Nanostructured 3C-SiC on Si by a network of (111) platelets: a fully textured film generated by intrinsic growth anisotropy.

In this paper, we address the unique nature of fully textured, high surface-to-volume 3C-SiC films, as produced by intrinsic growth anisotropy, in turn generated by the high velocity of the stacking fault growth front in two-dimensional (111) platelets. Structural interpretation of high resolution scanning electron microscopy and transmission electron microscopy data is carried out for samples grown in a hot-wall low-pressure chemical vapour deposition reactor with trichlorosilane and ethylene precursors, under suitable deposition conditions. By correlating the morphology and the X-ray diffraction analysis we also point out that twinning along (111) planes is very frequent in such materials, which changes the free-platelet configuration.

Voltage-tunable dual-band Ge/Si photodetector operating in VIS and NIR spectral range.

Extending and controlling the spectral range of light detectors is very appealing for several sensing and imaging applications. Here we report on a normal incidence dual band photodetector operating in the visible and near infrared with a bias tunable spectral response. The device architecture is a germanium on silicon epitaxial structure made of two back-to-back connected photodiodes. The photodetectors show a broad photoresponse extending from 390nm to 1600nm with the capability to electronically select the shorter (400-1100 nm) or the longer (1000-1600 nm) portion with a relatively low applied voltage. Devices exhibit peak VIS and NIR responsivities of 0.33 and 0.63 A/W, respectively, a low optical crosstalk (<-30dB), a wide dynamic range (>120dB) and, thanks to their low voltage operation, maximum specific detectivities of 7·1011cmHz1/2/W and 2·1010cmHz1/2/W in the VIS and NIR, respectively.

Ultra-wideband Ge-rich silicon germanium mid-infrared polarization rotator with mode hybridization flattening.

In this work we investigate the implementation of ultra-wideband polarization rotator in the mid-infrared spectral region. A new design method of the rotation section is proposed, yielding a polarization rotator with an extinction ratio of at least 15 dB in a wavelength range of 2 µm. For a spectral range wider than 3.8 µm, an extinction ratio of at least 10 dB is achieved for this design. The device is 1660 µm long and the associated insertion loss is below 1.2 dB on the full operational wavelength range. The influence of geometrical parameters with respect to the design method to obtain such a broadband behavior is discussed. Finally, to increase the tolerance to fabrication errors, a tapered rotator design is proposed. Such a device can support up to ± 100 nm fabrication errors and still guarantees remarkable broadband behavior. To the best of our knowledge, this is the first time an integrated polarization rotator is designed to operate for the wavelength range of 4 to 9 µm with a bandwidth exceeding 2 µm.

Graded SiGe waveguides with broadband low-loss propagation in the mid infrared.

Mid-infrared (mid-IR) silicon photonics is expected to lead key advances in different areas including spectroscopy, remote sensing, nonlinear optics or free-space communications, among others. Still, the inherent limitations of the silicon-on-insulator (SOI) technology, namely the early mid-IR absorption of silicon oxide and silicon at λ~3.6 µm and at λ ~8.5 µm respectively, remain the main stumbling blocks that prevent this platform to fully exploit the mid-IR spectrum (λ ~2-20 µm). Here, we propose using a compact Ge-rich graded-index Si1-xGex platform to overcome this constraint. A flat propagation loss characteristic as low as 2-3 dB/cm over a wavelength span from λ = 5.5 µm to 8.5 µm is demonstrated in Ge-rich Si1-xGex waveguides of only 6 µm thick. The comparison of three different waveguides design with different vertical index profiles demonstrates the benefit of reducing the fraction of the guided mode that overlaps with the Si substrate to obtain such flat low loss behavior. Such Ge-rich Si1-xGex platforms may open the route towards the implementation of mid-IR photonic integrated circuits with low-loss beyond the Si multi-phonon absorption band onset, hence truly exploiting the full Ge transparency window up to λ ~15 µm.

Ge-rich graded-index Si1-xGex waveguides with broadband tight mode confinement and flat anomalous dispersion for nonlinear mid-infrared photonics.

This work explores the use of Ge-rich graded-index Si1-xGex rib waveguides as building blocks to develop integrated nonlinear optical devices for broadband operation in the mid-IR. The vertical Ge gradient concentration in the waveguide core renders unique properties to the guided optical mode, providing tight mode confinement over a broadband mid-IR wavelength range from λ = 3 µm to 8 µm. Additionally, the gradual vertical confinement pulls the optical mode upwards in the waveguide core, overlapping with the Ge-rich area where the nonlinear refractive index is larger. Moreover, the Ge-rich graded-index Si1-xGex waveguides allow efficient tailoring of the chromatic dispersion curves, achieving flat anomalous dispersion for the quasi-TM optical mode with D ≤ 14 ps/nm/km over a ~1.4 octave span while retaining an optimum third-order nonlinear parameter, γeff. These results confirm the potential of Ge-rich graded-index Si1-xGex waveguides as an attractive platform to develop mid-IR nonlinear approaches requiring broadband dispersion engineering.

Analysis of Ge micro-cavities with in-plane tensile strains above 2.

Ge on Si micro-disk, ring and racetrack cavities are fabricated and strained using silicon nitride stressor layers. Photoluminescence measurements demonstrate emission at wavelengths ≥ 2.3 µm, and the highest strained samples demonstrate in-plane, tensile strains of > 2 %, as measured by Raman spectroscopy. Strain analysis of the micro-disk structures demonstrate that shear strains are present in circular cavities, which can detrimentally effect the carrier concentration for direct band transitions. The advantages and disadvantages of each type of proposed cavity structure are discussed.

Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1.

Ambiguous abdominal situs, asplenia/polysplenia and severe cardiac malformations characterize heterotaxy in humans. These anomalies result from the inability of the developing embryo to establish normal left-right asymmetry. We have studied an interesting family in which the heterotaxy phenotype segregates as an X-linked recessive trait. In order to map the heterotaxy locus (HTX), we have analysed 39 family members using highly-polymorphic microsatellite markers from the X chromosome. One of these markers, DXS994, shows no recombination with the disease locus in 20 informative meioses. Linkage analysis results in a maximum lod score of 6.37. Current genetic and physical mapping data assign the order of loci in Xq24-q27.1 as cen-DXS1001-(DXS994, HTX)-DXS984-tel. These results establish the first mapping assignment of situs abnormalities in humans.

Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting.

Kallmann syndrome is a genetic disorder characterized by a defect in olfactory system development, which appears to be due to an abnormality in the migration of olfactory axons and gonadotropin releasing hormone (Gn-RH) producing neurons. The X-linked Kallmann syndrome gene shares significant similarities with molecules involved in neural development. We have now isolated the evolutionarily conserved chicken homologue of the Kallmann gene. In the developing and adult chicken, high levels of expression were found in the mitral cells of the olfactory bulb (the target of olfactory axons) and in the Purkinje cells of the cerebellar cortex, both areas affected in patients with Kallmann syndrome. We propose a model in which the Kallmann syndrome gene product is a signal molecule required for neuronal targeting throughout life.

Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.

The X-linked Kallmann syndrome gene was recently cloned and homologous sequences of unknown functional significance identified on the Y chromosome. We now describe a patient with Kallmann syndrome carrying an X;Y translocation resulting from abnormal pairing and precise recombination between the X-linked Kallmann syndrome gene and its homologue on the Y. The translocation created a recombinant, non-functional Kallmann syndrome gene identical to the normal X-linked gene with the exception of the 3' end which is derived from the Y. Our findings indicate that the 3' portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position' effect remains a formal possibility.

Kallmann syndrome gene on the X and Y chromosomes: implications for evolutionary divergence of human sex chromosomes.

The recently identified gene for X-linked Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has a closely related homologue on the Y chromosome. The X and Y copies of this gene are located in a large region of X/Y homology, on Xp22.3 and Yq11.2, respectively. Comparison of the structure of the X-linked Kallmann syndrome gene and its Y homologue shed light on the evolutionary history of this region of the human sex chromosomes. Our data show that the Y homologue is not functional. Comparative analysis of X/Y sequence identity at several loci on Xp22.3 and Yq11.2 suggests that the homology between these two regions is the result of a complex series of events which occurred in the recent evolution of sex chromosomes.

Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice.

We report the unprecedented finding of a gene with a different map position in two mouse strains. The Clcn4 gene was found to map to the X chromosome in the wild Mediterrean mouse, Mus spretus but to chromosome 7 in the inbred strain of laboratory mouse C57BL/6J. These data indicate that a recent evolutionary rearrangement occurred on the mouse sex chromosomes, very close to the pseudoautosomal region. Our data provide molecular evidence for a major divergence near the pseudoautosomal region, consistent with the hypothesis that hybrid sterility in these species results from abnormal pairing of sex chromosomes during male meiosis.

The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.

Clustered attacks of epileptic episodes originating from the frontal lobe during sleep are the main symptoms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, MIM 600513). Despite the clinical homogeneity, three forms of ADNFLE have been associated with chromosomes 20 (ENFL1; ref. 1), 15 (ENFL2; ref. 2) and 1 (ENFL3; ref. 3). Mutations of the gene encoding the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4 ) have been found in ADNFLE-ENFL1 families, but these mutations account for only a small proportion of ADNFLE cases. The newly identified locus associated with ENFL3 harbours several candidate genes, including CHRNB2 (ref. 8), whose gene product, the beta 2 nicotinic acetylcholine receptor (nAChR) subunit, co-assembles with the alpha 4 nAChR subunit to form the active receptor.

Identification and mapping of human cDNAs homologous to Drosophila mutant genes through EST database searching.

Cross-species comparison is an effective tool used to identify genes and study their function in both normal and pathological conditions. We have applied the power of Drosophila genetics to the vast resource of human cDNAs represented in the expressed sequence tag (EST) database (dbEST) to identify novel human genes of high biological interest. Sixty-six human cDNAs showing significant homology to genes causing Drosophila mutant phenotypes were identified by screening dbEST using the "text string' option, and their map position was determined using both fluorescence in situ hybridization (FISH) and radiation hybrid mapping. Comparison between these genes and their putative partners in Drosophila may provide important insights into their function in mammals. Furthermore, integration of these genes into the transcription map of the human genome contributes to the positional candidate approach for disease gene identification.

A high resolution deletion map of human chromosome Xp22.

We have developed a 32-interval deletion panel for human chromosome Xp22 spanning about 30 megabases of genomic DNA. DNA samples from 50 patients with chromosomal rearrangements involving Xp22 were tested with 60 markers using a polymerase chain reaction strategy. The ensuing deletion map allowed us to confirm and refine the order of previously isolated and newly developed markers. Our mapping panel will provide the framework for mapping new sequences, for orienting chromosome walks in the region and for projects aimed at isolating genes responsible for diseases mapping to Xp22.

Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome.

Ocular albinism type 1 (OA1) is an X-linked disorder characterized by severe impairment of visual acuity, retinal hypopigmentation and the presence of macromelanosomes. We isolated a novel transcript from the OA1 critical region in Xp22.3-22.2 which is expressed at high levels in RNA samples from retina, including the retinal pigment epithelium, and from melanoma. This gene encodes a protein of 424 amino acids displaying several putative transmembrane domains and sharing no similarities with previously identified molecules. Five intragenic deletions and a 2 bp insertion resulting in a premature stop codon were identified from DNA analysis of patients with OA1, indicating that we have identified the OA1 gene.

Ocular albinism: evidence for a defect in an intracellular signal transduction system.

G protein-coupled receptors (GPCRs) participate in the most common signal transduction system at the plasma membrane. The wide distribution of heterotrimeric G proteins in the internal membranes suggests that a similar signalling mechanism might also be used at intracellular locations. We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins. Moreover, we show that OA1 is not found at the plasma membrane, being instead targeted to specialized intracellular organelles, the melanosomes. Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR and support the hypothesis that GPCR-mediated signal transduction systems also operate at the internal membranes in mammalian cells.

SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive multisystem disorder found mainly in Finland and Italy. On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive. Hepatosplenomegaly, osteoporosis and a life-threatening pulmonary involvement (alveolar proteinosis) are also seen. LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine and orotic aciduria. The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined. We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region. Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI. In five Italian patients, we found either an insertion or deletion in the coding sequence, which provides evidence of a causative role of SLC7A7 in LPI. Furthermore, we detected a splice acceptor change resulting in a frameshift and premature translation termination in four unrelated Finnish patients. This mutation may represent the founder LPI allele in Finland.

Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22.

Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22, MID1 (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families. MID1 encodes a member of the B-box family of proteins, which contain protein-protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MID1 with OS suggests an important role for this gene in midline development.

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Disease pathogenesis explained by basic science: lysosomal storage diseases as autophagocytic disorders.

Lysosomal storage diseases (LSDs) are characterized by intra-lysosomal accumulation of undegraded metabolites due to the defective activity of lysosomal enzymes. There is a paucity of data, however, relating to the mechanisms that link this accumulation with disease pathology. Several LSDs can be attributed to deficiencies in the activity of sulfatase enzymes. The gene responsible for the post-translational modification that activates sulfatases, sulfatase modifying factor 1 (SUMF1), is defective in the rare autosomal recessive disorder multiple sulfatase deficiency (MSD). A mouse model of MSD (Sumf1 knockout mouse) exhibits a similar phenotype to patients with MSD, with marked lysosomal storage of undegraded metabolites, and increased expression of inflammatory markers and apoptotic markers. Investigation of disease pathology in mouse models of two LSDs (MSD and mucopolysaccharidosis (MPS) Type IIIA) has revealed an increased number of autophagosomes in these animals compared with wild-type mice. This appears to result from impaired autophagosome-lysosome fusion, which may in turn lead to an absence of autophagy. The suggestion that LSDs can be defined as disorders of autophagy implies that there may be some overlap between pathological mechanisms of LSDs and more common neurodegenerative diseases, and this may help provide direction for future therapeutic strategies.