Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction

Citation: Marquez-Miranda, V., Araya-Duran, I., Camarada, M. B., Comer, J., Valencia-Gallegos, J. A., & Gonzalez-Nilo, F. D. (2016). Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction. Scientific Reports, 6, 15. https://doi.org/10.1038/srep29436An ideal nucleic-acid transfection system should combine the physical and chemical characteristics of cationic lipids and linear polymers to decrease cytotoxicity and uptake limitations. Previous research described new types of carriers termed amphiphilic dendrimers (ADs), which are based on polyamidoamine dendrimers (PAMAM). These ADs display the cell membrane affinity advantage of lipids and preserve the high affinity for DNA possessed by cationic dendrimers. These lipid/dendrimer hybrids consist of a low-generation, hydrophilic dendron (G2, G1, or G0) bonded to a hydrophobic tail. The G2-18C AD was reported to be an efficient siRNA vector with significant gene silencing. However, shorter tail ADs (G2-15C and G2-13C) and lower generation (G0 and G1) dendrimers failed as transfection carriers. To date, the self-assembly phenomenon of this class of amphiphilic dendrimers has not been molecularly explored using molecular simulation methods. To gain insight into these systems, the present study used coarse-grained molecular dynamics simulations to describe how ADs are able to self-assemble into an aggregate, and, specifically, how tail length and generation play a key role in this event. Finally, explanations are given for the better efficiency of G2/18-C as gene carrier in terms of binding of siRNA. This knowledge could be relevant for the design of novel, safer ADs with well-optimized affinity for siRNA

Dynamin-2 R465W mutation induces long range perturbation in highly ordered oligomeric structures

High order oligomers are crucial for normal cell physiology, and protein function perturbed by missense mutations underlies several autosomal dominant diseases. Dynamin-2 is one of such protein forming helical oligomers that catalyze membrane fission. Mutations in this protein, where R465W is the most frequent, cause dominant centronuclear myopathy, but the molecular mechanisms underpinning the functional modifications remain to be investigated. To unveil the structural impact of this mutation in dynamin-2, we used full-atom molecular dynamics simulations and coarse-grained models and built dimers and helices of wild-type (WT) monomers, mutant monomers, or both WT and mutant monomers combined. Our results show that the mutation R465W causes changes in the interactions with neighbor amino acids that propagate through the oligomer. These new interactions perturb the contact between monomers and favor an extended conformation of the bundle signaling element (BSE), a dynamin region that transmits the conformational changes from the GTPase domain to the rest of the protein. This extended configuration of the BSE that is only relevant in the helices illustrates how a small change in the microenvironment surrounding a single residue can propagate through the oligomer structures of dynamin explaining how dominance emerges in large protein complexes. © 2020, The Author(s).Indexación Scopushttps://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-020-75216-

Modeling the high-energy emission in GRB 110721A and implications on the early multiwavelength and polarimetric observations

GRB 110721A was detected by the Gamma-ray Burst Monitor and the Large Area Telescope (LAT) onboard the Fermi satellite and the Gamma-ray Burst Polarimeter onboard the IKAROS solar mission. Previous analysis done of this burst showed: i) a linear polarization signal with position angle stable ($\phi_p= 160^\circ\pm11$) and high degree of $\Pi=84^{+16}_{-28}$, ii) an extreme peak energy of a record-breaking at 15$\pm$2 MeV, and iii) a subdominant prompt thermal component observed right after the onset of this burst. In this paper, the LAT data around the reported position of GRB 110721A are analysed with the most recent software and then, the LAT light curve above 100 MeV was obtained. The LAT light curve is modelled in terms of adiabatic early-afterglow external shocks when the outflow propagates into a stellar wind. Additionally, we discuss the possible origins and also study the implications of the early-afterglow external shocks on the extreme peak energy observed at 15$\pm$2 MeV, the polarization observations and the subdominant prompt thermal component.Comment: 9 pages and one figure. Accepted for publication in Ap

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Promotoras as Mental Health Practitioners in Primary Care: A Multi-Method Study of an Intervention to Address Contextual Sources of Depression

We assessed the role of promotoras—briefly trained community health workers—in depression care at community health centers. The intervention focused on four contextual sources of depression in underserved, low-income communities: underemployment, inadequate housing, food insecurity, and violence. A multi-method design included quantitative and ethnographic techniques to study predictors of depression and the intervention’s impact. After a structured training program, primary care practitioners (PCPs) and promotoras collaboratively followed a clinical algorithm in which PCPs prescribed medications and/or arranged consultations by mental health professionals and promotoras addressed the contextual sources of depression. Based on an intake interview with 464 randomly recruited patients, 120 patients with depression were randomized to enhanced care plus the promotora contextual intervention, or to enhanced care alone. All four contextual problems emerged as strong predictors of depression (chi square, p < .05); logistic regression revealed housing and food insecurity as the most important predictors (odds ratios both 2.40, p < .05). Unexpected challenges arose in the intervention’s implementation, involving infrastructure at the health centers, boundaries of the promotoras’ roles, and “turf” issues with medical assistants. In the quantitative assessment, the intervention did not lead to statistically significant improvements in depression (odds ratio 4.33, confidence interval overlapping 1). Ethnographic research demonstrated a predominantly positive response to the intervention among stakeholders, including patients, promotoras, PCPs, non-professional staff workers, administrators, and community advisory board members. Due to continuing unmet mental health needs, we favor further assessment of innovative roles for community health workers

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.

Search for additional heavy neutral Higgs and gauge bosons in the ditau final state produced in 36 fb−1 of pp collisions at √s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons and Z′ bosons is performed using a data sample corresponding to an integrated luminosity of 36.1 fb−1 from proton-proton collisions at √s=13 TeV recorded by the ATLAS detector at the LHC during 2015 and 2016. The heavy resonance is assumed to decay to τ+τ− with at least one tau lepton decaying to final states with hadrons and a neutrino. The search is performed in the mass range of 0.2-2.25 TeV for Higgs bosons and 0.2-4.0 TeV for Z′ bosons. The data are in good agreement with the background predicted by the Standard Model. The results are interpreted in benchmark scenarios. In the context of the hMSSM scenario, the data exclude tan β > 1.0 for mA= 0.25 TeV and tan β > 42 for mA=1.5 TeV at the 95% confidence level. For the Sequential Standard Model, ZSSM′ with mZ′< 2.42 TeV is excluded at 95% confidence level, while Z NU′ with mZ ′ < 2.25 TeV is excluded for the non-universal G(221) model that exhibits enhanced couplings to third-generation fermions