VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

Estimation of the Young's Modulus of Nanometer-Thick Films Using Residual Stress-Driven Bilayer Cantilevers.

Precise prediction of mechanical behavior of thin films at the nanoscale requires techniques that consider size effects and fabrication-related issues. Here, we propose a test methodology to estimate the Young's modulus of nanometer-thick films using micromachined bilayer cantilevers. The bilayer cantilevers which comprise a well-known reference layer and a tested film deflect due to the relief of the residual stresses generated during the fabrication process. The mechanical relationship between the measured residual stresses and the corresponding deflections was used to characterize the tested film. Residual stresses and deflections were related using analytical and finite element models that consider intrinsic stress gradients and the use of adherence layers. The proposed methodology was applied to low pressure chemical vapor deposited silicon nitride tested films with thicknesses ranging from 46 nm to 288 nm. The estimated Young's modulus values varying between 213.9 GPa and 288.3 GPa were consistent with nanoindentation and alternative residual stress-driven techniques. In addition, the dependence of the results on the thickness and the intrinsic stress gradient of the materials was confirmed. The proposed methodology is simple and can be used to characterize diverse materials deposited under different fabrication conditions.

Triboelectric Energy Harvester Based on Stainless Steel/MoS2 and PET/ITO/PDMS for Potential Smart Healthcare Devices.

The smart healthcare devices connected with the internet of things (IoT) for medical services can obtain physiological data of risk patients and communicate these data in real-time to doctors and hospitals. These devices require power sources with a sufficient lifetime to supply them energy, limiting the conventional electrochemical batteries. Additionally, these batteries may contain toxic materials that damage the health of patients and environment. An alternative solution to gradually substitute these electrochemical batteries is the development of triboelectric energy harvesters (TEHs), which can convert the kinetic energy of ambient into electrical energy. Here, we present the fabrication of a TEH formed by a stainless steel substrate (25 mm × 15 mm) coated with a molybdenum disulfide (MoS2) film as top element and a polydimethylsiloxane (PDMS) film deposited on indium tin oxide coated polyethylene terephthalate substrate (PET/ITO). This TEH has a generated maximum voltage of 2.3 V and maximum output power of 112.55 µW using a load resistance of 47 kΩ and a mechanical vibration to 59.7 Hz. The proposed TEH could be used to power potential smart healthcare devices.

Electromechanical Modeling of Vibration-Based Piezoelectric Nanogenerator with Multilayered Cross-Section for Low-Power Consumption Devices.

Piezoelectric nanogenerators can convert energy from ambient vibrations into electrical energy. In the future, these nanogenerators could substitute conventional electrochemical batteries to supply electrical energy to consumer electronics. The optimal design of nanogenerators is fundamental in order to achieve their best electromechanical behavior. We present the analytical electromechanical modeling of a vibration-based piezoelectric nanogenerator composed of a double-clamped beam with five multilayered cross-sections. This nanogenerator design has a central seismic mass (910 µm thickness) and substrate (125 µm thickness) of polyethylene terephthalate (PET) as well as a zinc oxide film (100 nm thickness) at the bottom of each end. The zinc oxide (ZnO) films have two aluminum electrodes (100 nm thickness) through which the generated electrical energy is extracted. The analytical electromechanical modeling is based on the Rayleigh method, Euler-Bernoulli beam theory and Macaulay method. In addition, finite element method (FEM) models are developed to estimate the electromechanical behavior of the nanogenerator. These FEM models consider air damping at atmospheric pressure and optimum load resistance. The analytical modeling results agree well with respect to those of FEM models. For applications under accelerations in y-direction of 2.50 m/s2 and an optimal load resistance of 32,458 Ω, the maximum output power and output power density of the nanogenerator at resonance (119.9 Hz) are 50.44 µW and 82.36 W/m3, respectively. This nanogenerator could be used to convert the ambient mechanical vibrations into electrical energy and supply low-power consumption devices.

Design of a Novel MEMS Microgripper with Rotatory Electrostatic Comb-Drive Actuators for Biomedical Applications.

Primary tumors of patients can release circulating tumor cells (CTCs) to flow inside of their blood. The CTCs have different mechanical properties in comparison with red and white blood cells, and their detection may be employed to study the efficiency of medical treatments against cancer. We present the design of a novel MEMS microgripper with rotatory electrostatic comb-drive actuators for mechanical properties characterization of cells. The microgripper has a compact structural configuration of four polysilicon layers and a simple performance that control the opening and closing displacements of the microgripper tips. The microgripper has a mobile arm, a fixed arm, two different actuators and two serpentine springs, which are designed based on the SUMMiT V surface micromachining process from Sandia National Laboratories. The proposed microgripper operates at its first rotational resonant frequency and its mobile arm has a controlled displacement of 40 µm at both opening and closing directions using dc and ac bias voltages. Analytical models are developed to predict the stiffness, damping forces and first torsional resonant frequency of the microgripper. In addition, finite element method (FEM) models are obtained to estimate the mechanical behavior of the microgripper. The results of the analytical models agree very well respect to FEM simulations. The microgripper has a first rotational resonant frequency of 463.8 Hz without gripped cell and it can operate up to with maximum dc and ac voltages of 23.4 V and 129.2 V, respectively. Based on the results of the analytical and FEM models about the performance of the proposed microgripper, it could be used as a dispositive for mechanical properties characterization of circulating tumor cells (CTCs).

Publisher Correction: Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.

The previously published version of this Article contained errors in Fig. 6. In panel h the units of the x axis were incorrectly given as mM and should have been given as µM. Also, the IC50s for RU.365, RU.332 and RU.521 within panel h were incorrectly given as mM and should have been given as µM. These errors have been corrected in both the PDF and HTML versions of the Article.

Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.

Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutières syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype. Here, we report the discovery of a class of cyclic GMP-AMP synthase inhibitors identified by a high-throughput screen. These compounds possess defined structure-activity relationships and we present crystal structures of cyclic GMP-AMP synthase, double-stranded DNA, and inhibitors within the enzymatic active site. We find that a chemically improved member, RU.521, is active and selective in cellular assays of cyclic GMP-AMP synthase-mediated signaling and reduces constitutive expression of interferon in macrophages from a mouse model of Aicardi-Goutières syndrome. RU.521 will be useful toward understanding the biological roles of cyclic GMP-AMP synthase and can serve as a molecular scaffold for development of future autoimmune therapies.Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.

Recent Advances of MEMS Resonators for Lorentz Force Based Magnetic Field Sensors: Design, Applications and Challenges.

Microelectromechanical systems (MEMS) resonators have allowed the development of magnetic field sensors with potential applications such as biomedicine, automotive industry, navigation systems, space satellites, telecommunications and non-destructive testing. We present a review of recent magnetic field sensors based on MEMS resonators, which operate with Lorentz force. These sensors have a compact structure, wide measurement range, low energy consumption, high sensitivity and suitable performance. The design methodology, simulation tools, damping sources, sensing techniques and future applications of magnetic field sensors are discussed. The design process is fundamental in achieving correct selection of the operation principle, sensing technique, materials, fabrication process and readout systems of the sensors. In addition, the description of the main sensing systems and challenges of the MEMS sensors are discussed. To develop the best devices, researches of their mechanical reliability, vacuum packaging, design optimization and temperature compensation circuits are needed. Future applications will require multifunctional sensors for monitoring several physical parameters (e.g., magnetic field, acceleration, angular ratio, humidity, temperature and gases).

Small-Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA-Deficient Cancers.

Suppression of RAD52 causes synthetic lethality in BRCA-deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-DL-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-Dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small-molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA-deficient cancers.

Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors.

Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer.

Avaliaçäo da eficácia da halcinonida em aplicaçäo tópica diária única, näo oclusiva em dermatite de contato / Evaluation of the efficacy of halcinonide in the topical once daily dosage administration without occlusive dress in contact dermatitis

Trinta pacientes portadores de dermatite contato em fases aguda e subaguda forma submetidos a tratamento tópico com creme de halcinonida a 0,1% empregando uma única aplicaçäo diária do fármaco, sem penso oclusivo. As afecçöes foram consideradas como de intensidade moderada em 27 casos (90%), sendo que nove pacientes já haviam recebido tratamento anteriores para esta patologia. A eficácia da terapêutica foi avaliada de forma subjetiva e objetiva por meio de controles semanais por um período máximo de quatro semanas. O resultado final foi considerado satisfatório em 93,34% dos casos (28 pacientes classificados como avaliaçäo excelente e boa) e regular em apenas dois casos (6,66%). Näo se observaram reaçöes de hipersensibilidade ou irritaçäo local em nenhum dos casos. A terapêutica, em aplicaçäo única diária, demonstrou excelentes resultados aliados à facilidade de aplicaçäo e insençäo de efeitos adversos