Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a ...classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype.
Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the
gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility
. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (
), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g.
,
,
,
,
,
), and also identified other potentially relevant candidates including
,
, and
Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
IFMIF-DONES is a facility under construction in Granada, whose main goal is the validation and characterization of materials under a fusion prototypic irradiation field. This field is created by the ...interaction of a high energy intense continuous deuteron beam and a flowing liquid lithium target. The requirements imposed on the beam at the interaction point are a complex trade-off among the scientific experimental needs for the materials irradiation defined at the top-level requirements (20 dpa in a volume of 0.3 dm3 and 50 dpa in 0.1 dm3), and the technical constraints of several systems such as the Accelerator Systems, the Lithium Systems, and the Test Systems. Recent simulations with the initial definition of beam-on-target requirements showed the necessity of redefining them in order to fulfill the irradiation needs. This contribution will address the main challenges to gather the inputs for the definition and reassessment of the beam-on-target requirements. A comparison detailing the main changes compared to the previous ones will be given, together with a short overview of the studies ongoing by different systems to analyze the impact of each beam-on-target requirements on the performance of the whole facility.
•Fusion materials irradiation.•Deuteron accelerator.•High current accelerator.•Beam delivery system.•Beam on-target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the field of multiple comparison procedures, adjusted p‐values are an important tool to evaluate the significance of a test statistic while taking the multiplicity into account. In this paper, we ...introduce adjusted p‐values for the recently proposed Sequential Goodness‐of‐Fit (SGoF) multiple test procedure by letting the level of the test vary on the unit interval. This extends previous research on the SGoF method, which is a method of high interest when one aims to increase the statistical power in a multiple testing scenario. The adjusted p‐value is the smallest level at which the SGoF procedure would still reject the given null hypothesis, while controlling for the multiplicity of tests. The main properties of the adjusted p‐values are investigated. In particular, we show that they are a subset of the original p‐values, being equal to 1 for p‐values above a certain threshold. These are very useful properties from a numerical viewpoint, since they allow for a simplified method to compute the adjusted p‐values. We introduce a modification of the SGoF method, termed majorant version, which rejects the null hypotheses with adjusted p‐values below the level. This modification rejects more null hypotheses as the level increases, something which is not in general the case for the original SGoF. Adjusted p‐values for the conservative version of the SGoF procedure, which estimates the variance without assuming that all the null hypotheses are true, are also included. The situation with ties among the p‐values is discussed too. Several real data applications are investigated to illustrate the practical usage of adjusted p‐values, ranging from a small to a large number of tests.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The sequential goodness-of-fit (SGoF) multiple testing method has recently been proposed as an alternative to the familywise error rate- and the false discovery rate-controlling procedures in ...high-dimensional problems. For discrete data, the SGoF method may be very conservative. In this paper, we introduce an alternative SGoF-type procedure that takes into account the discreteness of the test statistics. Like the original SGoF, our new method provides weak control of the false discovery rate/familywise error rate but attains false discovery rate levels closer to the desired nominal level, and thus it is more powerful. We study the performance of this method in a simulation study and illustrate its application to a real pharmacovigilance data set.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Beta-binomial sequential goodness-of-fit (or BB-SGoF) method for multiple testing has been recently proposed as a suitable modification of the sequential goodness-of-fit (SGoF) multiple testing ...method when the tests are correlated in blocks. In this paper we investigate for the first time the power, the FDR and the conservativeness of BB-SGoF in an intensive Monte Carlo simulation study. Important features such as automatic selection of the number of existing blocks and preliminary testing for independence are explored. Our study reveals that (a) BB-SGoF method roughly maintains the properties of original SGoF in the dependent case, reporting a small value for the probability that the number of false positives exceeds the number of false negatives with
p
value below
γ
; (b) BB-SGoF weakly controls for FDR even when the beta-binomial model is violated and the number of blocks
k
is unknown; and that (c) the loss of power of the automatic selector for the number of blocks relative to the benchmark method which uses the true
k
varies depending on the proportion and the type (strong, intermediate or weak) of the effects, being strongly influenced by the within-block correlation too.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Many annelids can regenerate missing body parts or reproduce asexually, generating all cell types in adult stages. However, the putative adult stem cell populations involved in these processes, and ...the diversity of cell types generated by them, are still unknown. To address this, we recover 75,218 single cell transcriptomes of the highly regenerative and asexually-reproducing annelid Pristina leidyi. Our results uncover a rich cell type diversity including annelid specific types as well as novel types. Moreover, we characterise transcription factors and gene networks that are expressed specifically in these populations. Finally, we uncover a broadly abundant cluster of putative stem cells with a pluripotent signature. This population expresses well-known stem cell markers such as vasa, piwi and nanos homologues, but also shows heterogeneous expression of differentiated cell markers and their transcription factors. We find conserved expression of pluripotency regulators, including multiple chromatin remodelling and epigenetic factors, in piwi+ cells. Finally, lineage reconstruction analyses reveal computational differentiation trajectories from piwi+ cells to diverse adult types. Our data reveal the cell type diversity of adult annelids by single cell transcriptomics and suggest that a piwi+ cell population with a pluripotent stem cell signature is associated with adult cell type differentiation.
Naїve CD4
T cells, which suffer different polarizing signals during T cell receptor activation, are responsible for an adequate immune response. In this study, we aimed to evaluate the behavior of ...human CD4
CD45RA
T cells after in vitro activation by anti-CD3/CD28 bead stimulation for 14 days. We also wanted to check the role of the VIP system during this process. The metabolic biomarker Glut1 was increased, pointing to an increase in glucose requirement whereas Hif-1α expression was higher in resting than in activated cells. Expression of Th1 markers increased at the beginning of activation, whereas Th17-associated biomarkers augmented after that, showing a pathogenic Th17 profile with a possible plasticity to Th17/1. Foxp3 mRNA expression augmented from day 4, but no parallel increases were observed in IL-10, IL-2, or TGFβ mRNA expression, meaning that these potential differentiated Treg could not be functional. Both VIP receptors were located on the plasma membrane, and expression of VPAC
receptor increased significantly with respect to the VPAC
receptor from day 4 of CD4
CD45RA
T activation, pointing to a shift in VPAC receptors. VIP decreased IFNγ and IL-23R expression during the activation, suggesting a feasible modulation of Th17/1 plasticity and Th17 stabilization through both VPAC receptors. These novel results show that, without polarizing conditions, CD4
CD45RA
T cells differentiate mainly to a pathogenic Th17 subset and an unpaired Treg subset after several days of activation. Moreover, they confirm the important immunomodulatory role of VIP, also on naїve Th cells, stressing the importance of this neuropeptide on lymphocyte responses in different pathological or non-pathological situations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in ...high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).
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