Correcting the impact of docking pose generation error on binding affinity prediction

International audienceAbstractBackgroundPose generation error is usually quantified as the difference between the geometry of the pose generated by the docking software and that of the same molecule co-crystallised with the considered protein. Surprisingly, the impact of this error on binding affinity prediction is yet to be systematically analysed across diverse protein-ligand complexes.ResultsAgainst commonly-held views, we have found that pose generation error has generally a small impact on the accuracy of binding affinity prediction. This is also true for large pose generation errors and it is not only observed with machine-learning scoring functions, but also with classical scoring functions such as AutoDock Vina. Furthermore, we propose a procedure to correct a substantial part of this error which consists of calibrating the scoring functions with re-docked, rather than co-crystallised, poses. In this way, the relationship between Vina-generated protein-ligand poses and their binding affinities is directly learned. As a result, test set performance after this error-correcting procedure is much closer to that of predicting the binding affinity in the absence of pose generation error (i.e. on crystal structures). We evaluated several strategies, obtaining better results for those using a single docked pose per ligand than those using multiple docked poses per ligand.ConclusionsBinding affinity prediction is often carried out on the docked pose of a known binder rather than its co-crystallised pose. Our results suggest than pose generation error is in general far less damaging for binding affinity prediction than it is currently believed. Another contribution of our study is the proposal of a procedure that largely corrects for this error. The resulting machine-learning scoring function is freely available at http://istar.cse.cuhk.edu.hk/rf-score-4.tgzand http://ballester.marseille.inserm.fr/rf-score-4.tgz

The Quantum Geometric Phase between Orthogonal States

We show that the geometric phase between any two states, including orthogonal states, can be computed and measured using the notion of projective measurement, and we show that a topological number can be extracted in the geometric phase change in an infinitesimal loop near an orthogonal state. Also, the Pancharatnam phase change during the passage through an orthogonal state is shown to be either $\pi$ or zero (mod $2\pi$). All the off-diagonal geometric phases can be obtained from the projective geometric phase calculated with our generalized connection

Treatment with methylphenidate for attention deficit hyperactivity disorder (ADHD) and the risk of all-cause poisoning in children and adolescents: a self-controlled case series study

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5–18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33–5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06–4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study

Treatment with Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) and the Risk of All-Cause Poisoning in Children and Adolescents:A Self-Controlled Case Series Study

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5–18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33–5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06–4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40263-021-00824-x

Whole transcriptome analysis reveals non-coding RNA's competing endogenous gene pairs as novel form of motifs in serous ovarian cancer

Publisher Copyright: © 2022The non-coding RNA (ncRNA) regulation appears to be associated to the diagnosis and targeted therapy of complex diseases. Motifs of non-coding RNAs and genes in the competing endogenous RNA (ceRNA) network would probably contribute to the accurate prediction of serous ovarian carcinoma (SOC). We conducted a microarray study profiling the whole transcriptomes of eight human SOCs and eight controls and constructed a ceRNA network including mRNAs, long ncRNAs, and circular RNAs (circRNAs). Novel form of motifs (mRNA-ncRNA-mRNA) were identified from the ceRNA network and defined as non-coding RNA's competing endogenous gene pairs (ceGPs), using a proposed method denoised individualized pair analysis of gene expression (deiPAGE). 18 cricRNA's ceGPs (cceGPs) were identified from multiple cohorts and were fused as an indicator (SOC index) for SOC discrimination, which carried a high predictive capacity in independent cohorts. SOC index was negatively correlated with the CD8+/CD4+ ratio in tumour-infiltration, reflecting the migration and growth of tumour cells in ovarian cancer progression. Moreover, most of the RNAs in SOC index were experimentally validated involved in ovarian cancer development. Our results elucidate the discriminative capability of SOC index and suggest that the novel competing endogenous motifs play important roles in expression regulation and could be potential target for investigating ovarian cancer mechanism or its therapy.Peer reviewe

Unveiling falling urban trees before and during Typhoon Higos (2020): empirical case study of potential structural failure using tilt sensor

Urban trees in a densely populated environment may pose risks to the public’s safety in terms of the potential danger of injuries and fatalities, loss of property, impacts on traffic, etc. The biological and mechanical features of urban trees may change over time, thereby affecting the stability of the tree structure. This can be a gradual process but can also be drastic, especially after typhoons or heavy rainstorms. Trees may fall at any time with no discernible signs of failure being exhibited or detected. It is always a challenge in urban tree management to develop a preventive alert system to detect the potential failure of hazardous urban trees and hence be able to have an action plan to handle potential tree tilting or tree collapse. Few studies have considered the comparison of tree morphology to the tilt response relative to uprooting failure in urban cities. New methods involving numerical modeling and sensing technologies provide tools for an effective and deeper understanding of the interaction of root-plate movement and windstorm with the application of the tailor-made sensor. In this study, root-plate tilt variations of 889 trees with sensors installed during Typhoon Higos (2020) are investigated, especially the tilting pattern of the two trees that failed in the event. The correlation of tree response during the typhoon among all trees with tilt measurements was also evaluated. The results from two alarm levels developed in the study, i.e., Increasing Trend Alarm and Sudden Increase Alarm indicated that significant root-plate movement to wind response is species-dependent. These systems could help inform decision making to identify the problematic trees in the early stage. Through the use of smart sensors, the data collected by the alert system provides a very useful analysis of the stability of tree structure and tree health in urban tree management

Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial

Background: Research suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD). Aims: To compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive–behavioural therapy-based psychoeducation and usual care. Method: In total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels. Results: Linear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only. Conclusions: These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms

DORA: Dynamic Optimal Random Access for Vehicle-to-Roadside Communications

Abstract-In this paper, we study random access in a drivethru scenario, where roadside access points (APs) are installed on a highway to provide temporary Internet access for vehicles. We consider vehicle-to-roadside (V2R) communications for a vehicle that aims to upload a file when it is within the APs' coverage ranges, where both the channel contention level and transmission data rate vary over time. The vehicle will pay a fixed amount each time it tries to access the APs, and will incur a penalty if it cannot finish the file uploading when leaving the APs. First, we consider the problem of finding the optimal transmission policy with a single AP and random vehicular traffic arrivals. We formulate it as a finite-horizon sequential decision problem, solve it using dynamic programming (DP), and design a general dynamic optimal random access (DORA) algorithm. We derive the conditions under which the optimal transmission policy has a threshold structure, and propose a monotone DORA algorithm with a lower computational complexity for this special case. Next, we consider the problem of finding the optimal transmission policy with multiple APs and deterministic vehicular traffic arrivals thanks to perfect traffic estimation. We again obtain the optimal transmission policy using DP and propose a joint DORA algorithm. Simulation results based on a realistic vehicular traffic model show that our proposed algorithms achieve the minimal total cost and the highest upload ratio as compared with some other heuristic schemes. In particular, we show that the joint DORA scheme achieves an upload ratio 130% and 207% better than the heuristic schemes at low and high traffic densities, respectively. Index Terms-Random access, medium access control, vehicular ad hoc networks, dynamic programming, Markov decision processes, threshold policy