Fuzzy oil drop model to interpret the structure of antifreeze proteins and their mutants

Mutations in proteins introduce structural changes and influence biological activity: the specific effects depend on the location of the mutation. The simple method proposed in the present paper is based on a two-step model of in silico protein folding. The structure of the first intermediate is assumed to be determined solely by backbone conformation. The structure of the second one is assumed to be determined by the presence of a hydrophobic center. The comparable structural analysis of the set of mutants is performed to identify the mutant-induced structural changes. The changes of the hydrophobic core organization measured by the divergence entropy allows quantitative comparison estimating the relative structural changes upon mutation. The set of antifreeze proteins, which appeared to represent the hydrophobic core structure accordant with “fuzzy oil drop” model was selected for analysis

Brief Report: Inhibitory Control of Socially Relevant Stimuli in Children with High Functioning Autism

The current study explored whether inhibitory control deficits in high functioning autism (HFA) emerged when socially relevant stimuli were used and whether arousal level affected the performance. A Go/NoGo paradigm, with socially relevant stimuli and varying presentation rates, was applied in 18 children with HFA (including children with autism or Asperger syndrome) and 22 typically developing children (aged 8–13 years). Children with HFA did not show inhibitory control deficits compared to the control group, but their performance deteriorated in the slow presentation rate condition. Findings were unrelated to children’s abilities to recognize emotions. Hence, rather than a core deficit in inhibitory control, low arousal level in response to social stimuli might influence the responses given by children with HFA

Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms

<p>Abstract</p> <p>Background</p> <p>Recent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD.</p> <p>Methods</p> <p>Children aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used.</p> <p>Results</p> <p>There was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task.</p> <p>Conclusion</p> <p>Our findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.</p

Dissociable Components of Cognitive Control: An Event-Related Potential (ERP) Study of Response Inhibition and Interference Suppression

Background: Cognitive control refers to the ability to selectively attend and respond to task-relevant events while resisting interference from distracting stimuli or prepotent automatic responses. The current study aimed to determine whether interference suppression and response inhibition are separable component processes of cognitive control. Methodology/Principal Findings: Fourteen young adults completed a hybrid Go/Nogo flanker task and continuous EEG data were recorded concurrently. The incongruous flanker condition (that required interference suppression) elicited a more centrally distributed topography with a later N2 peak than the Nogo condition (that required response inhibition). Conclusions/Significance: These results provide evidence for the dissociability of interference suppression and response inhibition, indicating that taxonomy of inhibition is warranted with the integration of research evidence from neuroscience

Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either gram negative or gram positive bacteria

<p>Abstract</p> <p>Background</p> <p>In the ICU, bacteremia is a life-threatening infection whose prognosis is highly dependent on early recognition and treatment with appropriate antibiotics. Procalcitonin levels have been shown to distinguish between bacteremia and noninfectious inflammatory states accurately and quickly in critically ill patients. However, we still do not know to what extent the magnitude of PCT elevation at the onset of bacteremia varies according to the Gram stain result.</p> <p>Methods</p> <p>Review of the medical records of every patient treated between May, 2004 and December, 2006 who had bacteremia caused by either Gram positive (GP) or Gram negative (GN) bacteria, and whose PCT dosage at the onset of infection was available.</p> <p>Results</p> <p>97 episodes of either GN bacteremia (<it>n </it>= 52) or GP bacteremia (<it>n </it>= 45) were included. Procalcitonin levels were found to be markedly higher in patients with GN bacteremia than in those with GP bacteremia, whereas the SOFA score value in the two groups was similar. Moreover, in the study population, a high PCT value was found to be independently associated with GN bacteremia. A PCT level of 16.0 ng/mL yielded an 83.0% positive predictive value and a 74.0% negative predictive value for GN-related bacteremia in the study cohort (AUROCC = 0.79; 95% CI, 0.71–0.88).</p> <p>Conclusion</p> <p>In a critically ill patient with clinical sepsis, GN bacteremia could be associated with higher PCT values than those found in GP bacteremia, regardless of the severity of the disease.</p

Impact of previous sepsis on the accuracy of procalcitonin for the early diagnosis of blood stream infection in critically ill patients

<p>Abstract</p> <p>Background</p> <p>Blood stream infections (BSI) are life-threatening infections in intensive care units (ICU), and prognosis is highly dependent on early detection. Procalcitonin levels have been shown to accurately and quickly distinguish between BSI and noninfectious inflammatory states in critically ill patients. It is, however, unknown to what extent a recent history of sepsis (namely, secondary sepsis) can affect diagnosis of BSI using PCT.</p> <p>Methods</p> <p>review of the medical records of every patient with BSI in whom PCT dosage at the onset of sepsis was available between 1^stSeptember, 2006 and 31^stJuly, 2007.</p> <p>Results</p> <p>179 episodes of either primary (<it>n </it>= 117) or secondary (<it>n </it>= 62) sepsis were included. Procalcitonin levels were found to be markedly lower in patients with secondary sepsis than in those without (6.4 [9.5] vs. 55.6 [99.0] ng/mL, respectively; <it>p </it>< 0.001), whereas the SOFA score was similar in the two groups. Although patients in the former group were more likely to have received steroids and effective antibiotic therapy prior to the BSI episode, and despite a higher proportion of candidemia in this group, a low PCT value was found to be independently associated with secondary sepsis (Odd Ratio = 0.33, 95% Confidence Interval: 0.16–0.70; <it>p </it>= 0.004). Additional patients with suspected but unconfirmed sepsis were used as controls (<it>n </it>= 23). Thus, diagnostic accuracy of PCT as assessed by the area under the receiver-operating characteristic curves (AUROCC) measurement was decreased in the patients with secondary sepsis compared to those without (AUROCC = 0.805, 95% CI: 0.699–0.879, vs. 0.934, 95% CI: 0.881–0.970, respectively; <it>p </it>< 0.050).</p> <p>Conclusion</p> <p>In a critically ill patient with BSI, PCT elevation and diagnosis accuracy could be lower if sepsis is secondary than in those with a first episode of infection.</p

Large neutral amino acids in the treatment of PKU: from theory to practice

Notwithstanding the success of the traditional dietary phenylalanine restriction treatment in phenylketonuria (PKU), the use of large neutral amino acid (LNAA) supplementation rather than phenylalanine restriction has been suggested. This treatment modality deserves attention as it might improve cognitive outcome and quality of life in patients with PKU. Following various theories about the pathogenesis of cognitive dysfunction in PKU, LNAA supplementation may have multiple treatment targets: a specific reduction in brain phenylalanine concentrations, a reduction in blood (and consequently brain) phenylalanine concentrations, an increase in brain neurotransmitter concentrations, and an increase in brain essential amino acid concentrations. These treatment targets imply different treatment regimes. This review summarizes the treatment targets and the treatment regimens of LNAA supplementation and discusses the differences in LNAA intake between the classical dietary phenylalanine-restricted diet and several LNAA treatment forms

Conserved expression and functions of PDE4 in rodent and human heart

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts

Mechanosensing is critical for axon growth in the developing brain.

During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.This work was supported by the German National Academic Foundation (scholarship to D.E.K.), Wellcome Trust and Cambridge Trusts (scholarships to A.J.T.), Winston Churchill Foundation of the United States (scholarship to S.K.F.), Herchel Smith Foundation (Research Studentship to S.K.F.), CNPq 307333/2013-2 (L.d.F.C.), NAP-PRP-USP and FAPESP 11/50761-2 (L.d.F.C.), UK EPSRC BT grant (J.G.), Wellcome Trust WT085314 and the European Research Council 322817 grants (C.E.H.); an Alexander von Humboldt Foundation Feodor Lynen Fellowship (K.F.), UK BBSRC grant BB/M021394/1 (K.F.), the Human Frontier Science Program Young Investigator Grant RGY0074/2013 (K.F.), the UK Medical Research Council Career Development Award G1100312/1 (K.F.) and the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R21HD080585 (K.F.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/nn.439