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.

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.

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.

Evidence that amylase is released from two distinct pools of secretory proteins in the pancreas.

Previous experiments demonstrated the existence of at least two pools of secretory proteins in the exocrine pancreas. We have measured the specific activities of amylase released under resting conditions and of amylase in the zymogen granules. Specific activity of resting secretion was twice that found under stimulated conditions or in zymogen granules. Secretory proteins were pulse-labeled and amylase was measured after precipitation of the enzyme with glycogen. Pancreatic juice collected at 45-50 min post-pulse contained 10-25-times the amylase activity found in zymogen granules. These results confirm the existence of at least two distinct pools of secretory proteins in the exocrine pancreas and suggest the existence of an intracellular route of secretory proteins which would bypass the zymogen granule compartment.

Identification and localization of ATP-diphosphohydrolase (apyrase) in bovine aorta: relevance to vascular tone and platelet aggregation.

In this work, we confirm the existence of an ATP-diphosphohydrolase (apyrase) in bovine aorta and we show that its properties are different from the previously described pancreas ATP-diphosphohydrolase. Hence the aorta enzyme should be considered as a novel type of apyrase. The demonstration is based on pH dependency profiles, heat denaturation curves, 60Co irradiation-inactivation curves and enzyme localization after polyacrylamide gel electrophoresis under non-denaturing conditions. In addition, the irradiation-inactivation curves clearly showed that for both pancreas and aorta enzymes preparations, the same catalytic site is responsible for the hydrolysis of ATP and ADP. The molecular masses of enzymes calculated with this method are 132 +/- 19 kDa (mean +/- S.D.) and 189 +/- 30 kDa (mean +/- S.D.) for the pancreas and aorta enzymes, respectively. Preliminary observations on isolated bovine brain capillaries revealed a high level of enzyme activity strongly suggesting that an ATP-diphosphohydrolase is associated with endothelial cells. The presence of the enzyme on this type of cells was confirmed with pulmonary endothelial cells in culture. Considering the high proportions of smooth muscle cells relative to endothelial cells and the high level of enzyme activity in the aorta preparation, an ATP-diphosphohydrolase activity is definitely present in smooth muscle cells. The ATP-diphosphohydrolase activities described above could regulate the relative concentrations of purine nucleotides both in the plasma and within the vascular wall and hence could play a role both in platelet aggregation and in the control of vascular tone.

Lipid analysis of a novel type of cell secretion in the exocrine pancreas: the pancreasomes.

A novel type of cell secretion termed 'microvesicular secretion' has been described recently in the exocrine pancreas. According to this process, microvesicles are released by acinocytes in the pancreas acinar lumen. These microvesicles, identified as 'pancreasomes', were characterized by the presence of a major glycoprotein component originating in the exocrine acinar cell. In the present work, phospholipids of pancreasomes have been identified. Five classes of phospholipid were found: phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylcholines, sphingomyelins and another minor class of ninhydrin-positive phospholipid (phosphatidylserines or lysophosphatidylethanolamines). The ratios of neutral lipids to phospholipids were particularly high (3:1), as estimated by GLC of their fatty acid content. Analysis of fatty acid composition of pancreasomes lipids revealed a very high proportion of two saturated fatty acids, palmitic (40%) and stearic (24%), whereas two main unsaturated fatty acids, oleic (17%) and linoleic (8%), were found in smaller proportions. Differential scanning calorimeter studies on washed pancreasomes indicated that there was no lipid phase transition in their membrane, despite the absence of cholesterol. Our observations show that pancreasomes have an unusual lipid composition and confirm our previous conclusion based on protein analysis that the release of pancreasomes occurs according to an hitherto undescribed type of secretion, in which a glycoprotein is released associated with specific domains of the luminal plasma membrane.

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.

Cytochemical and immunocytochemical characterization of a fibrillar network (GP2) in pancreatic juice: possible role as a sieve in the pancreatic ductal system.

The secretory product of the exocrine pancreas contains sedimentable and non-sedimentable materials. Electron microscopy of the pellet obtained after ultracentrifugation reveals two major components: microvesicles (pancreasomes) and a fibrillar network of small mesh size. Negative staining of an unfixed pellet demonstrated that these structures are not fixation artifacts. Cytochemical analysis showed that pancreasomes are reactive to osmication and uranyl acetate staining, whereas the fibrillar network was unreactive thereby indicating that the latter does not contain lipids; however, lead citrate staining reveals the network. Alcian blue, known to bind sulfate groups of mucosubstances, reacted strongly with the fibrillar network. The pellet was also characterized by immunocytochemistry with specific antibodies to amylase and glycoprotein 2 (GP2). Both antibodies were located only on the fibrillar network. Washing of the pellet with 100 mM KCl-250 mM NaBr had little effect on GP2 content, but reduced considerably alpha-amylase associated with the reticular matrix. It appeared that GP2 was the major component of the scaffolding that gives rise to the fibrillar network and that other proteins such as alpha-amylase could reversibly bind to it. When double-labeling immunocytochemistry was carried out on the unwashed pellet, labeling of the first antigen reduced the labeling of the second. Removal of amylase by washing the pellet increased the GP2 signal. These results indicate that amylase is bound on the GP2 network. Although the function of the GP2 network is still not clearly defined several possibilities could be envisaged at the level of the pancreatic duct system: 1) The network could drain off any aggregates or precipitates forming in small ducts. 2) The small mesh of the network would present a physical barrier to infecting bacteria that could enter into the duct system from the intestine, especially in conditions of low flow rates. 3) The network may exert a mechanical pressure on the membranes bordering the acinar lumen and small ducts thereby preventing their collapse in basal conditions.

Isolation of zymogen granules from rat pancreas and characterization of their membrane proteins.

A zymogen granule fraction has been isolated from rat pancreas, and its purity has been assessed by biochemical and morphological criteria. Specific activities of two marker enzymes, amylase and chymotrypsin, are increased by 4.6 and 5.4-fold, respectively, as compared to the homogenate. The purified fraction is devoid of detectable RNA, DNA and 5'-nucleotidase, glucose-6-phosphatase, and cytochrome c oxidase activities. Electron micrographs confirm the absence of mitochondria, lysosomes, and rough endoplasmic reticulum fragments. Zymogen granule membranes were isolated from this fraction on a sucrose gradient following lysis in alkaline buffer. Secretory contaminants were efficiently removed from the membranes as indicated by experiments in which labeled secretory proteins were added during the isolation procedure and secondly by measuring residual levels of amylase and chymotrypsin. Three enzyme activities were found in the membranes: thiamine pyrophosphatase, ATP-diphosphohydrolase, and low levels of acid phosphatase. Membrane proteins were solubilized by urea-Triton X-100 and separated in double-dimension (isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Isoelectric point and molecular weight of each protein band were determined.

Heterogeneity of the zymogen granule membranes in rat pancreas.

Zymogen granules (ZG) of rat pancreas have been isolated by the procedure of Pâquet et al. The granules lysed when exposed to alkaline pH (pH 8.2), and their membranes could be subfractionated by centrifugation on a sucrose gradient. Four discrete types of membranes corresponding to densities of 1.105, 1.085, 1.075, and 1.020 were obtained, designated types A, B, C, and D, respectively and characterized both by morphological and biochemical criteria. Electrophoretic profiles showed that they contain the same protein bands but in different proportions. Type A membranes are comprised of four major bands corresponding to molecular weights of 80, 69, 54, and 20 kDa, being in higher concentration than the others. Types B and C contain three major bands at 80, 54 and 20 kDa whereas type D is comprised of only two major bands at 69 and 54 kDa, the latter polypeptide corresponding to ATP-diphosphohydrolase activity which is present in all four membrane types. Freeze-fracture of rapidly frozen membranes, followed by transmission electron microscopy (TEM) showed that type A are large superimposed sheets of membranes with amorphous material between sheets. The surface area of these sheets corresponds grossly to the surface of an intact ZG with a few intramembrane particles (IMP) distributed at random or in small aggregates on large smooth fracture planes. Types B and C exhibit a totally different aspect, forming closed vesicles about the size of a small ZG with few IMP distributed at random or in small aggregates on smooth fracture planes. Type D membranes are very small vesicles with no detectable IMP on relatively smooth fracture planes.(ABSTRACT TRUNCATED AT 250 WORDS)

The origin of the zymogen granule membrane of the pancreatic acinar cell as examined by ultrastructural cytochemistry of acid phosphatase, thiamine pyrophosphatase, and ATP-diphosphohydrolase activities.

Cytochemical distributions of acid phosphatase, thiamine pyrophosphatase, and ATP-diphosphohydrolase activities have been examined on thin sections of rat pancreas and on isolated zymogen-granule membranes. Acid phosphatase was found in the rigid lamellae separated from the Golgi stacked cisternae, in condensing vacuoles, and in the trans-saccules of Golgi apparatus; it was not detected in purified zymogen-granule membranes. Thiamine pyrophosphatase was detected in trans-saccules of the Golgi apparatus, in purified zymogen-granule membranes, and in the plasmalemma of the acinar cell. It was absent in condensing vacuoles. The ATP-diphosphohydrolase activity has a distribution similar to thiamine pyrophosphatase. These observations illustrate the similarity between the trans-saccules of the Golgi apparatus and the membrane of mature zymogen granules and the disparity between the latter membrane and the membrane of the condensing vacuole. They suggest that the condensing vacuole might not be the immediate precursor of the zymogen granule as commonly assumed. An alternative possibility would be that condensing vacuoles would fuse with the trans-saccule (transition) of the Golgi apparatus which in turn would form mature zymogen granules.

Immunocytochemical localization of the [3H]estradiol-binding protein in rat pancreatic acinar cells.

Significant amounts of an estradiol-binding protein (EBP) are present in pancreatic acinar cells. This protein differs from the one found in female reproductive tissues and secondary sex organs (which is commonly referred to as estrogen receptor). EBP has now been purified from rat pancreas and was used as an antigen to induce polyclonal antibodies in rabbits. The antiserum obtained was purified initially by ammonium sulfate fractionation and then still further by interaction with a protein fraction from pancreas that was devoid of estradiol-binding activity. The latter procedure was used to precipitate nonspecific immunoglobulin Gs. Western blot analysis demonstrated that the anti-EBP antibody reacted specifically with a doublet of protein bands having mol wt of 64K and 66K. When this purified antibody was used as an immunocytochemical probe in conjunction with protein-A-gold, acinar cells were labeled on the surface of the endoplasmic reticulum, on the plasma membrane, and in mitochondria. This specific labeling pattern was not observed when preimmune serum was used. No labeling was observed over the nucleus, Golgi apparatus, or zymogen granules with purified anti-EBP antibodies. The unexpected distribution of EBP in both the endoplasmic reticulum and mitochondria is discussed.

Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared to normal acinar cells.

[3H]Estradiol can bind to a specific protein in normal rat pancreatic acinar cells. Electron microscopic immunocytochemical analysis has shown this protein to be localized primarily in the rough endoplasmic reticulum and mitochondria. Rat exocrine pancreatic tumor cell lines, whether grown in tissue culture (AR42J) or as a tumor mass after sc injection into rats (DSL-2), lacked detectable amounts of this [3H]estradiol-binding protein (EBP), as determined by the dextran-coated charcoal assay. Furthermore, primary exocrine pancreatic neoplasms induced with the carcinogen azaserine contained little or no detectable [3H]estradiol-binding activity. However, electron immunocytochemical studies of transformed cells indicated the presence of material that cross-reacted with antibodies prepared against the [3H]EBP. The immunopositive reaction in transformed cells was localized almost exclusively in lipid granules. Such lipid organelles in normal acinar cells, although present less frequently than in transformed cells, have never been observed to contain EBP-like immunopositive material. Presumably, the aberrant localization of EBP in these acinar tumor cells results in loss of function of this protein, which in normal pancreatic acinar cells appears to exert a modulating influence on zymogen granule formation and the process of secretion.

Steroids and the secretory function of the exocrine pancreas.

The influence of steroids on the exocrine pancreas of male rats was examined by removing steroid producing tissue and by introducing individual steroids into these animals at a later date. Castration had no demonstrable morphological effect on acinar cells, whereas castration combined with adrenalectomy caused a marked depletion of zymogen granules as well as widening of peri- and interlobular spaces. Treatment of castrated-adrenalectomized rats with estradiol restored a normal appearance of the pancreas within about 9 h. Triamcinolone acetonide produced similar results. These morphological changes were accompanied by significant alterations of the relative amounts of digestive enzymes present in zymogen granules. A marked reduction of amylase occurred in the castrated-adrenalectomized group. Neither estradiol nor triamcinolone could reverse these effects within 9 h. Castration alone had no significant effect on the relative proportion of amylase; however, it increased the relative amount of proteases. This effect was reversed by estradiol treatment. Estradiol also induced significant changes in the proportion of proelastase in castrated-adrenalectomized animals. Replacement therapy in castrated-adrenalectomized rats with dexamethasone or triamcinolone partially restored the level of amylase in the pancreas, whereas estradiol did not cause any significant effect. At the ultrastructural level, castration and adrenalectomy caused swelling of the Golgi apparatus and accumulation of condensing vacuoles. These effects were reversed by either estradiol or triamcinolone. Also, after acute treatment of these animals with estradiol, two unusual features of acini were noted. In some acini, a type of granule that we termed halo granule appeared. These halo granules were either distinctly separated organelles or formed composite structures that did not appear to be associated with the luminal membrane. Freeze-fracture studies revealed that secretory vesicles in apparently normal acini adhered to each other at specific contact sites characterized by aggregates of intramembrane particles. Multiple sites of contact could be seen in the same vesicle. From our observations it is clear that steroids from the testes and adrenals exert major effects on the secretory apparatus of pancreas; more specifically on the mechanisms that determine the proportions of the different digestive enzyme and on their packaging in the zymogen granules.

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.

Ultrastructural localization of GP2 in acinar cells of pancreas: presence of GP2 in endocytic and exocytic compartments.

GP2 is a glycoprotein found in pancreatic acinar cells. Its subcellular distribution suggests that it may be involved both in exocytosis and endocytosis. Immunocytochemical studies have demonstrated GP2 to be present on the membrane and in the matrix of zymogen granules, on Golgi saccules, on the apical and basolateral surfaces of the plasma membrane, and in the lumina of acini. In addition, this protein was observed in small vacuoles and tubular structures previously identified as "basal lysosomes," "snake-like tubules," and in lysosomes. Because the latter group of structures are involved in endocytosis, it is possible that GP2 may be involved in this phenomenon. GP2 was readily detectable in pancreatic juice and was totally sedimentable by ultracentrifugation, as assessed by Western blot analysis. Induced lysis of isolated zymogen granules also caused release of GP2 in a sedimentable form which, by electron microscopy, appeared as a fibrillar structure. Immunocytochemical localization of amylase was studied in parallel with GP2 and was found in the secretory product to be associated with thread-like structures, presumably the pancreatic thread protein. The physiological significance of these observations is discussed.