Association of metabolic syndrome and change in Unified Parkinson\u27s Disease Rating Scale scores.

OBJECTIVE: To explore the association between metabolic syndrome and the Unified Parkinson\u27s Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT). METHODS: This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome. RESULTS: Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p \u3c 0.0001), were more likely to be male (75.3% vs 57.0%; p \u3c 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p \u3c 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores. CONCLUSIONS: Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding. CLINICALTRIALSGOV IDENTIFIER: NCT00449865

The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion.

Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.This work was funded by a Medical Research Council Research Training Fellowship to CAF (G0900329), Addenbrooke’s Charitable Trust (ACT), CUHNHSFT, Papworth Hospital NHS Foundation Trust and the NIHR Cambridge Biomedical Research Centre. CAF received a Raymond and Beverly Sackler Studentship.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.016010

Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance

Validation of the ITS2 Region as a Novel DNA Barcode for Identifying Medicinal Plant Species

BACKGROUND: The plant working group of the Consortium for the Barcode of Life recommended the two-locus combination of rbcL+matK as the plant barcode, yet the combination was shown to successfully discriminate among 907 samples from 550 species at the species level with a probability of 72%. The group admits that the two-locus barcode is far from perfect due to the low identification rate, and the search is not over. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compared seven candidate DNA barcodes (psbA-trnH, matK, rbcL, rpoC1, ycf5, ITS2, and ITS) from medicinal plant species. Our ranking criteria included PCR amplification efficiency, differential intra- and inter-specific divergences, and the DNA barcoding gap. Our data suggest that the second internal transcribed spacer (ITS2) of nuclear ribosomal DNA represents the most suitable region for DNA barcoding applications. Furthermore, we tested the discrimination ability of ITS2 in more than 6600 plant samples belonging to 4800 species from 753 distinct genera and found that the rate of successful identification with the ITS2 was 92.7% at the species level. CONCLUSIONS: The ITS2 region can be potentially used as a standard DNA barcode to identify medicinal plants and their closely related species. We also propose that ITS2 can serve as a novel universal barcode for the identification of a broader range of plant taxa

Organization and molecular evolution of a disease-resistance gene cluster in coffee trees

<p>Abstract</p> <p>Background</p> <p>Most disease-resistance (R) genes in plants encode NBS-LRR proteins and belong to one of the largest and most variable gene families among plant genomes. However, the specific evolutionary routes of NBS-LRR encoding genes remain elusive. Recently in coffee tree (<it>Coffea arabica</it>), a region spanning the <it>S</it>_<it>H</it><it>3 </it>locus that confers resistance to coffee leaf rust, one of the most serious coffee diseases, was identified and characterized. Using comparative sequence analysis, the purpose of the present study was to gain insight into the genomic organization and evolution of the <it>S</it>_<it>H</it><it>3 </it>locus.</p> <p>Results</p> <p>Sequence analysis of the <it>S</it>_<it>H</it><it>3 </it>region in three coffee genomes, E^aand C^asubgenomes from the allotetraploid <it>C. arabica </it>and C^cgenome from the diploid <it>C. canephora</it>, revealed the presence of 5, 3 and 4 R genes in E^a, C^a, and C^cgenomes, respectively. All these R-gene sequences appeared to be members of a CC-NBS-LRR (CNL) gene family that was only found at the <it>S</it>_<it>H</it><it>3 </it>locus in <it>C. arabica</it>. Furthermore, while homologs were found in several dicot species, comparative genomic analysis failed to find any CNL R-gene in the orthologous regions of other eudicot species. The orthology relationship among the <it>S</it>_<it>H</it><it>3</it>-CNL copies in the three analyzed genomes was determined and the duplication/deletion events that shaped the <it>S</it>_<it>H</it><it>3 </it>locus were traced back. Gene conversion events were detected between paralogs in all three genomes and also between the two sub-genomes of <it>C. arabica</it>. Significant positive selection was detected in the solvent-exposed residues of the <it>S</it>_<it>H</it><it>3</it>-CNL copies.</p> <p>Conclusion</p> <p>The ancestral <it>S</it>_<it>H</it><it>3</it>-CNL copy was inserted in the <it>S</it>_<it>H</it><it>3 </it>locus after the divergence between Solanales and Rubiales lineages. Moreover, the origin of most of the <it>S</it>_<it>H</it><it>3</it>-CNL copies predates the divergence between <it>Coffea </it>species. The <it>S</it>_<it>H</it><it>3</it>-CNL family appeared to evolve following the birth-and-death model, since duplications and deletions were inferred in the evolution of the <it>S</it>_<it>H</it><it>3 </it>locus. Gene conversion between paralog members, inter-subgenome sequence exchanges and positive selection appear to be the major forces acting on the evolution of <it>S</it>_<it>H</it><it>3</it>-CNL in coffee trees.</p

Titin-truncating variants affect heart function in disease cohorts and the general population

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease

Drivers and Socioeconomic Impacts of Tourism Participation in Protected Areas

Nature-based tourism has the potential to enhance global biodiversity conservation by providing alternative livelihood strategies for local people, which may alleviate poverty in and around protected areas. Despite the popularity of the concept of nature-based tourism as an integrated conservation and development tool, empirical research on its actual socioeconomic benefits, on the distributional pattern of these benefits, and on its direct driving factors is lacking, because relevant long-term data are rarely available. In a multi-year study in Wolong Nature Reserve, China, we followed a representative sample of 220 local households from 1999 to 2007 to investigate the diverse benefits that these households received from recent development of nature-based tourism in the area. Within eight years, the number of households directly participating in tourism activities increased from nine to sixty. In addition, about two-thirds of the other households received indirect financial benefits from tourism. We constructed an empirical household economic model to identify the factors that led to household-level participation in tourism. The results reveal the effects of local households' livelihood assets (i.e., financial, human, natural, physical, and social capitals) on the likelihood to participate directly in tourism. In general, households with greater financial (e.g., income), physical (e.g., access to key tourism sites), human (e.g., education), and social (e.g., kinship with local government officials) capitals and less natural capital (e.g., cropland) were more likely to participate in tourism activities. We found that residents in households participating in tourism tended to perceive more non-financial benefits in addition to more negative environmental impacts of tourism compared with households not participating in tourism. These findings suggest that socioeconomic impact analysis and change monitoring should be included in nature-based tourism management systems for long-term sustainability of protected areas

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE