Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene

Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined and is associated with high (H) and low (L) expression alleles identified by a HindIII restriction fragment-length polymorphism (RFLP) in intron 27 of the CR1 gene. The L allele confers protection against severe malaria in Papua New Guinea, probably because erythrocytes with low CR1 expression, are less able to form pathogenic rosettes with Plasmodium falciparum-infected erythrocytes. Despite the biological importance of erythrocyte CR1, the genetic mutation controlling CR1 expression level remains unknown. We investigated the possibility that mutations in the upstream or 3′ untranslated regions of the CR1 gene could control erythrocyte CR1 level. We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. Therefore, high and low erythrocyte CR1 levels cannot be explained by polymorphisms in transcriptional control elements in the upstream or 3′ untranslated regions of the CR1 gene

Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study

Introduction: The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015. Methods: Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint‐bleed rate (ABR/AJBR) from Haemtrack (HT) in HT‐compliant patients. Results: We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT‐compliant children <12 years with SHA, falling to 74.1% (n = 123/166) aged ≥40 years. Median ABR increased with age (1.0, IQR 0.0‐5.0, <12 years; 3.0 IQR, 1.0‐8.0, ≥40 years). Inhibitors were present in 159 (8.8%) SHA and 34 (3.9%) MHA. Median ABR increased from 2.0 (<12 years) to 21.(≥40 years) in SHA inhibitor patients using prophylaxis. Prophylaxis was used by 68.8% of HT‐compliant MHA patients (n = 106) (median FVIII baseline 0.01 IU/mL) associated with a median (IQR) ABR of 3.0 (1.0‐7.0). Median HJHS (n = 453) increased with age in SHA and MHA. Median (IQR) HJHS was higher in SHA inhibitor (17.0, 0.0‐64.5) than non‐ or past inhibitor patients (7.0, 0.0‐23.0). Conclusions: Increasing ABR with age persists despite current prophylaxis regimens.SHA and MHA had similar ABR/AJBR and HJHS, leading to a suspicion that a subgroup of MHA may be relatively undertreated. More intensive prophylaxis may improve outcomes, but this requires further study

Absence of the zero bias peak in vortex tunneling spectra of high temperature superconductors?

The c-axis tunneling matrix of high-Tc superconductors is shown to depend strongly on the in-plane momentum of electrons and vanish along the four nodal lines of the d(x^2-y^2)-wave energy gap. This anisotropic tunneling matrix suppresses completely the contribution of the most extended quasiparticles in the vortex core to the c-axis tunneling current and leads to a spectrum similar to that of a nodeless superconductor. Our results give a natural explanation of the absence of the zero bias peak as well as other features observed in the vortex tunneling spectra of high-Tc cuprates.Comment: 4 pages 3 figures, minor corrections, to appear in Phys Rev

Semiconductor-based Geometrical Quantum Gates

We propose an implementation scheme for holonomic, i.e., geometrical, quantum information processing based on semiconductor nanostructures. Our quantum hardware consists of coupled semiconductor macroatoms addressed/controlled by ultrafast multicolor laser-pulse sequences. More specifically, logical qubits are encoded in excitonic states with different spin polarizations and manipulated by adiabatic time-control of the laser amplitudes . The two-qubit gate is realized in a geometric fashion by exploiting dipole-dipole coupling between excitons in neighboring quantum dots.Comment: 4 Pages LaTeX, 3 Figures included. To appear in PRB (Rapid Comm.

Holonomic quantum gates: A semiconductor-based implementation

We propose an implementation of holonomic (geometrical) quantum gates by means of semiconductor nanostructures. Our quantum hardware consists of semiconductor macroatoms driven by sequences of ultrafast laser pulses ({\it all optical control}). Our logical bits are Coulomb-correlated electron-hole pairs (excitons) in a four-level scheme selectively addressed by laser pulses with different polarization. A universal set of single and two-qubit gates is generated by adiabatic change of the Rabi frequencies of the lasers and by exploiting the dipole coupling between excitons.Comment: 10 Pages LaTeX, 10 Figures include

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

Altres ajuts: Max Planck Society (Germany).The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors