Mid-infrared n-Ge on Si Plasmonic Based Microbolometer Sensors

The detection and amplification of molecular absorption lines from a chemical weapons simulant is demonstrated using plasmonic antennas fabricated from n-Ge epitaxially grown on Si. A free-standing Si0.25Ge0.75 microbolometer detector with n-Ge plasmonic antenna is demonstrated as an integrated mid-infrared plasmonic sensor

AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease

Pompe disease (PD) is a metabolic myopathy due to acid alpha-glucosidase deficiency and characterized by extensive glycogen storage and impaired autophagy. We previously showed that modulation of autophagy and lysosomal exocytosis by overexpression of the transcription factor EB (TFEB) gene was effective in improving muscle pathology in PD mice injected intramuscularly with an AAV-TFEB vector. Here we have evaluated the effects of TFEB systemic delivery on muscle pathology and on functional performance, a primary measure of efficacy in a disorder like PD. We treated 1-month-old PD mice with an AAV2.9-MCK-TFEB vector. An animal cohort was analyzed at 3 months for muscle and heart pathology. A second cohort was followed at different timepoints for functional analysis. In muscles from TFEB-treated mice we observed reduced PAS staining and improved ultrastructure, with reduced number and increased translucency of lysosomes, while total glycogen content remained unchanged. We also observed statistically significant improvements in rotarod performance in treated animals compared to AAV2.9-MCK-eGFP-treated mice at 5 and 8 months. Cardiac echography showed significant reduction in left-ventricular diameters. These results show that TFEB overexpression and modulation of autophagy result in improvements of muscle pathology and of functional performance in the PD murine model, with delayed disease progression

Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44.

Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion

n-Ge on Si for Mid-Infrared Plasmonic Sensors

The detection and amplification of molecular absorption lines from a mustard gas simulant is demonstrated using plasmonic antennas fabricated from n-Ge epitaxially grown on Si. Approaches to integrated sensors will be presented along with a review of n-Ge compared to other mid-infrared plasmonic materials

Autophagy in Lysosomal Storage Disorders

Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. As a consequence, many tissues and organ systems are affected, including brain, viscera, bone and cartilage. The progressive nature of phenotype development is one of the hallmarks of LSDs. In recent years biochemical and cell biology studies of LSDs have revealed an ample spectrum of abnormalities in a variety of cellular functions. These include defects in signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking. Lysosomes also play a fundamental role in the autophagic pathway by fusing with autophagosomes and digesting their content. Considering the highly integrated function of lysosomes and autophagosomes it was reasonable to expect that lysosomal storage in LSDs would have an impact upon autophagy. The goal of this review is to provide readers with an overview of recent findings that have been obtained through analysis of the autophagic pathway in several types of LSDs, supporting the idea that LSDs could be seen primarily as “autophagy disorders.

Heavily-doped Germanium on Silicon with Activated Doping Exceeding 1020 cm−3 as an Alternative to Gold for Mid-infrared Plasmonics

Ge-on-Si has been demonstrated as a platform for Si foundry compatible plasmonics. We use laser thermal annealing to demonstrate activated doping levels >1020 cm-3 which allows most of the 3 to 20 μm mid-infrared sensing window to be covered with enhancements comparable to gold plasmonics

Tunability and Losses of Mid-infrared Plasmonics in Heavily Doped Germanium Thin Films

Heavily-doped semiconductor films are very promising for application in mid-infrared plasmonic devices because the real part of their dielectric function is negative and broadly tunable in this wavelength range. In this work we investigate heavily n-type doped germanium epilayers grown on different substrates, in-situ doped in the $10^{17}$ to $10^{19}$ cm$^{-3}$ range, by infrared spectroscopy, first principle calculations, pump-probe spectroscopy and dc transport measurements to determine the relation between plasma edge and carrier density and to quantify mid-infrared plasmon losses. We demonstrate that the unscreened plasma frequency can be tuned in the 400 - 4800 cm$^{-1}$ range and that the average electron scattering rate, dominated by scattering with optical phonons and charged impurities, increases almost linearly with frequency. We also found weak dependence of losses and tunability on the crystal defect density, on the inactivated dopant density and on the temperature down to 10 K. In films where the plasma was optically activated by pumping in the near-infrared, we found weak but significant dependence of relaxation times on the static doping level of the film. Our results suggest that plasmon decay times in the several-picosecond range can be obtained in n-type germanium thin films grown on silicon substrates hence allowing for underdamped mid-infrared plasma oscillations at room temperature.Comment: 18 pages, 10 figure

DG-CST (Disease Gene Conserved Sequence Tags), a database of human�mouse conserved elements associated to disease genes

The identification and study of evolutionarily conserved genomic sequences that surround disease-related genes is a valuable tool to gain insight into the functional role of these genes and to better elucidate the pathogenetic mechanisms of disease. We created the DG-CST (Disease Gene Conserved Sequence Tags) database for the identification and detailed annotation of human–mouse conserved genomic sequences that are localized within or in the vicinity of human disease-related genes. CSTs are defined as sequences that show at least 70% identity between human and mouse over a length of at least 100 bp. The database contains CST data relative to over 1088 genes responsible for monogenetic human genetic diseases or involved in the susceptibility to multifactorial/polygenic diseases. DG-CST is accessible via the internet at http://dgcst.ceinge.unina.it/ and may be searched using both simple and complex queries. A graphic browser allows direct visualization of the CSTs and related annotations within the context of the relative gene and its transcripts

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease

Nonlinear Properties of Ge-rich Si1-xGexMaterials with Different Ge Concentrations

Silicon photonics is a large volume and large scale integration platform for applications from long-haul optical telecommunications to intra-chip interconnects. Extension to the mid-IR wavelength range is now largely investigated, mainly driven by absorption spectroscopy applications. Germanium (Ge) is particularly compelling as it has a broad transparency window up to 15 μm and a much higher third-order nonlinear coefficient than silicon which is very promising for the demonstration of efficient non-linear optics based active devices. Si1-xGexalloys have been recently studied due to their ability to fine-Tune the bandgap and refractive index. The material nonlinearities are very sensitive to any modification of the energy bands, so Si1-xGexalloys are particularly interesting for nonlinear device engineering. We report on the first third order nonlinear experimental characterization of Ge-rich Si1-xGexwaveguides, with Ge concentrations x ranging from 0.7 to 0.9. The characterization performed at 1580 nm is compared with theoretical models and a discussion about the prediction of the nonlinear properties in the mid-IR is introduced. These results will provide helpful insights to assist the design of nonlinear integrated optical based devices in both the near-and mid-IR wavelength ranges