Verbal instructions and top-down saccade control.

Few studies have addressed the interaction between instruction content and saccadic eye movement control. To assess the impact of instructions on top-down control, we instructed 20 healthy volunteers to deliberately delay saccade triggering, to make inaccurate saccades or to redirect saccades--i.e. to glimpse towards and then immediately opposite to the target. Regular pro- and antisaccade tasks were used for comparison. Bottom-up visual input remained unchanged and was a gap paradigm for all instructions. In the inaccuracy and delay tasks, both latencies and accuracies were detrimentally impaired by either type of instruction and the variability of latency and accuracy was increased. The intersaccadic interval (ISI) required to correct erroneous antisaccades was shorter than the ISI for instructed direction changes in the redirection task. The word-by-word instruction content interferes with top-down saccade control. Top-down control is a time consuming process, which may override bottom-up processing only during a limited time period. It is questionable whether parallel processing is possible in top-down control, since the long ISI for instructed direction changes suggests sequential planning.

Role of diuretics, blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study

OBJECTIVE To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. DESIGN Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. SETTING NAVIGATOR trial. PARTICIPANTS Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. MAIN OUTCOME MEASURES Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. RESULTS During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). CONCLUSIONS Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant.

Whole-body motion discrimination in the visually impaired

Visually impaired people show superior abilities in various perception tasks such as auditory attention, auditory temporal resolution, auditory spatial tuning, and odor discrimination. However, with the use of psychophysical methods, auditory and olfactory detection thresholds typically do not differ between visually impaired and sighted participants. Using a motion platform we investigated thresholds of passive whole-body motion discrimination in nine visually impaired participants and nine age-matched sighted controls. Participants were rotated in yaw, tilted in roll, and translated along the y-axis at two different frequencies (0.3 Hz and 2 Hz). An adaptive 3-down 1-up staircase procedure was used along with a two-alternative direction (leftward vs. rightward) discrimination task. Superior performance of visually impaired participants was found in the 0.3 Hz roll tilt condition. No differences between the visually impaired and controls were observed in all other types of motion. The superior performance in the 0.3 Hz roll tilt condition could reflect differences in the integration of extra-vestibular cues and increased sensitivity towards changes in the direction of the gravito-inertial force. In the absence of visual information, roll tilts entail a more pronounced risk of falling, and this could eventually account for the group difference. It is argued that differences in experimental procedures (i.e. detection vs. discrimination of stimuli) explain the discrepant findings across perceptual tasks comparing blind and sighted participants.

Nonverbal social communication and gesture control in schizophrenia

Schizophrenia patients are severely impaired in nonverbal communication, including social perception and gesture production. However, the impact of nonverbal social perception on gestural behavior remains unknown, as is the contribution of negative symptoms, working memory, and abnormal motor behavior. Thus, the study tested whether poor nonverbal social perception was related to impaired gesture performance, gestural knowledge, or motor abnormalities. Forty-six patients with schizophrenia (80%), schizophreniform (15%), or schizoaffective disorder (5%) and 44 healthy controls matched for age, gender, and education were included. Participants completed 4 tasks on nonverbal communication including nonverbal social perception, gesture performance, gesture recognition, and tool use. In addition, they underwent comprehensive clinical and motor assessments. Patients presented impaired nonverbal communication in all tasks compared with controls. Furthermore, in contrast to controls, performance in patients was highly correlated between tasks, not explained by supramodal cognitive deficits such as working memory. Schizophrenia patients with impaired gesture performance also demonstrated poor nonverbal social perception, gestural knowledge, and tool use. Importantly, motor/frontal abnormalities negatively mediated the strong association between nonverbal social perception and gesture performance. The factors negative symptoms and antipsychotic dosage were unrelated to the nonverbal tasks. The study confirmed a generalized nonverbal communication deficit in schizophrenia. Specifically, the findings suggested that nonverbal social perception in schizophrenia has a relevant impact on gestural impairment beyond the negative influence of motor/frontal abnormalities.

Impaired top-down modulation of saccadic latencies in patients with schizophrenia but not in first-degree relatives

Impaired eye movements have a long history in schizophrenia research and meet the criteria of a reliable biomarker. However, the effects of cognitive load and task difficulty on saccadic latencies (SL) are less understood. Recent studies showed that SL are strongly task dependent: SL are decreased in tasks with higher cognitive demand, and increased in tasks with lower cognitive demand. The present study investigates SL modulation in patients with schizophrenia and their first-degree relatives. A group of 13 patients suffering from ICD-10 schizophrenia, 10 first-degree relatives, and 24 control subjects performed two different types of visual tasks: a color task and a Landolt ring orientation task. We used video-based oculography to measure SL. We found that patients exhibited a similar unspecific SL pattern in the two different tasks, whereas controls and relatives exhibited 20–26% shorter average latencies in the orientation task (higher cognitive demand) compared to the color task (lower cognitive demand). Also, classification performance using support vector machines suggests that relatives should be assigned to the healthy controls and not to the patient group. Therefore, visual processing of different content does not modulate SL in patients with schizophrenia, but modulates SL in the relatives and healthy controls. The results reflect a specific oculomotor attentional dysfunction in patients with schizophrenia that is a potential state marker, possibly caused by impaired top-down disinhibition of the superior colliculus by frontal/prefrontal areas such as the frontal eye fields.

The role of self-control strength in the development of state anxiety in test situations

Self-control strength may affect state anxiety because emotion regulation is impaired in individuals whose self-control strength has been temporarily depleted. Increases in state anxiety were expected to be larger for participants with depleted compared to nondepleted self-control strength, and trait test anxiety should predict increases in state anxiety more strongly if self-control strength is depleted. In a sample of 76 university students, trait test anxiety was assessed, self-control strength experimentally manipulated, and state anxiety measured before and after the announcement of a test. State anxiety increased after the announcement. Trait test anxiety predicted increases in state anxiety only in students with depleted self-control strength, suggesting that increased self-control strength may be useful for coping with anxiety.

What is self-control depleting in sports? Effects of vicarious experiences on performance

In the present study, we investigated the influence of sport specific vicarious depletion of self-control strength on performance in a Stroop task. In a betweensubject design N = 40 participants were randomly assigned to either a depletion condition in which they read a story about a soccer player who had to strongly regulate himself, or a non-depletion condition in which they read a story about a soccer player who did not have to regulate himself. Participants in both conditions were instructed to relive the soccer players' thoughts and feelings and we hypothesized that in the depletion condition participants would perform worse in a subsequent self-control task. The results were as expected as depleted participants showed longer latencies on the Stroop task. This study delivers a first indication that athletes are confronted with self-control demanding situations during sporting competitions which can lead to a depletion of self-control strength and impaired performance.

Impaired Cell Cycle Regulation in a Natural Equine Model of Asthma.

Recurrent airway obstruction (RAO) is a common and potentially debilitating lower airway disease in horses, which shares many similarities with human asthma. In susceptible horses RAO exacerbation is caused by environmental allergens and irritants present in hay dust. The objective of this study was the identification of genes and pathways involved in the pathology of RAO by global transcriptome analyses in stimulated peripheral blood mononuclear cells (PBMCs). We performed RNA-seq on PBMCs derived from 40 RAO affected and 45 control horses belonging to three cohorts of Warmblood horses: two half-sib families and one group of unrelated horses. PBMCs were stimulated with hay dust extract, lipopolysaccharides, a recombinant parasite antigen, or left unstimulated. The total dataset consisted of 561 individual samples. We detected significant differences in the expression profiles between RAO and control horses. Differential expression (DE) was most marked upon stimulation with hay dust extract. An important novel finding was a strong upregulation of CXCL13 together with many genes involved in cell cycle regulation in stimulated samples from RAO affected horses, in addition to changes in the expression of several HIF-1 transcription factor target genes. The RAO condition alters systemic changes observed as differential expression profiles of PBMCs. Those changes also depended on the cohort and stimulation of the samples and were dominated by genes involved in immune cell trafficking, development, and cell cycle regulation. Our findings indicate an important role of CXCL13, likely macrophage or Th17 derived, and the cell cycle regulator CDC20 in the immune response in RAO.

Statistical Learning, Syllable Processing, and Speech Production in Healthy Hearing and Hearing-Impaired Preschool Children: A Mismatch Negativity Study

OBJECTIVES The objectives of the present study were to investigate temporal/spectral sound-feature processing in preschool children (4 to 7 years old) with peripheral hearing loss compared with age-matched controls. The results verified the presence of statistical learning, which was diminished in children with hearing impairments (HIs), and elucidated possible perceptual mediators of speech production. DESIGN Perception and production of the syllables /ba/, /da/, /ta/, and /na/ were recorded in 13 children with normal hearing and 13 children with HI. Perception was assessed physiologically through event-related potentials (ERPs) recorded by EEG in a multifeature mismatch negativity paradigm and behaviorally through a discrimination task. Temporal and spectral features of the ERPs during speech perception were analyzed, and speech production was quantitatively evaluated using speech motor maximum performance tasks. RESULTS Proximal to stimulus onset, children with HI displayed a difference in map topography, indicating diminished statistical learning. In later ERP components, children with HI exhibited reduced amplitudes in the N2 and early parts of the late disciminative negativity components specifically, which are associated with temporal and spectral control mechanisms. Abnormalities of speech perception were only subtly reflected in speech production, as the lone difference found in speech production studies was a mild delay in regulating speech intensity. CONCLUSIONS In addition to previously reported deficits of sound-feature discriminations, the present study results reflect diminished statistical learning in children with HI, which plays an early and important, but so far neglected, role in phonological processing. Furthermore, the lack of corresponding behavioral abnormalities in speech production implies that impaired perceptual capacities do not necessarily translate into productive deficits.

Acetate metabolism and the control of environmental pH in Candida albicans and Saccharomyces cerevisiae

Candida albicans is the most common opportunistic fungal pathogen of humans. The balance between commensal and pathogenic C. albicans is maintained largely by phagocytes of the innate immune system. Analysis of transcriptional changes after macrophage phagocytosis indicates the C. albicans response is broadly similar to starvation, including up-regulation of alternate carbon metabolism. Systems known and suspected to be part of acetate/acetyl-CoA metabolism were also up-regulated, importantly the ACH and ACS genes, which manage acetate/acetyl-CoA interconversion, and the nine-member ATO gene family, thought to participate in transmembrane acetate transport and also linked to the process of environmental alkalinization. ^ Studies into the roles of Ach, Acs1 and Acs2 function in alternate carbon metabolism revealed a substantial role for Acs2 and lesser, but distinct roles, for Ach and Acs1. Deletion mutants were made in C. albicans and were phenotypically evaluated both in vitro and in vivo. Loss of Ach function resulted in mild growth defects on ethanol and acetate and no significant attenuation in virulence in a disseminated mouse model of infection. While loss of Acs1 did not produce any significant phenotypes, loss of Acs2 greatly impaired growth on multiple carbon sources, including glucose, ethanol and acetate. We also concluded that ACS1 and ACS2 likely comprise an essential gene pair. Expression analyses indicated that ACS2 is the predominant form under most growth conditions. ^ ATO gene function had been linked to the process of environmental alkalinization, an ammonium-mediated phenomenon described here first in C. albicans. During growth in glucose-poor, amino acid-rich conditions C. albicans can rapidly change its extracellular pH. This process was glucose-repressible and was accompanied by hyphal formation and changes in colony morphology. We showed that introduction of the ATO1G53D point mutant to C. albicans blocked alkalinization, as did over-expression of C. albicans ATO2, the only C. albicans ATO gene to lack the conserved N-terminal domain. A screen for alkalinization-deficient mutants revealed that ACH1 is essential for alkalinization. However, addition of acetate to the media restored alkalinization to the ach1 mutant. We proposed a model of ATO function in which Atos regulated the cellular co-export of ammonium and acetate. ^

Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice

Calretinin (Cr) is a Ca2+ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr−/−) mice by gene targeting and have investigated the associated phenotype. Cr−/− mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr−/− mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr−/− mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABAA receptor antagonist bicuculline, suggesting that in Cr−/− dentate gyrus an excess of γ-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr−/− mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr−/− mice represent a useful tool to understand the role of dentate LTP in learning and memory.

Control of Meristem Development by CLAVATA1 Receptor Kinase and Kinase-Associated Protein Phosphatase Interactions1

The CLAVATA1 (CLV1) gene encodes a putative receptor kinase required for the proper balance between cell proliferation and differentiation in Arabidopsis shoot and flower meristems. Impaired CLV1 signaling results in masses of undifferentiated cells at the shoot and floral meristems. Although many putative receptor kinases have been identified in plants, the mechanism of signal transduction mediated by plant receptor-like kinases is largely unknown. One potential effector of receptor kinase signaling is kinase-associated protein phosphatase (KAPP), a protein that binds to multiple plant receptor-like kinases in a phosphorylation-dependent manner. To examine a possible role for KAPP in CLV1-dependent plant development, the interaction of CLV1 and KAPP was investigated in vitro and in vivo. KAPP binds directly to autophosphorylated CLV1 in vitro and co-immunoprecipitates with CLV1 in plant extracts derived from meristematic tissue. Reduction of KAPP transcript accumulation in an intermediate clv1 mutant suppresses the mutant phenotype, and the degree of suppression is inversely correlated with KAPP mRNA levels. These data suggest that KAPP functions as a negative regulator of CLV1 signaling in plant development. This may represent a general model for the interaction of KAPP with receptor kinases.

Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.

Globin genes are subject to tissue-specific and developmental stage-specific regulation. A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage. Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Krüppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter. To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene. We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold. Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch. Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.

Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling.

The Brn-3 subfamily of POU domain genes are expressed in sensory neurons and in select brainstem nuclei. Earlier work has shown that targeted deletion of the Brn-3b and Brn-3c genes produce, respectively, defects in the retina and in the inner ear. We show herein that targeted deletion of the Brn-3a gene results in defective suckling and in uncoordinated limb and trunk movements, leading to early postnatal death. Brn-3a (-/-) mice show a loss of neurons in the trigeminal ganglia, the medial habenula, the red nucleus, and the caudal region of the inferior olivary nucleus but not in the retina and dorsal root ganglia. In the trigeminal and dorsal root ganglia, but not in the retina, there is a marked decrease in the frequency of neurons expressing Brn-3b and Brn-3c, suggesting that Brn-3a positively regulates Brn-3b and Brn-3c expression in somatosensory neurons. Thus, Brn-3a exerts its major developmental effects in somatosensory neurons and in brainstem nuclei involved in motor control. The pheno-types of Brn-3a, Brn-3b, and Brn-3c mutant mice indicate that individual Brn-3 genes have evolved to control development in the auditory, visual, or somatosensory systems and that despite differences between these systems in transduction mechanisms, sensory organ structures, and central information processing, there may be fundamental homologies in the genetic regulatory events that control their development.

Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions.

Functional roles of the cortical backward signal in long-term memory formation were studied in monkeys performing a visual pair-association task. Before the monkeys learned the task, the anterior commissure was transected, disconnecting the anterior temporal cortex of each hemisphere. After training with 12 pairs of pictures, single units were recorded from the inferotemporal cortex of the monkeys as the control. By injecting a grid of ibotenic acid, we unilaterally lesioned the entorhinal and perirhinal cortex, which provides massive direct and indirect backward projections ipsilaterally to the inferotemporal cortex. After the lesion, the monkeys fixated the cue stimulus normally, relearned the preoperatively learned set (set A), and learned a new set (set B) of paired associates. Then, single units were recorded from the same area as for the prelesion control. We found that (i) in spite of the lesion, the sampled neurons responded strongly and selectively to both the set A and set B patterns and (ii) the paired associates elicited significantly correlated responses in the control neurons before the lesion but not in the cells tested after the lesion, either for set A or set B stimuli. We conclude that the ability of inferotemporal neurons to represent association between picture pairs was lost after the lesion of entorhinal and perirhinal cortex, most likely through disruption of backward neural signals to the inferotemporal neurons, while the ability of the neurons to respond to a particular visual stimulus was left intact.