Brain function operates through the coordinated activation of neuronal assemblies. Graph theory predicts that scale-free topologies, which include "hubs" (superconnected nodes), are an effective ...design to orchestrate synchronization. Whether hubs are present in neuronal assemblies and coordinate network activity remains unknown. Using network dynamics imaging, online reconstruction of functional connectivity, and targeted whole-cell recordings in rats and mice, we found that developing hippocampal networks follow a scale-free topology, and we demonstrated the existence of functional hubs. Perturbation of a single hub influenced the entire network dynamics. Morphophysiological analysis revealed that hub cells are a subpopulation of γ-aminobutyric acid-releasing (GABAergic) interneurons possessing widespread axonal arborizations. These findings establish a central role for GABAergic interneurons in shaping developing networks and help provide a conceptual framework for studying neuronal synchrony.
•Drivers adopting maladaptive styles have a higher level of general difficulties in emotion regulation.•Specific driving styles are associated with specific emotional regulation ...difficulties.•Maladaptive driving styles are related to low trait forgivingness.•Patient and careful drivers had fewer difficulties in all aspects of emotion regulation.•Patient and careful drivers had higher trait forgivingness.
Joining worldwide efforts to better understand factors associated with driving behaviors, the current study is aimed at examining the associations between emotional regulation and trait forgivingness, on one hand, and driving styles, on the other. A sample of 287 Israeli drivers completed scales assessing their driving styles, emotion regulation difficulties, and trait forgivingness. Results show that drivers adopting the three maladaptive driving styles (reckless and careless, angry and hostile, anxious) were characterized by a higher level of general difficulties in emotion regulation and by low trait forgivingness. In contrast, drivers adopting the patient and careful driving style had fewer difficulties in all aspects of emotion regulation, as well as higher trait forgivingness. The theoretical contribution of the study lays in showing that difficulties in emotion regulation and forgivingness are closely associated with maladaptive driving styles- an issue crucial for promoting the substantial efforts being invested in the attempts to reduce road crashes.
We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now ...hypothesized the BRV-HRV continuum originates in pacemaker cells.
To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node.
We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell-derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual.
Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincaré plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs (P < .05) and the in situ heart (the latter two were similar; P > .05). We also compared BRV magnitude among single cells, small EBs (~5-10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P < .05). Disrupting intracellular Ca(2+) handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm.
The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca(2+) handling determine HRV in humans and cardiomyocyte networks.
Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M ...(Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.
Background & Aims The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve ...patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure. Methods We collected data from 2099 participants in the HCV-TARGET study with complete virologic data (per-protocol population). We analyzed data from 1788 patients receiving ledipasvir-sofosbuvir (282 for 8 weeks, 910 for 12 weeks, 510 for 24 weeks, and 86 for a different duration) and 311 receiving ledipasvir-sofosbuvir plus ribavirin (212 for 12 weeks and 81 for 24 weeks, 18 for other duration) to estimate SVR12 (with 95% confidence interval CI), and logistic regression methods to identify factors that predicted an SVR12. Results The overall study population was 25% black, 66% with HCV genotype 1A infection, 41% with cirrhosis, 50% treatment-experienced, and 30% receiving proton pump inhibitors at start of treatment. In the per-protocol population, SVR12s were achieved by 96% of patients receiving ledipasvir-sofosbuvir for 8 weeks (95% CI, 93%−98%), 97% receiving the drugs for 12 weeks (95% CI, 96%−98%), and 95% receiving the drugs for 24 weeks (95% CI, 93%−97%). Among patients also receiving ribavirin, SVR12 was achieved by 97% of the patients receiving the drugs for 12 weeks (95% CI, 94%−99%) and 95% receiving the drugs for 24 weeks (95% CI, 88%−99%). Of the 586 patients who qualified for 8 weeks of treatment, only 255 (44%) received the drugs for 8 weeks. The rate of SVR12 among those who qualified for and received 8 weeks of therapy was similar in those who qualified for 8 weeks but received 12 weeks therapy (96%; 95% CI, 92%−99% vs 98%; 95% CI, 95%−99%). Factors that predicted SVR12 were higher albumin (≥3.5 g/dL), lower total bilirubin (≤1.2 g/dL), absence of cirrhosis, and absence of proton pump inhibitor use. Conclusions Regimens containing ledipasvir and sofosbuvir are highly effective for a broad spectrum of patients with HCV genotype 1 infection treated in different clinical practice settings. Expanded use of 8-week treatment regimens for eligible patients is supported by these real-world results. Modification of proton pump inhibitor use may increase rates of SVR. ClinicalTrials.gov no. NCT01474811.
Co-culture of the detritivorous flathead grey mullet (Mugil cephalus) and gilthead seabream (Sparus aurata) in land-based Integrated Multi-Trophic Aquaculture (IMTA) system was evaluated with respect ...to yield, Specific Growth Rate (SGR), Food Conversion Ratio (FCR), survival, nitrogen assimilation rate and efficiency. Water from the Gulf of Aqaba was pumped into three cylindrical m3 tanks. Each tank was stocked with seventy 11.37±3.7g mullets. In each tank three floating rectangular cages were placed, each stocked with 100, 42.9±7.5g seabream. Seabream were fed a pelleted diet (46% protein) throughout the day. Sludge of the seabream sank to the bottom where the mullets fed on them. Final yields were 170.7kg of seabream (100% survival) and 9.68kg of grey mullet (82% survival), i.e., a biomass yield ratio of 1kg mullet vs.17kg seabream. Co-culture of seabream and mullet increased the overall biomass production by 4–8%, increased nitrogen assimilation by the fish by 6–8%, reduced FCR by 10–15%, reduced amount of the sludge by 98%, and increased dissolved nitrogen emissions by 7%. Since the income from the mullet yield is relatively marginal, mullet co-culture in an IMTA system should be evaluated considering the specific site, the local market price of the mullet, the local water treatment costs and relevant environmental factors.
While several studies have considered the mullet as a potential candidate for co-culture with feed-fed fish underneath sea cages very little quantitative data on the ability of mullet to remove sludge has been provided. The present study evaluated grey mullet (Mugil cephalus) performance as a detritivore and potential by-product in co-culture with seabream (Sparus aurata) in a land-based IMTA. This study gives, for the first time quantitative data, including nitrogen budget of the seabream/mullet co-culture and evaluation of the criteria for using mullet as a biofilter in land based facilities.
•Increased the overall biomass production by 4-8% and nitrogen assimilation by the fish by 6-8%.•Reduced of organic matter biomass of the settled faeces by 85% and the amount of nitrogen in the faeces by 98%.•Reduced FCR by 10-15%.•Increased dissolved nitrogen emissions by 10%.
Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, ...raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study,(1) we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3-11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90-D0; P<0.004 treated vs placebo), Clinical Global Impressions (P<0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean ± s.d.; n=9) were removed (Wilcoxon test: P-value=0.031; Student's t-test: P-value=0.017). Side effects were restricted to an occasional mild hypokalaemia (3.0-3.5 mM l(-1) K(+)) that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al., submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment.
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