Development of a next generation SNP genotyping array for wheat

High-throughput genotyping arrays have provided a cost-effective, reliable and interoperable system for genotyping hexaploid wheat and its relatives. Existing, highly cited arrays including our 35K Wheat Breeder's array and the Illumina 90K array were designed based on a limited amount of varietal sequence diversity and with imperfect knowledge of SNP positions. Recent progress in wheat sequencing has given us access to a vast pool of SNP diversity, whilst technological improvements have allowed us to fit significantly more probes onto a 384-well format Axiom array than previously possible. Here we describe a novel Axiom genotyping array, the ‘Triticum aestivum Next Generation’ array (TaNG), largely derived from whole genome skim sequencing of 204 elite wheat lines and 111 wheat landraces taken from the Watkins ‘Core Collection’. We used a novel haplotype optimization approach to select SNPs with the highest combined varietal discrimination and a design iteration step to test and replace SNPs which failed to convert to reliable markers. The final design with 43 372 SNPs contains a combination of haplotype-optimized novel SNPs and legacy cross-platform markers. We show that this design has an improved distribution of SNPs compared to previous arrays and can be used to generate genetic maps with a significantly higher number of distinct bins than our previous array. We also demonstrate the improved performance of TaNGv1.1 for Genome-wide association studies (GWAS) and its utility for Copy Number Variation (CNV) analysis. The array is commercially available with supporting marker annotations and initial genotyping results freely available

Disability and Homelessness: A Critical Analysis of Terminology in the United Kingdom

The intersection between co-current experiences of homelessness and Disability is rarely addressed, despite lived experience of this very occurrence being commonplace. While both phenomena are underpinned by a variety of perspectives, the prevailing ideologies for both stand in contention; in the United Kingdom, Disability is increasingly discussed through an identity-first lens (“Disabled person”) whereas homelessness is conceptualized through person-first language (“persons experiencing homelessness”). In relation to homelessness policy and support provision, conceptualizations of “homelessness” and “Disability” are inconsistent, representing a terminological discord. This discord has significant implications for how Disabled people experiencing homelessness are understood and supported.Building on theory from Social Constructionism and Critical Disability Studies, this chapter explores the language used in the homelessness sector in the UK context. It begins by examining how Disability and homelessness are conceptualized at a theoretical level. It then considers contentions in terminology from two perspectives. Firstly, an analysis at policy and service level is presented. This outlines how opposing, misinformed, and narrow categorizations can misrepresent the scale of intersection between Disability and homelessness in the United Kingdom as well as limiting opportunities and access to service provision. Secondly, this chapter discusses the real-life implications of obtaining Disability labels in the homelessness space. It reflects upon how processes of reducing, categorizing, and politicizing lived realities impacts those that these labels apply to in both the short- and long-term

Lower Bounds for the Large Deviations of Selberg's Central Limit Theorem

Let δ>0 and $σ=\frac{1}{2}+\tfracδ{\log T}$. We prove that, for any α>0 and $V\sim α\log \log T$ as $T\to\infty$, \frac{1}{T}\text{meas}\big\{t\in [T,2T]: \log|ζ(σ+\rm{i} τ)|>V\big\}\geq C_α(δ)\int_V^\infty \frac{e^{-y^2/\log\log T}}{\sqrt{π\log\log T}} \rm{d} y, where $δ$ is large enough depending on $α$. The result is unconditional on the Riemann hypothesis. As a consequence, we recover the sharp lower bound for the moments on the critical line proved by Heap & Soundararajan and Radziwiłł & Soundararajan. The constant $C_α(δ)$ is explicit and is compared to the one conjectured by Keating & Snaith for the moments

Mapping between measurement scales in meta-analysis, with application to measures of body mass index in children

Quantitative evidence synthesis methods aim to combine data from multiple medical trials to infer relative effects of different interventions. A challenge arises when trials report continuous outcomes on different measurement scales. To include all evidence in one coherent analysis, we require methods to “map” the outcomes onto a single scale. This is particularly challenging when trials report aggregate rather than individual data. We are motivated by a meta-analysis of interventions to prevent obesity in children. Trials report aggregate measurements of body mass index (BMI) either expressed as raw values or standardized for age and sex. We develop three methods for mapping between aggregate BMI data using known or estimated relationships between measurements on different scales at the individual level. The first is an analytical method based on the mathematical definitions of z-scores and percentiles. The other two approaches involve sampling individual participant data on which to perform the conversions. One method is a straightforward sampling routine, while the other involves optimization with respect to the reported outcomes. In contrast to the analytical approach, these methods also have wider applicability for mapping between any pair of measurement scales with known or estimable individual-level relationships. We verify and contrast our methods using simulation studies and trials from our data set which report outcomes on multiple scales. We find that all methods recreate mean values with reasonable accuracy, but for standard deviations, optimization outperforms the other methods. However, the optimization method is more likely to underestimate standard deviations and is vulnerable to non-convergence

The timing and mode of southern Andean human migrations

While recent genomic and isotopic information show that migration has been pervasive along human history, southern Andean archaeology has largely overlooked its importance in shaping human trajectories of sociocultural change. Building on previous isotopic research that identified the presence of migrant farmers in the Uspallata Valley (Mendoza, Argentina), we present chronological and bioarchaeological results that help to characterize the timing and mode of human migrations in the southern Andes. The burials with migrants show the representation of the different age classes, including a high abundance of children, as well as both men and women, suggesting that family groups were likely involved. The Bayesian modeling of 16 direct dates for migrants indicates that these migrations started between 1210–1275 CE (median 1255 CE) and finished at 1320–1425 CE (median 1360 CE), indicating that there is nearly no overlap between the commencement of this migration phase and the southwards expansion of the Inka Empire. The model defines a diachronic process that lasted between 55 and 195 years, implying that migration to Uspallata was a multi-generational process that involved between two and eight generations (median of four generations). Our contextual, bioarchaeological and chronological evidence indicates that the conditions fostering migration to Uspallata were sustained through time, inviting to explore persisting push-pull dynamics acting during this period. 87Sr/86Sr results show that migration occurred across the daily territories of these groups and may have involved movement across social or ethnic frontiers

6 degree of freedom positional object tracking for physical prototype digitisation

Underpinning much work on the use of Virtual Reality technologies in design prototyping, is the need to reliably track the 3D position of a physical object in real space, then allowing synchronisation with a digital counterpart. With many tracking methods requiring changes to object geometry, this work develops and benchmarks four minimally invasiveness 6 DoF tracking approaches, before discussing their use in a prototyping context. Results show that using AI and point cloud methods, accuracies of 20mm at 20Hz are achievable on low-end hardware with no alterations to the prototype needed

IQGAP1 and NWASP promote human cancer cell dissemination and metastasis by regulating β1-integrin via FAK and MRTF/SRF

Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that β1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of β1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase β1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/ MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL