Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1 , SIX6 , and OTX2 resulting from a complex chromosomal rearrangement

We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an ∼11.79 Mb duplication of chromosome 14q22.3–q23.3 and a loss of an ∼4.38 Mb sequence in 13q21.31–q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3–q23.3 contains 51 genes, including SIX1 , SIX6 , and OTX2 . A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3–q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1 , SIX6 , or OTX2 may be responsible for the BOR and OAVS-like features in this family. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60991/1/32398_ftp.pd

Mosaicism for r(X) and der(X)del(X)(p11.23)dup(X)(p11.21p11.22) provides insight into the possible mechanism of rearrangement

We report a patient with a unique and complex cytogenetic abnormality involving mosaicism for a small ring X and deleted Xp derivative chromosome with tandem duplication at the break point. The patient presented with failure to thrive, muscular hypotonia, and minor facial anatomic anomalies, all concerning for Turner syndrome. Brain MRI revealed mild thinning of the corpus callosum, an apparent decrease in ventricular white matter volume, and an asymmetric myelination pattern. Array comparative genome hybridization analysis revealed mosaicism for the X chromosome, deletion of the short arm of an X chromosome, and a duplication of chromosome region Xp11.21-p11.22. G-banded chromosome and FISH analyses revealed three abnormal cell lines: 46,X,der(X)del(X)(p11.23)dup(X)(p11.21p11.22)/46,X,r(X)(q11.1q13.1)/45,X. The small ring X chromosome was estimated to be 5.2 Mb in size and encompassed the centromere and Xq pericentromeric region. X chromosome inactivation (XCI) studies demonstrated a skewed pattern suggesting that the ring X remained active, likely contributing to the observed clinical features of brain dysmyelination. We hypothesize that a prezygotic asymmetric crossing over within a loop formed during meiosis in an X chromosome with a paracentric inversion resulted in an intermediate dicentric chromosome. An uneven breakage of the dicentric chromosome in the early postzygotic period might have resulted in the formation of one cell line with the X chromosome carrying a terminal deletion and pericentromeric duplication of the short arm and the second cell line with the X chromosome carrying a complete deletion of Xp. The cell line carrying the deletion of Xp could have then stabilized through self-circularization and formation of the ring X chromosome

Two-step stabilization of orbital order and the dynamical frustration of spin in the model charge-transfer insulator KCuF3

We report a combined experimental and theoretical study of KCuF3, which offers - because of this material's relatively simple lattice structure and valence configuration (d9, i.e., one hole in the d-shell) - a particularly clear view of the essential role of the orbital degree of freedom in governing the dynamical coupling between the spin and lattice degrees of freedom. We present Raman and x-ray scattering evidence that the phase behaviour of KCuF3 is dominated above the Neel temperature (T_N = 40 K) by coupled orbital/lattice fluctuations that are likely associated with rotations of the CuF6 octahedra, and we show that these orbital fluctuations are interrupted by a static structural distortion that occurs just above T_N. A detailed model of the orbital and magnetic phases of KCuF3 reveals that these orbital fluctuations - and the related frustration of in-plane spin-order-are associated with the presence of nearly degenerate low-energy spin-orbital states that are highly susceptible to thermal fluctuations over a wide range of temperatures. A striking implication of these results is that the ground state of KCuF3 at ambient pressure lies near a quantum critical point associated with an orbital/spin liquid phase that is obscured by emergent Neel ordering of the spins; this exotic liquid phase might be accessible via pressure studies.Comment: 13 pages, 3 figure

Area-wide eradication of the invasive European grapevine moth Lobesia botrana in California, USA

17openBothIn the fall of 2009, the first confirmed North American detection of the European grapevine moth (EGVM) Lobesia botrana (Denis & Schiffermüller) occurred in Napa County, California, USA. Based on its status as a significant grape pest in other parts of the world, the establishment of EGVM in California presented significant production and export issues for grapes, as well as for other fresh market agricultural commodities. Over the following seven years, an intensive California state-wide survey and area-wide eradication campaign was undertaken in partnership with agricultural officials at local, state and federal levels, university scientists and the wine, table grape and raisin industries. These efforts resulted in a dramatic decline in moth captures in pheromone traps from over 100 000 moths in 2010, to one in 2014, and none in 2015. In August of 2016, eradication was declared for all previously infested areas in California. The decision to pursue the eradication effort was based on the limited host range and geographic area of the EGVM infestation, the availability of effective tools for monitoring and control, and the strong support of the affected grape production and export industries. The eradication campaign employed coordinated logistical, regulatory, and technical efforts that included: 1) state-wide-monitoring using a network of pheromone-baited traps and in field monitoring; these findings were recorded in a geographic information system that was used to regularly communicate survey results to programme officials; 2) an area-wide application of mating disruption dispensers to infested vineyards, including use in urban environments within infested zones; 3) implementation by coordinators of area-wide insecticide treatments with application timing determined by degree-day modelling for each infested region; 4) a robust regulatory programme that initiated and maintained a quarantine of infested areas that regulated movement of fruit, farming equipment and winery processing waste; 5) an extensive outreach programme to grape growers, wineries, pest control specialists and the public; 6) formation of a technical working group that provided recommendations to the operational programme. An extensive methods development effort supported the programme. This included developing enhanced detection methods for vineyards under mating disruption, testing efficacy and residual control of insecticides, testing mating disruption formulations, evaluating the impacts of winery processing methods on EGVM mortality, developing methods to determine the timing of the development of successive EGVM generations (or biofix) under California conditions to improve degree-day models, developing EGVM rearing methods, testing the quality of pheromone lures and trap monitoring; and a spatial analysis of trapping data to determine programme effectiveness and to analyse invasion pathwaysopenSimmons, G.S.; Varela, L.; Daugherty, M.; Cooper, M.; Lance, D.; Mastro, V.; Carde, R.T.; Lucchi, A.; Ioriatti, C.; Bagnoli, B.; Steinhauer, R.; Broadway, R.; Stone Smith, B.; Hoffman, K.; Clark, G.; Whitmer, D.; Johnson, R.Simmons, G.S.; Varela, L.; Daugherty, M.; Cooper, M.; Lance, D.; Mastro, V.; Carde, R.T.; Lucchi, A.; Ioriatti, C.; Bagnoli, B.; Steinhauer, R.; Broadway, R.; Stone Smith, B.; Hoffman, K.; Clark, G.; Whitmer, D.; Johnson, R

Cloud condensation nuclei as a modulator of ice processes in Arctic mixed-phase clouds

We propose that cloud condensation nuclei (CCN) concentrations are important for modulating ice formation of Arctic mixed-phase clouds, through modification of the droplet size distribution. Aircraft observations from the Aerosol, Radiation, and Cloud Processes affecting Arctic Climate (ARCPAC) study in northern Alaska in April 2008 allow for identification and characterization of both aerosol and trace gas pollutants, which are then compared with cloud microphysical properties. Consistent with previous studies, we find that the concentration of precipitating ice particles (>400 μm) is correlated with the concentration of large droplets (>30 μm). We are further able to link the observed microphysical conditions to aerosol pollution, originating mainly from long range transport of biomass burning emissions. The case studies demonstrate that polluted mixed-phase clouds have narrower droplet size distributions and contain 1–2 orders of magnitude fewer precipitating ice particles than clean clouds at the same temperature. This suggests an aerosol indirect effect leading to greater cloud lifetime, greater cloud emissivity, and reduced precipitation. This result is opposite to the glaciation indirect effect, whereby polluted clouds are expected to precipitate more readily due to an increase in the concentration of particles acting as ice nuclei

A survey of South Carolina pharmacists\u27 readiness to prescribe human immunodeficiency virus pre-exposure prophylaxis

Introduction: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is largely underutilized in the Southern United States. Given their community presence, pharmacists are well positioned to provide PrEP within rural, Southern regions. However, pharmacists\u27 readiness to prescribe PrEP in these communities remains unknown. Objective: To determine the perceived feasibility and acceptability of prescribing PrEP by pharmacists in South Carolina (SC). Methods: We distributed a 43-question online descriptive survey through the University of South Carolina Kennedy Pharmacy Innovation Center\u27s listserv of licensed SC pharmacists. We assessed pharmacists\u27 comfort, knowledge, and readiness to provide PrEP. Results: A total of 150 pharmacists responded to the survey. The majority were White (73%, n = 110), female (62%, n = 93), and non-Hispanic (83%, n = 125). Pharmacists practiced in retail (25%, n = 37), hospital (22%, n = 33), independent (17%, n = 25), community (13%, n = 19), specialty (6%, n = 9), and academic settings (3%, n = 4); 11% (n = 17) practiced in rural locales. Pharmacists viewed PrEP as both effective (97%, n = 122/125) and beneficial (74% n = 97/131) for their clients. Many pharmacists reported being ready (60% n = 79/130) and willing (86% n = 111/129) to prescribe PrEP, although over half (62% n = 73/118) cited lack of PrEP knowledge as a barrier. Pharmacists described pharmacies as an appropriate location to prescribe PrEP (72% n = 97/134). Conclusions: Most SC pharmacists surveyed considered PrEP to be effective and beneficial for individuals who frequent their pharmacy and are willing to prescribe this therapy if statewide statutes allow. Many felt that pharmacies are an appropriate location to prescribe PrEP but lack a complete understanding of required protocols to manage these patients. Further investigation into facilitators and barriers of pharmacy-driven PrEP is needed to enhance utilization within communities

Clinical Implementation of Chromosomal Microarray Analysis: Summary of 2513 Postnatal Cases

BACKGROUND: Array Comparative Genomic Hybridization (a-CGH) is a powerful molecular cytogenetic tool to detect genomic imbalances and study disease mechanism and pathogenesis. We report our experience with the clinical implementation of this high resolution human genome analysis, referred to as Chromosomal Microarray Analysis (CMA). METHODS AND FINDINGS: CMA was performed clinically on 2513 postnatal samples from patients referred with a variety of clinical phenotypes. The initial 775 samples were studied using CMA array version 4 and the remaining 1738 samples were analyzed with CMA version 5 containing expanded genomic coverage. Overall, CMA identified clinically relevant genomic imbalances in 8.5% of patients: 7.6% using V4 and 8.9% using V5. Among 117 cases referred for additional investigation of a known cytogenetically detectable rearrangement, CMA identified the majority (92.5%) of the genomic imbalances. Importantly, abnormal CMA findings were observed in 5.2% of patients (98/1872) with normal karyotypes/FISH results, and V5, with expanded genomic coverage, enabled a higher detection rate in this category than V4. For cases without cytogenetic results available, 8.0% (42/524) abnormal CMA results were detected; again, V5 demonstrated an increased ability to detect abnormality. Improved diagnostic potential of CMA is illustrated by 90 cases identified with 51 cryptic microdeletions and 39 predicted apparent reciprocal microduplications in 13 specific chromosomal regions associated with 11 known genomic disorders. In addition, CMA identified copy number variations (CNVs) of uncertain significance in 262 probands; however, parental studies usually facilitated clinical interpretation. Of these, 217 were interpreted as familial variants and 11 were determined to be de novo; the remaining 34 await parental studies to resolve the clinical significance. CONCLUSIONS: This large set of clinical results demonstrates the significantly improved sensitivity of CMA for the detection of clinically relevant genomic imbalances and highlights the need for comprehensive genetic counseling to facilitate accurate clinical correlation and interpretation

Prediction of cardiovascular outcomes with machine learning techniques: application to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study.

Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. Clinical Trial Registration: ClinicalTrials.gov, NCT00081731

Characteristics, sources, and transport of aerosols measured in spring 2008 during the aerosol, radiation, and cloud processes affecting Arctic Climate (ARCPAC) Project

We present an overview of the background, scientific goals, and execution of the Aerosol, Radiation, and Cloud Processes affecting Arctic Climate (ARCPAC) project of April 2008. We then summarize airborne measurements, made in the troposphere of the Alaskan Arctic, of aerosol particle size distributions, composition, and optical properties and discuss the sources and transport of the aerosols. The aerosol data were grouped into four categories based on gas-phase composition. First, the background troposphere contained a relatively diffuse, sulfate-rich aerosol extending from the top of the sea-ice inversion layer to 7.4 km altitude. Second, a region of depleted (relative to the background) aerosol was present within the surface inversion layer over sea-ice. Third, layers of dense, organic-rich smoke from open biomass fires in southern Russia and southeastern Siberia were frequently encountered at all altitudes from the top of the inversion layer to 7.1 km. Finally, some aerosol layers were dominated by components originating from fossil fuel combustion. <br></br> Of these four categories measured during ARCPAC, the diffuse background aerosol was most similar to the average springtime aerosol properties observed at a long-term monitoring site at Barrow, Alaska. The biomass burning (BB) and fossil fuel layers were present above the sea-ice inversion layer and did not reach the sea-ice surface during the course of the ARCPAC measurements. The BB aerosol layers were highly scattering and were moderately hygroscopic. On average, the layers produced a noontime net heating of ~0.1 K day<sup>−1</sup> between 3 and 7 km and a slight cooling at the surface. The ratios of particle mass to carbon monoxide (CO) in the BB plumes, which had been transported over distances >5000 km, were comparable to the high end of literature values derived from previous measurements in wildfire smoke. These ratios suggest minimal precipitation scavenging and removal of the BB particles between the time they were emitted and the time they were observed in dense layers above the sea-ice inversion layer