Mouse antibody of IgM class is prone to non-enzymatic cleavage between CH1 and CH2 domains

Abstract IgM is a multivalent antibody which evolved as a first line defense of adaptive immunity. It consists of heavy and light chains assembled into a complex oligomer. In mouse serum there are two forms of IgM, a full-length and a truncated one. The latter contains μ’ chain, which lacks a variable region. Although μ’ chain was discovered many years ago, its origin has not yet been elucidated. Our results indicate that μ’ chain is generated from a full-length heavy chain by non-enzymatic cleavage of the protein backbone. The cleavage occurred specifically after Asn209 and is prevented by mutating this residue into any other amino acid. The process requires the presence of other proteins, preferentially with an acidic isoelectric point, and is facilitated by neutral or alkaline pH. This unique characteristic of the investigated phenomenon distinguishes it from other, already described, Asn-dependent protein reactions. A single IgM molecule is able to bind up to 12 epitopes via its antigen binding fragments (Fabs). The cleavage at Asn209 generates truncated IgM molecules and free Fabs, resulting in a reduced IgM valence and probably affecting IgM functionality in vivo

Simvastatin After Orthotopic Heart Transplantation: Costs and Consequences

Objective: Recent data indicate that the combination of a low cholesterol diet and simvastatin following heart transplantation is associated with significant reduction of serum cholesterol levels, lower incidence of graft vessel disease (GVD) and significantly superior 4-year survival rates than dietary treatment alone. On the basis of this first randomised long term study evaluating survival as the clinical end-point, we investigated the cost effectiveness of the above regimens as well as the long term consequences for the patient and for heart transplantation as a high-tech procedure. Design and setting: The perspective of the economic analysis was that of the German health insurance fund. Life-years gained were calculated on the basis of the Kaplan-Meier survival curves from the 4-year clinical trial and from the International Society for Heart and Lung Transplantation (ISHLT) overall survival statistics. Incremental costs and incremental cost-effectiveness ratios were determined using various sources of data, and both costs and consequences were discounted by 3% per year. Sensitivity analyses using alternative assumptions were conducted in addition to the base-case analysis. Patients and participants: As in the original clinical trial, the target population of the economic evaluation comprised all heart transplant recipients on standard triple immunosuppression consisting of cyclosporin, azathioprine and prednisolone, regardless of the postoperative serum lipid profile. Interventions: The therapeutic regimens investigated in the analysis were the American Heart Association (AHA) step II diet plus simvastatin (titrated to a maximum dosage of 20 mg/day) and AHA step II diet alone. Main outcome measures and results: Four years of treatment with simvastatin (mean dosage 8.11 mg/day) translated into an undiscounted survival benefit per patient of 2.27 life-years; 0.64 life-years within the trial period and 1.63 life-years thereafter. Discounted costs per year of life gained were $US1050 (sensitivity analyses$US800 to $US15 400) for simvastatin plus diet versus diet alone and$US18 010 (sensitivity analyses $US17 130 to$US21 090) for heart transplantation plus simvastatin versus no transplantation (all costs reflect 1997 values; $US1 = 1.747 Deutschmarks). Conclusions: Prevention of GVD with simvastatin after heart transplantation was cost effective in all the scenarios examined with impressive prolongation of life expectancy for the heart recipient. Simvastatin also achieved an internationally robust 21% improvement in the cost effectiveness of heart transplantation compared with historical cost-effectiveness data.Pharmacoeconomics, Simvastatin, Cost-effectiveness, Coronary-disorders, Hypercholesterolaemia, Randomised-controlled-trials, Heart-transplant, HMG-CoA-reductase-inhibitors, Graft-versus-host-disorders, Mortality

Additional file 1 of Study protocol of the OrkA project: orofacial and communicative activation in old age– a cluster randomized prevention study in long-term care facilities in Lower Saxony, Germany

Supplementary Material

SANS contrast matching for the unambiguous localization of anionic dye in cationic surfactant micelles

Müller W, Schweins R, Nöcker B, Egold H, Hannappel Y, Huber K. SANS contrast matching for the unambiguous localization of anionic dye in cationic surfactant micelles. Nanoscale Advances. 2023;5(19):5367-5384.Contrast variation in small-angle neutron scattering (SANS) was successfully applied to localize the anionic azo dye Blue in co-assemblies with the cationic surfactant dodecyltrimethylammoniumbromide (DTAB). For this purpose, the scattering contrast between DTAB and the aqueous solvent was eliminated by SANS contrast matching, leaving only the scattering signal from Blue to be detected. Results obtained by contrast matching were confirmed by NOESY NMR-spectroscopy, showing that Blue interacts with the positively charged DTAB head groups and with up to the 4th neighbouring methylene group of the DTAB C12-alkyl chain. Its localization in the outer layer of the Blue-DTAB co-assembly explains the uniaxial growth of spheroidal DTAB micelles to wormlike micelles with increasing [Blue] : [DTAB] ratio from 0 : 1 to 1 : 3. This is in line with the concept of the packing parameter for amphiphilic substances. The complementary use of SANS contrast matching and NMR-spectroscopy permits the unambiguous localization of an anionic dye in dodecyl trimethyl-ammonium bromide micelles

Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior

Growth differentiation factor 15 (GDF15) is a mitochondrial stress-induced cytokine that modulates energy balance in an endocrine manner. However, the importance of its brainstem-restricted receptor GDNF family receptor alpha-like (GFRAL) to mediate endocrine GDF15 signaling to the brain upon mitochondrial dysfunction is still unknown. Using a mouse model with muscle-specific mitochondrial dysfunction, we here show that GFRAL is required for activation of systemic energy metabolism via daytime-restricted anorexia but not responsible for muscle wasting. We further find that muscle mitochondrial stress response involves a GFRAL-dependent induction of hypothalamic corticotropin-releasing hormone, without elevated corticosterone levels. Finally, we identify that GFRAL signaling governs an anxiety-like behavior in male mice with muscle mitochondrial dysfunction, with females showing a less robust GFRAL-dependent anxiety-like phenotype. Together, we here provide novel evidence of a mitochondrial stress-induced muscle–brain crosstalk via the GDF15-GFRAL axis to modulate food intake and anxiogenic behavior

Two Cases of Severe Tick-Borne Encephalitis in Rituximab-Treated Patients in Germany: Implications for Diagnosis and Prevention

Rituximab (RTX) has become a standard therapy for certain B cell malignancies and autoimmune diseases. We report 2 RTX-treated patients who developed severe tick-borne encephalitis virus (TBEV) infection. The inability to generate new antibody responses renders RTX-treated patients susceptible to TBEV, impedes laboratory diagnosis, and necessitates preventive vaccination in endemic areas

Impact of Additive Hydrophilicity on Mixed Dye-Nonionic Surfactant Micelles: Micelle Morphology and Dye Localization

The nonionic surfactant pentaethylene glycol-monododecylether C12E5 forms micelles in aqueous solutions with a lower critical solution temperature. This characteristic solution behavior of C12E5 is independent of the pH. Such micelles are used to solubilize a large variety of active guest molecules like for instance dyestuffs. An example is an acidic azo dye termed Blue used as a hair colorant. Depending on the pH, Blue gradually changes its hydrophilicity from the protonated BlueH at pH = 2 to the bivalent anion Blue2– at pH = 13 while keeping the shape and size of Blue essentially unchanged. These features of C12E5 and Blue offer the unique chance to investigate the sole impact of a tunable hydrophilicity of a guest molecule on the solution behavior of mixed micelles of the guest and C12E5. Accordingly, the present work establishes a phase diagram of Blue-C12E5 micelles and analyzes their morphology including the spatial distribution of Blue in the micelles as a function of the hydrophilicity of Blue. Small angle neutron scattering reveals the size and shape of the micelles, and detailed contrast matching of the C12E5 supported by 1H NMR with NOESY provided insight into the localization of Blue within the micelles as its hydrophilicity changes