Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development

The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardat

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Optimaal plannen van onderhoudstaken voor windmolenparken op zee | Albert H. Schrotenboer 20 Paul de Octopus 2.0; hoe we met statistiek en machine-learning het WK voetbal probeerden te voorspellen | Hans Van Eetvelde & Christophe Ley 24 De afdeling als atelier; het ontwerpen van zorg | Bob van Limburg 30 Is de Nederlandse lotto wel vernieuwend genoeg?column | Henk Tijms 34 De apologie voorbij; kansrekening en het feilbare denken | Richard Starmans 40 De opa van Robbert Dijkgraaf-column | Gerard Sierksma 42 Turning the tide; getijdenenergie veelbelovend voor het Britse energienetwerk | Lotte Konings 46 Lean Six Sigma-pionier Ronald Does wint Shewhart Medal | Bendert Zevenbergen 48 Young Statisticians are looking for a new board member STAtOR Jaargang 20, nummer 1, maart 2019 STAtOR is een uitgave van de Vereniging voor Statistiek en Operations Research (VVSOR). STAtOR wil leden, bedrijven en overige geïnteresseerden op de hoogte houden van ontwikkelingen en nieuws over toepassingen van statistiek en operations research. Verschijnt 4 keer per jaar

Spermatogonial Stem Cell Niche and Spermatogonial Stem Cell Transplantation in Zebrafish

Background Spermatogonial stem cells (SSCs) are the foundation of spermatogenesis, and reside within a specific microenvironment in the testes called “niche” which regulates stem cell properties, such as, self-renewal, pluripotency, quiescence and their ability to differentiate. Methodology/Principal Findings Here, we introduce zebrafish as a new model for the study of SSCs in vertebrates. Using 5′-bromo-2′-deoxyuridine (BrdU), we identified long term BrdU-retaining germ cells, type A undifferentiated spermatogonia as putative stem cells in zebrafish testes. Similar to rodents, these cells were preferentially located near the interstitium, suggesting that the SSC niche is related to interstitial elements and might be conserved across vertebrates. This localization was also confirmed by analyzing the topographical distribution of type A undifferentiated spermatogonia in normal, vasa::egfp and fli::egfp zebrafish testes. In the latter one, the topographical arrangement suggested that the vasculature is important for the SSC niche, perhaps as a supplier of nutrients, oxygen and/or signaling molecules. We also developed an SSC transplantation technique for both male and female recipients as an assay to evaluate the presence, biological activity, and plasticity of the SSC candidates in zebrafish. Conclusions/Significance We demonstrated donor-derived spermato- and oogenesis in male and female recipients, respectively, indicating the stemness of type A undifferentiated spermatogonia and their plasticity when placed into an environment different from their original niche. Similar to other vertebrates, the transplantation efficiency was low. This might be attributed to the testicular microenvironment created after busulfan depletion in the recipients, which may have caused an imbalance between factors regulating self-renewal or differentiation of the transplanted SSCs

Salt tolerance of halophytes, research questions reviewed in the perspective of saline agriculture

Halophytes of the lower coastal salt marsh show increased salt tolerance, and under high salinity they grow faster than upper marsh species. We could not show reduced growth rate of halophytes compared with glycophytes when grown under non-saline conditions. This indicates limited energy costs associated with high-salt tolerance in plants of genera such as Salicornia, providing a good perspective of saline agriculture cultivating Salicornia as a vegetable crop.We show that halophytes do not occur on non-saline or inland sites because of a reduced growth rate at low soil salinity, but probably due to other ecological traits of glycophytic upper marsh species. These traits provide competitive advantage over lower salt marsh halophytes, such as earlier germination and increased growing season length.Some halophytic Amaranthaceae (Salicornioideae, Chenopodioideae and Suaedoideae) are not just highly salt tolerant, their growth rate is stimulated at a salinity range of 150–300 mM NaCl. Alternatively this may be described as depressed growth at low salinity.Selective pressure for such high-salt tolerance and salt stimulated growth likely occurred with prevailing arid climate and saline soil conditions. Under such conditions highly-salt tolerant succulent Salicornioideae, Chenopodioidea and Suaedoideae may have evolved about 65 Mya. In the context of evolution and diversication of land plants this origin of highly-salt tolerant succulent plants is relatively recent.Such high-salt tolerance might be characterized as constitutive in comparison with inducible (lower) salt tolerance of other dicotyledonae and monocotyledonae (Poaceae) species. Levels of salt tolerance of the latter type span a large range of low, intermediate to high-salt tolerance, but do not include salt stimulated growth. Salt tolerant traits of the latter inducible type appear to have evolved repeatedly and independently.Early highly-salt tolerant succulent Salicornioideae, Chenopodioidea and Suaedoideae were perennial and frost sensitive and occurred in warm temperate and Mediterranean regions. A shift from the perennial Sarcocornia to an annual life form has been phylogenetically dated circa 9.4–4.2 Mya and enabled evolution of annual hygrohalophytes in more northern coastal locations up to boreal and subarctic coastal sites avoiding damage of winter frost. Diversification of such hygrohalophytes was facilitated by polyploidization (e.g. occurrence of tetraploid and diploid Salicornia species), and a high degree of inbreeding allowing sympatric occurrence of Salicornia species in coastal salt marshes.High-level salt tolerance is probably a very complex polygenic trait. It is unlikely that glycophytes would accommodate the appropriate allelic variants at all the loci involved in halophyte salt tolerance. This might explain why attempts to improve crop salt tolerance through conventional breeding and selection have been unsuccessful to date.Genetic engineering provides a viable alternative, but the choice for the appropriate transgenes is hampered by a fundamental lack of knowledge of the mechanisms of salt tolerance in halophytes. The chances to identify the determinant genes through QTL analyses, or comparisons among near isogenic lines (NILS) are limited. Salt-tolerance is usually a species-wide trait in halophytes, and intra-specific divergence in salt tolerance in facultative halophytes seems to be often associated with chromosomal incompatibility.A variety of candidate salt tolerance genes been identified in Arabidopsis thaliana, among which genes encoding Na+ and K+ transporters, and genes involved in the general stress or anti-oxidant response, or in compatible solute metabolism. Many of these genes have been over-expressed in different glycophytic hosts, which usually appeared to alleviate, to some degree, the response to high salinity levels. However, with few exceptions, there are no indications that the same genes would be responsible for the superior salt tolerance in (eu)halophytes. Comparisons of gene expression and gene promoter activity patterns between halophytes and glycophytes are, with few exceptions, virtually lacking, which is a major omission in current day salt tolerance research.Full-genome transcriptomic comparisons between halophytes and related glycophytes through deep sequencing seem to be the most promising strategy to identify candidate genetic determinants of the difference in salt tolerance between halophytes and glycophytes.The most reliable validation of any candidate gene is through silencing the gene in the halophytic genetic background, preferably down to the level at which it is expressed in the glycophyte reference species. This requires genetically accessible halophyte models, which are not available to date, with the exception of Thellungiella halophila. However, more models are required, particularly because T. halophila is not a typical halophyte. Eventually, the pyramiding of validated salt tolerance genes under suitable promoters may be expected to be a viable strategy for crop salt tolerance improvement

ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Propagation of bovine spermatogonial stem cells in vitro

The access to sufficient numbers of spermatogonial stem cells (SSCs) is a prerequisite for the study of their regulation and further biomanipulation. A specialized medium and several growth factors were tested to study the in vitro behavior of bovine type A spermatogonia, a cell population that includes the SSCs and can be specifically stained for the lectin Dolichos biflorus agglutinin. During short-term culture (2 weeks), colonies appeared, the morphology of which varied with the specific growth factor(s) added. Whenever the stem cell medium was used, round structures reminiscent of sectioned seminiferous tubules appeared in the core of the colonies. Remarkably, these round structures always contained type A spermatogonia. When leukemia inhibitory factor (LIF), epidermal growth factor (EGF), or fibroblast growth factor 2 (FGF2) were added, specific effects on the numbers and arrangement of somatic cells were observed. However, the number of type A spermatogonia was significantly higher in cultures to which glial cell line-derived neurotrophic factor (GDNF) was added and highest when GDNF, LIF, EGF, and FGF2 were all present. The latter suggests that a proper stimulation of the somatic cells is necessary for optimal stimulation of the germ cells in culture. Somatic cells present in the colonies included Sertoli cells, peritubular myoid cells, and a few Leydig cells. A transplantation experiment, using nude mice, showed the presence of SSCs among the cultured cells and in addition strongly suggested a more than 10 000-fold increase in the number of SSCs after 30 days of culture. These results demonstrate that bovine SSC self-renew in our specialized bovine culture system and that this system can be used for the propagation of these cell