Controlling heme redox properties in peptide amphiphile fibers with sequence and heme loading ratio.

Controlling the reduction midpoint potential of heme B is a key factor in many bioelectrochemical reactions, including long-range electron transport. Currently, there are a number of globular model protein systems to study this biophysical parameter; however, there are none for large polymeric protein model systems (e.g., the OmcS protein from G. sulfurreducens). Peptide amphiphiles, short peptides with a lipid tail that polymerize into fibrous structures, fill this gap. Here, we show a peptide amphiphile model system where one can tune the electrochemical potential of heme B by changing the loading ratio and peptide sequence. Changing the loading ratio resulted in the most significant increase, with values as high as -22 mV down to -224 mV. Circular dichroism spectra of certain sequences show Cotton effects at lower loading ratios that disappear as more heme B is added, indicating an ordered environment that becomes disrupted if heme B is overpacked. These findings can contribute to the design of functional self-assembling biomaterials.

Progress on the Cu-Catalyzed 1,4-Conjugate Addition to Thiochromones.

Carbon-carbon bond formation is one of the most important tools in synthetic organic chemists' toolbox. It is a fundamental transformation that allows synthetic chemists to synthesize the carbon framework of complex molecules from inexpensive simple starting materials. Among the many synthetic methodologies developed for the construction of carbon-carbon bonds, organocopper reagents are one of the most reliable organometallic reagents for this purpose. The versatility of organocuprate reagents or the reactions catalyzed by organocopper reagents were demonstrated by their applications in a variety of synthetic transformations including the 1,4-conjugate addition reactions. Sulfur-containing heterocyclic compounds are a much less studied area compared to oxygen-containing heterocycles but have gained more and more attention in recent years due to their rich biological activities and widespread applications in pharmaceuticals, agrochemicals, and material science. This paper will provide a brief review on recent progress on the synthesis of an important class of sulfur-heterocycles-2-alkylthiochroman-4-ones and thioflavanones via the conjugate additions of Grignard reagents to thiochromones catalyzed by copper catalysts. Recent progress on the synthesis of 2-substituted thiochroman-4-ones via alkynylation and alkenylation of thiochromones will also be covered in this review.

Fairness norms and theory of mind in an ultimatum game: judgments, offers, and decisions in school-aged children.

The sensitivity to fairness undergoes relevant changes across development. Whether such changes depend on primary inequity aversion or on sensitivity to a social norm of fairness is still debated. Using a modified version of the Ultimatum Game that creates informational asymmetries between Proposer and Responder, a previous study showed that both perceptions of fairness and fair behavior depend upon normative expectations, i.e., beliefs about what others expect one should do in a specific situation. Individuals tend to comply with the norm when risking sanctions, but disregard the norm when violations are undetectable. Using the same methodology with children aged 8-10 years, the present study shows that children's beliefs and behaviors differ from what is observed in adults. Playing as Proposers, children show a self-serving bias only when there is a clear informational asymmetry. Playing as Responders, they show a remarkable discrepancy between their normative judgment about fair procedures (a coin toss to determine the offer) and their behavior (rejection of an unfair offer derived from the coin toss), supporting the existence of an outcome bias effect. Finally, our results reveal no influence of theory of mind on children's decision-making behavior.

Within-session score gains for repeat examinees on a standardized patient examination.

PURPOSE: Previous studies on standardized patient (SP) exams reported score gains both across attempts when examinees failed and retook the exam and over multiple SP encounters within a single exam session. The authors analyzed the within-session score gains of examinees who repeated the United States Medical Licensing Examination Step 2 Clinical Skills to answer two questions: How much do scores increase within a session? Can the pattern of increasing first-attempt scores account for across-session score gains? METHOD: Data included encounter-level scores for 2,165 U.S. and Canadian medical students and graduates who took Step 2 Clinical Skills twice between April 1, 2005 and December 31, 2010. The authors modeled examinees' score patterns using smoothing and regression techniques and applied statistical tests to determine whether the patterns were the same or different across attempts. In addition, they tested whether any across-session score gains could be explained by the first-attempt within-session score trajectory. RESULTS: For the first and second attempts, the authors attributed examinees' within-session score gains to a pattern of score increases over the first three to six SP encounters followed by a leveling off. Model predictions revealed that the authors could not attribute the across-session score gains to the first-attempt within-session score gains. CONCLUSIONS: The within-session score gains over the first three to six SP encounters of both attempts indicate that there is a temporary "warm-up" effect on performance that "resets" between attempts. Across-session gains are not due to this warm-up effect and likely reflect true improvement in performance.

Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia.

CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

Cerebellar development in childhood onset schizophrenia and non-psychotic siblings.

We explored regional and total volumetric cerebellar differences in probands and their unaffected full siblings relative to typically developing participants. Participants included 94 (51 males) patients diagnosed with childhood onset schizophrenia (COS), 80 related non-psychotic siblings (37 males) and 110 (64 males) typically developing participants scanned longitudinally. The sample mean age was 16.87(S.D.=4.7; range 6.5 to 29). We performed mixed model regressions to examine group differences in trajectory and volume. The COS group had smaller bilateral anterior lobes and anterior and total vermis volumes than controls. The COS group diverged from controls over time in total, left, right, and bilateral posterior inferior cerebellum. Siblings did not have any fixed volumetric differences relative to controls but differed from controls in developmental trajectories of total and right cerebellum, left inferior posterior, left superior posterior, and superior vermis. Results are consistent with previous COS findings and several reports of decreased cerebellar volume in adult onset schizophrenia. Sibling trajectories may represent a trait marker, although the effect size for volumetric differences in early adulthood may be small.

Effects of clozapine and olanzapine on cortical thickness in childhood-onset schizophrenia.

BACKGROUND: Little is known about the effects of antipsychotic medications on gray matter (GM) in schizophrenia. Although clozapine remains the most effective antipsychotic medication in treatment-refractory cases, it is unknown whether it has a differential effect on GM development. METHODS: In an exploratory analysis, we used automated cortical thickness measurements and prospectively scanned childhood-onset schizophrenia (COS) patients who were maintained on one medication. Two atypical antipsychotic medications, clozapine (n=12, 37 scans) and olanzapine (n=12, 33 scans) were compared with respect to effects on cortical development, in contrast to GM trajectories of matched controls. RESULTS: There were no significant differences in the trajectories of cortical thickness between the two treatment groups with the exception of a small circumscribed area in the right prefrontal cortex, where the olanzapine group showed thicker cortex. As expected, both groups showed thinner GM compared to matched controls. CONCLUSIONS: Although these analyses do not rule out effects of antipsychotic medications on GM development in schizophrenia, they show no differential effect between clozapine and olanzapine on GM trajectory.

Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited.

OBJECTIVE: To highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS). METHOD: Clinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed. RESULTS: In the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism. CONCLUSIONS: Biological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.

Three-dimensional brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-based morphometry.

Earlier studies revealed progressive cortical gray matter (GM) loss in childhood-onset schizophrenia (COS) across both lateral and medial surfaces of the developing brain. Here, we use tensor-based morphometry to visualize white matter (WM) growth abnormalities in COS throughout the brain. Using high-dimensional elastic image registration, we compared 3D maps of local WM growth rates in COS patients and healthy children over a 5-year period, based on analyzing longitudinal brain MRIs from 12 COS patients and 12 healthy controls matched for age, gender, and scan interval. COS patients showed up to 2.2% slower growth rates per year than healthy controls in WM (P = 0.02, all P values corrected). The greatest differences were in the right hemisphere (P = 0.006). This asymmetry was attributable to a right slower than left hemisphere growth rate mapped in COS patients (P = 0.037) but not in healthy controls. WM growth rates reached 2.6% per year in healthy controls (P = 0.0002). COS patients showed only a 1.3% per year trend for growth in the left hemisphere (P = 0.066). In COS, WM growth rates were associated with improvement in the Children's Global Assessment Scale (R = 0.64, P = 0.029). Growth rates were reduced throughout the brain in COS, but this process appeared to progress in a front-to-back (frontal-parietal) fashion, and this effect was not attributable to lower IQ. Growth rates were correlated with functional prognosis and were visualized as detailed 3D maps. Finally, these findings also confirm that the progressive GM deficits seen in schizophrenia are not the result of WM overgrowth.