Welcome to PathoGenetics

Disease gene identification has made enormous strides in the past twenty years through functional, positional and candidate gene approaches, and more recently by the exploitation of genome-wide strategies. However, although pathogenic mutations in over 2000 genes have been identified as causative of human diseases, much less is known about the relationship between the molecular defects and mechanisms that lead to disease pathology and symptoms. Recent advances in diverse fields such as genomics, proteomics, cell biology, as well as studies on transgenic animals have greatly accelerated our understanding of the biochemical and cellular basis of many diseases but much still remains to be discovered. The current challenge is to understand the molecular and metabolic pathways by which a particular pathogenic variation leads to a specific phenotype. The study of abnormal conditions is of crucial importance for the understanding of normal physiology and often provides us with the rationale for the development of novel therapeutic strategies

Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties

<p>Abstract</p> <p>Background</p> <p>The TRIM family is composed of multi-domain proteins that display the Tripartite Motif (RING, B-box and Coiled-coil) that can be associated with a C-terminal domain. TRIM genes are involved in ubiquitylation and are implicated in a variety of human pathologies, from Mendelian inherited disorders to cancer, and are also involved in cellular response to viral infection.</p> <p>Results</p> <p>Here we defined the entire human TRIM family and also identified the TRIM sets of other vertebrate (mouse, rat, dog, cow, chicken, tetraodon, and zebrafish) and invertebrate species (fruitfly, worm, and ciona). By means of comparative analyses we found that, after assembly of the tripartite motif in an early metazoan ancestor, few types of C-terminal domains have been associated with this module during evolution and that an important increase in TRIM number occurred in vertebrate species concomitantly with the addition of the SPRY domain. We showed that the human TRIM family is split into two groups that differ in domain structure, genomic organization and evolutionary properties. Group 1 members present a variety of C-terminal domains, are highly conserved among vertebrate species, and are represented in invertebrates. Conversely, group 2 is absent in invertebrates, is characterized by the presence of a C-terminal SPRY domain and presents unique sets of genes in each mammal examined. The generation of independent sets of group 2 genes is also evident in the other vertebrate species. Comparing the murine and human TRIM sets, we found that group 1 and 2 genes evolve at different speeds and are subject to different selective pressures.</p> <p>Conclusion</p> <p>We found that the TRIM family is composed of two groups of genes with distinct evolutionary properties. Group 2 is younger, highly dynamic, and might act as a <it>reservoir </it>to develop novel TRIM functions. Since some group 2 genes are implicated in innate immune response, their evolutionary features may account for species-specific battles against viral infection.</p

TFEB-mTORC1 feedback loop in metabolism and cancer

no abstract avalabl

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

Assessing the potential of Ge/SiGe quantum dots as hosts for singlet-triplet qubits

We study double quantum dots in a Ge/SiGe heterostructure and test their maturity towards singlet-triplet ($S-T_0$) qubits. We demonstrate a large range of tunability, from two single quantum dots to a double quantum dot. We measure Pauli spin blockade and study the anisotropy of the $g$-factor. We use an adjacent quantum dot for sensing charge transitions in the double quantum dot at interest. In conclusion, Ge/SiGe possesses all ingredients necessary for building a singlet-triplet qubit

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 &gt;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

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

Lack of Sik1 in Mouse Embryonic Stem Cells Impairs Cardiomyogenesis by Down-Regulating the Cyclin-Dependent Kinase Inhibitor p57kip2

Sik1 (salt inducible kinase 1) is a serine/threonine kinase that belongs to the stress- and energy-sensing AMP-activated protein kinase family. During murine embryogenesis, sik1 marks the monolayer of future myocardial cells that will populate first the primitive ventricle, and later the primitive atrium suggesting its involvement in cardiac cell differentiation and/or heart development. Despite that observation, the involvement of sik1 in cardiac differentiation is still unknown. We examined the sik1 function during cardiomyocyte differentiation using the ES-derived embryoid bodies. We produced a null embryonic stem cell using a gene-trap cell line carrying an insertion in the sik1 locus. In absence of the sik1 protein, the temporal appearance of cardiomyocytes is delayed. Expression profile analysis revealed sik1 as part of a genetic network that controls the cell cycle, where the cyclin-dependent kinase inhibitor p57Kip2 is directly involved. Collectively, we provided evidence that sik1-mediated effects are specific for cardiomyogenesis regulating cardiomyoblast cell cycle exit toward terminal differentiation

Modeling of second harmonic generation in hole-doped silicon-germanium quantum wells for mid-infrared sensing

The development of Ge and SiGe chemical vapor deposition techniques on silicon wafers has enabled the integration of multi-quantum well structures in silicon photonics chips for nonlinear optics with potential applications to integrated nonlinear optics, however research has focused up to now on undoped quantum wells and interband optical excitations. In this work, we present model calculations for the giant nonlinear coefficients provided by intersubband transitions in hole-doped Ge/SiGe and Si/SiGe multi-quantum wells. We employ a valence band-structure model for Si1-xGex to calculate the confined hole states of asymmetric-coupled quantum wells for second-harmonic generation in the mid-infrared. We calculate the nonlinear emission spectra from the second-order susceptibility tensor, including the particular vertical emission spectra of valence-band quantum wells. Two possible nonlinear mid-infrared sensor architectures, one based on waveguides and another based on metasurfaces, are described as perspective application