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Institute
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
First measurement of 𝚲+c production down to 𝑝T = 0 in pp and p–Pb collisions at √𝑠NN = 5.02 TeV
(2023)
The production of prompt Λ+c baryons has been measured at midrapidity in the transverse momentum interval 0<pT<1 GeV/c for the first time, in pp and p-Pb collisions at a centre-of-mass energy per nucleon-nucleon collision sNN−−−√=5.02 TeV. The measurement was performed in the decay channel Λ+c→pK0S by applying new decay reconstruction techniques using a Kalman-Filter vertexing algorithm and adopting a machine-learning approach for the candidate selection. The pT-integrated Λ+c production cross sections in both collision systems were determined and used along with the measured yields in Pb-Pb collisions to compute the pT-integrated nuclear modification factors RpPb and RAA of Λ+c baryons, which are compared to model calculations that consider nuclear modification of the parton distribution functions. The Λ+c/D0 baryon-to-meson yield ratio is reported for pp and p-Pb collisions. Comparisons with models that include modified hadronisation processes are presented, and the implications of the results on the understanding of charm hadronisation in hadronic collisions are discussed. A significant (3.7σ) modification of the mean transverse momentum of Λ+c baryons is seen in p-Pb collisions with respect to pp collisions, while the pT-integrated Λ+c/D0 yield ratio was found to be consistent between the two collision systems within the uncertainties.
First measurement of Λ+c production down to pT = 0 in pp and p-Pb collisions at √𝑠NN = 5.02 TeV
(2023)
The production of prompt +c baryons has been measured at midrapidity in the transverse momentum interval 0 < pT < 1 GeV/c for the first time, in pp and p–Pb collisions at a center-of-mass energy per nucleon-nucleon collision √sNN = 5.02 TeV. The measurement was performed in the decay channel +c → pK0S by applying new decay reconstruction techniques using a Kalman-Filter vertexing algorithm and adopting a machine-learning approach for the candidate selection. The pT -integrated +c production cross sections in both collision systems were determined and used along with the measured yields in Pb–Pb collisions to compute the pT -integrated nuclear modification factors RpPb and RAA of +c baryons, which are compared to model calculations that consider nuclear modification of the parton distribution functions. The +c /D0 baryon-to-meson yield ratio is reported for pp and p–Pb collisions. Comparisons with models that include modified hadronization processes are presented, and the implications of the results on the understanding of charm hadronization in hadronic collisions are discussed. A significant (3.7σ) modification of the mean transverse momentum of + c baryons is seen in p–Pb collisions with respect to pp collisions, while the pT -integrated +c /D0 yield ratio was found to be consistent between the two collision systems within the uncertainties.
First measurement of 𝚲+c production down to 𝑝T = 0 in pp and p–Pb collisions at √𝑠NN = 5.02 TeV
(2023)
The production of prompt Λ+c baryons has been measured at midrapidity in the transverse momentum interval 0<pT<1 GeV/c for the first time, in pp and p-Pb collisions at a centre-of-mass energy per nucleon-nucleon collision sNN−−−√=5.02 TeV. The measurement was performed in the decay channel Λ+c→pK0S by applying new decay reconstruction techniques using a Kalman-Filter vertexing algorithm and adopting a machine-learning approach for the candidate selection. The pT-integrated Λ+c production cross sections in both collision systems were determined and used along with the measured yields in Pb-Pb collisions to compute the pT-integrated nuclear modification factors RpPb and RAA of Λ+c baryons, which are compared to model calculations that consider nuclear modification of the parton distribution functions. The Λ+c/D0 baryon-to-meson yield ratio is reported for pp and p-Pb collisions. Comparisons with models that include modified hadronisation processes are presented, and the implications of the results on the understanding of charm hadronisation in hadronic collisions are discussed. A significant (3.7σ) modification of the mean transverse momentum of Λ+c baryons is seen in p-Pb collisions with respect to pp collisions, while the pT-integrated Λ+c/D0 yield ratio was found to be consistent between the two collision systems within the uncertainties.
The insertion of membrane proteins requires proteinaceous complexes in the cytoplasm, the membrane, and the lumen of organelles. Most of the required complexes have been described, while the components for insertion of β‐barrel‐type proteins into the outer membrane of chloroplasts remain unknown. The same holds true for the signals required for the insertion of β‐barrel‐type proteins. At present, only the processing of Toc75‐III, the β‐barrel‐type protein of the central chloroplast translocon with an atypical signal, has been explored in detail. However, it has been debated whether Toc75‐V/ outer envelope protein 80 (OEP80), a second protein of the same family, contains a signal and undergoes processing. To substantiate the hypothesis that Toc75‐V/OEP80 is processed as well, we reinvestigated the processing in a protoplast‐based assay as well as in native membranes. Our results confirm the existence of a cleavable segment. By protease protection and pegylation, we observed intermembrane space localization of the soluble N‐terminal domain. Thus, Toc75‐V contains a cleavable N‐terminal signal and exposes its polypeptide transport‐associated domains to the intermembrane space of plastids, where it likely interacts with its substrates.
Improved risk stratification in prevention by use of a panel of selected circulating microRNAs
(2017)
Risk stratification is crucial in prevention. Circulating microRNAs have been proposed as biomarkers in cardiovascular disease. Here a miR panel consisting of miRs related to different cardiovascular pathophysiologies, was evaluated to predict outcome in the context of prevention. MiR-34a, miR-223, miR-378, miR-499 and miR-133 were determined from peripheral blood by qPCR and combined to a risk panel. As derivation cohort, 178 individuals of the DETECT study, and as validation cohort, 129 individuals of the SHIP study were used in a case-control approach. Overall mortality and cardiovascular events were outcome measures. The Framingham Risk Score(FRS) and the SCORE system were applied as risk classification systems. The identified miR panel was significantly associated with mortality given by a hazard ratio(HR) of 3.0 (95% (CI): 1.09–8.43; p = 0.034) and of 2.9 (95% CI: 1.32–6.33; p = 0.008) after adjusting for the FRS in the derivation cohort. In a validation cohort the miR-panel had a HR of 1.31 (95% CI: 1.03–1.66; p = 0.03) and of 1.29 (95% CI: 1.02–1.64; p = 0.03) in a FRS/SCORE adjusted-model. A FRS/SCORE risk model was significantly improved to predict mortality by the miR panel with continuous net reclassification index of 0.42/0.49 (p = 0.014/0.005). The present miR panel of 5 circulating miRs is able to improve risk stratification in prevention with respect to mortality beyond the FRS or SCORE.
The metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion.
Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.
Background: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, Major Depressive Disorder (MDD), patients only marginally differ from healthy individuals on the group-level. Whether Precision Psychiatry can solve this discrepancy and provide specific, reliable biomarkers remains unclear as current Machine Learning (ML) studies suffer from shortcomings pertaining to methods and data, which lead to substantial over-as well as underestimation of true model accuracy.
Methods: Addressing these issues, we quantify classification accuracy on a single-subject level in N=1,801 patients with MDD and healthy controls employing an extensive multivariate approach across a comprehensive range of neuroimaging modalities in a well-curated cohort, including structural and functional Magnetic Resonance Imaging, Diffusion Tensor Imaging as well as a polygenic risk score for depression.
Findings Training and testing a total of 2.4 million ML models, we find accuracies for diagnostic classification between 48.1% and 62.0%. Multimodal data integration of all neuroimaging modalities does not improve model performance. Similarly, training ML models on individuals stratified based on age, sex, or remission status does not lead to better classification. Even under simulated conditions of perfect reliability, performance does not substantially improve. Importantly, model error analysis identifies symptom severity as one potential target for MDD subgroup identification.
Interpretation: Although multivariate neuroimaging markers increase predictive power compared to univariate analyses, single-subject classification – even under conditions of extensive, best-practice Machine Learning optimization in a large, harmonized sample of patients diagnosed using state-of-the-art clinical assessments – does not reach clinically relevant performance. Based on this evidence, we sketch a course of action for Precision Psychiatry and future MDD biomarker research.