Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function

Ischemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca(2+) and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders

Waveguide-coupled detector in zero-change complementary metal–oxide–semiconductor

We report a waveguide-coupled photodetector realized in a standard CMOS foundry without requiring changes to the process flow (zero-change CMOS). The photodetector exploits carrier generation in the silicon-germanium normally utilized as stressor in pFETs. The measured responsivity and 3 dB bandwidth are of 0.023 A/W at a wavelength of 1180 nm and 32 GHz at −1 V bias (18 GHz at 0 V bias). The dark current is less than 10 pA and the dynamic range is larger than 60 dB.United States. Defense Advanced Research Projects Agency. Photonically Optimized Embedded Microprocessors Program (Award HR0011-11-C-0100)United States. Defense Advanced Research Projects Agency. Photonically Optimized Embedded Microprocessors Program (Contract HR0011-11-9-0009

Silicon-Organic Hybrid (SOH) and Plasmonic-Organic Hybrid (POH) integration

Silicon-organic hybrid (SOH) and plasmonic-organic hybrid (POH) integration combines organic clectro-optic materials with silicon photonic and plasmonic waveguides, The concept enables fast and power-efficient modulators that support advanced modulation formats such as QPSK and 16QAM

Silicon-Organic Hybrid (SOH) and Plasmonic-Organic Hybrid (POH) integration

Silicon photonics offers tremendous potential for inexpensive high-yield photonic-electronic integration. Besides conventional dielectric waveguides, plasmonic structures can also be efficiently realized on the silicon photonic platform, reducing device footprint by more than an order of magnitude. However, nei-ther silicon nor metals exhibit appreciable second-order optical nonlinearities, thereby making efficient electro-optic modulators challenging to realize. These deficiencies can be overcome by the concepts of silicon-organic hybrid (SOH) and plasmonic-organic hybrid integration, which combine SOI waveguides and plasmonic nanostructures with organic electro-optic cladding materials

Silicon-organic hybrid electro-optical devices

Organic materials combined with strongly guiding silicon waveguides open the route to highly efficient electro-optical devices. Modulators based on the so-called silicon-organic hybrid (SOH) platform have only recently shown frequency responses up to 100 GHz, high-speed operation beyond 112 Gbit/s with fJ/bit power consumption. In this paper, we review the SOH platform and discuss important devices such as Mach-Zehnder and IQ-modulators based on the linear electro-optic effect. We further show liquid-crystal phase-shifters with a voltage-length product as low as V pi L = 0.06 V.mm and sub-mu W power consumption as required for slow optical switching or tuning optical filters and devices

Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity

Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers

100 GHz silicon-organic hybrid modulator

Electro-optic modulation at frequencies of 100 GHz and beyond is important for photonic-electronic signal processing at the highest speeds. To date, however, only a small number of devices exist that can operate up to this frequency. In this study, we demonstrate that this frequency range can be addressed by nanophotonic, silicon-based modulators. We exploit the ultrafast Pockels effect by using the silicon–organic hybrid (SOH) platform, which combines highly nonlinear organic molecules with silicon waveguides. Until now, the bandwidth of these devices was limited by the losses of the radiofrequency (RF) signal and the RC (resistor-capacitor) time constant of the silicon structure. The RF losses are overcome by using a device as short as 500 µm, and the RC time constant is decreased by using a highly conductive electron accumulation layer and an improved gate insulator. Using this method, we demonstrate for the first time an integrated silicon modulator with a 3dB bandwidth at an operating frequency beyond 100 GHz. Our results clearly indicate that the RC time constant is not a fundamental speed limitation of SOH devices at these frequencies. Our device has a voltage–length product of only VπL=11 V mm, which compares favorably with the best silicon-photonic modulators available today. Using cladding materials with stronger nonlinearities, the voltage–length product is expected to improve by more than an order of magnitude

Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function

Protein degradation by the ubiquitin-proteasome system in neurons depends on the correct delivery of the proteasome complex. In neurodegenerative diseases, aggregation and accumulation of proteins in axons link transport defects with degradation impairments; however, the transport properties of proteasomes remain unknown. Here, using in vivo experiments, we reveal the fast anterograde transport of assembled and functional 26S proteasome complexes. A high-resolution tracking system to follow fluorescent proteasomes revealed three types of motion: actively driven proteasome axonal transport, diffusive behavior in a viscoelastic axonema and proteasome-confined motion. We show that active proteasome transport depends on motor function because knockdown of the KIF5B motor subunit resulted in impairment of the anterograde proteasome flux and the density of segmental velocities. Finally, we reveal that neuronal proteasomes interact with intracellular membranes and identify the coordinated transport of fluorescent proteasomes with synaptic precursor vesicles, Golgi-derived vesicles, lysosomes and mitochondria. Taken together, our results reveal fast axonal transport as a new mechanism of proteasome delivery that depends on membrane cargo ‘hitch-hiking’ and the function of molecular motors. We further hypothesize that defects in proteasome transport could promote abnormal protein clearance in neurodegenerative diseases.Fil: Otero, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Almenar Queralt, Angels. University of California at San Diego; Estados UnidosFil: Encalada, Sandra E.. University of California at San Diego; Estados UnidosFil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bruno, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Goldstein, Lawrence S. B.. University of California at San Diego; Estados UnidosFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin