Magnetic Ground States of the Rare-Earth Tripod Kagome Lattice Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er).

We present the structural and magnetic properties of a new compound family, Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er), with a hitherto unstudied frustrating lattice, the "tripod kagome" structure. Susceptibility (ac, dc) and specific heat exhibit features that are understood within a simple Luttinger-Tisza-type theory. For RE=Gd, we found long-ranged order (LRO) at 1.65 K, which is consistent with a 120° structure, demonstrating the importance of diople interactions for this 2D Heisenberg system. For RE=Dy, LRO at 0.37 K is related to the "kagome spin ice" physics for a 2D system. This result shows that the tripod kagome structure accelerates the transition to LRO predicted for the related pyrochlore systems. For RE=Er, two transitions, at 80 mK and 2.1 K are observed, suggesting the importance of quantum fluctuations for this putative XY system.

Extremely correlated Fermi-liquid description of normal-state ARPES in cuprates.

The normal-state single particle spectral function of the high temperature superconducting cuprates, measured by the angle-resolved photoelectron spectroscopy (ARPES), has been considered both anomalous and crucial to understand. Here, we report an unprecedented success of the new extremely correlated Fermi liquid theory by one of us [B. S. Shastry, Phys. Rev. Lett. 107, 056403 (2011)] to describe both laser and conventional synchrotron ARPES data (nodal cut at optimal doping) on Bi(2)Sr(2)CaCu(2)O(8+δ) and synchrotron data on La(1.85)Sr(0.15)CuO(4). It fits all data sets with the same physical parameter values, satisfies the particle sum rule and successfully addresses two widely discussed kink anomalies in the dispersion.

Evaluation of the CYP1B1 gene as a candidate gene in beagles with primary open-angle glaucoma (POAG).

PURPOSE: In humans, primary open-angle glaucoma (POAG) is a complex genetic disorder and is the leading cause of visual impairment. Although all relevant genes were not identified, a small subset of the condition is found to be caused by mutations in the MYOC and CYP1B1 genes. Inherited glaucoma also occurs in several breeds of dogs including beagles. Primary glaucoma in beagles is inherited as an autosomal recessive trait. The purpose of this study is to investigate the role of the CYP1B1 gene in beagles with POAG. METHODS: For the purpose of genetic analysis, total RNAs from the spleen of the canines were isolated and CYP1B1 cDNA was prepared. Genomic DNA from five affected, two carriers, and 13 randomly selected normal beagles with no sign of glaucoma was amplified by the polymerase chain reaction (PCR) using four pairs of primers. The amplified products were directly sequenced using BigDye terminator cycle sequencing. RESULTS: Genomic DNA analyses have identified a substitution polymorphism (109A-->C) in the 5'-untranslated region (UTR) as well as a missense mutation (P93R) in exon 2 of the gene. Three affected, two carriers, and nine normal dogs are heterozygous while two affected and three normal dogs are homozygous for the missense mutation. One normal dog did not show this alteration. Normal dogs also contain the substitution polymorphism in the 5'-UTR. Similar experiments with exon 3 did not identify any additional mutation in the gene. CONCLUSIONS: The above results suggest that CYP1B1 alterations in the coding and UTR are not the primary cause of glaucoma in beagles by possible monogenic association. They may be classified as polymorphisms or they may modify glaucoma phenotype.

Assessment of the contribution of insulin-like growth factor I receptor 3174 G-->A polymorphism to the progression of advanced retinopathy of prematurity.

PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children with short gestational age and low birthweight. The condition can cause abnormal vessel development that can lead to retinal detachment and blindness. It has been recently reported that a low level of insulin-like growth factor I (IGF-I) is associated with ROP. However, the most prevalent polymorphism of IGF-I receptor (IGF-IR 3174 G-->A) that was reported to be producing low level of IGF-I was not found to be associated with ROP in a certain population. In order to reproduce this data in a different cohort and to learn more about the contribution of IGF-IR polymorphism to ROP, the authors hypothesized that it is possible that such a polymorphism would occur more frequently in a different cohort of infants with advanced ROP than those children with mild or no disease. METHODS: For genetic analysis, eligible patients were selected consecutively by experienced pediatric ophthalmologists and leukocyte DNA from affected (n=52) and normal patients (n=33) were amplified by polymerase chain reaction. The amplified products were subjected to restriction enzyme digestion with 10 units of MnlI enzyme. The digested products were analyzed by polyacrylamide gel electrophoresis followed by ethidium bromide staining to visualize the restriction fragment length polymorphism. RESULTS: The analysis suggests that there is no statistically significant difference in allelic frequency of the most prevalent IGF-IR gene polymorphism between normal subjects and patients with ROP in this cohort. The G-->A polymorphism did not occur more frequently in patients with ROP. CONCLUSIONS: The results do not support the association of the most prevalent IGF-IR gene polymorphism and the risk of advanced ROP in a different cohort, confirming the earlier report.

Pharmacogenetics and the concept of individualized medicine.

Adverse drug reaction in patients causes more than 2 million hospitalizations including 100,000 deaths per year in the United States. This adverse drug reaction could be due to multiple factors such as disease determinants, environmental and genetic factors. In order to improve the efficacy and safety and to understand the disposition and clinical consequences of drugs, two rapidly developing fields--pharmacogenetics (focus is on single genes) and pharmacogenomics (focus is on many genes)--have undertaken studies on the genetic personalization of drug response. This is because many drug responses appear to be genetically determined and the relationship between genotype and drug response may have a very valuable diagnostic value. Identification and characterization of a large number of genetic polymorphisms (biomarkers) in drug metabolizing enzymes and drug transporters in an ethnically diverse group of individuals may provide substantial knowledge about the mechanisms of inter-individual differences in drug response. However, progress in understanding complex diseases, its negative psychosocial consequences, violation of privacy or discrimination, associated cost and availability and its complexity (extensive geographic variations in genes) may become potential barriers in incorporating this pharmacogenetic data in risk assessment and treatment decisions. In addition, it requires increased enthusiasm and education in the clinical community and an understanding of pharmacogenetics itself by the lay public. Although individualized medications remain as a challenge for the future, the pharmacogenetic approach in drug development should be still continued. If it becomes a reality, it delivers benefits to improve public health and allow genetically subgroup diseases thereby avoiding adverse drug reactions (by knowing in advance who should be treated with what drug and how).

Cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a bilateral, clinically and genetically heterogeneous hereditary eye disorder that affects both the retina and the vitreous body. The condition has a high degree of penetrance and variable expressivity. In some cases of autosomal dominant FEVR (AD FEVR), mutations in the frizzled-4 gene (FZD-4) have been shown to be involved in FEVR pathology. In this study, we report that a second unlinked gene (Factor V) is also mutated (Leiden mutation) in the same family, which harbors the FZD-4 gene mutation. These results show for the first time that some families with FEVR could be digenic. While this is unlikely to be a widespread problem, the occurrence of digenic disorders with apparently simple Mendelian inheritance patterns renders the current method of analysis of monogenic disorders by linkage and mutation screening incomplete.

Hubbard model on decorated lattices.

We introduce a family of lattices for which the Hubbard model and its natural extensions can be quasiexactly solved, i.e., solved for the ground and low energy states. In particular, we show rigorously that the ground state of the Hubbard model with off-site Coulomb repulsions on a decorated Kagomè lattice is an ordered array of local currents. The low energy theory describing this chiral state is an S=1 / 2 XY model, where each spin degree of freedom represents the two possible chiralities of each local current.

Factor V Leiden mutation (R506Q) and the risk of advanced retinopathy of prematurity.

The coagulation factor V Leiden mutation was reported to be a significant (10.7%) risk factor for pre-term deliveries. It is also well known that a portion (10%) of very low birth weight premature babies develop advanced retinopathy of prematurity (ROP) which is a leading cause of blindness in children. However, the relationship between the Leiden mutation and development of advanced ROP is not known. In order to understand this relationship as well as genetic contribution to ROP, in this study, we have analyzed 100 pre-term infants with advanced ROP (stage 4B/5), 20 term babies with a clinically similar disease called familial exudative vitreoretinopathy (FEVR) and 16 normal babies from four different ethnic backgrounds. Our extensive analysis has identified a heterozygous Leiden mutation in four patients (4%) with advanced ROP and in one patient (5%) with sporadic FEVR. DNA sequence analysis has further confirmed this base change as well as heterozygosity. However, the frequency observed in the patients analyzed in our study is lower than reported frequency in the general population (5.4%). Therefore, statistically factor V mutation on its own is not a major risk factor for the above two disorders. However, it may be associated with other additive factors as might be expected for a complex genetic trait.

Multiple field-induced phase transitions in the geometrically frustrated dipolar magnet: Gd(2) Ti(2)O(7).

Field-driven phase transitions generally arise from competition between Zeeman energy and exchange or crystal-field anisotropy. Here we present the phase diagram of a frustrated pyrochlore magnet Gd(2)Ti(2)O(7), where crystal-field splitting is small compared to the dipolar energy. We find good agreement between zero-temperature critical fields and those obtained from a mean-field model. Here, dipolar interactions couple real space and spin space, so the transitions in Gd(2)Ti(2)O(7) arise from field-induced "cooperative anisotropy," reflecting the broken spatial symmetries of the pyrochlore lattice.

Molecular and cell biological aspects of Alzheimer disease.

Alzheimer disease (AD) is one of several types of chronic and very common dementing disorders, affecting individuals aged 65 years or older. During the last five years, an enormous growth in the field has enriched our understanding of this complex condition. Molecular genetic studies have identified at least three genes that, when mutated, cause the autosomal dominant, early-onset familial form of the disease. The late-onset, most common forms of the disease are likely to be associated with various genetic susceptibility factors. The application of cell biological techniques has given insight into basic aspects of the functions of important proteins involved in disease progression, and transgenic animal studies have further enriched our knowledge of the pathophysiological aspects of the disease. More efficient therapeutic drugs to retard its progression have been developed, as well as techniques to identify the preclinical phase of the disorder. Although we are still lacking the molecular basis and order of events involved in the disease process, the future for AD research, as well as for AD patients, is more promising than ever before.

Spin dynamics of Sr14Cu24O41 two-leg ladder studied by Raman spectroscopy.

The two-magnon (2M) excitation at 3000 cm(-1) in Sr14Cu24O41 two-leg ladder is studied by Raman scattering. A slight anisotropy of the superexchange coupling J(perpendicular)/J(parallel) approximately 0.8 with J(parallel) = 110+/-20 meV is proposed from the analysis of the magnetic scattering. The resonant coupling across the charge transfer gap increases the 2M intensity by orders of magnitude. The anisotropy of Raman scattering is dependent upon the excitation energy. The 2M relaxation is found to be correlated with the temperature dependent electronic Raman continuum at low frequencies.

Parkinson disease: etiology, pathogenesis and future of gene therapy.

Parkinson disease (PD) is a progressive neurological disorder with a prevalence of 1-2% in people over the age of 50. It has a world-wide distribution and has no gender preference. The neurological hallmark of PD is the presence of Lewy bodies and is characterized by the degeneration of nigrostriatal dopaminergic neurons. The causes of PD are unknown but considerable evidence suggests a multifactorial etiology involving genetic and environmental factors. A molecular genetic approach identified three genes and at least two additional loci in rare familial forms of PD. Two of these genes are involved in the ubiquitin mediated pathway of protein degradation and the third one is a highly expressed protein in the synaptic terminal and is called alpha-synuclein. In animal models, it has been shown that use of the household pesticide which is known to contain rotenone, causes PD. Thus, a combined action of genetic and environmental factors is responsible for the pathogenesis of PD. Although use of levodopa or dopamine agonists can substantially reduce clinical symptoms, and transplantation of fetal nerve tissue still remains as an alternative therapy (although it has been recently shown to be having no overall benefit), directed delivery of glial cell derived neurotrophic factor (known to have trophic effects on dopaminergic neurons) may also be a beneficial therapeutic option for PD patients.

Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a leading cause of blindness in premature children. It is a multifactorial disorder which causes fibrovascular tissue changes that affect the retina in low birth-weight and short gestational age infants. To determine the prevalence of Norrie disease (ND) gene mutations, clinical examination and molecular genetic analyses were performed in 100 pre-term babies of different ethnic backgrounds who developed advanced ROP. The leukocyte DNA was extracted, amplified by the polymerase chain reaction (PCR), and analyzed by single-strand conformation polymorphism (SSCP), G/T and C/A scanning, and by DNA sequencing. All three exons, including splice sites and the 3'-untranslated region, were screened. Of the 100 patients analyzed, 2 patients with advanced ROP showed a mobility shift in the DNA. In 1 patient, this mobility shift was caused by the insertion of an additional 12-bp CT repeat in exon 1, and in the second patient, there was a 14-bp deletion in the same exon of the ND gene, as evidenced by direct sequencing of the amplified products. Similar analyses of exons 2 and 3 and the 3'-untranslated region failed to detect additional mutations in the gene. None of the 130 normal, unrelated controls revealed similar changes. Taking into account the above results, as well as those of other studies, it appears that the ND gene mutations can account for 3% of cases of advanced ROP. Although the ND gene is not frequently involved in advanced ROP, the present large-scale study further supports the hypothesis that genetic influences may play an important role in the development of severe ROP in some premature infants.

Evaluation of RP2 and RP3 genes in an X-linked RP family manifesting loss of central vision and preserved peripheral function.

X-Linked retinitis pigmentosa is a most severe and heterogeneous disorder of the retina. Recently, genes (RP2 and RPGR) from two X-linked loci have been positionally cloned and mutations have been identified in many families. To further evaluate allelic and non-allelic heterogeneity and the genotype--phenotype relationships, and to determine the prevalence of mutations in the gene, we have analyzed one previously unreported X-linked retinitis pigmentosa family, using a combination of haplotype analysis and DNA sequencing. Our extensive analysis of the RP2 gene failed to detect any disease--causing or polymorphic mutations. In the case of the RP3 gene, the alleles of the dinucleotide repeat marker did not segregate with the disease. Although we cannot completely exclude the possibility of the RP2 and RP3 genes as candidate genes, the above results suggest that structural and functional changes associated with the RP2 gene are not responsible for the phenotype in the family analyzed. Further identification of the X-linked genes may facilitate the elucidation of the molecular basis of the disorder in the family analyzed.

X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci?

Juvenile retinoschisis (RS) and Norrie disease (ND) are X-linked recessive retinal disorders. Both disorders, in the majority of cases, are monogenic and are caused by mutations in the RS and ND genes, respectively. Here we report the identification of a family in which mutations in both the RS and ND genes are segregating with RS pathology. Although the mutations identified in this report were not functionally characterized with regard to their pathogenicity, it is likely that both of them are involved in RS pathology in the family analyzed. This suggests the complexity and digenic nature of monogenic human disorders in some cases. If this proves to be a widespread problem, it will complicate the strategies used to identify the genes involved in diseases and to develop methods for intervention.

Coats' disease and congenital retinoschisis in a single eye: a case report and DNA analysis.

The clinical features of Coats' disease and congenital retinoschisis (RS) are distinctly different. Therefore, finding changes consistent with Coats' disease and congenital RS in a single eye is an unusual occurrence. The following report describes two cases with a Coats' telangiectatic lesion in one region of the retina separated by normal retina and the presence of central and peripheral congenital RS. Molecular genetic analysis of the Norrie disease and RS genes failed to identify disease-causing or polymorphic mutations in either of the genes, suggesting that the above condition is clinically and genetically a different disorder. Further studies are needed to identify the genes responsible for the above disorder and associated ocular manifestations.

Molecular genetics of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder affecting almost exclusively females. It affects approximately one in 15000 females and is characterized by a loss of purposeful hand use, autism, ataxia and seizure. The disorder is usually sporadic, but rare familial cases have also been reported. Recently it has been shown that familial cases are an X-linked dominant disorder and the disease locus maps to Xq28. A candidate gene called methyl-CpG-binding protein 2 was identified from the Xq28 region and was shown to contain mutations in about 77% of Rett syndrome patients. Since the encoded protein was previously shown to be a global transcriptional repressor, undesired expression of yet unidentified genes that are normally repressed is considered to be pathogenic in Rett syndrome.