The genetic origin of human skin pigmentation remains an open question in biology. Several skin disorders and diseases originate from mutations in conserved pigmentation genes, including albinism, ...vitiligo, and melanoma. Teleosts possess the capacity to modify their pigmentation to adapt to their environmental background to avoid predators. This background adaptation occurs through melanosome aggregation (white background) or dispersion (black background) in melanocytes. These mechanisms are largely regulated by melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH), two hypothalamic neuropeptides also involved in mammalian skin pigmentation. Despite evidence that the exogenous application of MCH peptides induces melanosome aggregation, it is not known if the MCH system is physiologically responsible for background adaptation. In zebrafish, we identify that MCH neurons target the pituitary gland-blood vessel portal and that endogenous MCH peptide expression regulates melanin concentration for background adaptation. We demonstrate that this effect is mediated by MCH receptor 2 (Mchr2) but not Mchr1a/b. mchr2 knock-out fish cannot adapt to a white background, providing the first genetic demonstration that MCH signaling is physiologically required to control skin pigmentation. mchr2 phenotype can be rescued in adult fish by knocking-out pomc, the gene coding for the precursor of α-MSH, demonstrating the relevance of the antagonistic activity between MCH and α-MSH in the control of melanosome organization. Interestingly, MCH receptor is also expressed in human melanocytes, thus a similar antagonistic activity regulating skin pigmentation may be conserved during evolution, and the dysregulation of these pathways is significant to our understanding of human skin disorders and cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of ...tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a “common pathway” to both AKI and CKD still remains to be adequately tested.
Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported ...from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort.
Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region (HMIP) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region (HMIP) and BCL11A affect both other hematological indices and rates of hospitalization.
This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
dementia is a highly prevalent acquired cognitive disorder that interferes with activities of daily living, relationships and quality of life. Recognition and effective management strategies are ...necessary to provide comprehensive care for these patients and their families. High-quality clinical practice guidelines can improve the quality and consistency of care in all aspects of dementia diagnosis and management by clarifying interventions supported by sound evidence and by alerting clinicians to interventions without proven benefit.
we aimed to offer a synthesis of existing practice recommendations for the diagnosis and management of dementia, based upon moderate-to-high quality dementia guidelines.
we performed a systematic search in EMBASE and MEDLINE as well as the grey literature for guidelines produced between 2008 and 2013.
thirty-nine retrieved practice guidelines were included for quality appraisal by the Appraisal of Guidelines Research and Evaluation II (AGREE-II) tool, performed by two independent reviewers. From the 12 moderate-to-high quality guidelines included, specific practice recommendations for the diagnosis and/or management of any aspect of dementia were extracted for comparison based upon the level of evidence and strength of recommendation.
there was a general agreement between guidelines for many practice recommendations. However, direct comparisons between guidelines were challenging due to variations in grading schemes.
Chemical mutagenesis efficiently generates phenotypic variation in otherwise homogeneous genetic backgrounds, enabling functional analysis of genes. Advances in mutation detection have brought the ...utility of induced mutant populations on par with those produced by insertional mutagenesis, but systematic cataloguing of mutations would further increase their utility. We examined the suitability of multiplexed global exome capture and sequencing coupled with custom-developed bioinformatics tools to identify mutations in well-characterized mutant populations of rice (Oryza sativa) and wheat (Triticum aestivum). In rice, we identified ~18,000 induced mutations from 72 independent M2 individuals. Functional evaluation indicated the recovery of potentially deleterious mutations for >2600 genes. We further observed that specific sequence and cytosine methylation patterns surrounding the targeted guanine residues strongly affect their probability to be alkylated by ethyl methanesulfonate. Application of these methods to six independent M2 lines of tetraploid wheat demonstrated that our bioinformatics pipeline is applicable to polyploids. In conclusion, we provide a method for developing large-scale induced mutation resources with relatively small Investments that is applicable to resource-poor organisms. Furthermore, our results demonstrate that large libraries of sequenced mutations can be readily generated, providing enhanced opportunities to study gene function and assess the effect of sequence and chromatin context on mutations.
Discovery of rare mutations in populations requires methods, such as TILLING (for Targeting Induced Local Lesions in Genomes), for processing and analyzing many individuals in parallel. Previous ...TILLING protocols employed enzymatic or physical discrimination of heteroduplexed from homoduplexed target DNA. Using mutant populations of rice (Oryza sativa) and wheat (Triticum durum), we developed a method based on Illumina sequencing of target genes amplified from multidimensionally pooled templates representing 768 individuals per experiment. Parallel processing of sequencing libraries was aided by unique tracer sequences and barcodes allowing flexibility in the number and pooling arrangement of targeted genes, species, and pooling scheme. Sequencing reads were processed and aligned to the reference to identify possible single-nucleotide changes, which were then evaluated for frequency, sequencing quality, intersection pattern in pools, and statistical relevance to produce a Bayesian score with an associated confidence threshold. Discovery was robust both in rice and wheat using either bidimensional or tridimensional pooling schemes. The method compared favorably with other molecular and computational approaches, providing high sensitivity and specificity.
Summary
Micro‐albuminuria and glomerular hyperfiltration are primary indicators of renal dysfunctions in Sickle Cell Disease (SCD), with more severe manifestations previously associated with variants ...in APOL1 and HMOX1 among African Americans. We have investigated 413 SCD patients from Cameroon. Anthropometric variables, haematological indices, crude albuminuria, albumin‐to‐creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured. Patients were genotyped for 3·7 kb alpha‐globin gene (HBA1/HBA2) deletion, and for variants in APOL1 (G1/G2; rs60910145, rs73885319, rs71785313) and HMOX1 (rs3074372, rs743811). The median age was 15 years; the majority presented with micro‐albuminuria (60·9%; n = 248), and approximately half with glomerular hyperfiltration (49·5%; n = 200). Age, male sex, haemoglobin level, leucocyte count, mean corpuscular volume, blood pressure, body mass index and creatinine levels significantly affected albuminuria and/or eGFR. Co‐inheritance of alpha‐thalassaemia was protective against macro‐albuminuria (P = 0·03). APOL1 G1/G2 risk variants were significantly associated with the ACR (P = 0·01) and borderline with eGFR (P = 0·07). HMOX1 ‐ rs743811 was borderline associated with micro‐albuminuria (P = 0·07) and macro‐albuminuria (P = 0·06). The results revealed a high proportion of micro‐albuminuria and glomerular hyperfiltration among Cameroonian SCD patients, and support the possible use of targeted genetic biomarkers for risks assessment.
Carotenoids, which are pigments known to have many health benefits, such as their antioxidant properties, are being researched for their potential as a feed additive for production animals. These ...pigments are found in varying quantities in different breeds of corn, and their impact on the chicken microbiome requires further investigation. This 35 d laying hen (Novagen White) feeding trial involved varying the levels and composition of carotenoids by changing the corn source: white (0.9 µg total carotinoids/g total diet), yellow (5.7 µg/g), and orange (24.9 µg/g). For each of the three corn diet treatments, 6 replicate cages were randomly assigned. The cecal microbial community composition of the hens was then studied by 16S rRNA gene amplicon sequencing. The composition of the cecal bacterial community, as determined by Bray-Curtis dissimilarity, was different (P < 0.05) in chickens fed the orange corn diet, compared to chickens on the white corn diet, but there was no statistical difference between animals fed yellow corn compared to the white or orange corn groups. There was no change in the alpha diversity between any of the groups. Within Lactobacillus, which is one of the most abundant genera, 2 amplicon sequence variants (ASVs) were decreased and one ASV was increased in the orange corn group compared to both the white and yellow corn groups. While previous studies showed that orange corn did not alter the community composition in broilers, it appears that orange corn based feed may alter the community composition of laying hens.
The Targeting Induced Local Lesions in Genomes (TILLING) technology is a reverse genetic strategy broadly applicable to every kind of genome and represents an attractive tool for functional genomic ...and agronomic applications. It consists of chemical random mutagenesis followed by high-throughput screening of point mutations in targeted genomic regions. Although multiple methods for mutation discovery in amplicons have been described, next-generation sequencing (NGS) is the tool of choice for mutation detection because it quickly allows for the analysis of a large number of amplicons. The aim of the present work was to screen a previously generated sunflower TILLING population and identify alterations in genes involved in several important and complex physiological processes. Twenty-one candidate sunflower genes were chosen as targets for the screening. The TILLING by sequencing strategy allowed us to identify multiple mutations in selected genes and we subsequently validated 16 mutations in 11 different genes through Sanger sequencing. In addition to addressing challenges posed by outcrossing, our detection and validation of mutations in multiple regulatory loci highlights the importance of this sunflower population as a genetic resource.
Hereditary spinocerebellar ataxias are a group of genetic neurological disorders that result in degeneration of the cerebellum and brainstem, leading to difficulty in controlling balance and muscle ...coordination.
A family affected by spinocerebellar ataxia was identified in Argentina and investigated using whole exome sequencing to determine the genetic etiology. The proband, a female white Hispanic aged 48, was noted to have slowly progressive gait ataxia, dysarthria, nystagmus, and moderate cerebellar atrophy. Whole exome sequencing was performed on three affected and two unaffected family members and revealed a dominant pathogenic variant, p.Gln127Arg (19:54392986 A>G), in the protein kinase C gamma gene, and the family was diagnosed with spinocerebellar ataxia type 14.
To our knowledge, no previous cases of spinocerebellar ataxia type 14 have been reported in Argentina, expanding the global presence of this neurological disorder. This diagnosis supports whole exome sequencing as a high-yield method for identifying coding variants causing cerebellar ataxias and emphasizes the importance of broadening the clinical availability of whole exome sequencing for undiagnosed patients and families.
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