In Situ Smoothing of Facets on Spalled GaAs(100) Substrates during OMVPE Growth of III-V Epilayers, Solar Cells, and Other Devices: The Impact of Surface Impurities/Dopants.

One possible pathway toward reducing the cost of III-V solar cells is to remove them from their growth substrate by spalling fracture, and then reuse the substrate for the growth of multiple cells. Here we consider the growth of III-V cells on spalled GaAs(100) substrates, which typically have faceted surfaces after spalling. To facilitate the growth of high-quality cells, these faceted surfaces should be smoothed prior to cell growth. In this study, we show that these surfaces can be smoothed during organometallic vapor-phase epitaxy growth, but the choice of epilayer material and modification of the various surfaces by impurities/dopants greatly impacts whether or not the surface becomes smooth, and how rapidly the smoothing occurs. Representative examples are presented along with a discussion of the underlying growth processes. Although this work was motivated by solar cell growth, the methods are generally applicable to the growth of any III-V device on a nonplanar substrate.

Solution Cathode Glow Discharge Coupled to Atmospheric Pressure Chemical Ionization for Elemental Detection of S and P in Organic Compounds.

We report a post-plasma chemical ionization approach to evaluate solution cathode glow discharge (SCGD) for S and P elemental analysis. Here, the SCGD serves as a reactor to produce chemical vapors for S and P from organic compounds containing these elements, while a corona discharge operated in negative mode is used to ionize the products. The approach creates long-lived ions in atmospheric pressure, enabling direct investigation of chemical vapor products via mass spectrometric and ion mobility separations. The investigations indicate that SCGD converts S and P to H2SO4 and H3PO4, respectively. These species are then ionized as HSO4HNO3 - and H3PO4NO3HNO3- via reactions with NO3HNO3- produced by corona discharge. The response factors for P among several small molecules varies within 10% of the average response from the compounds, suggesting a reasonable species-independent characteristic. The response factors for S show larger variations among compounds, indicating a higher dependence of chemical vapor generation efficiency on analytes' chemical structures. Detection limits of 15 and 29 ng/mL are achieved for P and S detection, respectively. These figures are limited by background equivalent concentrations and low ion flux in the utilized ion mobility-time of flight mass spectrometer, indicating potential for significant improvements. In particular, the specificity of clustering for S and P-containing ions produced in this approach suggest facile analysis of S and P using quadrupole-based mass spectrometers for improved analytical performance.

Mechanism of Insoluble Aggregate Formation in a Reconstituted Solution of Spray-Dried Protein Powder.

BACKGROUND: Spray-drying is considered a promising alternative drying method to lyophilization (freeze-drying) for therapeutic proteins. Particle counts in reconstituted solutions of dried solid dosage forms of biologic drug products are closely monitored to ensure product quality. We found that high levels of particles formed after reconstitution of protein powders that had been spray-dried under suboptimal conditions. METHODS: Visible and subvisible particles were evaluated. Soluble proteins in solution before spray-drying and in the reconstituted solution of spray-dried powder were analyzed for their monomer content levels and melting temperatures. Insoluble particles were collected and analyzed by Fourier transform infrared microscopy (FTIR), and further analyzed with hydrogen-deuterium exchange (HDX). RESULTS: Particles observed after reconstitution were shown not to be undissolved excipients. FTIR confirmed their identity as proteinaceous in nature. These particles were therefore considered to be insoluble protein aggregates, and HDX was applied to investigate the mechanism underlying aggregate formation. Heavy-chain complementarity-determining region 1 (CDR-1) in the aggregates showed significant protection by HDX, suggesting CDR-1 was critical for aggregate formation. In contrast, various regions became more conformationally dynamic globally, suggesting the aggregates have lost protein structural integrity and partially unfolded after spray-drying. DISCUSSION: The spray-drying process could have disrupted the higher-order structure of proteins and exposed the hydrophobic residues in CDR-1 of the heavy chain, contributing to the formation of aggregate through hydrophobic interactions upon reconstitution of spray-dried powder. These results can contribute to efforts to design spray-dry resilient protein constructs and improve the robustness of the spray-drying process.

Terrestrial surface stabilisation by modern analogues of the earliest land plants: A multi-dimensional imaging study.

The evolution of the first plant-based terrestrial ecosystems in the early Palaeozoic had a profound effect on the development of soils, the architecture of sedimentary systems, and shifts in global biogeochemical cycles. In part, this was due to the evolution of complex below-ground (root-like) anchorage systems in plants, which expanded and promoted plant-mineral interactions, weathering, and resulting surface sediment stabilisation. However, little is understood about how these micro-scale processes occurred, because of a lack of in situ plant fossils in sedimentary rocks/palaeosols that exhibit these interactions. Some modern plants (e.g., liverworts, mosses, lycophytes) share key features with the earliest land plants; these include uni- or multicellular rhizoid-like anchorage systems or simple roots, and the ability to develop below-ground networks through prostrate axes, and intimate associations with fungi, making them suitable analogues. Here, we investigated cryptogamic ground covers in Iceland and New Zealand to better understand these interactions, and how they initiate the sediment stabilisation process. We employed multi-dimensional and multi-scale imaging, including scanning electron microscopy (SEM) and X-ray Computed Tomography (µCT) of non-vascular liverworts (Haplomitriopsida and complex thalloids) and mosses, with additional imaging of vascular lycopods. We find that plants interact with their substrate in multiple ways, including: (1) through the development of extensive surface coverings as mats; (2) entrapment of sediment grains within and between networks of rhizoids; (3) grain entwining and adherence by rhizoids, through mucilage secretions, biofilm-like envelopment of thalli on surface grains; and (4) through grain entrapment within upright 'leafy' structures. Significantly, µCT imaging allows us to ascertain that rhizoids are the main method for entrapment and stabilisation of soil grains in the thalloid liverworts. This information provides us with details of how the earliest land plants may have significantly influenced early Palaeozoic sedimentary system architectures, promoted in situ weathering and proto-soil development, and how these interactions diversified over time with the evolution of new plant organ systems. Further, this study highlights the importance of cryptogamic organisms in the early stages of sediment stabilisation and soil formation today.

T-cell responses induced by ChAdOx1 nCoV-19 (AZD1222) vaccine to wild-type severe acute respiratory syndrome coronavirus 2 among people with and without HIV in South Africa.

OBJECTIVES: This study aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell responses 14 days after single-dose ChAdOx1 nCoV-19 (AZD1222) vaccination in black Africans with and without HIV in South Africa, as well as determine the effect of AZD1222 vaccination on cell-mediated immune responses in people with HIV (PWH) with prior SARS-CoV-2 infection. METHODS: A total of 70 HIV-uninfected people and 104 PWH were prospectively enrolled in the multicentre, randomized, double-blinded, placebo-controlled, phase Ib/IIa trial (COV005). Peripheral blood mononuclear cells (PBMCs) were collected from trial participants 14 days after receipt of first dose of study treatment (placebo or AZD1222 vaccine). T-cell responses against the full-length spike (FLS) glycoprotein of wild-type SARS-CoV-2 and mutated S-protein regions found in the Alpha, Beta and Delta variants were assessed using an ex-vivo ELISpot assay. RESULTS: Among AZD1222 recipients without preceding SARS-CoV-2 infection, T-cell responses to FLS of wild-type SARS-CoV-2 were similarly common in PWH and HIV-uninfected people (30/33, 90.9% vs. 16/21, 76.2%; P = 0.138); and magnitude of response was similar among responders (78 vs. 56 SFCs/106 PBMCs; P = 0.255). Among PWH, AZD1222 vaccinees with prior SARS-CoV-2 infection, displayed a heightened T-cell response magnitude compared with those without prior infection (186 vs. 78 SFCs/106 PBMCs; P = 0.001); and similar response rate (14/14, 100% vs. 30/33, 90.9%; P = 0.244). CONCLUSION: Our results indicate comparable T-cell responses following AZD1222 vaccination in HIV-uninfected people and PWH on stable antiretroviral therapy. Our results additionally show that hybrid immunity acquired through SARS-CoV-2 infection and AZD1222 vaccination, induce a heightened T-cell response.

A performance comparison between GaInP-on-Si and GaAs-on-Si 3-terminal tandem solar cells.

The pursuit of ever-higher solar cell efficiencies has focused heavily on multijunction technologies. In tandem cells, subcells are typically either contacted via two terminals (2T) or four terminals (4T). Simulations show that the less-common three-terminal (3T) design may be comparable to 4T tandem cells in its compatibility with a range of materials, operating conditions, and methods for subcell integration, yet the 3T design circumvents shading losses of the 4T intermediate conductive layers. This study analyzes the performance of two superstrate 3T III-V-on-Si (III-V//Si) tandem cells: One has slightly greater current contribution from the Si bottom cell (GaInP//Si) and the other has substantially greater current contribution from the GaAs top cell (GaAs//Si). Our results show that both tandem cells exhibit the same efficiency (21.3%), thereby demonstrating that the third terminal allows for flexibility in the selection of the top cell material, similar to the 4T design.

High-Resolution Elemental Mass Spectrometry Using LC-ICP-Nanospray-Orbitrap for Simultaneous and Species-Independent Quantitation of Fluorinated and Chlorinated Compounds.

Simultaneous elemental detection of F and Cl offers quantitation of fluorinated and chlorinated compounds and their transformation products without compound-specific standards. Despite wide-ranging applications, this capability has been hindered by fundamental and technical shortcomings of current inductively coupled plasma (ICP)-MS methods in ion formation and isobaric interference elimination. These hurdles are alleviated here via a chemical ionization method. Fluorine and chlorine in analytes are first converted to HF and HCl by an ICP with post-plasma recombination and subsequently react with barium-containing ions supplied by a nanospray, yielding BaF+ and BaCl+ as elemental reporter ions. Notably, the method is readily interfaced to an Orbitrap MS which eliminates isobaric interferences at resolving powers as low as 35,000, far greater than that of current ICP-MS instruments. Moreover, the instrument is easily reverted to the ESI-MS mode for complementary molecular characterization. To demonstrate analytical capabilities, a workflow for rapid quantitation of compounds separated by reversed-phase liquid chromatography is developed using a species-independent calibration. The independent F and Cl measurements agree with each other, providing recoveries of >90% and LODs of 8-12 pmol Cl and 5-12 pmol F on the column. The workflow along with LC-ESI-MS on the same instrument is then applied to identify and quantify in-vitro drug metabolites, yielding total drug-related material recoveries of >80% and quantitation of minor metabolites summing to 8% of the total drug-related compounds. These results highlight the strengths of simultaneous F and Cl speciation for rapid quantitation with applications in early drug development.

Consideration of the Intricacies Inherent in Molecular Beam Epitaxy of the NaCl/GaAs System.

The high cost of substrates for III-V growth can be cost limiting for technologies that require large semiconductor areas. Thus, being able to separate device layers and reuse the original substrate is highly desirable, but existing techniques to lift a film from a substrate have substantial drawbacks. This work discusses some of the complexities with the growth of a water-soluble, alkali halide salt thin film between a III-V substrate and overlayer. Much of the difficulty stems from the growth of GaAs on an actively decomposing NaCl surface at elevated temperatures. Interestingly, the presence of an in situ electron beam incident on the NaCl surface, prior to and during GaAs deposition, affects the crystallinity and morphology of the III-V overlayer. Here, we investigate a wide range of growth temperatures and the timing of the impinging flux of both elemental sources and high energy electrons at different points during the growth. We show that an assortment of morphologies (discrete islands, porous material, and fully dense layers with sharp interfaces) and crystallinity (amorphous, crystalline, and highly textured) occur depending on the specific growth conditions, driven largely by changes in GaAs nucleation which is greatly affected by the presence of the reflection high energy electron diffraction beam.

Sensory features in autism: Findings from a large population-based surveillance system.

Sensory features (i.e., atypical responses to sensory stimuli) are included in the current diagnostic criteria for autism spectrum disorder. Yet, large population-based studies have not examined these features. This study aimed to determine the prevalence of sensory features among autistic children, and examine associations between sensory features, demographics, and co-occurring problems in other areas. Analysis for this study included a sample comprised of 25,627 four- or eight-year-old autistic children identified through the multistate Autism and Developmental Disabilities Monitoring Network (2006-2014). We calculated the prevalence of sensory features and applied multilevel logistic regression modeling. The majority (74%; 95% confidence interval: 73.5%-74.5%) of the children studied had documented sensory features. In a multivariable model, children who were male and those whose mothers had more years of education had higher odds of documented sensory features. Children from several racial and ethnic minority groups had lower odds of documented sensory features than White, non-Hispanic children. Cognitive problems were not significantly related to sensory features. Problems related to adaptive behavior, emotional states, aggression, attention, fear, motor development, eating, and sleeping were associated with higher odds of having documented sensory features. Results from a large, population-based sample indicate a high prevalence of sensory features in autistic children, as well as relationships between sensory features and co-occurring problems. This study also pointed to potential disparities in the identification of sensory features, which should be examined in future research. Disparities should also be considered clinically to avoid reduced access to supports for sensory features and related functional problems. LAY SUMMARY: In a large, population-based sample of 25,627 autistic children, 74% had documented differences in how they respond to sensation. We also identified significant associations of sensory features with adaptive behavior and problems in other domains. Sensory features were less common among girls, children of color, and children of mothers with fewer years of education, suggesting potential disparities in identification.

Surveillance of the rabies-related lyssavirus, Mokola in non-volant small mammals in South Africa.

The reservoir host of Mokola virus (MOKV), a rabies-related lyssavirus species endemic to Africa, remains unknown. Only sporadic cases of MOKV have been reported since its first discovery in the late 1960s, which subsequently gave rise to various reservoir host hypotheses. One particular hypothesis focusing on non-volant small mammals (e.g. shrews, sengis and rodents) is buttressed by previous MOKV isolations from shrews (Crocidura sp.) and a single rodent (Lophuromys sikapusi). Although these cases were only once-off detections, it provided evidence of the first known lyssavirus species has an association with non-volant small mammals. To investigate further, retrospective surveillance was conducted in 575 small mammals collected from South Africa. Nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay of 329 brain samples did not detect any lyssavirus ribonucleic acid (RNA). Serological surveillance using a micro-neutralisation test of 246 serum samples identified 36 serum samples that were positive for the presence of MOKV neutralising antibodies (VNAs). These serum samples were all collected from Gerbilliscus leucogaster (Bushveld gerbils) rodents from Meletse in Limpopo province (South Africa). Mokola virus infections in Limpopo province have never been reported before, and the high MOKV seropositivity of 87.80% in these gerbils may indicate a potential rodent reservoir.

The impact of the wake maintenance zone on attentional capacity, physiological drowsiness, and subjective task demands during sleep deprivation.

We aimed to investigate the impact of the Wake Maintenance Zone (WMZ) on measures of drowsiness, attention, and subjective performance under rested and sleep deprived conditions. We studied 23 healthy young adults (18 males; mean age = 25.41 ± 5.73 years) during 40 hr of total sleep deprivation under constant routine conditions. Participants completed assessments of physiological drowsiness (EEG-scored slow eye movements and microsleeps), sustained attention (PVT), and subjective task demands every two hours, and four-hourly ocular motor assessment of inhibitory control (inhibition of reflexive saccades on an anti-saccade task). Tests were analyzed relative to dim light melatonin onset (DLMO); the WMZ was defined as the 3 hr prior to DLMO, and the preceding 3 hr window was deemed the pre-WMZ. The WMZ did not mitigate the adverse impact of ~37 hr sleep deprivation on drowsiness, sustained attention, response inhibition, and self-rated concentration and difficulty, relative to rested WMZ performance (~13 hr of wakefulness). Compared to the pre-WMZ, though, the WMZ improved measures of sustained attention, and subjective concentration and task difficulty, during sleep deprivation. Cumulatively, these results expand on previous work by characterizing the beneficial effects of the WMZ on operationally-relevant indices of drowsiness, inhibitory attention control, and self-rated concentration and task difficulty relative to the pre-WMZ during sleep deprivation. These results may inform scheduling safety-critical tasks at more optimal circadian times to improve workplace performance and safety.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Perturbation-induced high-frequency pulsing of nano-ESI with facile ion selection at atmospheric pressure.

Nano-ESI is a commonly used ionization technique with continually expanding analytical advantages. Here, we report a facile way for high-frequency (500-3800 Hz) pulsing of nano-ESI, providing a high flux of mobility-selected ions. The pulsing is accomplished using a relatively low-voltage modulation (80 V peak-to-peak) of an electrode placed <1 cm downstream of a nano-ESI emitter biased to a constant potential. Configuring the electrode as an ion gate enables mobility-based ion selection by scanning the modulation frequency. Our investigations indicate that the electrode modulation perturbs continuous nano-ESI, resulting in solution accumulation at the emitter tip between spray pulses. Selective transmission of ions occurs at frequencies corresponding to harmonics of a fundamental frequency determined by the travel time of each ion from the emitter to the ion gate (pulsing electrode). Remarkably, the intensities of ions selected in this fashion are similar across the harmonics, suggesting that the ionization efficiencies of analytes have minimal dependence on the accumulated volume at the emitter tip. Moreover, intensities of ion-mobility-selected analytes using this technique reach >50% of those in continuous nano-ESI without ion selection, underscoring efficient ion generation via high-frequency pulsing. These findings indicate the potential of the pulsed nano-ESI for enhanced analytical utility, such as a high-flux selected-reagent-ion supplier at atmospheric pressure, and chart new avenues to further enhance the analytical performance of nano-ESI.

The impact of structured sleep schedules prior to an in-laboratory study: Individual differences in sleep and circadian timing.

INTRODUCTION: Many sleep and circadian studies require participants to adhere to structured sleep-wake schedules designed to stabilize sleep outcomes and circadian phase prior to in-laboratory testing. The effectiveness of this approach has not been rigorously evaluated, however. We therefore investigated the differences between participants' unstructured and structured sleep over a three-week interval. METHODS: Twenty-three healthy young adults completed three weeks of sleep monitoring, including one week of unstructured sleep and two weeks of structured sleep with consistent bed and wake times. Circadian phase was assessed via salivary dim light melatonin onset (DLMO) during both the unstructured and structured sleep episodes. RESULTS: Compared to their unstructured sleep schedule, participants' bed- and wake times were significantly earlier in their structured sleep, by 34 ± 44 mins (M ± SD) and 44 ± 41 mins, respectively. During structured sleep, circadian phase was earlier in 65% of participants (40 ± 32 mins) and was later in 35% (41 ± 25 mins) compared to unstructured sleep but did not change at the group level. While structured sleep reduced night-to-night variability in sleep timing and sleep duration, and improved the alignment (phase angle) between sleep onset and circadian phase in the most poorly aligned individuals (DLMO < 1h or > 3h before sleep onset time; 25% of our sample), sleep duration and quality were unchanged. CONCLUSION: Our results show adherence to a structured sleep schedule results in more regular sleep timing, and improved alignment between sleep and circadian timing for those individuals who previously had poorer alignment. Our findings support the use of structured sleep schedules prior to in-laboratory sleep and circadian studies to stabilize sleep and circadian timing in healthy volunteers.

Estimated Minimum Life Span of the Jezero Fluvial Delta (Mars).

The paleo-lake floor at the edge of the Jezero delta has been selected as the NASA 2020 rover landing site. In this article, we demonstrate the sequences of lake filling and delta formation and constrain the minimum life span of the Jezero paleo-lake from sedimentological and hydrological analyses. Two main phases of delta evolution can be recognized by utilizing imagery provided by the High Resolution Imaging Science Experiment (NASA Mars Reconnaissance Orbiter) and High Resolution Stereo Camera (ESA Mars Express): (1) basin infilling before the breaching of the Jezero rim and (2) the delta formation itself. Our results suggest that delta formation occurred over a minimum period of 90-550 years of hydrological activity. Breaching of the Jezero rim occurred in at least three distinct episodes, which spanned a far longer time-period than overall delta formation. This evolutionary history implies that the Jezero-lake floor would have been a haven for fine-grained sediment accumulation and hosted an active environment of significant astrobiological importance.

Sustained fluvial deposition recorded in Mars' Noachian stratigraphic record.

Orbital observation has revealed a rich record of fluvial landforms on Mars, with much of this record dating 3.6-3.0 Ga. Despite widespread geomorphic evidence, few analyses of Mars' alluvial sedimentary-stratigraphic record exist, with detailed studies of alluvium largely limited to smaller sand-bodies amenable to study in-situ by rovers. These typically metre-scale outcrop dimensions have prevented interpretation of larger scale channel-morphology and long-term basin evolution, vital for understanding the past Martian climate. Here we give an interpretation of a large sedimentary succession at Izola mensa within the NW Hellas Basin rim. The succession comprises channel and barform packages which together demonstrate that river deposition was already well established >3.7 Ga. The deposits mirror terrestrial analogues subject to low-peak discharge variation, implying that river deposition at Izola was subject to sustained, potentially perennial, fluvial flow. Such conditions would require an environment capable of maintaining large volumes of water for extensive time-periods, necessitating a precipitation-driven hydrological cycle.

Pulsed Nano-ESI: Application in Ion Mobility-MS and Insights into Spray Dynamics.

We have previously shown that pulsed nano-ESI offers direct ion introduction into an AP-IM cell in the absence of conventional gates and desolvation. Here, we further characterize this ion injection method and utilize it to gain insights into nano-ESI pulsed spray dynamics. We demonstrate that a pulsed nano-ESI operated at 20 Hz with ion generation pulses of 170-510 µs offers reproducible ion arrival times (0.09-0.21% RSD). Arrival times are then translated to effective collision cross sections (CCSs) using tetraalkylammonium ions as CCS internal standards. For ions with low solvent affinity, effective CCS values match those reported for fully desolvated ions. For amino acids and a series of alkylamine homologues, the effective CCS values are higher than those for fully desolvated ions and correlate with solvent affinity, suggesting that ions with high hydration affinities traverse the mobility cell as hydrated ions. Notably, hydrates are not observed in the MS spectra due to ion activation during the transport into vacuum. Using these observations as a framework to interpret effective CCS values, we investigate the impact of nano-ESI pulse duration on ion properties. We observe that longer pulse durations lead to the enhancement of ion abundance for low-ionization-efficiency analytes and a reduction in clustering. However, effective CCSs are not significantly altered by spray pulse duration, implying that similar ion structures emerge rapidly at all investigated pulse durations. Ion abundance results suggest a temporal evolution of droplets in pulsed nano-ESI where droplets emitted later in the spray formation appear to be smaller, providing enhanced ionization.

A Taxonomy for Three-Terminal Tandem Solar Cells.

Tandem and multijunction solar cells offer the only demonstrated path to terrestrial 1-sun solar cell efficiency over 30%. Three-terminal tandem (3TT) solar cells can overcome some of the limitations of two-terminal and four-terminal tandem solar cell designs. However, the coupled nature of the cells adds a degree of complexity to the devices themselves and the ways that their performance can be measured and reported. While many different configurations of 3TT devices have been proposed, there is no standard taxonomy to discuss the device structure or loading topology. This Perspective proposes a taxonomy for 3TT solar cells to enable a common nomenclature for discussing these devices and their performance. It also provides a brief history of three-terminal devices in the literature and demonstrates that many different 3TT devices can work at efficiencies above 30% if properly designed.

A multiple lines of evidence approach for identifying geologic heterogeneities in conceptual site models for performance assessments.

Model-based decision making is commonly used in performance assessments to assure water resource protection for both human health and the environment for hundreds of years into the future. To make decisions regarding aquifer protection against potential contamination, a conceptual site model (CSM) describing the hydrodynamic behavior needs to account for subsurface heterogeneities in sufficient detail. When site-specific data are sparse, larger-scale geologic descriptions are adopted with the consequence of losing small-scale features (at the cm scale) that can control contaminant transport. In this study, a multiple lines of evidence approach is used to construct vadose zone CSMs based on an evaluation of several types of data, including geologic logs, borehole moisture content and concentration data, geophysical spectral gamma logging data, and groundwater concentration data for a tank farm at the Hanford Site in southeastern Washington State. The resulting CSMs of the unsaturated zone represent a synthesis of what is known about flow and transport processes at the site-scale and maintain consistency with knowledge that has been accumulated at the regional scale. Through a process of extensive data analyses, a systematic approach is described to create an evidence base that supports the evaluation and development of CSMs. Numerical models are then used to evaluate the impact that smaller-scale heterogeneities have on contaminant transport through the vadose zone for a performance assessment on waste tank closure. Together, the field data and the numerical experiments suggest that although small-scale features close to source releases can have an impact on horizontal spreading, overall there is a relatively minor impact on transport for the site under study as evaluated by differences in peak fluxes and arrival times for historical leak events, and for potential releases resulting from waste tank closure. Use of alternative CSMs, developed through careful examination of available characterization and monitoring data, provides confidence that geologic heterogeneities do not impact contaminant transport behavior significantly enough to alter the assessment of risk for closure at this site.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.