A missense mutation in PMEL17 is associated with the Silver coat color in the horse

BACKGROUND: The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype. RESULTS: Segregation data on the Silver locus (Z) were obtained within one half-sib family that consisted of a heterozygous Silver colored stallion with 34 offspring and their 29 non-Silver dams. We typed 41 genetic markers well spread over the horse genome, including one single microsatellite marker (TKY284) close to the candidate gene PMEL17 on horse chromosome 6 (ECA6q23). Significant linkage was found between the Silver phenotype and TKY284 (θ = 0, z = 9.0). DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys). This mutation showed complete association with the Silver phenotype across multiple horse breeds, and was not found among non-Silver horses with one clear exception; a chestnut colored individual that had several Silver offspring when mated to different non-Silver stallions also carried the exon 11 mutation. In total, 64 Silver horses from six breeds and 85 non-Silver horses from 14 breeds were tested for the exon 11 mutation. One additional mutation located in intron 9, only 759 bases from the missense mutation, also showed complete association with the Silver phenotype. However, as one could expect to find several non-causative mutations completely associated with the Silver mutation, we argue that the missense mutation is more likely to be causative. CONCLUSION: The present study shows that PMEL17 causes the Silver coat color in the horse and enable genetic testing for this trait

A hierarchical clustering method for land cover change detection and identification

A method to detect abrupt land cover changes using hierarchical clustering of multi-temporal satellite imagery was developed. The Autochange method outputs the pre-change land cover class, the change magnitude, and the change type. Pre-change land cover information is transferred to post-change imagery based on classes derived by unsupervised clustering, enabling using data from different instruments for pre- and post-change. The change magnitude and change types are computed by unsupervised clustering of the post-change image within each cluster, and by comparing the mean intensity values of the lower level clusters with their parent cluster means. A computational approach to determine the change magnitude threshold for the abrupt change was developed. The method was demonstrated with three summer image pairs Sentinel-2/Sentinel-2, Landsat 8/Sentinel-2, and Sentinel-2/ALOS 2 PALSAR in a study area of 12,372 km2 in southern Finland for the detection of forest clear cuts and tested with independent data. The Sentinel-2 classification produced an omission error of 5.6% for the cut class and 0.4% for the uncut class. Commission errors were 4.9% for the cut class and 0.4% for the uncut class. For the Landsat 8/Sentinel-2 classifications the equivalent figures were 20.8%, 0.2%, 3.4%, and 1.6% and for the Sentinel-2/ALOS PALSAR classification 16.7%, 1.4%, 17.8%, and 1.3%, respectively. The Autochange algorithm and its software implementation was considered applicable for the mapping of abrupt land cover changes using multi-temporal satellite data. It allowed mixing of images even from the optical and synthetic aperture radar (SAR) sensors in the same change analysis

Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease.

RATIONALE: The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. OBJECTIVES: To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. METHODS: Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate-severe (GOLD II-III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. RESULTS: Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)(+) dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin(+) dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. CONCLUSIONS: Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar-lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD

The effect of vitamin B supplementation on neuronal injury in people living with HIV – a randomised controlled trial

Effective antiretroviral therapy has radically changed the course of the HIV pandemic. However, despite efficient therapy, milder forms of neurocognitive symptoms are still present in people living with HIV. Plasma homocysteine is a marker of vitamin B deficiency and has been associated with cognitive impairment. People living with HIV have higher homocysteine concentrations than HIV-negative controls, and we have previously found an association between plasma homocysteine concentration and CSF concentration of neurofilament light protein, a sensitive marker for ongoing neuronal injury in HIV. This prompted us to perform this randomised controlled trial, to evaluate the effect of vitamin B supplementation on neuronal injury in a cohort of people living with HIV on stable antiretroviral therapy. At the Department of Infectious Diseases at Sahlgrenska University Hospital in Gothenburg, Sweden, 124 virally suppressed people living with HIV were screened to determine eligibility for this study. Sixty-one fulfilled the inclusion criteria by having plasma homocysteine levels at or above 12 μmol/L. They were randomised (1:1) to either active treatment (with cyanocobalamin 0.5 mg, folic acid 0.8 mg, and pyridoxine 3.0 mg) q.d. or to a control arm with a cross-over to active treatment after 12 months. Cognitive function was measured repeatedly during the trial, which ran for 24 months. We found a significant correlation between plasma neurofilament light protein and plasma homocysteine at screening (n = 124, r = 0.35, p < 0.0001). Plasma homocysteine levels decreased by 35% from a geometric mean of 15.7 μmol/L (95% CI 14.7–16.7) to 10.3 μmol/L (95% CI 9.3–11.3) in the active treatment arm between baseline and month 12. No significant change was detected in the control arm during the same time period (geometric mean 15.2 [95% CI 14.3–16.2] vs geometric mean 16.5 μmol/L [95% CI 14.7–18.6]). A significant difference in change in plasma homocysteine levels was seen between arms at 12 months (-40% [95% CI -48 – -30%], p < 0.001). However, no difference between arms was seen in either plasma neurofilament light protein levels (-6.5% [ -20–9%], p = 0.39), or cognitive measures (-0.08 [-0.33–0.17], p = 0.53). Our results do not support a vitamin B-dependent cause of the correlation between neurofilament light protein and homocysteine. Additional studies are needed to further elucidate this matter

The effect of vitamin B supplementation on neuronal injury in people living with HIV: a randomized controlled trial

Effective antiretroviral therapy has radically changed the course of the HIV pandemic. However, despite efficient therapy, milder forms of neurocognitive symptoms are still present in people living with HIV. Plasma homocysteine is a marker of vitamin B deficiency and has been associated with cognitive impairment. People living with HIV have higher homocysteine concentrations than HIV-negative controls, and we have previously found an association between plasma homocysteine concentration and CSF concentration of neurofilament light protein, a sensitive marker for ongoing neuronal injury in HIV. This prompted us to perform this randomized controlled trial, to evaluate the effect of vitamin B supplementation on neuronal injury in a cohort of people living with HIV on stable antiretroviral therapy. At the Department of Infectious Diseases at Sahlgrenska University Hospital in Gothenburg, Sweden, 124 virally suppressed people living with HIV were screened to determine eligibility for this study. Sixty-one fulfilled the inclusion criteria by having plasma homocysteine levels at or above 12 mu mol/l. They were randomized (1:1) to either active treatment (with cyanocobalamin 0.5 mg, folic acid 0.8 mg and pyridoxine 3.0 mg) q.d. or to a control arm with a cross over to active treatment after 12 months. Cognitive function was measured repeatedly during the trial, which ran for 24 months. We found a significant correlation between plasma neurofilament light protein and plasma homocysteine at screening (n = 124, r = 0.35, P < 0.0001). Plasma homocysteine levels decreased by 35% from a geometric mean of 15.7 mu mol/l (95% confidence interval 14.7-16.7) to 10.3 mu mol/l (95% confidence interval 9.3-11.3) in the active treatment arm between baseline and Month 12. No significant change was detected in the control arm during the same time period [geometric mean 15.2 (95% confidence interval 14.3-16.2) versus geometric mean 16.5 mu mol/l (95% confidence interval 14.7-18.6)]. A significant difference in change in plasma homocysteine levels was seen between arms at 12 months [-40% (95% confidence interval -48 to -30%), P < 0.001]. However, no difference between arms was seen in either plasma neurofilament light protein levels [-6.5% (-20 to 9%), P = 0.39], or cognitive measures [-0.08 (-0.33 to 0.17), P = 0.53]. Our results do not support a vitamin B-dependent cause of the correlation between neurofilament light protein and homocysteine. Additional studies are needed to further elucidate this matter. Tyrberg et al. report the results of a randomized controlled trial investigating the effect of vitamin B supplementation on neuronal injury in people living with HIV with effective antiretroviral therapy. Supplementation decreased levels of homocysteine but not neuronal injury measured by neurofilament light protein

Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

OBJECTIVE: To test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury. METHODS: We recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort. RESULTS: The patients with severe COVID-19 had higher plasma concentrations of GFAp (p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury. CONCLUSION: We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.This research was supported by grants from Alzheimer’s Research UK and the Wellcome Trust (to F.J.L.) and core funding to the Gurdon Trust from the Wellcome Trust and Cancer Research UK. N.S. was supported by a Woolf-Fisher Trust (NZ) PhD studentship. H.Z. was supported by the Wolfson Centre at UCL, and the UCLH Dementia BRU provided financial support for the collection of patient materials. F.J.L. is a Wellcome Trust Senior Investigator, K.B. is a Torsten So¨ derberg Academy Professor, and H.Z. is a Wallenberg Academy Fellow.This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S2211124715003599