Macro- and micro-scale studies on U(VI) immobilization in hardened cement paste

Wet chemistry and synchrotron-based (micro-)spectroscopic investigations have been carried out to determine the uptake and speciation of U(VI) in hardened cement paste (HCP). The wet chemistry experiments included kinetic studies and the determination of the sorption isotherm. The latter measurements allowed conditions for linear sorption to be distinguished from those where precipitation occurred. Micro-X-ray fluorescence and X-ray absorption spectroscopy (μ-XRF/XAS) were used to determine the elemental distribution and the coordination environment of U(VI) in an intact HCP sample at the atomic level. The sample was prepared by in-diffusion of U(VI) into HCP over 9months. Micro-XRF maps revealed a heterogeneous distribution of U(VI) in a ten micron thick layer on the surface of the HCP disk. Micro-XAS measurements on a U(VI) hot spot showed that the coordination environment of U(VI) is similar to that in U(VI) doped HCP and in C-S-H sorption samples. To the best of our knowledge this is the first synchrotron-based micro-spectroscopic study on the speciation of diffusing uranyl ions with micro-scale spatial resolutio

Out of the boxes, out of the silos: The need of interdisciplinary collaboration to reduce poor-quality medical products in the supply chain

In this paper, we argue that understanding and addressing the problem of poor-quality medical products requires a more interdisciplinary approach than has been evident to date. While prospective studies based on rigorous standardized methodologies are the gold standard for measuring the prevalence of poor-quality medical products and understanding their distribution nationally and internationally, they should be complemented by social science research to unpack the complex set of social, economic, and governance factors that underlie these patterns. In the following sections, we discuss specific examples of prospective quality surveys and of social science studies, highlighting the value of cross-sector partnerships in driving high-quality, policy-relevant research in this area

The proteins DotY and DotZ modulate the dynamics and localization of the type IVB coupling complex of Legionella pneumophila

Legionella pneumophila is an opportunistic pathogen infecting alveolar macrophages and protozoa species. Legionella utilizes a Type IV Secretion System (T4SS) to translocate over 300 effector proteins into its host cell. In a recent study, we isolated and solved the cryo-EM structure of the Type IV Coupling Complex (T4CC), a large cytoplasmic determinant associated with the inner membrane that recruits effector proteins for delivery to the T4SS for translocation. The T4CC is composed of a DotLMNYZ hetero-pentameric core from which the flexible IcmSW module flexibly protrudes. The DotY and DotZ proteins were newly reported members of this complex and their role remained elusive. In this study, we observed the effect of deleting DotY and DotZ on T4CC stability and localization. Furthermore, we found these two proteins are co-dependent, whereby the deletion of DotY resulted in DotZ absence from the coupling complex, and vice versa. Additional cryo-EM data analysis revealed the dynamic movement of the IcmSW module is modified by the DotY/Z proteins. We therefore determined the likely function of DotY and DotZ and revealed their importance on T4CC function

Mechanism of effector capture and delivery by the type IV secretion system from Legionella pneumophila

Legionella pneumophila is a bacterial pathogen that utilises a Type IV secretion (T4S) system to inject effector proteins into human macrophages. Essential to the recruitment and delivery of effectors to the T4S machinery is the membrane-embedded T4 coupling complex (T4CC). Here, we purify an intact T4CC from the Legionella membrane. It contains the DotL ATPase, the DotM and DotN proteins, the chaperone module IcmSW, and two previously uncharacterised proteins, DotY and DotZ. The atomic resolution structure reveals a DotLMNYZ hetero-pentameric core from which the flexible IcmSW module protrudes. Six of these hetero-pentameric complexes may assemble into a 1.6-MDa hexameric nanomachine, forming an inner membrane channel for effectors to pass through. Analysis of multiple cryo EM maps, further modelling and mutagenesis provide working models for the mechanism for binding and delivery of two essential classes of Legionella effectors, depending on IcmSW or DotM, respectively

Translations: effects of viewpoint, feature, naming and context on identifying repeatedly copied drawings

We explored the tension between bottom – up and top – down contributions to object recognition in a collaboration between a visual artist and a cognitive psychologist. Initial pictorial renderings of objects and animals from various viewpoints were iteratively copied, and a series of drawings that changed from highly concrete images into highly abstract images was produced. In drawing identification in which sets were shown in reverse order, participants were more accurate, more confident, and quicker to correctly identify the evolving image when it was originally displayed from a canonical viewpoint with all salient features present. In drawing identification in which images were shown in random order, more abstract images could be resolved as a result of previously identifying a more concrete iteration of the same drawing. The results raise issues about the influence of viewpoint and feature on the preservation of pictorial images and about the role of labelling in the interpretation of ambiguous stimuli. In addition, the study highlights a procedure in which visual stimuli can degrade without necessitating a substantial loss of complexity

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health

The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition.

Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances

Phylomemetics—Evolutionary Analysis beyond the Gene

Genes are propagated by error-prone copying, and the resulting variation provides the basis for phylogenetic reconstruction of evolutionary relationships. Horizontal gene transfer may be superimposed on a tree-like evolutionary pattern, with some relationships better depicted as networks. The copying of manuscripts by scribes is very similar to the replication of genes, and phylogenetic inference programs can be used directly for reconstructing the copying history of different versions of a manuscript text. Phylogenetic methods have also been used for some time to analyse the evolution of languages and the development of physical cultural artefacts. These studies can help to answer a range of anthropological questions. We propose the adoption of the term “phylomemetics” for phylogenetic analysis of reproducing non-genetic elements

Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10 <sup>-56</sup> ) and SLC2A9 (p = 4.5 × 10 <sup>-7</sup> ). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10 <sup>-3</sup> ). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout