Molecular estimation of neurodegeneration pseudotime in older brains.

The temporal molecular changes that lead to disease onset and progression in Alzheimer\u27s disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10-5), Aβ (CERAD score, P = 1.8 × 10-5), and cognitive diagnosis (P = 3.5 × 10-7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data

Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of amaryllidaceae

Background During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown.Results We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong.Conclusions Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities.<br /

Population genetics of a lethally managed medium-sized predator

Globally, levels of human–wildlife conflict are increasing as a direct consequence of the expansion of people into natural areas resulting in competition with wildlife for food and other resources. By being forced into increasingly smaller pockets of suitable habitat, many animal species are at risk of becoming susceptible to loss of genetic diversity, inbreeding depression and the associated inability to adapt to environmental changes. Predators are often lethally controlled due to their threat to livestock. Predators such as jackals (black backed, golden and side striped; Canis mesomelas, C. aureus and C. adustus, respectively), red foxes (Vulpes vulpes) and coyotes (C. latrans) are highly adaptable and may respond to ongoing persecution through compensatory reproduction such as reproducing at a younger age, producing larger litters and/or compensatory immigration including dispersal into vacant territories. Despite decades of lethal management, jackals are problematic predators of livestock in South Africa and, although considered a temporary measure, culling of jackals is still common. Culling may affect social groups, kinship structure, reproductive strategies and sex-biased dispersal in this species. Here, we investigated genetic structure, variation and relatedness of 178 culled jackals on private small-livestock farms in the central Karoo of South Africa using 13 microsatellites. Genetic variation was moderate to high and was similar per year and per farm. An absence of genetic differentiation was observed based on STRUCTURE, principal component analysis and AMOVA. Relatedness was significantly higher within farms (r = 0.189) than between farms (r = 0.077), a result corroborated by spatial autocorrelation analysis. We documented 18 occurrences of dispersal events where full siblings were detected on different farms (range: 0.78–42.93 km). Distance between identified parent–offspring varied from 0 to 36.49 km. No evidence for sex-biased dispersal was found. Our results suggest that in response to ongoing lethal management, this population is most likely able to maintain genetic diversity through physiological and behavioural compensation mechanisms.APPENDIX S1. Supplementary methods.SUPPLEMENTARY TABLES. TABLE S1. Primer details for microsatellite loci used to genotype black-backed jackals (Canis Mesomelas). TABLE S2. Per-locus summary statistics as calculated in Cervus v3.0.7. The non-exclusion probabilities and combined non-exclusion probabilities (final row, italics) are relevant indicators of the power of the loci for parentage and sibship analyses. TABLE S3. Summary statistics for 20 sampling localities (farms) with >1 sample and for all farms pooled. Produced using the basicStats command of the diveRsity package v1.9.90 in R v3.6.2 and RStudio v1.2.5033. Standard deviation was calculated across loci in Microsoft Excel (stdev.s). Sampling localities with only one sample are not shown. TABLE S4. Summary statistics per year and for all years pooled. Produced using the basicStats command of the diveRsity package v1.9.90 in R v3.6.2 and RStudio v1.2.5033. Standard deviation was calculated across loci in Microsoft Excel (STDEV.S). TABLE S5. Pairwise FST values between farms with the full dataset (below diagonal) and associated significance at a level of 0.05 (above diagonal), where significant values are indicated by a “+” and non-significant values by a “−”. Calculated in Arlequin 3.5.2.2. TABLE S6. Pairwise FST values between farms with relatives removed (below diagonal) and associated significance at a level of 0.05 (above diagonal), where significant values are indicated by a “+” and non-significant values by a “−”. Calculated in Arlequin 3.5.2.2. TABLE S7. Comparison of mean pairwise relatedness (r) between years and mean individual inbreeding coefficients (F) between years. P-values for the Wilcoxon tests for difference in means are shown on the inside of the table (bordered by grey), with P-values for inbreeding comparisons shown below the diagonal (bottom left) and P-values for relatedness comparisons shown above the diagonal (top right). The mean F for each year is shown in the left-most column “outside” the main table, with the mean r for each year shown in the top row “outside” the main table. The numbers in parentheses after each year are the number of observations/data points for that year (number of samples for F and number of pairwise relatedness comparisons for r).SUPPLEMENTARY FIGURES. FIGURE S1. STRUCTURE HARVESTER results for (a) Delta K values and (b) probability (-LnPr) of K = 1–27 averaged over 20 runs and (c) genetic differentiation between the jackal sample locations (farms) based on STRUCTURE analysis (performed with K = 2–6) of 1 = GV, 2 = BB, 3 = BR, 4 = BD, 5 = DS, 6 = GG, 7 = HK, 8 = KD, 9 = KW, 10 = KK, 11 = KT, 12 = NG, 13 = ND, 14 = OG, 15 = RV, 16 = RE, 17 = RT, 18 = RD, 19 = SG, 20 = SK, 21 = VR, 22 = WK, 23 = CL, 24 = KR, 25 = WB and 26 = TD. FIGURE S2. STRUCTURE HARVESTER results for (a) Delta K values and (b) probability (-LnPr) of K = 1–27 averaged over 20 runs and (c) genetic differentiation between the jackal sample locations (farms) based on STRUCTURE analysis (performed with K = 2–6 and K = 14) of 1 = GV, 2 = BB, 3 = BD, 4 = DS, 5 = GG, 6 = HK, 7 = KW, 8 = KT, 9 = NG, 10 = ND, 11 = OG, 12 = RV, 13 = RE, 14 = RD, 15 = SG, 16 = SK, 17 = VR, 18 = WK and 19 = CL. After removing relatives, some localities had no samples, hence fewer sampling localities as compared to the full dataset. Note: The Evanno method (DeltaK) does not evaluate K = 1. FIGURE S3. Principal component analysis (PCA) of the different jackal sampling locations (farms) with related individuals removed. FIGURE S4. Plot comparing the relatedness estimates using six estimators and simulated individuals of known relatedness. Di, Dyadic likelihood estimator “DyadML”; LL, Lynch-Li estimator; LR, Lynch and Ritland estimator; QG, Queller and Goodnight estimator; Tri, Triadic likelihood estimator “TrioML”; W, Wang estimator. Plot produced with ggplot2 3.3.0 (Wickham, 2016). FIGURE S5. Results of the spatial autocorrelation analysis for A females and B males. The blue line indicates the autocorrelation coefficient of the data, with the 95% confidence interval at each distance class indicated by the black error bars, as determined by 1000 bootstrap resampling replicates. The red dashed lines indicate the 95% confidence interval around the null hypothesis (no spatial structure, i.e. rauto = 0), as determined by permutation (999 steps). Thus, if the error bars around the blue line do not overlap with the red dashed lines in a distance class, then genotypes were more (positive rauto) or less (negative rauto) similar than expected under the null hypothesis in that distance class. Such cases are indicated with an asterisk (*).The National Zoological Gardens, Pretoria and the University of South Africa.https://zslpublications.onlinelibrary.wiley.com/journal/14697998hj2023BiochemistryGeneticsMicrobiology and Plant Patholog

Control of Neural Stem Cell Survival by Electroactive Polymer Substrates

Stem cell function is regulated by intrinsic as well as microenvironmental factors, including chemical and mechanical signals. Conducting polymer-based cell culture substrates provide a powerful tool to control both chemical and physical stimuli sensed by stem cells. Here we show that polypyrrole (PPy), a commonly used conducting polymer, can be tailored to modulate survival and maintenance of rat fetal neural stem cells (NSCs). NSCs cultured on PPy substrates containing different counter ions, dodecylbenzenesulfonate (DBS), tosylate (TsO), perchlorate (ClO4) and chloride (Cl), showed a distinct correlation between PPy counter ion and cell viability. Specifically, NSC viability was high on PPy(DBS) but low on PPy containing TsO, ClO4 and Cl. On PPy(DBS), NSC proliferation and differentiation was comparable to standard NSC culture on tissue culture polystyrene. Electrical reduction of PPy(DBS) created a switch for neural stem cell viability, with widespread cell death upon polymer reduction. Coating the PPy(DBS) films with a gel layer composed of a basement membrane matrix efficiently prevented loss of cell viability upon polymer reduction. Here we have defined conditions for the biocompatibility of PPy substrates with NSC culture, critical for the development of devices based on conducting polymers interfacing with NSCs

Quality of Reporting and Study Design of CKD Cohort Studies Assessing Mortality in the Elderly Before and After STROBE:A Systematic Review

BACKGROUND:The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement was published in October 2007 to improve quality of reporting of observational studies. The aim of this review was to assess the impact of the STROBE statement on observational study reporting and study design quality in the nephrology literature. STUDY DESIGN:Systematic literature review. SETTING & POPULATION:European and North American, Pre-dialysis Chronic Kidney Disease (CKD) cohort studies. SELECTION CRITERIA FOR STUDIES:Studies assessing the association between CKD and mortality in the elderly (>65 years) published from 1st January 2002 to 31st December 2013 were included, following systematic searching of MEDLINE & EMBASE. PREDICTOR:Time period before and after the publication of the STROBE statement. OUTCOME:Quality of study reporting using the STROBE statement and quality of study design using the Newcastle Ottawa Scale (NOS), Scottish Intercollegiate Guidelines Network (SIGN) and Critical Appraisal Skills Programme (CASP) tools. RESULTS:37 papers (11 Pre & 26 Post STROBE) were identified from 3621 potential articles. Only four of the 22 STROBE items and their sub-criteria (objectives reporting, choice of quantitative groups and description of and carrying out sensitivity analysis) showed improvements, with the majority of items showing little change between the period before and after publication of the STROBE statement. Pre- and post-period analysis revealed a Manuscript STROBE score increase (median score 77.8% (Inter-quartile range [IQR], 64.7-82.0) vs 83% (IQR, 78.4-84.9, p = 0.05). There was no change in quality of study design with identical median scores in the two periods for NOS (Manuscript NOS score 88.9), SIGN (Manuscript SIGN score 83.3) and CASP (Manuscript CASP score 91.7) tools. LIMITATIONS:Only 37 Studies from Europe and North America were included from one medical specialty. Assessment of study design largely reliant on good reporting. CONCLUSIONS:This study highlights continuing deficiencies in the reporting of STROBE items and their sub-criteria in cohort studies in nephrology. There was weak evidence of improvement in the overall reporting quality, with no improvement in methodological quality of CKD cohort studies between the period before and after publication of the STROBE statement

An association between polymorphism of the heme oxygenase-1 and -2 genes and age-related macular degeneration

Iron may be implicated in the generation of oxidative stress by the catalyzing the Haber–Weiss or Fenton reaction. On the other hand, oxidative stress has been implicated in the pathogenesis of age-related macular degeneration (AMD) and heme oxygenase-1 (HO-1), encoded by the HMOX1 gene and heme oxygenase-2 (HO-2), encoded by the HMOX2 gene are important markers of iron-related oxidative stress and its consequences. Therefore, variability of the HMOX1 and HMOX2 genes might be implicated in the pathogenesis of AMD through the modulation of the cellular reaction to oxidative stress. In the present work, we investigated the association between AMD and a G → C transversion at the 19 position in the HMOX1 gene (the 19G>C-HMOX1 polymorphism, rs2071747) and a A → G transition at the −42 + 1444 position in the HMOX2 gene (the −42 + 1444A>G-HMOX2 polymorphism, rs2270363) and its modulation by some environmental factors. 279 patients with AMD and 105 controls were recruited in this study and the polymorphisms were typed by restriction fragment length polymorphism and allele-specific polymerase chain reaction (PCR). We observed an association between the occurrence of dry AMD and the G/A genotype of the −42 + 1444A>G-HMOX2 polymorphism (odds ratio (OR) 2.72), whereas the G/G genotype reduced the risk of dry AMD (OR 0.41). The G/C genotype and the C allele of the 19 G>C-HMOX1 polymorphism and the G/G genotype and the G allele of the −42 + 1444A>G-HMOX2 polymorphism were associated with progression of AMD from dry to wet form (OR 4.83, 5.20, 2.55, 1.69, respectively). On the other hand, the G/G genotype and the G allele of the 19 G>C-HMOX1 polymorphism and the A/G genotype and the A allele of the −42 + 1444A>G-HMOX2 polymorphism protected against AMD progression (OR 0.19, 0.19, 0.34, 0.59, respectively). Therefore, the 19G>C-HMOX1 and the −42 + 1444A>G-HMOX2 polymorphisms may be associated with the occurrence and progression of AMD

Adult Height in Patients with Advanced CKD Requiring Renal Replacement Therapy during Childhood.

BACKGROUND AND OBJECTIVES: Growth and final height are of major concern in children with ESRD. This study sought to describe the distribution of adult height of patients who started renal replacement therapy (RRT) during childhood and to identify determinants of final height in a large cohort of RRT children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 1612 patients from 20 European countries who started RRT before 19 years of age and reached final height between 1990 and 2011 were included. Linear regression analyses were performed to calculate adjusted mean final height SD score (SDS) and to investigate its potential determinants. RESULTS: The median final height SDS was -1.65 (median of 168 cm in boys and 155 cm in girls). Fifty-five percent of patients attained an adult height within the normal range. Adjusted for age at start of RRT and primary renal diseases, final height increased significantly over time from -2.06 SDS in children who reached adulthood in 1990-1995 to -1.33 SDS among those reaching adulthood in 2006-2011. Older age at start of RRT, more recent period of start of RRT, cumulative percentage time on a functioning graft, and greater height SDS at initiation of RRT were independently associated with a higher final height SDS. Patients with congenital anomalies of the kidney and urinary tract and metabolic disorders had a lower final height than those with other primary renal diseases. CONCLUSIONS: Although final height remains suboptimal in children with ESRD, it has consistently improved over time

Regional variation in hemoglobin distribution among individuals with chronic kidney disease: the ISN International Network of Chronic Kidney Disease (iNET-CKD) Cohorts

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin.Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model.Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17–49 ml/min) and 3 pediatric cohorts (median eGFR range of 26–45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7–6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%–44% across cohorts).Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.</p

AIDS-related mycoses: the way forward.

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries

Rare germline copy number variants (CNVs) and breast cancer risk.

Funder: CIHRGermline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance