The biotechnology industry has become a key element in modern societies. Within this industry, the production of recombinant enzymes and biopharmaceutical proteins is of major importance. The global ...markets for such recombinant proteins are growing rapidly and, accordingly, there is a continuous need for new production platforms that can deliver protein products in greater yields, with higher quality and at lower costs. This calls for the development of next-generation super-secreting cell factories. One of the microbial cell factories that can meet these challenges is the Gram-positive bacterium Bacillus subtilis, an inhabitant of the upper layers of the soil that has the capacity to secrete proteins in the gram per litre range. The engineering of B. subtilis into a next-generation super-secreting cell factory requires combined Systems and Synthetic Biology approaches. In this way, the bacterial protein secretion machinery can be optimized from the single molecule to the network level while, at the same time, taking into account the balanced use of cellular resources. Although highly ambitious, this is an achievable objective due to recent advances in functional genomics and Systems- and Synthetic Biological analyses of B. subtilis cells.
Background A substantial subgroup of asthmatic patients have “nonallergic” or idiopathic asthma, which often takes a severe course and is difficult to treat. The cause might be allergic reactions to ...the gram-positive pathogen Staphylococcus aureus , a frequent colonizer of the upper airways. However, the driving allergens of S aureus have remained elusive. Objective We sought to search for potentially allergenic S aureus proteins and characterize the immune response directed against them. Methods S aureus extracellular proteins targeted by human serum IgG4 were identified by means of immunoblotting to screen for potential bacterial allergens. Candidate antigens were expressed as recombinant proteins and used to analyze the established cellular and humoral immune responses in healthy adults and asthmatic patients. The ability to induce a type 2 immune response in vivo was tested in a mouse asthma model. Results We identified staphylococcal serine protease–like proteins (Spls) as dominant IgG4 -binding S aureus proteins. SplA through SplF are extracellular proteases of unknown function expressed by S aureus in vivo . Spls elicited IgE antibody responses in most asthmatic patients. In healthy S aureus carriers and noncarriers, peripheral blood T cells elaborated TH 2 cytokines after stimulation with Spls, as is typical for allergens. In contrast, TH 1/TH 17 cytokines, which dominated the response to S aureus α-hemolysin, were of low concentration or absent. In mice inhalation of SplD without adjuvant induced lung inflammation characterized by TH 2 cytokines and eosinophil infiltration. Conclusion We identify Spls as triggering allergens released by S aureus , opening prospects for diagnosis and causal therapy of asthma.
Polypharmacy is an important aspect of medication management and particularly affects elderly and chronically ill people. Patients with dementia, Parkinson's disease (PD), or multiple sclerosis (MS) ...are at high risk of multi medication due to their complex symptomatology. Our aim was to provide an overview of different definitions of polypharmacy and to present the current state of research on polypharmacy in patients with dementia, PD, or MS. The most common definition of polypharmacy in the literature is the concomitant use of ≥5 medications (quantitative definition approach). Polypharmacy rates of up to >50% have been reported for patients with dementia, PD, or MS, although MS patients are on average significantly younger than those with dementia or PD. The main predictor of polypharmacy is the complex symptom profile of these neurological disorders. Potentially inappropriate medication (PIM), drug-drug interactions, poor treatment adherence, severe disease course, cognitive impairment, hospitalisation, poor quality of life, frailty, and mortality have been associated with polypharmacy in patients with dementia, PD, or MS. For patients with polypharmacy, either the avoidance of PIM (selective deprescribing) or the substitution of PIM with more suitable drugs (appropriate polypharmacy) is recommended to achieve a more effective therapeutic management.
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Given the chronic and heterogenous nature of the disease, treatment with various therapies is a frequent scenario ...in clinical practice. In persons with chronic morbidity such as MS patients, polypharmacy can give rise to considerable health problems.
The aim of the present study was to examine the frequency of polypharmacy among relapsing-remitting (RR) MS patients as well as to analyse sociodemographic and clinical factors, which might be associated with polypharmacy (use of five or more medications). Differences in medication between MS patients with and without secondary illnesses (PwSI and Pw/oSI), between men and women and between patients with and without polypharmacy (PwP and Pw/oP) were examined.
For 145 RRMS outpatients, we prospectively collected data by means of anamnesis, patient records, clinical examination and a structured patient interview. This was followed by comparative analyses of various patient subgroups (PwP vs. Pw/oP, PwSI vs. Pw/oSI, men vs. women).
The proportion of included MS patients with polypharmacy (use of ≥5 medications) was 30.3%. PwP were significantly older than Pw/oP (45.9 vs. 41.7 years), had a lower level of education and showed a significantly higher median EDSS score (3.0 vs. 2.0). Comorbidities (p<0.001; odds ratio OR = 6.293) and higher EDSS scores (p = 0.029; OR = 1.440) were associated with a higher risk of polypharmacy. The proportion of polypharmacy among PwSI was approximately four times higher than among Pw/oSI (46.8% vs. 11.8%). Particularly in the use of antihypertensives, gastrointestinal drugs and dietary supplements, there were differences between Pw/oP and PwP.
We found a high burden of polypharmacy in patients with RRMS. This particularly applies to more severely disabled MS patients who suffer from comorbidities.
Systems biology aims to develop mathematical models of biological systems by integrating experimental and theoretical techniques. During the last decade, many systems biological approaches that base ...on genome-wide data have been developed to unravel the complexity of gene regulation. This review deals with the reconstruction of gene regulatory networks (GRNs) from experimental data through computational methods. Standard GRN inference methods primarily use gene expression data derived from microarrays. However, the incorporation of additional information from heterogeneous data sources, e.g. genome sequence and protein–DNA interaction data, clearly supports the network inference process. This review focuses on promising modelling approaches that use such diverse types of molecular biological information. In particular, approaches are discussed that enable the modelling of the dynamics of gene regulatory systems. The review provides an overview of common modelling schemes and learning algorithms and outlines current challenges in GRN modelling.
Abstract Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, usually occurring in young adults and leading to disability. Despite the progress in technology ...and intensive research work of the last years, diagnosing MS can still be challenging. A heterogenic and complex pathophysiology with various types of disease courses makes MS unique for each patient. There is an urgent need to identify markers facilitating rapid and accurate diagnosis and prognostic assessments with regard to optimal therapy for each MS patient. Cerebrospinal fluid (CSF) is an outstanding source of specific markers related to MS pathology. Molecules reflecting specific pathological processes, such as inflammation, cellular damage, and loss of blood–brain-barrier integrity, are detectable in CSF. Clinically used biomarkers of CSF are oligoclonal bands, IgG-index, measles–rubella–zoster-reaction, anti-aquaporin 4 antibodies, and antibodies against John Cunningham virus. Many other potential biomarkers have been proposed in recent years. In this review we examine the current scientific knowledge on CSF molecular markers that could guide diagnosis and discrimination of different MS forms, support treatment decisions, or be helpful in monitoring and predicting disease progression, therapy response, and complications such as opportunistic infections.
Phytoplankton blooms characterize temperate ocean margin zones in spring. We investigated the bacterioplankton response to a diatom bloom in the North Sea and observed a dynamic succession of ...populations at genus-level resolution. Taxonomically distinct expressions of carbohydrate-active enzymes (transporters; in particular, TonB-dependent transporters) and phosphate acquisition strategies were found, indicating that distinct populations of Bacteroidetes, Gammaproteobacteria, and Alphaproteobacteria are specialized for successive decomposition of algal-derived organic matter. Our results suggest that algal substrate availability provided a series of ecological niches in which specialized populations could bloom. This reveals how planktonic species, despite their seemingly homogeneous habitat, can evade extinction by direct competition.
MicroRNAs (miRNAs) have been reported to contribute to the pathophysiology of multiple sclerosis (MS), an inflammatory disorder of the central nervous system. Here, we propose a new consensus-based ...strategy to analyse and integrate miRNA and gene expression data in MS as well as other publically available data to gain a deeper understanding of the role of miRNAs in MS and to overcome the challenges posed by studies with limited patient sample sizes. We processed and analysed microarray datasets, and compared the expression of genes and miRNAs in the blood of MS patients and controls. We then used our consensus and integration approach to construct two molecular networks dysregulated in MS: a miRNA- and a gene-based network. We identified 18 differentially expressed (DE) miRNAs and 128 DE genes that may contribute to the regulatory alterations behind MS. The miRNAs were linked to immunological and neurological pathways, and we exposed let-7b-5p and miR-345-5p as promising blood-derived disease biomarkers in MS. The results suggest that DE miRNAs are more informative than DE genes in uncovering pathways potentially involved in MS. Our findings provide novel insights into the regulatory mechanisms and networks underlying MS.
One of the strongest and most noticeable responses of Bacillus subtilis cells to a range of stress and starvation stimuli is the dramatic induction of about 150 SigB-dependent general stress genes. ...The activity of SigB itself is tightly regulated by a complex signal transduction cascade with at least three main signaling pathways that respond to environmental stress, energy depletion, or low temperature. The SigB-dependent response is conserved in related gram-positive bacteria but is missing in strictly anaerobic or in some facultatively anaerobic gram-positive bacteria. It covers functions from nonspecific and multiple stress resistance to the control of virulence in pathogenic bacteria. A comprehensive understanding of this crucial stress response is essential not only for bacterial physiology but also for applied microbiology, including pathogenicity and pathogen control.
Patients with multiple sclerosis (MS) often take multiple drugs at the same time to modify the course of disease, alleviate neurological symptoms and manage co-existing conditions. A major ...consequence for a patient taking different medications is a higher risk of treatment failure and side effects. This is because a drug may alter the pharmacokinetic and/or pharmacodynamic properties of another drug, which is referred to as drug-drug interaction (DDI). We aimed to predict interactions of drugs that are used by patients with MS based on a deep neural network (DNN) using structural information as input. We further aimed to identify potential drug-food interactions (DFIs), which can affect drug efficacy and patient safety as well. We used DeepDDI, a multi-label classification model of specific DDI types, to predict changes in pharmacological effects and/or the risk of adverse drug events when two or more drugs are taken together. The original model with ~34 million trainable parameters was updated using >1 million DDIs recorded in the DrugBank database. Structure data of food components were obtained from the FooDB database. The medication plans of patients with MS (
= 627) were then searched for pairwise interactions between drug and food compounds. The updated DeepDDI model achieved accuracies of 92.2% and 92.1% on the validation and testing sets, respectively. The patients with MS used 312 different small molecule drugs as prescription or over-the-counter medications. In the medication plans, we identified 3748 DDIs in DrugBank and 13,365 DDIs using DeepDDI. At least one DDI was found for most patients (
= 509 or 81.2% based on the DNN model). The predictions revealed that many patients would be at increased risk of bleeding and bradycardic complications due to a potential DDI if they were to start a disease-modifying therapy with cladribine (
= 242 or 38.6%) and fingolimod (
= 279 or 44.5%), respectively. We also obtained numerous potential interactions for Bruton's tyrosine kinase inhibitors that are in clinical development for MS, such as evobrutinib (
= 434 DDIs). Food sources most often related to DFIs were corn (
= 5456 DFIs) and cow's milk (
= 4243 DFIs). We demonstrate that deep learning techniques can exploit chemical structure similarity to accurately predict DDIs and DFIs in patients with MS. Our study specifies drug pairs that potentially interact, suggests mechanisms causing adverse drug effects, informs about whether interacting drugs can be replaced with alternative drugs to avoid critical DDIs and provides dietary recommendations for MS patients who are taking certain drugs.
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