Interaction between TBP and Condensin Drives the Organization and Faithful Segregation of Mitotic Chromosomes.

Genome/chromosome organization is highly ordered and controls various nuclear events, although the molecular mechanisms underlying the functional organization remain largely unknown. Here, we show that the TATA box-binding protein (TBP) interacts with the Cnd2 kleisin subunit of condensin to mediate interphase and mitotic chromosomal organization in fission yeast. TBP recruits condensin onto RNA polymerase III-transcribed (Pol III) genes and highly transcribed Pol II genes; condensin in turn associates these genes with centromeres. Inhibition of the Cnd2-TBP interaction disrupts condensin localization across the genome and the proper assembly of mitotic chromosomes, leading to severe defects in chromosome segregation and eventually causing cellular lethality. We propose that the Cnd2-TBP interaction coordinates transcription with chromosomal architecture by linking dispersed gene loci with centromeres. This chromosome arrangement can contribute to the efficient transmission of physical force at the kinetochore to chromosomal arms, thereby supporting the fidelity of chromosome segregation.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-ß precursor protein (APP) and extracellular Aß42 and Aß40 (the 42- and 40-residue isoforms of the amyloid-ß peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aß42 and Aß40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Involvement of condensin-directed gene associations in the organization and regulation of chromosome territories during the cell cycle.

Chromosomes are not randomly disposed in the nucleus but instead occupy discrete sub-nuclear domains, referred to as chromosome territories. The molecular mechanisms that underlie the formation of chromosome territories and how they are regulated during the cell cycle remain largely unknown. Here, we have developed two different chromosome-painting approaches to address how chromosome territories are organized in the fission yeast model organism. We show that condensin frequently associates RNA polymerase III-transcribed genes (tRNA and 5S rRNA) that are present on the same chromosomes, and that the disruption of these associations by condensin mutations significantly compromises the chromosome territory arrangement. We also find that condensin-dependent intra-chromosomal gene associations and chromosome territories are co-regulated during the cell cycle. For example, condensin-directed gene associations occur to the least degree during S phase, with the chromosomal overlap becoming largest. In clear contrast, condensin-directed gene associations become tighter in other cell-cycle phases, especially during mitosis, with the overlap between the different chromosomes being smaller. This study suggests that condensin-driven intra-chromosomal gene associations contribute to the organization and regulation of chromosome territories during the cell cycle.

Presenilin E318G variant and Alzheimer's disease risk: the Cache County study.

BACKGROUND: Alzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States. A vast number of genes regulate Alzheimer's disease, including Presenilin 1 (PSEN1). Multiple studies have attempted to locate novel variants in the PSEN1 gene that affect Alzheimer's disease status. A recent study suggested that one of these variants, PSEN1 E318G (rs17125721), significantly affects Alzheimer's disease status in a large case-control dataset, particularly in connection with the APOEε4 allele. METHODS: Our study looks at the same variant in the Cache County Study on Memory and Aging, a large population-based dataset. We tested for association between E318G genotype and Alzheimer's disease status by running a series of Fisher's exact tests. We also performed logistic regression to test for an additive effect of E318G genotype on Alzheimer's disease status and for the existence of an interaction between E318G and APOEε4. RESULTS: In our Fisher's exact test, it appeared that APOEε4 carriers with an E318G allele have slightly higher risk for AD than those without the allele (3.3 vs. 3.8); however, the 95 % confidence intervals of those estimates overlapped completely, indicating non-significance. Our logistic regression model found a positive but non-significant main effect for E318G (p = 0.895). The interaction term between E318G and APOEε4 was also non-significant (p = 0.689). CONCLUSIONS: Our findings do not provide significant support for E318G as a risk factor for AD in APOEε4 carriers. Our calculations indicated that the overall sample used in the logistic regression models was adequately powered to detect the sort of effect sizes observed previously. However, the power analyses of our Fisher's exact tests indicate that our partitioned data was underpowered, particularly in regards to the low number of E318G carriers, both AD cases and controls, in the Cache county dataset. Thus, the differences in types of datasets used may help to explain the difference in effect magnitudes seen. Analyses in additional case-control datasets will be required to understand fully the effect of E318G on Alzheimer's disease status.

Incorporation of subject-level covariates in quantile normalization of miRNA data.

BACKGROUND: Most currently-used normalization methods for miRNA array data are based on methods developed for mRNA arrays despite fundamental differences between the data characteristics. The application of conventional quantile normalization can mask important expression differences by ignoring demographic and environmental factors. We present a generalization of the conventional quantile normalization method, making use of available subject-level covariates in a colorectal cancer study. RESULTS: In simulation, our weighted quantile normalization method is shown to increase statistical power by as much as 10 % when relevant subject-level covariates are available. In application to the colorectal cancer study, this increase in power is also observed, and previously-reported dysregulated miRNAs are rediscovered. CONCLUSIONS: When any subject-level covariates are available, the weighted quantile normalization method should be used over the conventional quantile normalization method.

Centromeric motion facilitates the mobility of interphase genomic regions in fission yeast.

Dispersed genetic elements, such as retrotransposons and Pol-III-transcribed genes, including tRNA and 5S rRNA, cluster and associate with centromeres in fission yeast through the function of condensin. However, the dynamics of these condensin-mediated genomic associations remains unknown. We have examined the 3D motions of genomic loci including the centromere, telomere, rDNA repeat locus, and the loci carrying Pol-III-transcribed genes or long-terminal repeat (LTR) retrotransposons in live cells at as short as 1.5-second intervals. Treatment with carbendazim (CBZ), a microtubule-destabilizing agent, not only prevents centromeric motion, but also reduces the mobility of the other genomic loci during interphase. Further analyses demonstrate that condensin-mediated associations between centromeres and the genomic loci are clonal, infrequent and transient. However, when associated, centromeres and the genomic loci migrate together in a coordinated fashion. In addition, a condensin mutation that disrupts associations between centromeres and the genomic loci results in a concomitant decrease in the mobility of the loci. Our study suggests that highly mobile centromeres pulled by microtubules in cytoplasm serve as 'genome mobility elements' by facilitating physical relocations of associating genomic regions.

Printing-based assembly of quadruple-junction four-terminal microscale solar cells and their use in high-efficiency modules.

Expenses associated with shipping, installation, land, regulatory compliance and on-going maintenance and operations of utility-scale photovoltaics can be significantly reduced by increasing the power conversion efficiency of solar modules through improved materials, device designs and strategies for light management. Single-junction cells have performance constraints defined by their Shockley-Queisser limits. Multi-junction cells can achieve higher efficiencies, but epitaxial and current matching requirements between the single junctions in the devices hinder progress. Mechanical stacking of independent multi-junction cells circumvents these disadvantages. Here we present a fabrication approach for the realization of mechanically assembled multi-junction cells using materials and techniques compatible with large-scale manufacturing. The strategy involves printing-based stacking of microscale solar cells, sol-gel processes for interlayers with advanced optical, electrical and thermal properties, together with unusual packaging techniques, electrical matching networks, and compact ultrahigh-concentration optics. We demonstrate quadruple-junction, four-terminal solar cells with measured efficiencies of 43.9% at concentrations exceeding 1,000 suns, and modules with efficiencies of 36.5%.

A forest-based feature screening approach for large-scale genome data with complex structures.

BACKGROUND: Genome-wide association studies (GWAS) interrogate large-scale whole genome to characterize the complex genetic architecture for biomedical traits. When the number of SNPs dramatically increases to half million but the sample size is still limited to thousands, the traditional p-value based statistical approaches suffer from unprecedented limitations. Feature screening has proved to be an effective and powerful approach to handle ultrahigh dimensional data statistically, yet it has not received much attention in GWAS. Feature screening reduces the feature space from millions to hundreds by removing non-informative noise. However, the univariate measures used to rank features are mainly based on individual effect without considering the mutual interactions with other features. In this article, we explore the performance of a random forest (RF) based feature screening procedure to emphasize the SNPs that have complex effects for a continuous phenotype. RESULTS: Both simulation and real data analysis are conducted to examine the power of the forest-based feature screening. We compare it with five other popular feature screening approaches via simulation and conclude that RF can serve as a decent feature screening tool to accommodate complex genetic effects such as nonlinear, interactive, correlative, and joint effects. Unlike the traditional p-value based Manhattan plot, we use the Permutation Variable Importance Measure (PVIM) to display the relative significance and believe that it will provide as much useful information as the traditional plot. CONCLUSION: Most complex traits are found to be regulated by epistatic and polygenic variants. The forest-based feature screening is proven to be an efficient, easily implemented, and accurate approach to cope whole genome data with complex structures. Our explorations should add to a growing body of enlargement of feature screening better serving the demands of contemporary genome data.

Latent classes of course in Alzheimer's disease and predictors: the Cache County Dementia Progression Study.

OBJECTIVE: Several longitudinal studies of Alzheimer's disease (AD) report heterogeneity in progression. We sought to identify groups (classes) of progression trajectories in the population-based Cache County Dementia Progression Study (N = 328) and to identify baseline predictors of membership for each group. METHODS: We used parallel-process growth mixture models to identify latent classes of trajectories on the basis of Mini-Mental State Exam (MMSE) and Clinical Dementia Rating sum of boxes scores over time. We then used bias-corrected multinomial logistic regression to model baseline predictors of latent class membership. We constructed receiver operating characteristic curves to demonstrate relative predictive utility of successive sets of predictors. RESULTS: We fit four latent classes; class 1 was the largest (72%) and had the slowest progression. Classes 2 (8%), 3 (11%), and 4 (8%) had more rapid worsening. In univariate analyses, longer dementia duration, presence of psychosis, and worse baseline MMSE and Clinical Dementia Rating sum of boxes were associated with membership in class 2, relative to class 1. Lower education was associated with membership in class 3. In the multivariate model, only MMSE remained a statistically significant predictor of class membership. Receiver operating characteristic areas under the curve were 0.98, 0.88, and 0.67, for classes 2, 3, and 4 relative to class 1. CONCLUSIONS: Heterogeneity in AD course can be usefully characterized using growth mixture models. The majority belonged to a class characterized by slower decline than is typically reported in clinical samples. Class membership could be predicted using baseline covariates. Further study may advance our prediction of AD course at the population level and in turn shed light on the pathophysiology of progression.

Mitochondrial genomic variation associated with higher mitochondrial copy number: the Cache County Study on Memory Health and Aging.

BACKGROUND: The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood. RESULTS: We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset. CONCLUSIONS: We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.

Population substructure in Cache County, Utah: the Cache County study.

BACKGROUND: Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Our findings show that the Cache County study is similar in ethnic diversity to the self-reported "Whites" in the ADNI sample and less homogenous than the HapMap CEU population. CONCLUSIONS: We conclude that the Cache County study is genetically representative of the general European American population in the USA and is an appropriate population for conducting broadly applicable genetic studies.

Passive coherent combination of a diode laser array with 35 elements.

A monolithic diode laser array with 35 elements is operated as a coherent array through the use of a Self-Fourier cavity. By analyzing the far field interference pattern, the coherence was measured to be 0.57 with all 35 elements operating and was measured to be approximately constant for arrays with greater than 15 elements. These results are in rough agreement with previous analyses which predict a coherence equal to 0.65 for very large arrays of passively coupled laser elements and demonstrate how the use of regenerative feedback benefits the passive phasing of coherent laser arrays. These results demonstrate that it is possible to circumvent previous cold cavity theories that predict poor phasing properties for arrays with greater than ~10 elements.

An ultra-specific avian antibody to phosphorylated tau protein reveals a unique mechanism for phosphoepitope recognition.

Highly specific antibodies to phosphoepitopes are valuable tools to study phosphorylation in disease states, but their discovery is largely empirical, and the molecular mechanisms mediating phosphospecific binding are poorly understood. Here, we report the generation and characterization of extremely specific recombinant chicken antibodies to three phosphoepitopes on the Alzheimer disease-associated protein tau. Each antibody shows full specificity for a single phosphopeptide. The chimeric IgG pT231/pS235_1 exhibits a K(D) of 0.35 nm in 1:1 binding to its cognate phosphopeptide. This IgG is murine ortholog-cross-reactive, specifically recognizing the pathological form of tau in brain samples from Alzheimer patients and a mouse model of tauopathy. To better understand the underlying binding mechanisms allowing such remarkable specificity, we determined the structure of pT231/pS235_1 Fab in complex with its cognate phosphopeptide at 1.9 Å resolution. The Fab fragment exhibits novel complementarity determining region (CDR) structures with a "bowl-like" conformation in CDR-H2 that tightly and specifically interacts with the phospho-Thr-231 phosphate group, as well as a long, disulfide-constrained CDR-H3 that mediates peptide recognition. This binding mechanism differs distinctly from either peptide- or hapten-specific antibodies described to date. Surface plasmon resonance analyses showed that pT231/pS235_1 binds a truly compound epitope, as neither phosphorylated Ser-235 nor free peptide shows any measurable binding affinity.

Effect of Kerr and resonant nonlinearities on phase locking of a multistable fiber amplifier array.

An analysis is presented, based on a rigorous solution of the propagation equations, of an array of saturable fiber amplifiers with scatter in length that is subject to global feedback. Passively phase-locked states exhibiting multistability due to resonant or Kerr nonlinearity are predicted in respectively low and high regimes of optical feedback.

Enhanced ultraviolet responses in thin-film InGaP solar cells by down-shifting.

Layers of poly(methyl methacrylate) doped with the Eu complex Eu(DPEPO)(hfac)3 (EuDH) provide a means for down-shifting incident ultraviolet (UV) light into the visible range, with beneficial effects on the performance of solar cells, as demonstrated with thin-film InGaP devices formed by epitaxial liftoff. Experimental and computational results establish important aspects of gain and loss mechanisms in the UV range. Measurements show that InGaP cells with coatings of EuDH doped PMMA exhibit enhanced currents (8.68 mA cm(-2)) and power conversion efficiencies (9.48%), both due to increased responses at wavelengths between 300-360 nm.

Baseline disability in activities of daily living predicts dementia risk even after controlling for baseline global cognitive ability and depressive symptoms.

OBJECTIVES: Late-life disability in activities of daily living (ADL) is theorized to be driven by underlying cognitive and/or physical impairment, interacting with psychological and environmental factors. Although we expect that cognitive deficits would explain associations between ADL disability and dementia risk, the current study examined ADL as a predictor of future dementia after controlling for global cognitive status. METHODS: The population-based Cache County Memory Study (N = 3547) assessed individuals in four triennial waves (average age 74.9 years, years of education 13.36 years; 57.9% were women). Cox proportional hazards regression models assessed whether baseline ADL disability (presence of 2+ Instrumental ADL and/or 1+ Personal ADL) predicted incident dementia after controlling for APOE status, gender, age, baseline cognitive ability (Modified Mini-mental State Exam, 3MS-R; adjusted for education level), and baseline depressive symptoms (Diagnostic Interview Schedule). RESULTS: Over the course of study, 571 cases of incident dementia were identified through in-depth cognitive assessment, ending in expert consensus diagnosis. Results from Cox models suggest that ADL disability is a statistically significant predictor of incident dementia (adjusted hazard ratio = 1.83, p < 0.001), even after controlling for covariates. CONCLUSIONS: Findings suggest that ADL disability offers unique contributions in risk for incident dementia, even after controlling for global cognitive status. We discuss how physical impairment and executive function may play important roles in this relationship, and how ADL is useful, not just a diagnostic tool at, or after dementia onset, but also as a risk factor for future dementia, even in individuals not impaired on global cognitive tests.

Caregiver personality predicts rate of cognitive decline in a community sample of persons with Alzheimer's disease. The Cache County Dementia Progression Study.

BACKGROUND: Environmental influences on the rate of Alzheimer's disease (AD) progression have received little attention. Our objective was to test hypotheses concerning associations between caregiver personality traits and the rate of AD progression. METHODS: Care receivers (CR) were 161 persons with AD from a population-based dementia progression study; 55 of their caregivers were spouses and 106 were adult children. Cognitive status of the CR was measured with the Mini-Mental State Examination every six months, over an average of 5.6 (range: 1-14) years. Linear mixed models tested rate of cognitive decline as a function of caregiver personality traits from the NEO Five-Factor Inventory. RESULTS: Significantly faster cognitive decline was observed with higher caregiver Neuroticism overall; however, in stratified models, effects were significant for adult child but not spouse caregivers. Neuroticism facets of depression, anxiety, and vulnerability to stress were significantly associated with faster decline. Higher caregiver Extraversion was associated with slower decline in the CR when caregivers were adult children but not spouses. CONCLUSIONS: For adult child caregivers, caregiver personality traits are associated with rate of cognitive decline in CRs with AD regardless of co-residency. Results suggest that dementia caregiver interventions promoting positive care management strategies and ways to react to caregiving challenges may eventually become an important complement to pharmacologic and other approaches aimed at slower rate of decline in dementia.

The influences of perinatal challenge persist into the adolescent period in socially housed bonnet macaques (Macaca radiata).

Social challenges during the perinatal period influence the mother-infant relationship in nonhuman primates and may affect the offspring's response to later social challenge(s). Relocation of a breeding colony of monkeys (Macaca radiata) created two groups of infants: one group experienced social group relocation to a new housing facility during the perinatal period (ATYPICAL) and the second group developed within a constant environment (TYPICAL). At a mean age of 25 months, all animals were removed from their natal group and placed in same sex adolescent social groups. Behavioral observations were collected after group formation or introduction to a new group. ATYPICAL subjects showed increased aggression and reduced affiliation compared to TYPICAL subjects. Hair cortisol in male subjects collected 6 months after introduction was elevated in the ATYPICAL subjects compared to TYPICAL subjects. These findings demonstrate that early life challenges affect behavior as well as stress hormone responses to social challenge in adolescence.

Predictors of progression to severe Alzheimer's disease in an incidence sample.

BACKGROUND: Little is known about factors influencing time to severe Alzheimer's disease (AD). METHODS: Incident cases of AD in the cache county memory study were identified. Severe AD was defined as mini-mental state examination score of ≤10 or Clinical Dementia Rating Scale score of 3; cases with either mini-mental state examination score of ≥16 or clinical dementia rating <2 were not categorized as severe AD. Kaplan-Meier, log-rank tests, and Cox analyses were used to identify demographic, clinical, and genetic correlates of time to progression to severe AD. RESULTS: Sixty-eight of 335 cases of incident AD developed severe dementia. In bivariate analyses, female gender, less than high school education, at least one clinically significant Neuropsychiatric Inventory domain at baseline, and the youngest and oldest ages exhibited shorter time to severe AD. In competing risk analysis, subjects with mild or at least one clinically significant neuropsychiatric inventory domain score, and subjects with worse health were more likely to progress to severe dementia or death. CONCLUSIONS: Demographic and clinical variables predict progression to severe AD. Further study should examine whether these relationships are causal or correlational.

Oxidative balance and colon and rectal cancer: interaction of lifestyle factors and genes.

Pro-oxidant and anti-oxidant genetic and lifestyle factors can contribute to an individual's level of oxidative stress. We hypothesize that diet, lifestyle and genetic factors work together to influence colon and rectal cancer through an oxidative balance mechanism. We evaluated nine markers for eosinophil peroxidase (EPX), two for myeloperoxidase (MPO), four for hypoxia-inducible factor-1A (HIFIA), and 16 for inducible nitric oxide synthase (NOS2A) in conjunction with dietary antioxidants, aspirin/NSAID use, and cigarette smoking. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). Only NOS2A rs2297518 was associated with colon cancer (OR 0.86 95% CI 0.74, 0.99) and EPX rs2302313 and MPO rs2243828 were associated with rectal cancer (OR 0.75 95% CI 0.59, 0.96; OR 0.81 95% CI 0.67, 0.99 respectively) for main effects. However, after adjustment for multiple comparisons we observed the following significant interactions for colon cancer: NOS2A and lutein, EPX and aspirin/NSAID use, and NOS2A (4 SNPs) and cigarette smoking. For rectal cancer we observed the following interactions after adjustment for multiple comparisons: HIF1A and vitamin E, NOS2A (3SNPs) with calcium; MPO with lutein; HIF1A with lycopene; NOS2A with selenium; EPX and NOS2A with aspirin/NSAID use; HIF1A, MPO, and NOS2A (3 SNPs) with cigarette smoking. We observed significant interaction between a composite oxidative balance score and a polygenic model for both colon (p interaction 0.0008) and rectal cancer (p=0.0018). These results suggest the need to comprehensively evaluate interactions to assess the contribution of risk from both environmental and genetic factors.