The TALENT II study: a randomized controlled trial assessing the impact of an individual health management (IHM) on stress reduction

Background: Unfavorable lifestyle factors influence the risk of stress disorders. For risk reduction, lifestyle modifications, such as regular physical activity, balanced nutrition and competence in stress management, are a means of choice. The clinical study examines the efficacy of an intensive lifestyle intervention, named Individual Health Management (IHM), - with regard to a reduction of perceived stress. The study is supported by the major regional health insurance, which conducts, in cooperation with the Traditional Chinese Medicine (TCM) hospital, Bad Kotzting, a local model project offering insurants the IHM program as prevention measure against stress and related aftermath. Methods: The study is a controlled, randomized, monocentric trial with a 12-months intervention phase. Feasible persons are checked according to inclusion and exclusion criteria and assigned to the intervention or control group. Randomization ratio is 1:1. (A) Participants of the intervention group receive the lifestyle program IHM, have access to a web-based health portal (www.viterio.de), and join 3 full-day and 10 two-hour training sessions during the first 3 months. During the remaining 9 months, 4 training sessions and a weekly monitoring are performed with remote assistance. Besides measurement of perceived stress, examinations include burnout symptoms, heart rate variability, laboratory and physical findings. Further patient reported outcomes are documented (e.g. well-being, life satisfaction, severity of mood state, sense of coherence, psycho-vegetative test, cardio-metabolic risk factors, hypertension and diabetes risk (B) Participants in the control group have access to the intensive lifestyle intervention IHM after a waiting period of at least 6 months. Examinations are conducted at baseline, after 3 and 6 months and in the intervention group additionally after 9 and 12 months. The confirmatory analysis examines the differences between the two groups with regard to changes in perceived stress after 6 months compared to the initial value. Discussion: In order to enhance adherence, avoid attrition and to insure data quality, different measures will be implemented in the study. Based on a blended learning concept including a web-based e-health tool named VITERIO (R), the program promises to achieve sustainable effects in perceived stress

The TALENT II study: a randomized controlled trial assessing the impact of an individual health management (IHM) on stress reduction

Background Unfavorable lifestyle factors influence the risk of stress disorders. For risk reduction, lifestyle modifications, such as regular physical activity, balanced nutrition and competence in stress management, are a means of choice. The clinical study examines the efficacy of an intensive lifestyle intervention, named Individual Health Management (IHM), − with regard to a reduction of perceived stress. The study is supported by the major regional health insurance, which conducts, in cooperation with the Traditional Chinese Medicine (TCM) hospital, Bad Kötzting, a local model project offering insurants the IHM program as prevention measure against stress and related aftermath. Methods The study is a controlled, randomized, monocentric trial with a 12-months intervention phase. Feasible persons are checked according to inclusion and exclusion criteria and assigned to the intervention or control group. Randomization ratio is 1:1. (A) Participants of the intervention group receive the lifestyle program IHM, have access to a web-based health portal (www.viterio.de), and join 3 full-day and 10 two-hour training sessions during the first 3 months. During the remaining 9 months, 4 training sessions and a weekly monitoring are performed with remote assistance. Besides measurement of perceived stress, examinations include burnout symptoms, heart rate variability, laboratory and physical findings. Further patient reported outcomes are documented (e.g. well-being, life satisfaction, severity of mood state, sense of coherence, psycho-vegetative test, cardio-metabolic risk factors, hypertension and diabetes risk. (B) Participants in the control group have access to the intensive lifestyle intervention IHM after a waiting period of at least 6 months. Examinations are conducted at baseline, after 3 and 6 months and in the intervention group additionally after 9 and 12 months. The confirmatory analysis examines the differences between the two groups with regard to changes in perceived stress after 6 months compared to the initial value. Discussion In order to enhance adherence, avoid attrition and to insure data quality, different measures will be implemented in the study. Based on a blended learning concept including a web-based e-health tool named VITERIO®, the program promises to achieve sustainable effects in perceived stress

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action

Pandemic Drugs at Pandemic Speed: Infrastructure for Accelerating COVID-19 Drug Discovery with Hybrid Machine Learning- and Physics-based Simulations on High Performance Computers

The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie at the interface between machine learning methods, in this case, developed for linear accelerators, and physics-based methods. The two in silico methods, each have their own advantages and limitations which, interestingly, complement each other. Here, we present an innovative infrastructural development that combines both approaches to accelerate drug discovery. The scale of the potential resulting workflow is such that it is dependent on supercomputing to achieve extremely high throughput. We have demonstrated the viability of this workflow for the study of inhibitors for four COVID-19 target proteins and our ability to perform the required large-scale calculations to identify lead antiviral compounds through repurposing on a variety of supercomputers

IMPECCABLE: Integrated Modeling PipelinE for COVID Cure by Assessing Better LEads

The drug discovery process currently employed in the pharmaceutical industry typically requires about 10 years and $2–3 billion to deliver one new drug. This is both too expensive and too slow, especially in emergencies like the COVID-19 pandemic. In silico methodologies need to be improved both to select better lead compounds, so as to improve the efficiency of later stages in the drug discovery protocol, and to identify those lead compounds more quickly. No known methodological approach can deliver this combination of higher quality and speed. Here, we describe an Integrated Modeling PipEline for COVID Cure by Assessing Better LEads (IMPECCABLE) that employs multiple methodological innovations to overcome this fundamental limitation. We also describe the computational framework that we have developed to support these innovations at scale, and characterize the performance of this framework in terms of throughput, peak performance, and scientific results. We show that individual workflow components deliver 100 × to 1000 × improvement over traditional methods, and that the integration of methods, supported by scalable infrastructure, speeds up drug discovery by orders of magnitudes. IMPECCABLE has screened ∼ 1011 ligands and has been used to discover a promising drug candidate. These capabilities have been used by the US DOE National Virtual Biotechnology Laboratory and the EU Centre of Excellence in Computational Biomedicine

Failed back surgeries and minnesota multiphasic personality inventory (MMPI) profiles

MMPI profiles were evaluated for 105 prospective surgical patients who had previously undergone surgery or other procedures for treatment of back pain. Patients were classified into groups having undergone zero, one, two, three, or four or more previous surgeries. While all groups demonstrated a characteristic somatogenic profile, none of the MMPI validity or clinical scales significantly differentiated the groups and there was no relationship between increased number of surgeries and MMPI scale characteristics. These results support the nonoptimistic prognostication of the somatogenic MMPI profile for surgical intervention for back pain but show no clear relationship of MMPI profile characteristics to degree of experience of previously failed surgery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44850/1/10880_2005_Article_BF01999744.pd

Financial precautions, carbon dioxide leakage, and the European Directive 2009/31/EC on carbon capture and storage (CCS)

The phenomenon of anthropogenic climate change has been identified as a threat multiplier for many human-related concerns. Carbon capture and storage (CCS) can, in combination with several other mitigation technologies, alleviate global warming by reducing carbon dioxide (CO2) emissions. Reducing climate change-related risks via CCS creates another risk, smaller in extent: the risk that some of the stored CO2 leaks out of the storage complex. This article reviews European legislation and evaluates how one of its objectives, that private liabilities of CCS-related leakage risks are not socialized, is ensured. Slight modifications of European legislation are suggested in order to prevent an indefinite liability of CCS operators in case a storage complex turns out to be unexpectedly and unavoidably prone to CO2 leakages. Official German and Hungarian financial precaution specifications are contrasted and related to this article’s finding that the state budget is sufficiently hedged against the expected value of climate-related leakage compensation costs of poorly managed storage complexes if 3 to 6% of a CCS operator’s emission-related revenues are diverted into a financial precaution fund.Universität Hamburg (1037

Constitutive activity of the human histamine H4 receptor: Molecular modelling, binding and functional studies on wild-type and mutant H4R orthologs

The histamine H4R belongs to the class A of G-protein coupled receptors (GPCRs) and is considered as a promising drug target for the treatment of inflammatory diseases such as allergic asthma. The validation of the H4R in translational animal models is compromised by species-dependent differences regarding intrinsic activities, potencies and affinities of ligands, in particular, when comparing the hH4R (human) and the rodent orthologs, i. e., the mH4R (mouse) and rH4R (rat). In contrast to the mH4R and rH4R, the hH4R shows a high degree of constitutive activity. Therefore, H4R species orthologs represent ideal candidates to study the phenomenon of “constitutive activity”. As working hypothesis of the present project, the aforementioned species-dependent differences were supposed to be determined by one or several distinct amino acids in the ligand binding pocket of the human H4R compared to the orthologs of mouse and rat. Aiming at more detailed insights into the molecular determinants of ortholog-dependent ligand-receptor interactions, a series of H4R mutants were generated and expressed in Sf9 cells to determine and analyse radioligand binding and functional data ([35S]GTPγS assay) of selected ligands. In addition to F169, which was identified by Lim et al. as a key amino acid for distinct ligand binding affinities at H4R orthologs, suggested by molecular modelling studies, S179, S330 and R341 were replaced by the corresponding amino acids of the rodent H4Rs, resulting in hH4R-F169V, hH4R-S179M/A, hH4R-F169V+S179M/A, hH4R-S330R and hH4R-R341S. The reciprocal mH4R mutants, mH4R-V171F and mH4R-V171F+M181S, respectively, served as controls. Moreover, to study the role of the F168/F169 motif, which is also found in, e. g., the β2AR, H3R and the M2R, the mutated receptor protein hH4R-F168A was expressed in Sf9 cells. Additionally, R341 was replaced by the respective residue of the canine H4R, resulting in hH4R-R341E. Comparable expression levels and ratios of receptor to G-protein expression in Sf9 cell membranes were confirmed by [3H]histamine saturation binding and SDS-PAGE, followed by Coomassie staining and western blotting. Compared to the hH4R wild-type, especially UR-PI376, clozapine and isoloxapine revealed a significant decrease in potency and affinity at the hH4R-F169V single and the hH4R-F169V+A179M/A double mutants, respectively. The reverse mH4R mutants, mH4R-V171F and mH4R-V171F+M181S, respectively, became more hH4R-like. Moreover, the potency and/or affinity of most ligands was higher at the S179A than at the respective S179M mutants. Strikingly, the constitutive activity of the hH4R-F169V and the double mutants was significantly reduced compared to the wild-type hH4R. By contrast, an exchange of S179 by M or A alone did not significantly affect constitutive activity. The double mutants were comparable to the mH4R and to the rH4R, which are devoid of constitutive activity. The inverse agonism of thioperamide decreased from the hH4R via the hH4R-F169V mutant to the hH4R-F169V+S179M/A double mutants, respectively. The data for the hH4R-F168A mutant revealed a major contribution of F168 to ligand binding with a concomitant, up to over 100-fold decrease in ligand potencies and a complete loss of constitutive activity, compared to the wild-type hH4R. Thioperamide acted as a neutral antagonist and JNJ7777120 turned to partial agonism. Potencies and affinities of the ligands clozapine, isoloxapine and UR-PI376 slightly decreased at the hH4R-S330R mutant compared to the hH4R wild-type. Constitutive activities slightly decreased in case of the hH4R-S330R mutant. Compared to the hH4R, the affinity of UR-PI376 increased at the hH4R-R341E mutant. The constitutive activity of the hH4R-R341S mutant decreased slightly. Molecular modelling studies suggested that F168ECL2 and F169ECL2 interact with the surrounding hydrophobic and aromatic amino acids, which are supposed to be involved in the contraction of the binding pocket and, thus, in constitutive activity. S1795.43 was proposed to form an H-bond with T3236.55, which is precluded in case of mutation to M or A. S1795.43 alone was not the cause for the high constitutive activity of the hH4R. However, this amino acid in concert with F169ECL2 markedly contributes to the concomitant distal outward movement of TM5 and TM6. In conclusion, especially F168 and F169 alone or F169 in concert with S179 favour the conversion of the inactive to the active state of the human H4R. The fact that comparable amino acids are present in equivalent positions of other constitutively active GPCRs such as the β2AR or the H3R suggest a common mechanism of receptor activation

Financial precautions, carbon dioxide leakage, and the European Directive 2009/31/EC on carbon capture and storage (CCS)

The phenomenon of anthropogenic climate change has been identified as a threat multiplier for many human-related concerns. Carbon capture and storage (CCS) can, in combination with several other mitigation technologies, alleviate global warming by reducing carbon dioxide (CO₂) emissions. Reducing climate change-related risks via CCS creates another risk, smaller in extent: the risk that some of the stored CO₂ leaks out of the storage complex. This article reviews European legislation and evaluates how one of its objectives, that private liabilities of CCS-related leakage risks are not socialized, is ensured. Slight modifications of European legislation are suggested in order to prevent an indefinite liability of CCS operators in case a storage complex turns out to be unexpectedly and unavoidably prone to CO₂ leakages. Official German and Hungarian financial precaution specifications are contrasted and related to this article’s finding that the state budget is sufficiently hedged against the expected value of climate-related leakage compensation costs of poorly managed storage complexes if 3 to 6% of a CCS operator’s emission-related revenues are diverted into a financial precaution fund