received vehicle or a high dose of antagonist in a control region. In Experiment 2, postpartum female rats were infused with either a high or low dose of OT into the NA shell after a 15-minute maternal experience and tested for maternal behavior after a 10-day pup isolation period. There were no significant differences between the females infused with OT and females treated with a vehicle infused into the NA shell or with OT infused into the control region. One possible reason for a lack of facilitation is a floor effect, since females in the control groups displayed a rapid maternal response after the pup isolation period. These findings suggest that OT receptors, likely in combination with other neurotransmitters, in the NA shell play a role in the consolidation of maternal memory.

Submicrometre resolved optical characterization of green nanowire-based light emitting diodes.

The electroluminescent properties of InGaN/GaN nanowire-based light emitting diodes (LEDs) are studied at different resolution scales. Axial one-dimensional heterostructures were grown by plasma-assisted molecular beam epitaxy (PAMBE) directly on a silicon (111) substrate and consist of the following sequentially deposited layers: n-type GaN, three undoped InGaN/GaN quantum wells, p-type AlGaN electron blocking layer and p-type GaN. From the macroscopic point of view, the devices emit light in the green spectral range (around 550 nm) under electrical injection. At 100 mA DC current, a 1 mm2 chip that integrates around 10(7) nanowires emits an output power on the order of 10 µW. However, the emission of the nanowire-based LED shows a spotty and polychromatic emission. By using a confocal microscope, we have been able to improve the spatial resolution of the optical characterizations down to the submicrometre scale that can be assessed to a single nanowire. Detailed µ-electroluminescent characterization (emission wavelength and output power) over a representative number of single nanowires provides new insights into the vertically integrated nanowire-based LED operation. By combining both µ-electroluminescent and µ-photoluminescent excitation, we have experimentally shown that electrical injection failure is the major source of losses in these nanowire-based LEDs.

Dam parity and calf sex affect maternal and neonatal behaviors during the first week postpartum in stabled Maghrebi dairy camels.

Currently, a trend toward the commercialization of dromedary milk associated with recent intensive rearing systems has starting worldwide which impose constraints on animals affecting their behavioral repertoires and welfare status. The aim of this study was to investigate the effects of dam parity and calf sex on parturition, neonatal, and maternal behaviors in stabled Maghrebi dairy camels (Camelus dromedarius). Thirty-six (primiparas N = 10; multiparas N = 26) periparturient females were kept under video surveillance using a digital IR camera and 24-h sessions were chosen to assess calving, maternal, and neonatal behaviors in calving pens. Duration of restlessness, process of giving birth, and expulsion of fetal membranes were assessed. After first suckling, dams and their calves were moved into an individual enclosure to assess maternal behavior at 12 h, 24 h, 48 h, 72 h, and 7d postpartum. Behavior was assessed using a camcorder for 30 min after 1 h of young separation in an adjacent enclosure. Results showed an effect of parity on the duration of the birth process which was longer for primiparous than multiparous camels (P = 0.034). During this stage, primiparous females tended to raise their tails more often (P = 0.054) and spent more time standing (P = 0.001) than multiparous camels. Neonatal behavior was affected by calf sex. Female newborns took less time to raise their heads (P = 0.041) and to stand up (P = 0.048) for the first time and were the earliest to suckle their dams (P = 0.032). Multiparous dams stood up sooner (P = 0.019) after calving and suckled their calves earlier (P = 0.043) than primiparous dams. They emitted more bleats and exhibited more sniffing during the first week postpartum than primiparas. During the first postpartum week, both primiparas and multiparas showed a decrease in the total number of bleats (P < 0.001), low-pitch bleats (P < 0.001), and high-pitch bleats (P < 0.001), in sniffing frequency (P < 0.001) and sniffing duration (P < 0.001). This is the first study to describe in detail the calving, maternal, and neonatal behaviors of dromedary camels and to show the influence of parity and calf sex. Maternal care toward the newborn calf exhibited by a high level of bleating and sniffing activities in the first 2 days suggest that they play an important role in the establishment of mother-young relationship.

Modulation of proteasomal activity required for the generation of a cytotoxic T lymphocyte-defined peptide derived from the tumor antigen MAGE-3.

We have analyzed the presentation of human histocompatability leukocyte antigen-A*0201-associated tumor peptide antigen MAGE-3271-279 by melanoma cells. We show that specific cytotoxic T lymphocyte (CTL)-recognizing cells transfected with a minigene encoding the preprocessed fragment MAGE-3271-279 failed to recognize cells expressing the full length MAGE-3 protein. Digestion of synthetic peptides extended at the NH2 or COOH terminus of MAGE-3271-279 with purified human proteasome revealed that the generation of the COOH terminus of the antigenic peptide was impaired. Surprisingly, addition of lactacystin to purified proteasome, though partially inhibitory, resulted in the generation of the antigenic peptide. Furthermore, treatment of melanoma cells expressing the MAGE-3 protein with lactacystin resulted in efficient lysis by MAGE-3271-279-specific CTL. We therefore postulate that the generation of antigenic peptides by the proteasome in cells can be modulated by the selective inhibition of certain of its enzymaticactivities.

Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor.

In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the T cell receptor-CD3 complex (TCR/CD3) and inhibits T cell function via a previously unknown proximal target. Here we examine the mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 zeta chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on zeta chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion. Both PKA type I and Csk are targeted to lipid rafts where proximal T cell activation occurs, and phosphorylation of raft-associated Lck by Csk is increased in cells treated with forskolin. We propose a mechanism whereby PKA through activation of Csk intersects signaling by Src kinases and inhibits T cell activation.

Infrared conductivity of elemental bismuth under pressure: evidence for an avoided Lifshitz-type semimetal-semiconductor transition.

The application of pressure to elemental bismuth reduces its conduction-valence band overlap, and results in a semimetal-semiconductor (SMSC) transition around 25 kbar. This transition is nominally of the topological "Lifshitz" Fermi surface variety, but there are open questions about the role of interactions at low charge densities. Using a novel pressure cell with optical access, we have performed an extensive study of bismuth's infrared conductivity under pressure. In contrast to the expected pure band behavior we find signatures of enhanced interaction effects, including strongly coupled charge-plasmon (plasmaron) features and a plasma frequency that remains finite up to the transition. These effect are inconsistent with a pure Lifshitz bandlike transition. We postulate that interactions play a central role in driving the transition.

Evidence for cell proliferation in the sheep brain and its down-regulation by parturition and interactions with the young.

Production of new neurons continues throughout life in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus and is influenced by both endocrine and social factors. In sheep parturition is associated with the establishment of a selective bond with the young based on an olfactory learning. The possibility exists that endocrine changes at parturition together with interactions with the young modulate cell proliferation in the neurogenic zones. In the present study, we first investigated the existence of cell proliferation in sheep. Newly born cells labeled by the cell proliferation marker 5-bromo-2'-deoxyuridine (BrdU) were found in the SVZ, the main olfactory bulb (MOB) and the DG and completely co-localized with Ki-67, another mitotic marker. Forty to 50% of the BrdU-labeled cells contained GFAP suggestive of the presence of neural stem cells. Secondly, parturition with or without interactions with the lamb for 2 days, down-regulated the number of BrdU-labeled cells in the 3 proliferation sites in comparison to no pregnancy. An additional control provided evidence that this effect is specific to early postpartum period: estrus with interactions with males did not affect cell proliferation. Our results provide the first characterization of neural cell proliferation in the SVZ, the DG and unexpectedly in the MOB of adult sheep. We hypothesize that the down-regulation of cell proliferation observed in the early postpartum period could facilitate the olfactory perceptual and memory demands associated with maternal behavior by favouring the survival and integration of neurons born earlier.

Vaginocervical stimulation of Ewes induces the rapid formation of a new bond with an alien young without interfering with a previous bond.

Ewes form a selective olfactory memory for their lambs after 2 hr of mother-young interaction following parturition. Mothers will subsequently reject any strange lamb at suckling. The present study investigated whether artificial vaginocervical stimulation (VCS) allows the formation of a selective bond with an unfamiliar lamb and whether it interferes with the maintenance of the bond formed with the familiar lamb. At 2 hr postpartum, mothers were separated from their familiar lamb after having formed a selective bond with it and were given 10 min of mechanical VCS. In the "VCS + lamb" group (n = 24) an unfamiliar lamb was left with the ewe for 2 hr whereas in the "VCS no lamb" group (n = 26) the mother was left alone for the same period of time. Ewes of the "no VCS" group (n = 14) did not receive any VCS. In the majority of animals of the "VCS + lamb" group (23/24) VCS induced a complete acceptance of the unfamiliar lamb without any disruption of the bond previously formed with the familiar lamb. VCS or 2 hr of separation did not disrupt the maintenance of the selective bond initially formed with the familiar lamb since all the ewes of the "VCS no lamb" and "no VCS" groups accepted it at suckling.