A Condensation-Ordering Mechanism in Nanoparticle-Catalyzed Peptide Aggregation

Nanoparticles introduced in living cells are capable of strongly promoting the aggregation of peptides and proteins. We use here molecular dynamics simulations to characterise in detail the process by which nanoparticle surfaces catalyse the self- assembly of peptides into fibrillar structures. The simulation of a system of hundreds of peptides over the millisecond timescale enables us to show that the mechanism of aggregation involves a first phase in which small structurally disordered oligomers assemble onto the nanoparticle and a second phase in which they evolve into highly ordered beta-sheets as their size increases

Interventions to Influence Consulting and Antibiotic Use for Acute Respiratory Tract Infections in Children: A Systematic Review and Meta-Analysis

BACKGROUND: Respiratory tract infections (RTIs) are common in children and generally self-limiting, yet often result in consultations to primary care. Frequent consultations divert resources from care for potentially more serious conditions and increase the opportunity for antibiotic overuse. Overuse of antibiotics is associated with adverse effects and antimicrobial resistance, and has been shown to influence how patients seek care in ensuing illness episodes. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review and meta-analysis to assess the effectiveness of interventions directed towards parents or caregivers which were designed to influence consulting and antibiotic use for respiratory tract infections (RTIs) in children in primary care. Main outcomes were parental consulting rate, parental knowledge, and proportion of children subsequently consuming antibiotics. Of 5,714 references, 23 studies (representing 20 interventions) met inclusion criteria. Materials designed to engage children in addition to parents were effective in modifying parental knowledge and behaviour, resulting in reductions in consulting rates ranging from 13 to 40%. Providing parents with delayed prescriptions significantly decreased reported antibiotic use (Risk Ratio (RR) 0.46 (0.40, 0.54); moreover, a delayed or no prescribing approach did not diminish parental satisfaction. CONCLUSIONS: IN ORDER TO BE MOST EFFECTIVE, INTERVENTIONS TO INFLUENCE PARENTAL CONSULTING AND ANTIBIOTIC USE SHOULD: engage children, occur prior to an illness episode, employ delayed prescribing, and provide guidance on specific symptoms. These results support the wider implementation of interventions to reduce inappropriate antibiotic use in children

Short-Term Striatal Gene Expression Responses to Brain-Derived Neurotrophic Factor Are Dependent on MEK and ERK Activation

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. CONCLUSIONS: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression

The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses

Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are dynamic modules enriched in subset of lipids and specialized proteins that determine their structure and functions. The MERCs regulate lipid transfer, autophagosome formation, mitochondrial fission, Ca2+ homeostasis and apoptosis. Since these functions are essential for cell biology, it is therefore not surprising that MERCs also play a critical role in organ physiology among which the immune system stands by its critical host defense function. This defense system must discriminate and tolerate host cells and beneficial commensal microorganisms while eliminating pathogenic ones in order to preserve normal homeostasis. To meet this goal, the immune system has two lines of defense. First, the fast acting but unspecific innate immune system relies on anatomical physical barriers and subsets of hematopoietically derived cells expressing germline-encoded receptors called pattern recognition receptors (PRR) recognizing conserved motifs on the pathogens. Second, the slower but very specific adaptive immune response is added to complement innate immunity. Adaptive immunity relies on another set of specialized cells, the lymphocytes, harboring receptors requiring somatic recombination to be expressed. Both innate and adaptive immune cells must be activated to phagocytose and process pathogens, migrate, proliferate, release soluble factors and destroy infected cells. Some of these functions are strongly dependent on lipid transfer, autophagosome formation, mitochondrial fission, and Ca2+ flux; this indicates that MERCs could regulate immunity

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector

How wall properties control diffusion in grooved nanochannels: a molecular dynamics study

The effect of a geometrically-rough wall, amplified by its degree of wettability and stiffness on diffusion coefficient in cases of fluid flow in nanochannels is studied by non-equilibrium molecular dynamics. Diffusion coefficient values, either inside the grooves or as average channel values are affected by the rough wall characteristics. A significant anisotropy along the directions parallel and normal to the flow is observed inside the grooves, while a critical value of groove length below which this anisotropy is enhanced exists. Wall wettability is the property that affects diffusion the most and could be a means of controlling its behavior