Artificial intelligence (AI), and, in particular, deep learning as a subcategory of AI, provides opportunities for the discovery and development of innovative drugs. Various machine learning ...approaches have recently (re)emerged, some of which may be considered instances of domain-specific AI which have been successfully employed for drug discovery and design. This review provides a comprehensive portrayal of these machine learning techniques and of their applications in medicinal chemistry. After introducing the basic principles, alongside some application notes, of the various machine learning algorithms, the current state-of-the art of AI-assisted pharmaceutical discovery is discussed, including applications in structure- and ligand-based virtual screening, de novo drug design, physicochemical and pharmacokinetic property prediction, drug repurposing, and related aspects. Finally, several challenges and limitations of the current methods are summarized, with a view to potential future directions for AI-assisted drug discovery and design.
The study investigated the potential for obtaining more accurate spine joint reaction force (JRF) estimates from musculoskeletal models by incorporating dynamic stereo X-ray imaging (DSX)-based in ...vivo lumbar vertebral rotational and translational kinematics compared to generic, rhythm (RHY)-based kinematics, while also observing the influence of accompanying inputs: intervertebral segment stiffness and neutral state. A full-body OpenSim® musculoskeletal model, constructed by combining existing lower- and upper-body models, was driven based on one volunteer’s (female; age 25; 60.8 kg; 176 cm) anthropometrics and kinematics from a series of upright standing and straight-legged dynamic lifting tasks. The lumbar spine portion was modified in a step-wise manner to observe effects of: (1) RHY vs. DSX lumbar kinematics; (2) No disc (bushing) stiffness (NBS); generic, linear bushing stiffness (LBS); subject-specific nonlinear bushing stiffness (NLBS); (3) Upright standing (UP) vs. Supine (SUP) neutral state; (4) Weight lifted: 4.5 kg vs. 13.6 kg. L4L5 JRF from 24 model variations based on combinations of aforementioned parameters were compared. Rhythm-based kinematics without translational components tends to over-predict JRF (31% and 39% for compression and shear, respectively) compared to DSX-based kinematics. Additionally, differences due to accompanying passive stiffness and neutral state choice combinations were even larger (>50%), indicating heightened demand on the quality of these accompanying inputs. The study not only highlights model sensitivity to choices made regarding the three primary inputs—kinematics, passive stiffness and neutral state— separately, but also how interactions between these choices can result in significant variability in joint loading estimates.
The discovery of novel ligand chemotypes allows to explore uncharted regions in chemical space, thereby potentially improving synthetic accessibility, potency, and the drug-likeness of molecules. ...Here, we demonstrate the scaffold-hopping ability of the new Weighted Holistic Atom Localization and Entity Shape (WHALES) molecular descriptors compared to seven state-of-the-art molecular representations on 30,000 compounds and 182 biological targets. In a prospective application, we apply WHALES to the discovery of novel retinoid X receptor (RXR) modulators. WHALES descriptors identified four agonists with innovative molecular scaffolds, populating uncharted regions of the chemical space. One of the agonists, possessing a rare non-acidic chemotype, revealed high selectivity on 12 nuclear receptors and comparable efficacy as bexarotene on induction of ATP-binding cassette transporter A1, angiopoietin like protein 4 and apolipoprotein E. The outcome of this research supports WHALES as an innovative tool to explore novel regions of the chemical space and to detect novel bioactive chemotypes by straightforward similarity searching.
Intervertebral discs are important structural components of the spine but also are significant sources of morbidity, especially for the "low back" lumbar region. Mechanical damage to, or degeneration ...of, the lumbar discs can diminish their structural integrity and elicit debilitating low back pain. Advancement of reparative or regenerative means to treat damaged or degenerated discs is hindered by a lack of basic understanding of the disc load-deformation characteristics in vivo. The current study presents an in vivo analysis of the morphometry and deformation of lumbar (L2-S1) intervertebral discs in 10 healthy participants while performing a common lifting act, using novel dynamic radiographic imaging of the lumbar vertebral body motion. Data analyses show uniquely different (p < 0.05) characteristics in morphometry, normal and shear strain patterns of the L5S1 discs, while the rest of lumbar discs exhibit great similarity. In particular shear strains in L2-L5 discs exhibited stronger linear correlations (R
≥ 0.80) between strain changes and amount of lumbar flexion-extension motion compared to L5S1 (R
≤ 0.5). The study therefore advances the state of knowledge on in vivo mechanical responses of the lumbar intervertebral discs during functional tasks.
Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human ...cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue.
Using transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n = 577) and mouse (n = 57 across n = 8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers.
We developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours.
When applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package enables researchers to select suitable mouse models of human CRC subtype for their experimental testing.
Aortic aneurysm in children is rare, but has been described in the tuberous sclerosis complex (TSC) population. While surgical repair has been utilized as the primary means of intervention, we ...present the first known case reporting exclusion of a descending thoracic aortic aneurysm with percutaneous covered stent implantation in a pediatric patient with TSC. A review of the literature is also included herein.
The lumbar facet joint (FJ) is often associated with pathogenesis in the spine, but quantification of normal FJ motion remains limited to in vitro studies or static imaging of non-functional poses. ...The purpose of this study was to quantify lumbar FJ kinematics in healthy individuals during functional activity with dynamic stereo radiography (DSX) imaging. Ten asymptomatic participants lifted three known weights starting from a trunk-flexed (∼75°) position to an upright position while being imaged within the DSX system. High resolution computed tomography (CT) scan-derived 3D models of their lumbar vertebrae (L2-S1) were registered to the biplane 2D radiographs using a markerless model-based tracking technique providing instantaneous 3D vertebral kinematics throughout the lifting tasks. Effects of segment level and weight lifted were assessed using mixed-effect repeated measures ANOVA. Superior-inferior (SI) translation dominated FJ translation, with L5S1 showing significantly less translation magnitudes (Median (Md) = 3.5 mm, p < 0.0001) than L2L3, L3L4, and L4L5 segments (Md = 5.9 mm, 6.3 mm and 6.6 mm respectively). Linear regression-based slopes of continuous facet translations revealed strong linearity for SI translation (r2 > 0.94), reasonably high linearity for sideways sliding (Z-) (r2 > 0.8), but much less linearity for facet gap change (X-) (r2 ∼ 0.5). Caudal segments (L4-S1), particularly L5S1, displayed greater coupling compared to cranial (L2-L4) segments, revealing distinct differences overall in FJ translation trends at L5S1. No significant effect of weight lifted on FJ translations was detected. The study presents a hitherto unavailable and highly precise baseline dataset of facet translations measured during a functional, dynamic lifting task.
Sizing heart transplant donors in adults with congenital heart disease Clark, Daniel E.; Byrne, Ryan D.; Mazurek, Jeremy A. ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
08/2021, Letnik:
162, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Optimal donor sizing for heart transplantation (HT) in adults with congenital heart disease (CHD) remains unclear, given the propensity for pulmonary hypertension related to shunting, staged repairs, ...and periods of pulmonary overcirculation. We studied HT outcomes related to donor size matching in the adult CHD population.
We conducted a retrospective cohort analysis of patients with CHD undergoing HT in the United States from January 1, 2000, to December 31, 2015. Patients were selected from the United Network for Organ Sharing database; 827 patients met inclusion criteria and were analyzed.
At a median follow-up of 1462 days, 548 (66.3%) subjects were alive and 279 (33.7%) were deceased. All-cause mortality did not differ based on donor sizing (by predicted heart mass ratio: hazard ratio, 1.03; confidence interval, 0.86-1.23; P = .74). Pulmonary hypertension was not significantly associated with survival (by predicted heart mass ratio, χ2 = 2.01, P = .73).
Our data demonstrate that donor oversizing, to the extent used in current practice, does not affect survival after HT in adults with CHD. Our findings from the United Network for Organ Sharing database demonstrate that donor oversizing in these patients is not associated with improved mortality.
Donor size was not associated with post-heart transplantation all-cause mortality among adult congenital heart disease (ACHD) patients. Empirically oversizing donors in this population could impact waitlist times and requires further study. Display omitted
Objective:
To examine the lumbar facet joint kinematics in vivo during dynamic lifting and the effects of the load lifted.
Background:
Although extensive efforts have been dedicated to investigating ...the risk factors of low back pain (LBP) associated with load handling in the workplace, the biomechanics of lumbar facet joints during such activities is not well understood.
Method:
Fourteen healthy participants performed a load-lifting task while a dynamic stereo-radiography system captured their lumbar motion continuously. Data from 11 participants were included for subsequent analysis. A randomized block design was employed to study the load effect (4.5 kg, 9.0 kg, and 13.5 kg) on bilateral facet joint motions at approximately 60°, 40°, 20°, and 0° trunk-flexion postures. The facet orientations were also examined.
Results:
Significant load effects were found for the flexion and lateral bending and superior-inferior translation of the facet joints. The L5-S1 displayed greater lateral bending and twisting, which was due to its more posterolateral orientation than the L2-L3, L3-L4, and L4-L5 facet joints. The left-right asymmetry in facet orientation was observed, most prominently at L3-L4 and L5-S1 facet joints.
Conclusion:
The lumbar facet joint kinematics are affected by the magnitude of the lifted load and are dependent on the orientations of articulating adjacent facets.
Application:
This study provided new insights into the role of lumbar facet joints in vivo during lifting. Alterations in the facet joint kinematics due to vigorous functional demand can be one of the primary but overlooked mechanical factors in the causation of LBP.
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