Kirigami Actuators

Thin elastic sheets bend easily and, if they are patterned with cuts, can deform in sophisticated ways. Here we show that carefully tuning the location and arrangement of cuts within thin sheets enables the design of mechanical actuators that scale down to atomically-thin 2D materials. We first show that by understanding the mechanics of a single, non-propagating crack in a sheet we can generate four fundamental forms of linear actuation: roll, pitch, yaw, and lift. Our analytical model shows that these deformations are only weakly dependent on thickness, which we confirm with experiments at centimeter scale objects and molecular dynamics simulations of graphene and MoS$_{2}$ nanoscale sheets. We show how the interactions between non-propagating cracks can enable either lift or rotation, and we use a combination of experiments, theory, continuum computational analysis, and molecular dynamics simulations to provide mechanistic insights into the geometric and topological design of kirigami actuators.Comment: Soft Matter, 201

Photoactivated release of membrane impermeant sulfonates inside cells.

Photouncaging delivers compounds with high spatial and temporal control to induce or inhibit biological processes but the released compounds may diffuse out. We here demonstrate that sulfonate anions can be photocaged so that a membrane impermeable compound can enter cells, be uncaged by photoirradiation and trapped within the cell

Unprecedented in Vitro Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10- Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs

Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and ([Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), ([Mn(phen)2(H2O)2])2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, ([Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents. © 2018 McCarron, McCann, Devereux, Kavanagh, Skerry, Karakousis, Aor, Mello, Santos, Campos and Pavan

Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort

INTRODUCTION: Vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis and is over-expressed in breast cancer. At least four polymorphisms in the VEGF gene have been associated with changes in VEGF expression levels: -2578C/A, -1154G/A and -634G/C are all located in the promoter region; and +936C/T is located in the 3'-untranslated region. METHOD: We examined the association between these four VEGF polymorphisms and risk for breast cancer among postmenopausal women in CPS-II (Cancer Prevention Study II) Nutrition Cohort. This cohort was established in 1992 and participants were invited to provide a blood sample between 1998 and 2001. Included in this analysis were 501 postmenopausal women who provided a blood sample and were diagnosed with breast cancer between 1992 and 2001 (cases). Control individuals were 504 cancer-free postmenopausal women matched to the cases with respect to age, race/ethnicity, and date of blood collection (controls). RESULTS: We found no association between any of the polymorphisms examined and overall breast cancer risk. However, associations were markedly different in separate analyses of invasive cancer (n = 380) and in situ cancer (n = 107). The -2578C and -1154G alleles, which are both hypothesized to increase expression of VEGF, were associated with increased risk for invasive breast cancer (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.00–2.14 for -2578 CC versus AA; OR 1.64, 95% CI 1.02–2.64 for -1154 GG versus AA) but they were not associated with risk for in situ cancer. The +936C allele, which is also hypothesized to increase VEGF expression, was not clearly associated with invasive breast cancer (OR 1.21, 95% CI 0.88–1.67 for +936 CC versus TT/CT), but it was associated with reduced risk for in situ cancer (OR 0.59, 95% CI 0.37–0.93 for CC versus TT/CT). The -634 C/G polymorphism was not associated with either invasive or in situ cancer. CONCLUSION: Our findings provide limited support for the hypothesis that the -2578C and -1154G VEGF alleles are associated with increased risk for invasive but not in situ breast cancer in postmenopausal women

Spontaneous, pro-arrhythmic calcium signals disrupt electrical pacing in mouse pulmonary vein sleeve cells

The pulmonary vein, which returns oxygenated blood to the left atrium, is ensheathed by a population of unique, myocyte- like cells called pulmonary vein sleeve cells (PVCs). These cells autonomously generate action potentials that propagate into the left atrial chamber and cause arrhythmias resulting in atrial fibrillation; the most common, often sustained, form of cardiac arrhythmia. In mice, PVCs extend along the pulmonary vein into the lungs, and are accessible in a lung slice preparation. We exploited this model to study how aberrant Ca2+ signaling alters the ability of PVC networks to follow electrical pacing. Cellular responses were investigated using real-time 2-photon imaging of lung slices loaded with a Ca2+- sensitive fluorescent indicator (Ca2+ measurements) and phase contrast microscopy (contraction measurements). PVCs displayed global Ca2+ signals and coordinated contraction in response to electrical field stimulation (EFS). The effects of EFS relied on both Ca2+ influx and Ca2+ release, and could be inhibited by nifedipine, ryanodine or caffeine. Moreover, PVCs had a high propensity to show spontaneous Ca2+ signals that arose via stochastic activation of ryanodine receptors (RyRs). The ability of electrical pacing to entrain Ca2+ signals and contractile responses was dramatically influenced by inherent spontaneous Ca2+ activity. In PVCs with relatively low spontaneous Ca2+ activity (2+ activity (>1.5 Hz), electrical pacing was less effective; PVCs became unpaced, only partially-paced or displayed alternans. Because spontaneous Ca2+ activity varied between cells, neighboring PVCs often had different responses to electrical pacing. Our data indicate that the ability of PVCs to respond to electrical stimulation depends on their intrinsic Ca2+ cycling properties. Heterogeneous spontaneous Ca2+ activity arising from stochastic RyR opening can disengage them from sinus rhythm and lead to autonomous, pro-arrhythmic activity

Selective Uncoupling of Individual Mitochondria within a Cell Using a Mitochondria-Targeted Photoactivated Protonophore

Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Kinetic regulation of multi-ligand binding proteins

Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation. Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated. Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion

The Ischemic Stroke Genetics Study (ISGS) Protocol

BACKGROUND: The molecular basis for the genetic risk of ischemic stroke is likely to be multigenic and influenced by environmental factors. Several small case-control studies have suggested associations between ischemic stroke and polymorphisms of genes that code for coagulation cascade proteins and platelet receptors. Our aim is to investigate potential associations between hemostatic gene polymorphisms and ischemic stroke, with particular emphasis on detailed characterization of the phenotype. METHODS/DESIGN: The Ischemic Stroke Genetic Study is a prospective, multicenter genetic association study in adults with recent first-ever ischemic stroke confirmed with computed tomography or magnetic resonance imaging. Patients are evaluated at academic medical centers in the United States and compared with sex- and age-matched controls. Stroke subtypes are determined by central blinded adjudication using standardized, validated mechanistic and syndromic classification systems. The panel of genes to be tested for polymorphisms includes β-fibrinogen and platelet glycoprotein Ia, Iba, and IIb/IIIa. Immortalized cell lines are created to allow for time- and cost-efficient testing of additional candidate genes in the future. DISCUSSION: The study is designed to minimize survival bias and to allow for exploring associations between specific polymorphisms and individual subtypes of ischemic stroke. The data set will also permit the study of genetic determinants of stroke outcome. Having cell lines will permit testing of future candidate risk factor genes