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There is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown. We performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD. We identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeobox B (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 × 10⁻²⁰). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease. A substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population. ClinicalTrials.gov NCT00327860. This work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

BACKGROUND. There is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown. METHODS. We performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD. RESULTS. We identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeoboxB (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 x [10.sup.-20]). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease. CONCLUSION. A substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population. TRIAL REGISTRATION. ClinicalTrials.gov NCT00327860. FUNDING. This work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.

In the version of this article initially published, affiliation 38 incorrectly read “ICNU-Nephrology and Urology Department, Barcelona, Spain”; “Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain” is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

Fractionalization is a phenomenon in which strong interactions in a quantum system drive the emergence of excitations with quantum numbers that are absent in the building blocks. Outstanding examples are excitations with charge e /3 in the fractional quantum Hall effect 1 , 2 , solitons in one-dimensional conducting polymers 3 , 4 and Majorana states in topological superconductors 5 . Fractionalization is also predicted to manifest itself in low-dimensional quantum magnets, such as one-dimensional antiferromagnetic S  = 1 chains. The fundamental features of this system are gapped excitations in the bulk 6 and, remarkably, S  = 1/2 edge states at the chain termini 7 – 9 , leading to a four-fold degenerate ground state that reflects the underlying symmetry-protected topological order 10 , 11 . Here, we use on-surface synthesis 12 to fabricate one-dimensional spin chains that contain the S  = 1 polycyclic aromatic hydrocarbon triangulene as the building block. Using scanning tunnelling microscopy and spectroscopy at 4.5 K, we probe length-dependent magnetic excitations at the atomic scale in both open-ended and cyclic spin chains, and directly observe gapped spin excitations and fractional edge states therein. Exact diagonalization calculations provide conclusive evidence that the spin chains are described by the S  = 1 bilinear-biquadratic Hamiltonian in the Haldane symmetry-protected topological phase. Our results open a bottom-up approach to study strongly correlated phases in purely organic materials, with the potential for the realization of measurement-based quantum computation 13 . Using scanning tunnelling microscopy and spectroscopy, fractional edge excitations are observed in nanographene spin chains, enabling the potential to study strongly correlated phases in purely organic materials.

A pressure-gradient-induced laminar separation bubble (LSB) was examined using wind-tunnel experiments, direct numerical simulations (DNS) and linear local/global stability analysis. The LSB was experimentally generated on a flat plate using the favourable-to-adverse pressure gradient imposed by an inverted modified NACA $64_3-618$ airfoil. Direct numerical simulation was performed using boundary conditions extracted from a steady precursor simulation of the entire flow field. Despite good agreement in the upstream boundary layer with the experiment, DNS exhibited an approximately 25 % longer mean separation bubble, attributed to an earlier onset of transition due to the free-stream turbulence (FST) in the experiment. Introducing a very low level of isotropic FST in the DNS, similar to that measured in the experiment, caused earlier transition, decreased the mean bubble length and led to a remarkably good agreement between the DNS and experiments. Differences were observed for the dominant frequencies in the experiment and DNS, but both were within the band of most amplified frequencies predicted by LST. Proper orthogonal decomposition confirmed that dominant coherent structures from DNS and experiments are related to the inviscid Kelvin–Helmholtz instability and have similar characteristics despite slight differences in frequency. Local and global stability and dynamic mode decomposition analysis corroborated the convective nature of the dominant two-dimensional (2-D) instability and showed that the LSB is globally unstable to a range of 3-D wavenumbers, in agreement with 3-D structures observed in experiments. Results confirmed the strong impact of very low FST levels on the LSB and indicate a close agreement of the time-averaged and instability characteristics between the experiments and DNS.

Recent advances in the synthesis of graphene fragments that possess unpaired π-electrons and display high-spin ground states have unlocked possibilities to explore exotic physical phenomena related to magnetism. The high degree of spin-delocalisation makes these non-metal-based systems ideal building blocks for the construction of chains and lattices with strongly correlated magnetic ground states, which is the main requisite for measurement-based quantum computation. In this work, we demonstrate the magnetic bistability of a diradical nanographene that allows direct spin manipulation at the single-molecule level. To this end, we make use of solution-phase synthesis and tip-induced activation on a metallic surface to construct a helical non-Kekulé hydrocarbon spin switch, with a reversible transformation between a magnetic ground state and a non-magnetic one via intramolecular bond formation/breaking. The switching process is monitored by scanning tunnelling spectroscopy measurements, illustrating that this, and related systems, hold potential as spin-switch units for direct manipulation of magnetism and quantum information in entangled spin systems. Recent advances in the synthesis of graphene fragments that possess unpaired π-electrons and display high-spin ground states have unlocked possibilities to explore exotic physical phenomena related to magnetism. Here, the authors demonstrate the magnetic bistability of a diradical nanographene that allows direct spin manipulation at the single-molecule level.

Measurements of cross sections of inelastic and diffractive processes in proton–proton collisions at LHC energies were carried out with the ALICE detector. The fractions of diffractive processes in inelastic collisions were determined from a study of gaps in charged particle pseudorapidity distributions: for single diffraction (diffractive mass M X <200 GeV/ c 2 ) , and , respectively at centre-of-mass energies ; for double diffraction (for a pseudorapidity gap Δ η >3) σ DD / σ INEL =0.11±0.03,0.12±0.05, and , respectively at . To measure the inelastic cross section, beam properties were determined with van der Meer scans, and, using a simulation of diffraction adjusted to data, the following values were obtained:  mb at and at . The single- and double-diffractive cross sections were calculated combining relative rates of diffraction with inelastic cross sections. The results are compared to previous measurements at proton–antiproton and proton–proton colliders at lower energies, to measurements by other experiments at the LHC, and to theoretical models.

We develop the algebraic formalism of the formal ternary laws of C. Walter and we compare them to Buchstaber's 2-valued formal group laws. We also compute the \"elementary\" formal ternary laws (after inverting 2) using a computer program available online.

Ali Gharavi and colleagues report a genome-wide association analysis of IgA nephropathy in over 20,000 individuals of European and East Asian ancestry. They identify genome-wide significant signals at three new loci near VAV3 , CARD9 and ITGAM - ITGAX and correlations between genetic risk and pathogen diversity. We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM - ITGAX , VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA . We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host–intestinal pathogen interactions in shaping the genetic landscape of IgAN.