Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.

The sympathetic nervous system has been evolutionary selected to respond to stress and activates haematopoietic stem cells via noradrenergic signals. However, the pathways preserving haematopoietic stem cell quiescence and maintenance under proliferative stress remain largely unknown. Here we found that cholinergic signals preserve haematopoietic stem cell quiescence in bone-associated (endosteal) bone marrow niches. Bone marrow cholinergic neural signals increase during stress haematopoiesis and are amplified through cholinergic osteoprogenitors. Lack of cholinergic innervation impairs balanced responses to chemotherapy or irradiation and reduces haematopoietic stem cell quiescence and self-renewal. Cholinergic signals activate α7 nicotinic receptor in bone marrow mesenchymal stromal cells leading to increased CXCL12 expression and haematopoietic stem cell quiescence. Consequently, nicotine exposure increases endosteal haematopoietic stem cell quiescence in vivo and impairs hematopoietic regeneration after haematopoietic stem cell transplantation in mice. In humans, smoking history is associated with delayed normalisation of platelet counts after allogeneic haematopoietic stem cell transplantation. These results suggest that cholinergic signals preserve stem cell quiescence under proliferative stress

Association between heavy metals and metalloids in topsoil and mental health in the adult population of Spain

Despite the biological plausibility of the association between heavy metal exposure and mental health disorders, epidemiological evidence remains scarce. The objective was to estimate the association between heavy metals and metalloids in soil and the prevalence of mental disorders in the adult population of Spain. Methods Individual data came from the Spanish National Health Survey 2011–2012, 18,073 individuals residing in 1772 census sections. Mental health was measured with the 12-item General Health Questionnaire. The concentration estimates of heavy metal and metalloid levels in topsoil (upper soil horizon) came from the Geochemical Atlas of Spain based on 13,317 soil samples. Levels of lead (Pb), arsenic (As), cadmium (Cd) and manganese (Mn) were estimated in each census section by “ordinary Kriging”. Odds ratios (OR) were calculated by multilevel logistic regression models. Results Compared with the lowest Pb concentration levels quartile, the OR for the second quartile was 1.29 (95%CI: 1.11–1.50), increasing progressively to 1.37 (95%CI: 1.17–1.60) and 1.51 (95%CI: 1.27–1.79) in the third and fourth quartiles, respectively. For As, the association was observed in the third and fourth quartiles: 1.21 (95%CI: 1.04–1.41) and 1.42 (95% CI: 1.21–1.65), respectively. Cd was associated also following a gradient from the second quartile: 1.34 (95%CI: 1.15–1.57) through the fourth: 1.84 (95%CI: 1.56–2.15). In contrast, Mn only showed a positive association at the second quartile. Additionally, individuals consuming vegetables > once a day the OR for the fourth quartile of Pb concentration, vs. the first, increased to 2.93 (95%CI: 1.97–4.36); similarly for As: 3.00 (95%CI: 2.08–4.31), and for Cd: 3.49 (95%CI: 2.33–5.22). Conclusions Living in areas with a higher concentration of heavy metals and metalloids in soil was associated with an increased probability of having a mental disorder. These relationships were strengthened in individuals reporting consuming vegetables > once a dayThis work was supported by the Institute of Health Carlos III, Ministry of Science Innovation and Universities [grant number PI15CIII/00034, PI14CIII/00065 and PI17CIII/00040

Estimación de la mortalidad atribuible a gripe estacional en España. Temporadas 1980-2008.

El objetivo de este estudio es estimar los excesos de mortalidad atribuibles a gripe estacional por grupos de edad, durante el período 1980-2008 en España, según las causas de mortalidad por "gripe y neumonía", "circulatorias y respiratorias" o "todas las causas". Se aplicó un modelo de regresión cíclica (Serfling modificado) a los datos de mortalidad obtenidos del Instituto Nacional de Estadística (INE), estimándose los excesos de defunciones mensuales atribuidas a gripe en períodos de circulación viral, con respecto a un nivel basal de mortalidad esperada en ausencia de actividad gripal, para los grupos de causas y de edad planteados. Para todas las temporadas y grupos de causas, más del 90% de los excesos de defunciones atribuibles a gripe estacional se produjeron en el grupo de mayores de 64 años. Se estimó una tasa media anual de excesos de defunciones por gripe y neumonía de 2,68 (IC 95%: 2,65; 2,71) defunciones/100.000 habitantes

Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis.

OBJECTIVES: Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA. METHODS: Fluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations. RESULTS: Articular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone. CONCLUSION: Our findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA

Social factors related to the clinical severity of influenza cases in Spain during the A(H1N1)2009 virus pandemic

Background During the 2009 influenza pandemic, a change in the type of patients most often affected by influenza was observed. The objective of this study was to assess the role of individual and social determinants in hospitalizations due to influenza A (H1N1) 2009 infection. Methods We studied hospitalized patients (cases) and outpatients (controls) with confirmed influenza A (H1N1) 2009 infection. A standardized questionnaire was used to collect data. Variables that might be related to the hospitalization of influenza cases were compared by estimation of the odds ratio (OR) and 95% confidence intervals (CI) and the variables entered into binomial logistic regression models. Results Hospitalization due to pandemic A (H1N1) 2009 influenza virus infections was associated with non-Caucasian ethnicity (OR: 2.18, 95% CI 1.17 − 4.08), overcrowding (OR: 2.84, 95% CI 1.20 − 6.72), comorbidity and the lack of previous preventive information (OR: 2.69, 95% CI: 1.50 − 4.83). Secondary or higher education was associated with a lower risk of hospitalization (OR 0.56, 95% CI: 0.36 − 0.87) Conclusions In addition to individual factors such as comorbidity, other factors such as educational level, ethnicity or overcrowding were associated with hospitalization due to A (H1N1) 2009 influenza virus infections

MEGARA, the new intermediate-resolution optical IFU and MOS for GTC: getting ready for the telescope

MEGARA (Multi-Espectrógrafo en GTC de Alta Resolución para Astronomía) is an optical Integral-Field Unit (IFU) and Multi-Object Spectrograph (MOS) designed for the GTC 10.4m telescope in La Palma that is being built by a Consortium led by UCM (Spain) that also includes INAOE (Mexico), IAA-CSIC (Spain), and UPM (Spain). The instrument is currently finishing AIV and will be sent to GTC on November 2016 for its on-sky commissioning on April 2017. The MEGARA IFU fiber bundle (LCB) covers 12.5x11.3 arcsec2 with a spaxel size of 0.62 arcsec while the MEGARA MOS mode allows observing up to 92 objects in a region of 3.5x3.5 arcmin2 around the IFU. The IFU and MOS modes of MEGARA will provide identical intermediate-to-high spectral resolutions (RFWHM~6,000, 12,000 and 18,700, respectively for the low-, mid- and high-resolution Volume Phase Holographic gratings) in the range 3700-9800ÅÅ. An x-y mechanism placed at the pseudo-slit position allows (1) exchanging between the two observing modes and (2) focusing the spectrograph for each VPH setup. The spectrograph is a collimator-camera system that has a total of 11 VPHs simultaneously available (out of the 18 VPHs designed and being built) that are placed in the pupil by means of a wheel and an insertion mechanism. The custom-made cryostat hosts a 4kx4k 15-μm CCD. The unique characteristics of MEGARA in terms of throughput and versatility and the unsurpassed collecting are of GTC make of this instrument the most efficient tool to date to analyze astrophysical objects at intermediate spectral resolutions. In these proceedings we present a summary of the instrument characteristics and the results from the AIV phase. All subsystems have been successfully integrated and the system-level AIV phase is progressing as expected

Haematopoietic stem cells in perisinusoidal niches are protected from ageing.

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)