Interplay between pairing and correlations in spin-polarized bound states

We investigate the single and multiple defects embedded in a superconducting host, studying interplay between the proximity induced pairing and interactions. We explore influence of the spin-orbit coupling on energies, polarization and spatial patterns of the bound (Yu-Shiba-Rusinov) states of magnetic impurities in 2-dimensional square lattice. We also address the peculiar bound states in the proximitized Rashba chain, resembling the Majorana quasiparticles, focusing on their magnetic polarization which has been recently reported by S. Jeon et al., [Science 358, 772 (2017)]. Finally, we study leakage of these polarized Majorana quasiparticles on the side-attached nanoscopic regions and confront them with the subgap Kondo effect near to the singlet-doublet phase transition.Comment: 10 pages, 9 figure

Recent identity by descent in human genetic data - methods and applications

The thesis describes algorithms for detecting regions of recent identity by descent (IBD) from human genetic data and its applications in optimising resequencing studies, genomic predictions and detecting Mendelian subtypes of diseases. Firstly, we describe the algorithm ANCHAP, which scans pairs of multi-point SNP genotypes for sharing IBD of long haplotypes. A comparison with other methods shows that ANCHAP outperforms them in terms of speed or accuracy. We demonstrate the algorithm on data from population isolates - from Orcades, Croatian islands, and from a population of unrelated individuals. We compare the abundance of IBD segments between cohorts, and identify genetic regions where IBD is most common. Secondly, we verify the IBD regions detected from array data against exome sequence data. We estimate that where sharing IBD between a pair of individuals is inferred, this is confirmed by exome data in 98% of cases. Correctness of IBD detection varies with settings of ANCHAP, length of IBD segments, and position with respect to segment endpoints. We find that with sample sizes of 1000 individuals from an isolated population genotyped using a dense SNP array, and with 20% of these individuals sequenced, 65% of sequences of the un-sequenced subjects can be partially inferred. Implementation of such resequencing strategies requires an IBD-based imputation algorithm, which is outlined. Thirdly, we use recent IBD to detect carriers of Mendelian subtypes of colon cancer. We show this with the example of Lynch syndrome, which accounts for about 3% of colon cancer patients. We detect IBD sharing between known and unknown carriers around DNA mismatch-repair genes. Using the IBD relationship, we build and evaluate a model that predicts presence of Lynch Syndrome mutations. Finally, we discuss whether regions of identity by descent can be used for genomic predictions. We conclude that the utility of the inferred IBD regions depends on accuracy of detection, time to most recent common ancestors and mutation rates since

Utility of Non-rule-based Visual Matching as a Strategy to Allow Novices to Achieve Skin Lesion Diagnosis

Non-analytical reasoning is thought to play a key role in dermatology diagnosis. Considering its potential importance, surprisingly little work has been done to research whether similar identification processes can be supported in non-experts. We describe here a prototype diagnostic support software, which we have used to examine the ability of medical students (at the beginning and end of a dermatology attachment) and lay volunteers, to diagnose 12 images of common skin lesions. Overall, the non-experts using the software had a diagnostic accuracy of 98% (923/936) compared with 33% for the control group (215/648) (Wilcoxon p < 0.0001). We have demonstrated, within the constraints of a simplified clinical model, that novices’ diagnostic scores are significantly increased by the use of a structured image database coupled with matching of index and referent images. The novices achieve this high degree of accuracy without any use of explicit definitions of likeness or rule-based strategies

Short inverted repeats contribute to localized mutability in human somatic cells.

Selected repetitive sequences termed short inverted repeats (SIRs) have the propensity to form secondary DNA structures called hairpins. SIRs comprise palindromic arm sequences separated by short spacer sequences that form the hairpin stem and loop respectively. Here, we show that SIRs confer an increase in localized mutability in breast cancer, which is domain-dependent with the greatest mutability observed within spacer sequences (∼1.35-fold above background). Mutability is influenced by factors that increase the likelihood of formation of hairpins such as loop lengths (of 4-5 bp) and stem lengths (of 7-15 bp). Increased mutability is an intrinsic property of SIRs as evidenced by how almost all mutational processes demonstrate a higher rate of mutagenesis of spacer sequences. We further identified 88 spacer sequences showing enrichment from 1.8- to 90-fold of local mutability distributed across 283 sites in the genome that intriguingly, can be used to inform the biological status of a tumor

The genome as a record of environmental exposure.

Whole genome sequencing of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. Experimental investigations of the mutations and mutation spectra induced by environmental mutagens have traditionally focused on single genes. With the advent of faster cheaper sequencing platforms, it is now possible to assess mutation spectra in experimental models across the whole genome. As a proof of principle, we have examined the whole genome mutation profiles of mouse embryo fibroblasts immortalised following exposure to benzo[a]pyrene (BaP), ultraviolet light (UV) and aristolochic acid (AA). The results reveal that each mutagen induces a characteristic mutation signature: predominantly G→T mutations for BaP, C→T and CC→TT for UV and A→T for AA. The data are not only consistent with existing knowledge but also provide additional information at higher levels of genomic organisation. The approach holds promise for identifying agents responsible for mutations in human tumours and for shedding light on the aetiology of human cancer

Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly

Introduction: Periodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome. / Methods: A total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect‐size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups. / Results: At genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P‐tau. / Discussion: We show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ

Local exome sequences facilitate imputation of less common variants and increase power of genome wide association studies

The analysis of less common variants in genome-wide association studies promises to elucidate complex trait genetics but is hampered by low power to reliably detect association. We show that addition of population-specific exome sequence data to global reference data allows more accurate imputation, particularly of less common SNPs (minor allele frequency 1–10%) in two very different European populations. The imputation improvement corresponds to an increase in effective sample size of 28–38%, for SNPs with a minor allele frequency in the range 1–3%

Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome

Altres ajuts: This study was supported by National institutes of Health (NIH)/National Institute on Aging grants AG035137, AG032554, AG12101, AG022374, and AG13616, NIH DE023139-02, Alzheimer's Association NIRG-12-173937, and NIH/NCATS UL1 TR000038. Conflict of interest: No conflict of interest is reported for A.R.K., M.J., P.C., R.G.C., D.S., K.R.C.A., M.R., A.M., J.O.F., S.V., M.C.-I., and B.B. M.J. de Leon has a patent on an image analysis technology that was licensed to Abiant Imaging, Inc., by NYU, and has a financial interest in this license agreement, and NYU holds stock options on the company. M. de Leon has received compensation for consulting services from Abiant Imaging. Dr L. Glodzic was a principal investigator on an Investigator-Initiated project funded by Forest Laboratories and received an honorarium for serving as a consultant to Roche Pharma. Contributors: A.R.K., M.J.de.L., and J.F. wrote the manuscript. All the other authors reviewed the manuscript and contributed with the scientific literature, concepts, and modeling. All authors reviewed the manuscript for intellectual content and approved the final draft.People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD

Sleep oscillation-specific associations with Alzheimer’s disease CSF biomarkers : novel roles for sleep spindles and tau

Background: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ42, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. Methods: One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ42, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. Results: Spindle density during NREM stage 2 (N2) sleep was negatively correlated with CSF Aβ42, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD. Conclusions: Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline