Optimization of a small molecule inhibitor of secondary nucleation in α-synuclein aggregation

Parkinson’s disease is characterised by the deposition in the brain of amyloid aggregates of α-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of α-synuclein deposits. We report a procedure to enhance the potency of a small molecule to inhibit the aggregate proliferation process using a combination of in silico and in vitro methods. The optimized small molecule shows potency already at a compound:protein stoichiometry of 1:20. These results illustrate a strategy to accelerate the optimisation of small molecules against α-synuclein aggregation by targeting secondary nucleation

Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

Abstract: Significant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases

Understanding decisions about antibiotic prescribing in ICU: an application of the Necessity Concerns Framework

Background: Antibiotics are extensively prescribed in intensive care units (ICUs), yet little is known about how antibiotic-related decisions are made in this setting. We explored how beliefs, perceptions and contextual factors influenced ICU clinicians' antibiotic prescribing. Methods: We conducted 4 focus groups and 34 semistructured interviews with clinicians involved in antibiotic prescribing in four English ICUs. Focus groups explored factors influencing prescribing, whereas interviews examined decision-making processes using two clinical vignettes. Data were analysed using thematic analysis, applying the Necessity Concerns Framework. Results: Clinicians' antibiotic decisions were influenced by their judgement of the necessity for prescribing/not prescribing, relative to their concerns about potential adverse consequences. Antibiotic necessity perceptions were strongly influenced by beliefs that antibiotics would protect patients from deterioration and themselves from the ethical and legal consequences of undertreatment. Clinicians also reported concerns about prescribing antibiotics. These generally centred on antimicrobial resistance; however, protecting the individual patient was prioritised over these societal concerns. Few participants identified antibiotic toxicity concerns as a key influencer. Clinical uncertainty often complicated balancing antibiotic necessity against concerns. Decisions to start or continue antibiotics often represented € erring on the side of caution' as a protective response in uncertainty. This approach was reinforced by previous experiences of negative consequences ( € being burnt') which motivated prescribing € just in case' of an infection. Prescribing decisions were also context-dependent, exemplified by a lower perceived threshold to prescribe antibiotics out-of-hours, input from external team members and local prescribing norms. Conclusion: Efforts to improve antibiotic stewardship should consider clinicians' desire to protect with a prescription. Rapid molecular microbiology, with appropriate communication, may diminish clinicians' fears of not prescribing or of using narrower-spectrum antibiotics

VW Hyi: optical spectroscopy and Doppler tomography

We present high quality optical spectroscopy of the SU UMa-subtype dwarf nova, VW Hyi taken while the system was in quiescence. An S-wave is executed by the emission cores of the Hydrogen Balmer lines and by the emission lines of He I, Ca II, Fe II and He II. Using Doppler tomography we show it originates in the accretion stream-disc impact region. The He II emission is strongly phase-dependent, suggesting it originates exclusively within a hot cavity at the initial impact. We map the ionization structure of the stream-disc interaction region. One possible interpretation of this is that the Balmer hotspot lies downstream of the He II hotspot in the outer accretion disc, with the He I and Ca II hotspots at intermediate locations between the two. This suggests that Balmer emission is suppressed until material has cooled somewhat downstream of the impact site and is able to recombine. We favour a phase offset of 0.15+/-0.04 between the photometric ephemeris and inferior conjunction of the mass donor. The white dwarf contributes significantly to the optical continuum, with broad Balmer absorption and narrow Mg II 4481 absorption clearly apparent. This latter feature yields the gravitational redshift: v_grav=38+/-21 km s^-1, so M_1=0.71+0.18-0.26 M_sun. This implies M_2=0.11 +/- 0.03 M_sun and hence the donor is not a brown dwarf. A prominent Balmer jump is also observed. We note that the previously accepted system parameters for both VW Hyi and WX Hyi incoporate an algebraic error, and we provide a recalculated M_1(q) plane for WX Hyi.Comment: 10 pages (mn2e LaTeX), 9 figures, Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Relational Dynamics of Treatment Behavior Among Individuals with Tuberculosis in High-Income Countries: A Scoping Review

Although tuberculosis (TB) incidence has significantly declined in high-income, low-incidence (HILI) countries, challenges remain in managing TB in vulnerable populations who may struggle to stay on anti-TB treatment (ATT). Factors associated with non-adherence to ATT are well documented; however, adherence is often narrowly conceived as a fixed binary variable that places emphasis on individual agency and the act of taking medicines, rather than on the demands of being on treatment more broadly. Further, the mechanisms through which documented factors act upon the experience of being on treatment are poorly understood. Adopting a relational approach that emphasizes the embeddedness of individuals within dynamic social, structural, and health systems contexts, this scoping review aims to synthesize qualitative evidence on experiences of being on ATT and mechanisms through which socio-ecological factors influence adherence in HILI countries. Six electronic databases were searched for peer-reviewed literature published in English between January 1990 and May 2020. Additional studies were obtained by searching references of included studies. Narrative synthesis was used to analyze qualitative data extracted from included studies. Of 28 included studies, the majority (86%) reported on health systems factors, followed by personal characteristics (82%), structural influences (61%), social factors (57%), and treatment related factors (50%). Included studies highlighted three points that underpin a relational approach to ATT behavior: 1) individual motivation and capacity to take ATT is dynamic and intertwined with, rather than separate from, social, health systems, and structural factors; 2) individuals' pre-existing experiences of health-seeking influence their views on treatment and their ability to commit to long-term regular medicine-taking; and 3) social, cultural, and political contexts play an important role in mediating how specific factors work to support or hinder ATT adherence behavior in different settings. Based on our analysis, we suggest that person-centered clinical management of tuberculosis should 1) acknowledge the ways in which ATT both disrupts and is managed within the everyday lives of individuals with TB; 2) appreciate that individuals' circumstances and the support and resources they can access may change over the course of treatment; and 3) display sensitivity towards context-specific social and cultural norms affecting individual and collective experiences of being on ATT

Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter

Abstract: The aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation

Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter

Abstract: The aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

How to screen for non-adherence to antihypertensive therapy

The quality of assessment of non-adherence to treatment in hypertensive is poor. Within this review, we discuss the different methods used to assess adherence to blood-pressure-lowering medications in hypertension patients. Subjective reports such as physicians’ perceptions are inaccurate, and questionnaires completed by patients tend to overreport adherence and show a low diagnostic specificity. Indirect objective methods such as pharmacy database records can be useful, but they are limited by the robustness of the recorded data. Electronic medication monitoring devices are accurate but usually track adherence to only a single medication and can be expensive. Overall, the fundamental issue with indirect objective measures is that they do not fully confirm ingestion of antihypertensive medications. Detection of antihypertensive medications in body fluids using liquid chromatography–tandem mass spectrometry is currently, in our view, the most robust and clinically useful method to assess non-adherence to blood-pressure-lowering treatment. It is particularly helpful in patients presenting with resistant, refractory or uncontrolled hypertension despite the optimal therapy. We recommend using this diagnostic strategy to detect non-adherence alongside a no-blame approach tailoring support to address the perceptions (e.g. beliefs about the illness and treatment) and practicalities (e.g. capability and resources) influencing motivation and ability to adhere