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Abstract
Background
Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice.
Methods
IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology.
Results
IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, (P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening (P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells (P = 0.0002) and macrophages (P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells (P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages (P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps (P ≤ 0.002 in all).
Conclusions
The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. The data call for a clinical trial with IgG in DMD.
Abstract
Biocatalysis has found numerous applications in various fields as an alternative to chemical catalysis. The use of enzymes in organic synthesis, especially to make chiral compounds for pharmaceuticals as well for the flavors and fragrance industry, are the most prominent examples. In addition, biocatalysts are used on a large scale to make specialty and even bulk chemicals. This review intends to give illustrative examples in this field with a special focus on scalable chemical production using enzymes. It also discusses the opportunities and limitations of enzymatic syntheses using distinct examples and provides an outlook on emerging enzyme classes.
Abstract
Background
Heparin induced thrombocytopenia (HIT) is likely a misdirected bacterial host defense mechanism. Platelet factor 4 (PF4) binds to polyanions on bacterial surfaces exposing neo‐epitopes to which HIT antibodies bind. Platelets are activated by the resulting immune complexes via FcγRIIA, release bactericidal substances, and kill Gram‐negative Escherichia coli.
Objectives
To assess the role of PF4, anti‐PF4/H antibodies and FcγRIIa in killing of Gram‐positive bacteria by platelets.
Methods
Binding of PF4 to protein‐A deficient Staphylococcus aureus (SA113Δspa) and non‐encapsulated Streptococcus pneumoniae (D39Δcps) and its conformational change were assessed by flow cytometry using monoclonal (KKO,5B9) and patient derived anti‐PF4/H antibodies. Killing of bacteria was quantified by counting colony forming units (cfu) after incubation with platelets or platelet releasate. Using flow cytometry, platelet activation (CD62P‐expression, PAC‐1 binding) and phosphatidylserine (PS)‐exposure were analyzed.
Results
Monoclonal and patient‐derived anti‐PF4/H antibodies bound in the presence of PF4 to both S. aureus and S. pneumoniae (1.6‐fold increased fluorescence signal for human anti‐PF4/H antibodies to 24.0‐fold increase for KKO). Staphylococcus aureus (5.5 × 104cfu/mL) was efficiently killed by platelets (2.7 × 104cfu/mL) or their releasate (2.9 × 104cfu/mL). Killing was not further enhanced by PF4 or anti‐PF4/H antibodies. Blocking FcγRIIa had no impact on killing of S. aureus by platelets. In contrast, S. pneumoniae was not killed by platelets or releasate. Instead, after incubation with pneumococci platelets were unresponsive to TRAP‐6 stimulation and exposed high levels of PS.
Conclusions
Anti‐PF4/H antibodies seem to have only a minor role for direct killing of Gram‐positive bacteria by platelets. Staphylococcus aureus is killed by platelets or platelet releasate. In contrast, S. pneumoniae affects platelet viability.
Abstract
Higher biodiversity can stabilize the productivity and functioning of grassland communities when subjected to extreme climatic events. The positive biodiversity–stability relationship emerges via increased resistance and/or recovery to these events. However, invader presence might disrupt this diversity–stability relationship by altering biotic interactions. Investigating such disruptions is important given that invasion by non‐native species and extreme climatic events are expected to increase in the future due to anthropogenic pressure. Here we present one of the first multisite invader × biodiversity × drought manipulation experiment to examine combined effects of biodiversity and invasion on drought resistance and recovery at three semi‐natural grassland sites across Europe. The stability of biomass production to an extreme drought manipulation (100% rainfall reduction; BE: 88 days, BG: 85 days, DE: 76 days) was quantified in field mesocosms with a richness gradient of 1, 3, and 6 species and three invasion treatments (no invader, Lupinus polyphyllus, Senecio inaequidens). Our results suggest that biodiversity stabilized community productivity by increasing the ability of native species to recover from extreme drought events. However, invader presence turned the positive and stabilizing effects of diversity on native species recovery into a neutral relationship. This effect was independent of the two invader's own capacity to recover from an extreme drought event. In summary, we found that invader presence may disrupt how native community interactions lead to stability of ecosystems in response to extreme climatic events. Consequently, the interaction of three global change drivers, climate extremes, diversity decline, and invasive species, may exacerbate their effects on ecosystem functioning.
Abstract
Peatlands are lands with a peat layer at the surface, containing a large proportion of organic carbon. Such lands cover ≈1 000 000 km2 in Europe, which is almost 10% of the total surface area. In many countries, peatlands have been artificially drained over centuries, leading to not only enormous emissions of CO2 but also soil subsidence, mobilization of nutrients, higher flood risks, and loss of biodiversity. These problems can largely be solved by stopping drainage and rewetting the land. Wet peatlands do not release CO2, can potentially sequester carbon, help to improve water quality, provide habitat for rare and threatened biodiversity, and can still be used for production of biomass (“paludiculture”). Wisely adjusted land use on peatlands can substantially contribute to low‐emission goals and further benefits for farmers, the economy, society, and the environment.
Abstract
Methylation of free hydroxyl groups is an important modification for flavonoids. It not only greatly increases absorption and oral bioavailability of flavonoids, but also brings new biological activities. Flavonoid methylation is usually achieved by a specific group of plant O‐methyltransferases (OMTs) which typically exhibit high substrate specificity. Here we investigated the effect of several residues in the binding pocket of the Clarkia breweri isoeugenol OMT on the substrate scope and regioselectivity against flavonoids. The mutation T133M, identified as reported in our previous publication, increased the activity of the enzyme against several flavonoids, namely eriodictyol, naringenin, luteolin, quercetin and even the isoflavonoid genistein, while a reduced set of amino acids at positions 322 and 326 affected both, the activity and the regioselectivity of the methyltranferase. On the basis of this work, methylated flavonoids that are rare in nature were produced in high purity.
Summary
This study aimed to establish a robust and reliable metaproteomics protocol for an in‐depth characterization of marine particle‐associated (PA) bacteria. To this end, we compared six well‐established protein extraction protocols together with different MS‐sample preparation techniques using particles sampled during a North Sea spring algae bloom in 2009. In the final optimized workflow, proteins are extracted using a combination of SDS‐containing lysis buffer and cell disruption by bead‐beating, separated by SDS‐PAGE, in‐gel digested and analysed by LC–MS/MS, before MASCOT search against a metagenome‐based database and data processing/visualization with the in‐house‐developed bioinformatics tools Prophane and Paver. As an application example, free‐living (FL) and particulate communities sampled in April 2009 were analysed, resulting in an as yet unprecedented number of 9354 and 5034 identified protein groups for FL and PA bacteria, respectively. Our data suggest that FL and PA communities appeared similar in their taxonomic distribution, with notable exceptions: eukaryotic proteins and proteins assigned to Flavobacteriia, Cyanobacteria, and some proteobacterial genera were found more abundant on particles, whilst overall proteins belonging to Proteobacteria were more dominant in the FL fraction. Furthermore, our data points to functional differences including proteins involved in polysaccharide degradation, sugar‐ and phosphorus uptake, adhesion, motility, and stress response.
Abstract
Background
Identifying predictors for general cognitive training (GCT) success in healthy older adults has many potential uses, including aiding intervention and improving individual dementia risk prediction, which are of high importance in health care. However, the factors that predict training improvements and the temporal course of predictors (eg, do the same prognostic factors predict training success after a short training period, such as 6 weeks, as well as after a longer training period, such as 6 months?) are largely unknown.
Methods
Data (N = 4,184 healthy older individuals) from two arms (GCT vs. control) of a three‐arm randomized controlled trial were reanalyzed to investigate predictors of GCT success in five cognitive tasks (grammatical reasoning, spatial working memory, digit vigilance, paired association learning, and verbal learning) at three time points (after 6 weeks, 3 months, and 6 months of training). Possible investigated predictors were sociodemographic variables, depressive symptoms, number of training sessions, cognitive baseline values, and all interaction terms (group*predictor).
Results
Being female was predictive for improvement in grammatical reasoning at 6 weeks in the GCT group, and lower cognitive baseline scores were predictive for improvement in spatial working memory and verbal learning at 6 months.
Conclusion
Our data indicate that predictors seem to change over time; remarkably, lower baseline performance at study entry is only a significant predictor at 6 months training. Possible reasons for these results are discussed in relation to the compensation hypothesis. J Am Geriatr Soc 68:‐, 2020.
Abstract
Background
Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the abilities to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparin‐induced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6‐, 8‐, 10‐, and 12‐mer size and a hypersulfated 12‐mer (S12‐mer).
Methods
We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and anti‐PF4/heparin antibodies.
Results
The synthetic heparin‐like compounds display stronger binding characteristics to PF4 than animal‐derived heparins of corresponding lengths. Upon complexation with PF4, 6‐mer and S12‐mer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8‐, 10‐, and 12‐mer heparins. Anti‐PF4/heparin antibodies bind more weakly to complexes formed between PF4 and heparins ≤ 8‐mer than with complexes formed between PF4 and heparins ≥ 10‐mer. Addition of one sulfate group to the 12‐mer resulted in a S12‐mer, which showed substantial changes in its binding characteristics to PF4.
Conclusions
We provide a template for characterizing interactions of newly developed heparin‐based anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity.
Abstract
This work presents a stepwise reversible two‐electron transfer induced hydrogen shift leading to the conversion of a bis‐pyrrolinium cation to an E‐diaminoalkene and vice versa. Remarkably, the forward and the reverse reaction, which are both reversible, follow two completely different reaction pathways. Establishing such unprecedented property in this type of processes was possible by developing a novel synthetic route towards the starting dication. All intermediates involved in both the forward and the backward reactions were comprehensively characterized by a combination of spectroscopic, crystallographic, electrochemical, spectroelectrochemical, and theoretical methods. The presented synthetic route opens up new possibilities for the generation of multi‐pyrrolinium cation scaffold‐based organic redox systems, which constitute decidedly sought‐after molecules in contemporary chemistry.