Quantum simulation of the spin-boson model with a microwave circuit

We consider superconducting circuits for the purpose of simulating the spin-boson model. The spin-boson model consists of a single two-level system coupled to bosonic modes. In most cases, the model is considered in a limit where the bosonic modes are sufficiently dense to form a continuous spectral bath. A very well known case is the ohmic bath, where the density of states grows linearly with the frequency. In the limit of weak coupling or large temperature, this problem can be solved numerically. If the coupling is strong, the bosonic modes can become sufficiently excited to make a classical simulation impossible. Here, we discuss how a quantum simulation of this problem can be performed by coupling a superconducting qubit to a set of microwave resonators. We demonstrate a possible implementation of a continuous spectral bath with individual bath resonators coupling strongly to the qubit. Applying a microwave drive scheme potentially allows us to access the strong-coupling regime of the spin-boson model. We discuss how the resulting spin relaxation dynamics with different initialization conditions can be probed by standard qubit-readout techniques from circuit quantum electrodynamics.Comment: 23 pages, 10 figure

Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

The GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter-and intracellular signaling in autoimmune disease

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen alpha 3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3(CTT) mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3(CTT) mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3(CTT) mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control

Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6~months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6~months to 2.99~years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5~mg with dose escalation to 67.5~mg) or placebo for 12~months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.)

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study.

BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS: In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This work was also supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. K.S. is supported by Qatar National Research Fund (QNRF) grant no. NPRPC11-0115-180010. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology NTNU), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. The HUNT part of the project re-used protein data that was originally analysed and paid for by Somalogic Inc, CO, USA. Somalogic had no role in the design and conduct of the study; collection of phenotypic data, statistical analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Professor John Danesh is funded by the National Institute for Health Research [Senior Investigator Award]. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. RNA-sequencing experiments and kidney gene expression studies were supported by British Heart Foundation project grants [PG/17/35/33001 and PG/19/16/34270] and Kidney Research UK grants [ RP_017_20180302 and RP_013_20190305] to M.T. The German Diabetes Center is funded by the German Federal Ministry of Health (Berlin, Germany), the Ministry of Culture and Science of the state North Rhine-Westphalia (Düsseldorf, Germany), and grants from the German Federal Ministry of Education and Research (Berlin, Germany) to the German Center for Diabetes Research e.V. (DZD)

Bacterial expression of hantavirus genes

Hantaviren sind infektiöse Ursache des Hämorrhagischen Fiebers mit renalem Syndrom (HFRS), des Hanta Pulmonary Syndrome (HPS)und der Nephropathia epidemica (NE). Das hantavirale N-Protein (Nukleokapsidprotein), codiert durch das S-Segment, stellt sich als dabei als antigenetisches Hauptziel der humoralen Immunantwort dar. In der vorliegenden Arbeit wurde nach Anzucht der beiden Hantavirusstämme Puumala und Dobrava RNA des S-Segments extrahiert und durch RT-PCR in cDNA umgeschrieben und vervielfältigt. Die cDNA wurde anschließend in den pCR2.1-TOPO-Vektor (Fa. Invitrogen)kloniert und nachfolgend in den pRSETB Vektor (Fa. Invitrogen) umkloniert. Die beiden rekombinanten Plasmide pRSETBPuumalaN und pRSETBDobravaN wurden zur bakteriellen Expression der hantaviralen N-Proteine in kompetente Zellen gegeben. Nach Aufreinigung wurden die N-Proteine zur Antikörperproduktion durch Injektion in Kaninchen verbracht. Die dadurch erhaltenen polyklonalen Antikörper anti-PuumalaN-AK und anti-DobravaN-AK stehen für weitere Untersuchungen und Hantavirusforschung als molekulare Werkzeuge zu Verfügung.Hantavirus is infectious cause for hemorrhagic fever with renal syndrome (HFRS), for the hanta pulmonary syndrome (HPS) and for nephropathia epidemica (NE).Hantaviral N-protein (nucleocapsidprotein) is the immunogen major topic for the humoral immune reaction. After culture of the hantavirus subtypes Puumala and Dobrava we extracted the viral RNA of the s-segment. By RT-PCR we received cDNA. The cDNA was cloned into the pCR2.1-TOPO-vector (firm Invitrogen) and after this we cloned the cDNA into the pRSETB-vector (Invitrogen). As the result we generated the two recombinat plasmides pRSETBPuumalaN and pRSETBDobravaN. For bacterial expression of the hantaviral N-proteins we transfered the both recombinant plasmids into competent bacterial cells. After up-clean the received N-proteins we injected them into rabbits and got after immunisation the polyclonal antibodies anti-PuumalaN and anti-DobravaN. This polyclonal antibodies against the hantaviral N-protein can be now used for further workings and molecular tools in hantavirus researches

Dermatomal laser-evoked potentials : a diagnostic approach to the dorsal root ; norm data in healthy volunteers and changes in patients with radiculopathy

PeerReviewe

Plasma agouti-related protein concentrations are decreased in individuals with impaired awareness of hypoglycaemia

Background and aims: Individuals with type 1 diabetes may develop impaired awareness of hypoglycaemia (IAH). This is a complication characterized by a reduction or loss of hypoglycaemic symptoms. Adaptations in the central and/or damage in the peripheral nervous system likely contribute to the pathophysiology of IAH. In this study, a non-hypothesis driven proteomics analysis approach was used to investigate any potential pathophysiological pathways in IAH.Materials and methods: A nested-case control study was conducted using individuals participating in the Dutch Type 1 Diabetes Biomarker study. Individuals of Western European descent were included if they had completed the Dutch Clarke questionnaire and had a diabetes duration of greater than 10 years. Exclusion criteria was the presence of clinical cardiovascular disease. Targeted proteomics analysis was conducted using the Olink® target 96 Cardiovascular II panel (Uppsala, Sweden). Individuals with IAH were compared to age- and sex-matched controls. Statistical analyses were conducted using the OlinkAnalyze package in R. Differential expression of normalised protein expression (NPX) were statistically assessed with t-tests for univariate analyses and using linear regression in multivariate analyses.Results: The plasma protein from 67 individuals with IAH were compared to 108 individuals without IAH. Median age and diabetes duration were 44 years and 23 years, respectively. Mean HbA1c was 60mmol/mol (7.6%). In total, 162 samples and 92 proteins passed quality control and were analysed. In the univariate analysis, agouti-related peptide (AGRP) concentration was significantly lower in the IAH vs controls (6.12 NPX vs 6.44 NPX, FDR adjusted P = 0.013). In multivariate models adjusted for sex and diabetes duration, AGRP remained significant before p-value adjustment (p=0.000697), however, was not significant when adjusted for FDR.Conclusion: AGRP is secreted in the arcuate nucleus and the adrenal gland. In addition to the orexigenic effects, AGRP plays a role in hypothalamic pituitary adrenal (HPA) axis stimulation. AGRP secreting neurons in the arcuate nucleus can stimulate the HPA-axis through the paraventricular hypothalamus (PVH). Previous studies have hypothesized that glucose-sensing neurons are present in the PVH and ARC, which may further establish the importance of this pathway in the pathophysiology of IAH.Supported by: JDRF, DFN, FoDFDisclosure: R. Varkevisser: Grants; Juvenile DIabetes Research Foundation, DiabetesFonds NL, Friends of Diabeter Foundation