Modelling the unfolding pathway of biomolecules: theoretical approach and experimental prospect

We analyse the unfolding pathway of biomolecules comprising several independent modules in pulling experiments. In a recently proposed model, a critical velocity $v_{c}$ has been predicted, such that for pulling speeds $v>v_{c}$ it is the module at the pulled end that opens first, whereas for $v<v_{c}$ it is the weakest. Here, we introduce a variant of the model that is closer to the experimental setup, and discuss the robustness of the emergence of the critical velocity and of its dependence on the model parameters. We also propose a possible experiment to test the theoretical predictions of the model, which seems feasible with state-of-art molecular engineering techniques.Comment: Accepted contribution for the Springer Book "Coupled Mathematical Models for Physical and Biological Nanoscale Systems and Their Applications" (proceedings of the BIRS CMM16 Workshop held in Banff, Canada, August 2016), 16 pages, 6 figure

Metformin prevents metabolic side effects during systemic glucocorticoid treatment

Swiss National Research Foundatio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Implementing the number needed to harm in clinical practice: risk of myocardial infarction in HIV-1-infected patients treated with abacavir

Objectives The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir. Methods NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years. Results The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium-and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg). Conclusions We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension. Keywords: abacavir, antiretroviral treatment, myocardial infarction, number needed to harm Accepted 21 July 2009 Introduction Abacavir is a common antiretroviral used in the treatment of HIV-1 infection and is currently recommended as one of the possible components of initial combination antiretroviral treatment Presenting results as relative risks (RRs) is standard in observational studies 200 of an event according to whether the patient receives a given treatment or not and the NNH indicates the number of patients that need to be treated to observe the adverse effect of a treatment in one additional patient. This approach was first proposed in 1988 The aims of this paper were to apply NNH for an adverse event associated with HIV therapy and relate it to the underlying risk of this event. As an example of an adverse event, we used the recently reported association between current or recent exposure to abacavir and increased rate of MI Methods The NNH was calculated as the reciprocal of ARI (1/ARI) in accordance with standard methodology Relating NNH to underlying risk of MI and its components To relate NNH to different components contributing to the underlying risk of MI, we performed a series of calculations with different cardiovascular risk equation modifications, and profiles reflecting possible clinical interventions were presented with graphs. All graphs were created for male gender and stratified into four groups according to smoking status and lipid profile. Using National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines Assumptions about the prior history of cardiovascular disease The applied Framingham equation was developed for a population with no prior coronary heart disease (CHD) and thus does not reflect the risk of developing an MI in that patient group. According to the NCEP/ATP III guidelines, a history of CHD is considered to confer a 10-year CHD risk in excess of 20% Estimating uncertainty for NNH To summarize the uncertainty associated with NNH, the 95% confidence interval (CI) for the relative rate of MI (1.47, 2.45) reported by Sabin et al. [4] is incorporated in the calculations, as described below. Interpreting the results All NNH values represent the number of patients who need to be treated with abacavir for 5 years to observe MI in one additional patient as a consequence of this treatment. Using the 10 and 20% cut-offs proposed in the NCEP/ ATP III guidelines for assessing 10-year CHD risk Results Relation between NNH and underlying risk of MI for an adverse drug effect that is associated with increased risk of MI over a 5-year period The relationship between NNH and underlying risk of MI is reciprocal ( As the relationship is reciprocal, the same absolute change in the underlying risk of MI results in a small change in NNH for patients with a high MI risk and a large change for patients with a small underlying risk of MI. For example, a 5% decrease in the underlying risk of MI for an underlying risk of 15% reflects NNH changing from 7 to 11, while the same decrease for an underlying risk of 6% changes the NNH value from 18 to 111. Relating ARI to the underlying risk of MI is not capturing this relationship. Estimating uncertainty for NNH In order to determine the level of uncertainty we estimated the 95% CI for all NNH values presented in NNH in relation to underlying risk components To determine how different risk components contribute to the change in the underlying risk of MI and NNH variability, we performed a series of analyses using different risk assumptions over two different time periods When two risk components with unfavourable levels coexist at the same time and in the same patient, the NNH To derive NNH and ARI for a given underlying risk of MI, the dashed line should be used for NNH and the continuous line for ARI [e.g. if the underlying risk of MI is 5%, then NNH is 22 (using the dashed line) and ARI is 4.5% (using the continuous line)]. Extreme values of the underlying 5-year risk of an MI have been excluded from this figure (o0.6% and 420%) to make the figure clinically relevant for the majority of patients. drops from 1111 to around 100 for most pairs of risk factors, except smoking combined with unfavourable HDL cholesterol, for which the NNH decreases even further to 69. The NNH decreases to 7 when all risk factors are defined as unfavourable at the same time and the underlying 5-year risk of an MI is 15%. The NNH was further calculated after adjusting for the presence of a history of CVD, as defined in the Methods section, and was found to drop from 1111 to 22 and from 370 to 11, for 5-and 10-year risks of MI, respectively. To give a specific example, a 50-year-old, nonsmoking patient with favourable lipid profiles and sBP of 120 mmHg will have an NNH in the range of 200-500 (graph A), while a patient of the same age who smokes (but who also has favourable lipid profiles and sBP of 120 mmHg) will have an NNH in the range of 50-100 (graph B). For these patients, an increase in sBP from 120 to 150 mmHg will lead to an NNH of 100-200 for the nonsmoking patient and an NHH of 30-50 for the patient who smokes (graph B), and unfavourable lipid profiles will change the NNH values of these patients to 30-50 (graph C) and 20-30 (graph D), respectively. Coloured three-dimensional illustrations of these results Discussion In this paper we combine estimates of the underlying risk of MI with the increased risk of MI associated with abacavir reported by the D:A:D study, and present the data not only in terms of ARI but also as NNH. Using this approach we show it is possible to increase NNH values for patients that might use or start this drug by decreasing their underlying risk of MI. The clinical implication of this finding is simple -through regular screening for and proper management of established modifiable cardiovascular risk factors which determine the underlying risk of MI in HIV-1-infected patients, it may be possible to increase the number of patients who may be safely treated with a drug that is potentially associated with the development of a serious adverse event. The adjusted RR of an MI of 1.90 reported in the D:A:D study We have not investigated further the validity of the results of the D:A:D study or the possible causal mechanism. The example we chose served as a useful illustration, because the reported increased risk of MI occurred quickly after initiation of the drug, the increase was maintained and was stable irrespective of duration of use of the drug, and the increased risk ceased 6 months after drug cessation NNH in clinical practice: risk of MI and abacavir use in HIV patients 205