A Preliminary Evaluation of the Ability of Keratotic Tissue to Act as a Prognostic Indicator of Hip Fracture Risk

Studies have shown that Raman spectroscopic analysis of fingernail clippings can help differentiate between post-menopausal women who have and who have not suffered a fracture. However, all studies to date have been retrospective in nature, comparing the proteins in nails sourced from women, post-fracture. The objective of this study was to investigate the potential of a prospective test for hip fracture based on spectroscopic analysis of nail tissue. Archived toenail samples from post-menopausal women aged 50 to 63 years in the Nurses\u27 Health Study were obtained and analysed by Raman spectroscopy. Nails were matched case-controls sourced from 161 women; 82 who underwent a hip fracture up to 20 years after nail collection and 81 age-matched controls. A number of clinical risk factors (CRFs) from the Fracture Risk Assessment (FRAX) tool had been assessed at toenail collection. Using 80% of the spectra, models were developed for increasing time periods between nail collection and fracture. Scores were calculated from these models for the other 20% of the sample and the ability of the score to predict hip fracture was tested in model with and without the CRFs by comparing the odds ratios (ORs) per 1 SD increase in standardised predictive values. The Raman score successfully distinguished between hip fracture cases and controls. With only the score as a predictor, a statistically significant OR of 2.2 (95% confidence interval [CI]: 1.5-3.1) was found for hip fracture for up to 20 years after collection. The OR increased to 3.8 (2.6-5.4) when the CRFs were added to the model. For fractures limited to 13 years after collection, the OR was 6.3 (3.0-13.1) for the score alone. The test based on Raman spectroscopy has potential for identifying individuals who may suffer hip fractures several years in advance. Higher powered studies are required to evaluate the predictive capability of this test

Fundamental MHD scales -- II: the kinematic phase of the supersonic small-scale dynamo

The small-scale dynamo (SSD) amplifies weak magnetic fields exponentially fast via kinetic motions. While there exist well-established theories for SSDs in incompressible flows, many astrophysical SSDs operate in supersonic turbulence. To understand the impact of compressibility on amplified magnetic fields, we perform an extensive set of visco-resistive SSD simulations, covering a wide range of sonic Mach number $\mathcal{M}$, hydrodynamic Reynolds number Re, and magnetic Prandtl number Pm. We develop robust methods for measuring kinetic and magnetic energy dissipation scales $\ell_\nu$ and $\ell_\eta$, as well as the scale at which magnetic fields are strongest $\ell_p$ during the kinematic phase of these simulations. We show that $\ell_\nu/\ell_\eta \sim$ Pm$^{1/2}$ is a universal feature in the kinematic phase of Pm $\geq 1$ SSDs, regardless of $\mathcal{M}$ or Re, and we confirm earlier predictions that SSDs operating in incompressible plasmas (either $\mathcal{M} \leq 1$ or Re $<$ Re$_{\rm crit} \approx 100$) concentrate magnetic energy at the smallest scales allowed by magnetic dissipation, $\ell_p \sim \ell_\eta$, and produce fields organised with field strength and field-line curvature inversely correlated. However, we show that these predictions fail for compressible SSDs ($\mathcal{M} > 1$ and Re $>$ Re$_{\rm crit}$), where shocks concentrate magnetic energy in large-scale, over-dense, coherent structures, with size $\ell_p \sim (\ell_{\rm turb} / \ell_{\rm shock})^{1/3} \ell_\eta \gg \ell_\eta$, where $\ell_{\rm shock} \sim \mathcal{M}^2 / [$Re $(\mathcal{M} - 1)^2]$ is shock width, and $\ell_{\rm turb}$ is the turbulent outer scale; magnetic field-line curvature becomes almost independent of the field strength. We discuss the implications for galaxy mergers and for cosmic-ray transport models in the interstellar medium that are sensitive to field-line curvature statistics.Comment: 25 pages, 15 figures, submitted to MNRAS, json-file w/ dat

Raman Spectral Variation for Human Fingernails of Postmenopausal Women is Dependent on Fracture Risk and Osteoporosis Status

Patients diagnosed with osteoporosis have reported loss of fingernail resilience as the disease progresses. Keratin is the predominant protein in human nail tissue, and its structure has been postulated to be different in fingernails clipped from subjects who have sustained fragility fractures and those who have not, which may offer a window into the donor\u27s bone health. This study was designed to qualify these differences, which may lead to the development of a novel screening tool for fracture risk. Raman spectroscopy was used to measure the fingernails of 633 postmenopausal women who presented at six fracture clinics located across the UK and Ireland. The Raman signals from donor\u27s fingernails were compared between (1) fracture and nonfracture and (2) osteoporotic versus non-osteoporotic donors The data presented show differences in the protein changes observed for pervasive osteoporosis compared to a general increased risk of fragility fracture. For fracture risk, compositional changes falling into broad classes of amino acid residue (aliphatic, aromatic, acidic, amide and sulphurous) were observed, while a difference in disulphide bonding levels was reaffirmed. For pervasive osteoporosis, the disulphide mode suggested increasing disorder in disulphide bonding orientation. Fractures were associated with a transition from alpha helical secondary structure to random, while the pervasive osteoporosis cases were associated with a transition to beta sheet structure. General fracture risk is associated with a change in the structure and composition of the keratin protein. Osteoporosis is associated with different protein structural changes and an increase in free acid groups. Copyright © 2017 John Wiley & Sons, Ltd

Filamentous Fungal Carbon Catabolite Repression Supports Metabolic Plasticity and Stress Responses Essential for Disease Progression

Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors)

Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury.

Although axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, we administered C7 spinal cord hemisections to adult rhesus monkeys and analyzed behavioral, electrophysiological and anatomical adaptations. We found marked spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research

A Preliminary Evaluation of the Ability of Keratotic Tissue to Act as a Prognostic Indicator of Hip Fracture Risk

Studies have shown that Raman spectroscopic analysis of fingernail clippings can help differentiate between post-menopausal women who have and who have not suffered a fracture. However, all studies to date have been retrospective in nature, comparing the proteins in nails sourced from women, post-fracture. The objective of this study was to investigate the potential of a prospective test for hip fracture based on spectroscopic analysis of nail tissue. Archived toenail samples from post-menopausal women aged 50 to 63 years in the Nurses’ Health Study were obtained and analysed by Raman spectroscopy. Nails were matched case-controls sourced from 161 women; 82 who underwent a hip fracture up to 20 years after nail collection and 81 age-matched controls. A number of clinical risk factors (CRFs) from the Fracture Risk Assessment (FRAX) tool had been assessed at toenail collection. Using 80% of the spectra, models were developed for increasing time periods between nail collection and fracture. Scores were calculated from these models for the other 20% of the sample and the ability of the score to predict hip fracture was tested in model with and without the CRFs by comparing the odds ratios (ORs) per 1 SD increase in standardised predictive values. The Raman score successfully distinguished between hip fracture cases and controls. With only the score as a predictor, a statistically significant OR of 2.2 (95% confidence interval [CI]: 1.5-3.1) was found for hip fracture for up to 20 years after collection. The OR increased to 3.8 (2.6-5.4) when the CRFs were added to the model. For fractures limited to 13 years after collection, the OR was 6.3 (3.0-13.1) for the score alone. The test based on Raman spectroscopy has potential for identifying individuals who may suffer hip fractures several years in advance. Higher powered studies are required to evaluate the predictive capability of this test

Exome analysis of patients with concurrent pediatric inflammatory bowel disease (PIBD) and autoimmune disease

BACKGROUND: Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. METHODS: Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. RESULTS: Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1). CONCLUSIONS: One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients

Exome analysis of rare and common variants within the NOD signaling pathway

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p =  0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis

Raman Spectroscopic Analysis of Fingernail Clippings Can Help Differentiate between Postmenopausal Women Who Have and Have Not Suffered a Fracture

Raman spectroscopy was applied to nail clippings from 633 postmenopausal British and Irish women, from six clinical sites, of whom 42% had experienced a fragility fracture. The objective was to build a prediction algorithm for fracture using data from four sites (known as the calibration set) and test its performance using data from the other two sites (known as the validation set). Results from the validation set showed that a novel algorithm, combining spectroscopy data with clinical data, provided area under the curve (AUC) of 74% compared to an AUC of 60% from a reduced QFracture score (a clinically accepted risk calculator) and 61% from the dual-energy X-ray absorptiometry T-score, which is in current use for the diagnosis of osteoporosis. Raman spectroscopy should be investigated further as a noninvasive tool for the early detection of enhanced risk of fragility fracture

Horizontal Gene Acquisitions, Mobile Element Proliferation, and Genome Decay in the Host-Restricted Plant Pathogen \u3ci\u3eErwinia Tracheiphila\u3c/i\u3e

Modern industrial agriculture depends on high-density cultivation of genetically similar crop plants, creating favorable conditions for the emergence of novel pathogens with increased fitness in managed compared with ecologically intact settings. Here, we present the genome sequence of six strains of the cucurbit bacterial wilt pathogen Erwinia tracheiphila (Enterobacteriaceae) isolated from infected squash plants in New York, Pennsylvania, Kentucky, and Michigan. These genomes exhibit a high proportion of recent horizontal gene acquisitions, invasion and remarkable amplification of mobile genetic elements, and pseudogenization of approximately 20% of the coding sequences. These genome attributes indicate that E. tracheiphila recently emerged as a host-restricted pathogen. Furthermore, chromosomal rearrangements associated with phage and transposable element proliferation contribute to substantial differences in gene content and genetic architecture between the six E. tracheiphila strains and other Erwinia species. Together, these data lead us to hypothesize that E. tracheiphila has undergone recent evolution through both genome decay (pseudogenization) and genome expansion (horizontal gene transfer and mobile element amplification). Despite evidence of dramatic genomic changes, the six strains are genetically monomorphic, suggesting a recent population bottleneck and emergence into E. tracheiphila’s current ecological niche