CF2 Represses Actin 88F Gene Expression and Maintains Filament Balance during Indirect Flight Muscle Development in Drosophila

The zinc finger protein CF2 is a characterized activator of muscle structural genes in the body wall muscles of the Drosophila larva. To investigate the function of CF2 in the indirect flight muscle (IFM), we examined the phenotypes of flies bearing five homozygous viable mutations. The gross structure of the IFM was not affected, but the stronger hypomorphic alleles caused an increase of up to 1.5X in the diameter of the myofibrils. This size increase did not cause any disruption of the hexameric arrangement of thick and thin filaments. RT-PCR analysis revealed an increase in the transcription of several structural genes. Ectopic overexpression of CF2 in the developing IFM disrupts muscle formation. While our results indicate a role for CF2 as a direct negative regulator of the thin filament protein gene Actin 88F (Act88F), effects on levels of transcripts of myosin heavy chain (mhc) appear to be indirect. This role is in direct contrast to that described in the larval muscles, where CF2 activates structural gene expression. The variation in myofibril phenotypes of CF2 mutants suggest the CF2 may have separate functions in fine-tuning expression of structural genes to insure proper filament stoichiometry, and monitoring and/or controlling the final myofibril size

Impact of Visual Repetition Rate on Intrinsic Properties of Low Frequency Fluctuations in the Visual Network

BACKGROUND: Visual processing network is one of the functional networks which have been reliably identified to consistently exist in human resting brains. In our work, we focused on this network and investigated the intrinsic properties of low frequency (0.01-0.08 Hz) fluctuations (LFFs) during changes of visual stimuli. There were two main questions to be discussed in this study: intrinsic properties of LFFs regarding (1) interactions between visual stimuli and resting-state; (2) impact of repetition rate of visual stimuli. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed scanning sessions that contained rest and visual stimuli in various repetition rates with a novel method. The method included three numerical approaches involving ICA (Independent Component Analyses), fALFF (fractional Amplitude of Low Frequency Fluctuation), and Coherence, to respectively investigate the modulations of visual network pattern, low frequency fluctuation power, and interregional functional connectivity during changes of visual stimuli. We discovered when resting-state was replaced by visual stimuli, more areas were involved in visual processing, and both stronger low frequency fluctuations and higher interregional functional connectivity occurred in visual network. With changes of visual repetition rate, the number of areas which were involved in visual processing, low frequency fluctuation power, and interregional functional connectivity in this network were also modulated. CONCLUSIONS/SIGNIFICANCE: To combine the results of prior literatures and our discoveries, intrinsic properties of LFFs in visual network are altered not only by modulations of endogenous factors (eye-open or eye-closed condition; alcohol administration) and disordered behaviors (early blind), but also exogenous sensory stimuli (visual stimuli with various repetition rates). It demonstrates that the intrinsic properties of LFFs are valuable to represent physiological states of human brains

Local Oxidative and Nitrosative Stress Increases in the Microcirculation during Leukocytes-Endothelial Cell Interactions

Leukocyte-endothelial cell interactions and leukocyte activation are important factors for vascular diseases including nephropathy, retinopathy and angiopathy. In addition, endothelial cell dysfunction is reported in vascular disease condition. Endothelial dysfunction is characterized by increased superoxide (O2•−) production from endothelium and reduction in NO bioavailability. Experimental studies have suggested a possible role for leukocyte-endothelial cell interaction in the vessel NO and peroxynitrite levels and their role in vascular disorders in the arterial side of microcirculation. However, anti-adhesion therapies for preventing leukocyte-endothelial cell interaction related vascular disorders showed limited success. The endothelial dysfunction related changes in vessel NO and peroxynitrite levels, leukocyte-endothelial cell interaction and leukocyte activation are not completely understood in vascular disorders. The objective of this study was to investigate the role of endothelial dysfunction extent, leukocyte-endothelial interaction, leukocyte activation and superoxide dismutase therapy on the transport and interactions of NO, O2•− and peroxynitrite in the microcirculation. We developed a biotransport model of NO, O2•− and peroxynitrite in the arteriolar microcirculation and incorporated leukocytes-endothelial cell interactions. The concentration profiles of NO, O2•− and peroxynitrite within blood vessel and leukocytes are presented at multiple levels of endothelial oxidative stress with leukocyte activation and increased superoxide dismutase accounted for in certain cases. The results showed that the maximum concentrations of NO decreased ∼0.6 fold, O2•− increased ∼27 fold and peroxynitrite increased ∼30 fold in the endothelial and smooth muscle region in severe oxidative stress condition as compared to that of normal physiologic conditions. The results show that the onset of endothelial oxidative stress can cause an increase in O2•− and peroxynitrite concentration in the lumen. The increased O2•− and peroxynitrite can cause leukocytes priming through peroxynitrite and leukocytes activation through secondary stimuli of O2•− in bloodstream without endothelial interaction. This finding supports that leukocyte rolling/adhesion and activation are independent events

The development of spontaneous facial responses to others’ emotions in infancy. An EMG study

Viewing facial expressions often evokes facial responses in the observer. These spontaneous facial reactions (SFRs) are believed to play an important role for social interactions. However, their developmental trajectory and the underlying neurocognitive mechanisms are still little understood. In the current study, 4- and 7-month old infants were presented with facial expressions of happiness, anger, and fear. Electromyography (EMG) was used to measure activation in muscles relevant for forming these expressions: zygomaticus major (smiling), corrugator supercilii (frowning), and frontalis (forehead raising). The results indicated no selective activation of the facial muscles for the expressions in 4-month-old infants. For 7-month-old infants, evidence for selective facial reactions was found especially for happy faces (leading to increased zygomaticus major activation) and fearful faces (leading to increased frontalis activation), while angry faces did not show a clear differential response. This suggests that emotional SFRs may be the result of complex neurocognitive mechanisms which lead to partial mimicry but are also likely to be influenced by evaluative processes. Such mechanisms seem to undergo important developments at least until the second half of the first year of life

Anxiety and Depression in Adults with Autism Spectrum Disorder: A Systematic Review and Meta-analysis

Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety (n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression (n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations

Eukaryotic Protein Kinases (ePKs) of the Helminth Parasite Schistosoma mansoni

<p>Abstract</p> <p>Background</p> <p>Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The <it>Schistosoma mansoni </it>genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the <it>S. mansoni </it>predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.</p> <p>Results</p> <p>We have identified 252 ePKs, which corresponds to 1.9% of the <it>S. mansoni </it>predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that <it>S. mansoni </it>has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in <it>S. mansoni </it>or belong to an expanded family in this parasite. Only 16 <it>S. mansoni </it>ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.</p> <p>Conclusions</p> <p>Our approach has improved the functional annotation of 40% of <it>S. mansoni </it>ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of <it>S. mansoni </it>in response to diverse environments during the parasite development, vector interaction, and host infection.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.