Molecular Genetics of T Cell Development

T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment

Standardized Infant NeuroDevelopmental Assessment developmental and socio-emotional scales:reliability and predictive value in an at-risk population

AIM: To assess the reliability and predictive validity of the developmental and socio-emotional scales of the Standardized Infant NeuroDevelopmental Assessment (SINDA). METHOD: To assess reliability, two sets of three assessors forming eight assessor-pairs independently rated the developmental and socio-emotional scales of 60 infants. To evaluate predictive validity, 223 infants (gestational age 30wks [range 23-41wks]; 117 males, 106 females) attending a non-academic outpatient clinic were assessed by different assessors with SINDA's neurological, developmental, and socio-emotional scales. Atypical neurodevelopmental outcome at a corrected age of 24 months or older implied a Bayley Mental or Psychomotor Developmental Index score of less than 70 or neurological disorder (including cerebral palsy). Behavioural and emotional disorders were classified according to the International Classification of Diseases, 10th Revision. Predictive values were calculated from SINDA (2-12mo corrected age, median 7mo) and typical versus atypical outcome, and for intellectual disability only (Mental Developmental Index <70). RESULTS: Assessors highly agreed on the developmental and socio-emotional assessments (developmental scores: Spearman's rank correlation coefficient ρ=0.972; single socio-emotional behaviour items: Cohen's κ=0.783-0.896). At 24 months or older, 65 children had atypical outcome. Atypical neurological scores predicted atypical outcome (sensitivity 83%, specificity 96%); atypical developmental scores predicted intellectual disability (sensitivity 77%, specificity 92%). Atypical emotionality and atypical self-regulation were associated with behavioural and emotional disorders. INTERPRETATION: SINDA's three scales are reliable, and have a satisfactory predictive validity for atypical developmental outcome at 24 months or older in a non-academic outpatient setting. SINDA's developmental scale has promising predictive validity for intellectual disability. SINDA's socio-emotional scale is a tool for caregiver counselling. WHAT THIS PAPER ADDS: Standardized Infant NeuroDevelopmental Assessment (SINDA)'s developmental and socio-emotional scales have excellent interrater reliability. Replication of the satisfactory validity of SINDA's neurological scale for atypical outcome

Circuit dissection of the role of somatostatin in itch and pain

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide

The interaction between practice and performance pressure on the planning and control of fast target directed movement

Pressure to perform often results in decrements to both outcome accuracy and the kinematics of motor skills. Furthermore, this pressure-performance relationship is moderated by the amount of accumulated practice or the experience of the performer. However, the interactive effects of performance pressure and practice on the underlying processes of motor skills are far from clear. Movement execution involves both an offline pre-planning process and an online control process. The present experiment aimed to investigate the interaction between pressure and practice on these two motor control processes. Two groups of participants (control and pressure; N = 12 and 12, respectively) practiced a video aiming amplitude task and were transferred to either a non-pressure (control group) or a pressure condition (pressure group) both early and late in practice. Results revealed similar accuracy and movement kinematics between the control and pressure groups at early transfer. However, at late transfer, the introduction of pressure was associated with increased performance compared to control conditions. Analysis of kinematic variability throughout the movement suggested that the performance increase was due to participants adopting strategies to improve movement planning in response to pressure reducing the effectiveness of the online control system

Effectiveness of second-generation antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone

<p>Abstract</p> <p>Background</p> <p>No clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line second-generation antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes.</p> <p>Methods</p> <p>Patients ≥ 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years.</p> <p>Results</p> <p>A total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naïve. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups.</p> <p>Conclusions</p> <p>Quetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID; URL: <url>http://www.clinicaltrials.gov/</url>: NCT00932529</p

Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium

Protein N-terminal acetylation: NAT 2007–2008 Symposia

Protein N-terminal acetylation is a very common modification, but has during the past decades received relatively little attention. In order to put this neglected field back on the scientific map, we have in May 2007 and September 2008 arranged two international NAT symposia in Bergen, Norway. This supplement contains selected proceedings from these symposia reflecting the current status of the field, including an overview of protein N-terminal acetylation in yeast and humans, a novel nomenclature system for the N-terminal acetyltransferases (NATs) and methods for studying protein N-terminal acetylation in vitro and in vivo

Adverse childhood experiences and mental health in young adults: a longitudinal survey

BACKGROUND: Adverse childhood experiences (ACEs) have been consistently linked to psychiatric difficulties in children and adults. However, the long-term effects of ACEs on mental health during the early adult years have been understudied. In addition, many studies are methodologically limited by use of non-representative samples, and few studies have investigated gender and racial differences. The current study relates self-reported lifetime exposure to a range of ACEs in a community sample of high school seniors to three mental health outcomes–depressive symptoms, drug abuse, and antisocial behavior–two years later during the transition to adulthood. METHODS: The study has a two-wave, prospective design. A systematic probability sample of high school seniors (N = 1093) was taken from communities of diverse socioeconomic status. They were interviewed in person in 1998 and over the telephone two years later. Gender and racial differences in ACE prevalence were tested with chi-square tests. Each mental health outcome was regressed on one ACE, controlling for gender, race/ethnicity, and SES to obtain partially standardized regression coefficients. RESULTS: Most ACEs were strongly associated with all three outcomes. The cumulative effect of ACEs was significant and of similar magnitude for all three outcomes. Except for sex abuse/assault, significant gender differences in the effects of single ACEs on depression and drug use were not observed. However, boys who experienced ACEs were more likely to engage in antisocial behavior early in young adulthood than girls who experienced similar ACEs. Where racial/ethnic differences existed, the adverse mental health impact of ACEs on Whites was consistently greater than on Blacks and Hispanics. CONCLUSION: Our sample of young adults from urban, socio-economically disadvantaged communities reported high rates of adverse childhood experiences. The public health impact of childhood adversity is evident in the very strong association between childhood adversity and depressive symptoms, antisocial behavior, and drug use during the early transition to adulthood. These findings, coupled with evidence that the impact of major childhood adversities persists well into adulthood, indicate the critical need for prevention and intervention strategies targeting early adverse experiences and their mental health consequences

Root hydrotropism is controlled via a cortex-specific growth mechanism

Plants can acclimate by using tropisms to link the direction of growth to environmental conditions. Hydrotropism allows roots to forage for water, a process known to depend on abscisic acid (ABA) but whose molecular and cellular basis remains unclear. Here, we show that hydrotropism still occurs in roots after laser ablation removed the meristem and root cap. Additionally, targeted expression studies reveal that hydrotropism depends on the ABA signalling kinase, SnRK2.2, and the hydrotropism-specific MIZ1, both acting specifically in elongation zone cortical cells. Conversely, hydrotropism, but not gravitropism, is inhibited by preventing differential cell-length increases in the cortex, but not in other cell types. We conclude that root tropic responses to gravity and water are driven by distinct tissue-based mechanisms. In addition, unlike its role in root gravitropism, the elongation zone performs a dual function during a hydrotropic response, both sensing a water potential gradient and subsequently undergoing differential growth