Wave-Function Tomography of Topological Dimer Chains with Long-Range Couplings.

The ability to tailor with a high accuracy the intersite connectivity in a lattice is a crucial tool for realizing novel topological phases of matter. Here, we report the experimental realization of photonic dimer chains with long-range hopping terms of arbitrary strength and phase, providing a rich generalization of the Su-Schrieffer-Heeger model which, in its conventional form, is limited to nearest-neighbor couplings only. Our experiment is based on a synthetic dimension scheme involving the frequency modes of an optical fiber loop platform. This setup provides direct access to both the band dispersion and the geometry of the Bloch wave functions throughout the entire Brillouin zone allowing us to extract the winding number for any possible configuration. Finally, we highlight a topological phase transition solely driven by a time-reversal-breaking synthetic gauge field associated with the phase of the long-range hopping, providing a route for engineering topological bands in photonic lattices belonging to the AIII symmetry class.

Measuring Topological Invariants in a Polaritonic Analog of Graphene.

Topological materials rely on engineering global properties of their bulk energy bands called topological invariants. These invariants, usually defined over the entire Brillouin zone, are related to the existence of protected edge states. However, for an important class of Hamiltonians corresponding to 2D lattices with time-reversal and chiral symmetry (e.g., graphene), the existence of edge states is linked to invariants that are not defined over the full 2D Brillouin zone, but on reduced 1D subspaces. Here, we demonstrate a novel scheme based on a combined real- and momentum-space measurement to directly access these 1D topological invariants in lattices of semiconductor microcavities confining exciton polaritons. We extract these invariants in arrays emulating the physics of regular and critically compressed graphene where Dirac cones have merged. Our scheme provides a direct evidence of the bulk-edge correspondence in these systems and opens the door to the exploration of more complex topological effects, e.g., involving disorder and interactions.

Semi-Dirac Transport and Anisotropic Localization in Polariton Honeycomb Lattices.

Compression dramatically changes the transport and localization properties of graphene. This is intimately related to the change of symmetry of the Dirac cone when the particle hopping is different along different directions of the lattice. In particular, for a critical compression, a semi-Dirac cone is formed with massless and massive dispersions along perpendicular directions. Here we show direct evidence of the highly anisotropic transport of polaritons in a honeycomb lattice of coupled micropillars implementing a semi-Dirac cone. If we optically induce a vacancylike defect in the lattice, we observe an anisotropically localized polariton distribution in a single sublattice, a consequence of the semi-Dirac dispersion. Our work opens up new horizons for the study of transport and localization in lattices with chiral symmetry and exotic Dirac dispersions.

Orbital angular momentum bistability in a microlaser.

Light's orbital angular momentum (OAM) is an unbounded degree of freedom emerging in helical beams that appears very advantageous technologically. Using chiral microlasers, i.e., integrated devices that allow generating an emission carrying a net OAM, we demonstrate a regime of bistability involving two modes presenting distinct OAM (ℓ=0 and ℓ=2). Furthermore, thanks to an engineered spin-orbit coupling of light in these devices, these modes also exhibit distinct polarization patterns, i.e., circular and azimuthal polarizations. Using a dynamical model of rate equations, we show that this bistability arises from polarization-dependent saturation of the gain medium. Such a bistable regime appears very promising for implementing ultrafast optical switches based on the OAM of light. As well, it paves the way for the exploration of dynamical processes involving phase and polarization vortices.

High-Fidelity and Ultrafast Initialization of a Hole Spin Bound to a Te Isoelectronic Center in ZnSe.

We demonstrate the optical initialization of a hole-spin qubit bound to an isoelectronic center (IC) formed by a pair of Te impurities in ZnSe, an impurity-host system providing high optical homogeneity, large electric dipole moments, and potentially advantageous coherence times. The initialization scheme is based on the spin-preserving tunneling of a resonantly excited donor-bound exciton to a positively charged Te IC, thus forming a positive trion. The radiative decay of the trion within less than 50 ps leaves a heavy hole in a well-defined polarization-controlled spin state. The initialization fidelity exceeds 98.5% for an initialization time of less than 150 ps.

Complete quantum control of exciton qubits bound to isoelectronic centres.

In recent years, impressive demonstrations related to quantum information processing have been realized. The scalability of quantum interactions between arbitrary qubits within an array remains however a significant hurdle to the practical realization of a quantum computer. Among the proposed ideas to achieve fully scalable quantum processing, the use of photons is appealing because they can mediate long-range quantum interactions and could serve as buses to build quantum networks. Quantum dots or nitrogen-vacancy centres in diamond can be coupled to light, but the former system lacks optical homogeneity while the latter suffers from a low dipole moment, rendering their large-scale interconnection challenging. Here, through the complete quantum control of exciton qubits, we demonstrate that nitrogen isoelectronic centres in GaAs combine both the uniformity and predictability of atomic defects and the dipole moment of semiconductor quantum dots. This establishes isoelectronic centres as a promising platform for quantum information processing.

Genome-wide scan of obesity in the Old Order Amish.

To identify the genetic determinants of typical obesity, we performed a genome-wide scan of obesity-related traits using data from the Amish. Multipoint linkage analysis was performed using a variance components procedure on body mass index (BMI), waist circumference, percentage of body fat, and serum leptin concentrations. All 672 individuals were genotyped for 357 markers in 22 autosomes. We observed modest evidence for linkage, with the maximum log odds (lod) scores for linkage for these traits occurring on chromosomes 3p (percentage of body fat: lod = 1.61, near the peroxisome proliferator-activated receptor-alpha gene), 14q (waist: lod = 1.80), and 16p (leptin: lod = 1.72; BMI: lod = 1.68). We also tested for linkage to BMI-adjusted leptin concentrations and observed suggestive evidence for linkage on chromosome 10p (lod = 2.73), approximately 10-20 cM telomeric from obesity loci previously reported in French and German Caucasians. Two additional linkage signals for this trait were observed on chromosomes 7q (lod = 1.77, approximately 20 cM from the leptin gene) and 14q (lod = 2.47). Follow-up studies may be warranted to pursue some of these linkage signals, especially those detected near known obesity candidate genes, and those in regions coinciding with linkage signals reported previously.

Identifying susceptibility genes using linkage and linkage disequilibrium analysis in large pedigrees.

Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We investigated two approaches to identifying markers associated with disease. One method applied linkage analysis and then linkage disequilibrium tests to markers within linked regions. The other method looked for linkage disequilibrium with disease using all markers. Additionally, we investigated using Simes' test to combine p-values from linkage disequilibrium tests for nearby markers. We applied both approaches to all replicates of the Genetic Analysis Workshop 12 problem 2 isolated population data set. We reported results from the 25th replicate as if it were a real problem and assessed the power of our methods using all replicates. Using all replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linkage with disease and then testing markers within those regions for linkage disequilibrium with the implementations that we chose. Using Simes' test to combine p-values for linkage disequilibrium tests on correlated markers seemed to be of marginal value.

Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

Search for susceptibility genes, gene x gene interactions, and gene x environment interactions utilizing nonparametric linkage analysis.

There may be a different genetic basis for the two forms of the disease simulated in Problem 2 and the complex disease may be affected by environmental factors. Hence, we investigate the effects of two environmental factors. We selected 400 nuclear families from the data generated for Problem 2. Affection status was investigated in several ways. Individuals with severe and mild forms of the disease were both considered affected, individuals with only the severe form were considered affected while those with the mild form were considered unknown, and individuals with only the mild form were considered affected while those with the severe form were considered unknown. We found evidence of linkage between putative disease loci and markers in the D3G042-D3G049 and D5G031-D5G042 regions when we considered severely and mildly affected individuals as affected and also in the region D1G004-D1G013 when mildly affected individuals were considered unknown. We observed interactions between the first environmental factor and D1G043 among healthy sib pairs.

Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm.

BACKGROUND AND PURPOSE: There is convincing evidence that susceptibility to intracranial aneurysms (ICAs) has a genetic component. However, few studies have sought to identify functional variation in specific candidate genes that may predispose individuals to develop an ICA. METHODS: ICA cases and controls were genotyped for a simple length polymorphism in the promoter of matrix metalloproteinase-9 (MMP-9) to test for association between variation in the promoter and the occurrence of ICA. Alternative alleles were cloned into an in vitro reporter vector, transfected into human HT1080 fibroblasts, and assayed for promoter activity by beta-gal and luciferase assays. Electrophoretic gel shift assays were used to assess nuclear factor binding. RESULTS: A length polymorphism in the promoter of MMP-9 was nonrandomly associated with the occurrence of ICA in a case-control study. This polymorphism was shown, by direct sequencing of 36 individuals, to be the only sequence variation within a 736-base pair region proximal to the transcriptional start site of the gene. Variation in the length of this repetitive element was shown to modulate promoter activity in an in vitro reporter assay, with the highest promoter activity being observed in constructs bearing the longest [(CA)23] element. Electrophoretic mobility shift assays were used to show that the (CA) element is bound by a sequence-specific DNA-binding protein. CONCLUSIONS: Genetic variation in the promoter of the MMP-9 gene results in variation in its expression at the level of transcription. This may result in subtle differences in MMP-9 activity within the circle of Willis, leading to increased susceptibility to ICA formation.

Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice.

DBA/2J (D2) and C57BL/6J (B6) mice exhibit differential sensitivity to seizures induced by various chemical and physical methods, with D2 mice being relatively sensitive and B6 mice relatively resistant. We conducted studies in mature D2, B6, F1, and F2 intercross mice to investigate behavioral seizure responses to pentylenetetrazol (PTZ) and to map the location of genes that influence this trait. Mice were injected with PTZ and observed for 45 min. Seizure parameters included latencies to focal clonus, generalized clonus, and maximal seizure. Latencies were used to calculate a seizure score that was used for quantitative mapping. F2 mice (n = 511) exhibited a wide range of latencies with two-thirds of the group expressing maximal seizure. Complementary statistical analyses identified loci on proximal (near D1Mit11) and distal chromosome 1 (near D1Mit17) as having the strongest and most significant effects in this model. Another locus of significant effect was detected on chromosome 5 (near D5Mit398). Suggestive evidence for additional PTZ seizure-related loci was detected on chromosomes 3, 4, and 6. Of the seizure-related loci identified in this study, those on chromosomes 1 (distal), 4, and 5 map close to loci previously identified in a similar F2 population tested with kainic acid. Results document that the complex genetic influences controlling seizure response in B6 and D2 mice are partially independent of the nature of the chemoconvulsant stimulus with a locus on distal chromosome 1 being of fundamental importance.

Mapping quantitative trait loci for seizure response to a GABAA receptor inverse agonist in mice.

To define the genetic contributions affecting individual differences in seizure threshold, a beta carboline [methyl-beta-carboline-3-carboxylate (beta-CCM)]-induced model of generalized seizures was genetically dissected in mice. beta-CCM is a GABAA receptor inverse agonist and convulsant. By measuring the latency to generalized seizures after beta-CCM administration to A/J and C57BL6/J mice and their progeny, we estimated a heritability of 0.28 +/- 0.10. A genome wide screen in an F2 population of these parental strains (n = 273) mapped quantitative trait loci (QTLs) on proximal chromosome 7 [logarithm of the likelihood for linkage (LOD) = 3.71] and distal chromosome 10 (LOD = 4.29) for seizure susceptibility, explaining approximately 22 and 25%, respectively, of the genetic variance for this seizure trait. The best fitting logistic regression model suggests that the A/J allele at each locus increases the likelihood of seizures approximately threefold. In a subsequent backcross population (n = 223), we mapped QTLs on distal chromosome 4 (LOD = 2.88) and confirmed the distal chromosome 10 QTLs (LOD = 4.36). In the backcross, the C57BL/6J allele of the chromosome 10 QTL decreases the risk of seizures approximately twofold. These QTLs may ultimately lead to the identification of genes influencing individual differences in seizure threshold in mice and the discovery of novel anticonvulsant agents. The colocalization on distal chromosome 10 of a beta-CCM susceptibility QTL and a QTL for open field ambulation and vertical movement suggests the existence of a single, pleiotropic locus, which we have named Exq1.

A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

Multiple phenotype modeling in gene-mapping studies of quantitative traits: power advantages.

Genomewide searches for loci influencing complex human traits and diseases such as diabetes, hypertension, and obesity are often plagued by low power and interpretive difficulties. Attempts to remedy these difficulties have typically relied on, and have promoted the use of, novel subject-ascertainment schemes, larger sample sizes, a greater density of DNA markers, and more-sophisticated statistical modeling and analysis strategies. Many of these remedies can be costly to implement. We investigate the utility of a simple statistical model for the mapping of quantitative-trait loci that incorporates multiple phenotypic or diagnostic endpoints into a gene-mapping analysis. The approach considers finding a linear combination of multiple phenotypic values that maximizes the evidence for linkage to a locus. Our results suggest that substantial increases in the power to map loci can be obtained with the proposed technique, although the increase in power obtained is a function of the size and direction of the residual correlation among the phenotypes used in the analysis. Extensive simulation studies are described that justify these claims, for cases in which two phenotypic measures are analyzed. This approach can be easily extended to cover more-complex situations and may provide a basis for more insightful genetic-analysis paradigms.

Linkage analysis, kinship, and the short-term evolution of chromosomes.

Although all meiotic (or linkage) mapping strategies ultimately rely on Mendel's laws, the precise manner in which these laws are exploited in relevant statistical models determines the utility of each strategy for different traits and diseases. In this paper we review the motivation and principles behind each of the three most often used statistical strategies for mapping loci that influence complex, multifactorial traits and diseases (such as diabetes and hypertension), namely: pedigree-based parametric linkage, relative pair allele sharing analysis, and association or linkage disequilibrium analysis. It is our hope to show how Mendel's laws are exploited in each through use of two basic concepts: the short-term evolution of chromosomes, and kinship. Problems inherent in each strategy are described. We then consider how extensions, modifications, or novel derivatives of these three strategies might be fashioned that make better use of the concepts of kinship and short-term chromosome evolution. Two strategies receive emphasis: a haplotype sharing method, which considers the kinship of groups of individuals, and extended variance component models, which make use of genotype information in novel ways.

Automated atlas integration and interactive three-dimensional visualization tools for planning and guidance in functional neurosurgery.

Many critical functionally distinct subcortical structures are not distinguishable on anatomical magnetic resonance imaging (MRI) scans. In order to provide the neurosurgeon with this missing information, a deformable volumetric atlas of the basal ganglia and thalamus has been created from the Schaltenbrand and Wahren atlas of cryogenic slices. The volumetric atlas can be automatically deformed to an individual patient's MRI. To facilitate the clinical use of the atlas, a visualization platform has been developed for preoperative and intraoperative use which permits manipulation of the merged atlas and MRI data sets in two- and three-dimensional views. The platform includes graphical tools which allow the visualization of projections of a leukotome and other surgical tools with respect to the atlas data, as well as preregistered images from any other imaging modality. In addition, a graphical interface has been designed to create custom virtual lesions using computer models of neurosurgical tools for intraoperative planning. To date this system has been employed as an adjunct to over 30 functional neurosurgical cases including surgery for movement disorders.

Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.

Pseudoxanthoma elasticum (PXE) is a classic inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye and the cardiovascular system, resulting in skin lesions, decreased vision and vascular disease. Clinically, a more common autosomal recessive and a less common autosomal dominant pattern of inheritance, with high penetrance, have been described; the estimated prevalence of the disease is 1 in 70,000-100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen on a collection of 38 families with two or more affected siblings, using allele sharing algorithms. Excess allele sharing was found on the short arm of chromosome 16 and confirmed by conventional linkage analysis, localizing the disease gene under a recessive model with a maximum two point lod score of 21.27 on chromosome 16p13.1, an area so far devoid of any obvious candidate genes. Under a dominant transmission pattern linkage with a maximum two point lod score of 14.53 was observed to the same region. Linkage heterogeneity analysis predicted the presence of allelic heterogeneity with different variants of a single gene that resides in this chromosomal region accounting for recessive and dominant forms of PXE.

Mapping murine loci for seizure response to kainic acid.

Mature DBA/2J (D2) mice are very sensitive to seizures induced by various chemical and physical stimuli, whereas C57BL/6J (B6) mice are relatively seizure resistant. We have conducted a genome-wide search for quantitative trait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F2 intercross population. Parental, F1, and F2 mice (8-10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epilepticus were recorded and used to calculate an overall seizure score. Results of seizure testing indicated that the difference in susceptibility to KA-induced seizures between D2 and B6 mice is a polygenic phenomenon with at least 65% of the variance due to genetic factors. First-pass genome screening (10-cM marker intervals) in F2 progeny (n = 257) documented a QTL of moderate effect on Chromosome (Chr) 1 with a peak LOD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224-D11Mit14), 15 (D15Mit6-D15Mit46) and 18 (D18Mit9-D18Mit144). Multiple locus models generally confirmed the Mapmaker/QTL results and also provided evidence for another QTL on Chr 4 (D4Mit9). Multilocus analysis of seizure severity suggested that additional loci on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contribute to KA-induced seizure response. Overall, our results document a complex genetic determinism for KA-induced seizures in these mouse strains with contributions from as many as eight QTLs.

Ventilation and metabolism among rat strains.

We examined ventilation and metabolism in four rat strains with variation in traits for body weight and/or blood pressure regulation. Sprague-Dawley [SD; 8 males (M), 8 females (F)], Brown Norway (BN; 10 M, 11 F), and Zucker (Z; 11 M, 12 F) rats were compared with Koletsky (K; 11 M, 11 F) rats. With the use of noninvasive plethysmography, frequency, tidal volume, minute ventilation (VE), O2 consumption, and CO2 production were derived at rest during normoxia (room air) and during the 5th minute of exposure to each of the following: hyperoxia (100% O2), hypoxia (10% O2-balance N2), and hypercapnia (7% CO2-balance O2). Statistical methods probed for strain and sex effects, with covariant analysis by body weight, length, and body mass. During resting breathing, strain effects were found with respect to both frequency (BN, Z > K, SD) and tidal volume (SD > BN, Z) but not to VE. Sex influenced frequency (F > M) alone. Z rats had higher values for O2 consumption, CO2 production, and respiratory quotient than the other three strains, with no independent effect by sex. During hyperoxia, frequency was greater in BN and Z than in SD or K rats; SD rats had a larger tidal volume than BN or Z rats; Z rats had a greater VE than K rats; and M had a larger tidal volume than F. Strain differences persisted during hypercapnia, with Z rats exhibiting the highest frequency and VE values. During hypoxic exposure, strain effects were found to influence VE (SD > K, Z), frequency (BN > K), and tidal volume (SD > BN, K, Z). Body mass was only a modest predictor of VE during normoxia, of both VE and tidal volume with hypoxia, hypercapnia, or hyperoxia, and of frequency during hypercapnia. We conclude that strain of rats, more than their body mass or sex, has major and different influences on metabolism, the pattern and level of ventilation during air breathing, and ventilation during acute exposure to hypercapnia or hypoxia.