Activity-Directed Synthesis: A Flexible Approach for Lead Generation

Activity-directed synthesis (ADS) is a structure-blind, functional-driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed.     

Magnetic Resonance Signal Amplification by Reversible Exchange of Selective PyFALGEA Oligopeptide Ligands Towards Epidermal Growth Factor Receptors

The biorelevant PyFALGEA oligopeptide ligand, which is selective towards the epidermal growth factor receptor (EGFR), has been successfully employed as a substrate in magnetic resonance signal amplification by reversible exchange (SABRE) experiments. It is demonstrated that PyFALGEA and the iridium catalyst IMes form a PyFALGEA:IMes molecular complex. The interaction between PyFALGEA:IMes and H₂ results in a ternary SABRE complex. Selective 1D EXSY experiments reveal that this complex is labile, which is an essential condition for successful hyperpolarization by SABRE. Polarization transfer from parahydrogen to PyFALGEA is observed leading to significant enhancement of the ¹H NMR signals of PyFALGEA. Different iridium catalysts and peptides are inspected to discuss the influence of their molecular structures on the efficiency of hyperpolarization. It is observed that PyFALGEA oligopeptide hyperpolarization is more efficient when an iridium catalyst with a sterically less demanding NHC ligand system such as IMesBn is employed. Experiments with shorter analogues of PyFALGEA, that is, PyLGEA and PyEA, show that the bulky phenylalanine from the PyFALGEA oligopeptide causes steric hindrance in the SABRE complex, which hampers hyperpolarization with IMes. Finally, a single-scan ¹H NMR SABRE experiment of PyFALGEA with IMesBn revealed a unique pattern of NMR lines in the hydride region, which can be treated as a fingerprint of this important oligopeptide.     

Interpretable segmentation of medical free-text records based on word embeddings

Journal of Intelligent Information Systems - Medical free-text records store a lot of useful information that can be exploited in developing computer-supported medicine. However, extracting the...     

A novel hybrid hypervolume indicator and reference vector adaptation strategies based evolutionary algorithm for many-objective optimization

Engineering with Computers - A novel hybrid many-objective evolutionary algorithm called Reference Vector Guided Evolutionary Algorithm based on hypervolume indicator (H-RVEA) is proposed in this...     

Impact of military type footwear and load carrying workload on postural stability

Postural stability has been shown to be impacted by footwear and task performed. This study analysed the impact of two military footwear, standard boot (STB) and minimalist boot (MTB) on postural stability, before (PRE) and after (POST) a load carriage task. Sixteen participants were tested for postural stability using sensory organisation and motor control tests on Neurocom Equitest?. Postural sway, equilibrium scores and postural latencies were analysed using a two-factor repeated measures ANOVA: boot type (STB-MTB)?×?time (PRE-POST) load carriage task. Significantly greater postural sway variables, lower balance scores and slower postural latencies were seen in STB and POST load carriage conditions (p?<?.05). The results suggest that MTB exhibited greater balance compared to STB in balance conditions that rely on somatosensory feedback and that balance is lowered after a load carriage task. Decrements in postural stability could be attributed to boot design characteristics and muscular exertion due to the load carriage task.

Practitioner Summary: Maintaining optimal postural stability is crucial in military. Impact of military footwear types and load carriage task on postural stability are addressed. Findings provide footwear design and physical exertion implications on postural stability leading to potential interventions that reduce postural stability decrements; thereby, reducing potential falls and fall related injuries.     

Association between patient psychosocial characteristics and receipt of in‐center nocturnal hemodialysis among prevalent dialysis patients

Introduction: Compared to traditional in‐center hemodialysis (HD), in‐center nocturnal dialysis (INHD) is characterized by longer sessions and nighttime administration, which may lead to better outcomes for some patients. Given the importance of patient choice in the decision to initiate INHD, we explored associations between patients’ psychosocial characteristics and their receipt of INHD. Methods: Among hemodialysis patients at a medium‐sized dialysis organization, we identified INHD patients as those for whom ≥80% of dialysis sessions were INHD sessions—starting at 6:30 pm or later and lasting ≥5 hours—over the 3 months (≥20 sessions total) after their first INHD session. We extracted dialysis session data from electronic medical records and psychosocial data from social worker assessments. We tested associations of patients’ psychosocial characteristics—as well as demographic and clinical characteristics—with INHD receipt among all hemodialysis patients (INHD and HD) in bivariate analyses and multivariable logistic regression models. Findings: Among 759 patients with complete data, we identified 47 (6.2%) as INHD patients. On average, these patients were more likely than HD patients to be employed (full‐time 10.6% vs. 5.2%; part‐time 17.0% vs. 4.2%; P < 0.001), and they were significantly less likely to require ambulatory assistance (14.9% vs. 39.6%, P < 0.001). In multivariable regressions, we found that part‐time employment (versus being unemployed) was associated with a 7.1 percentage‐point higher likelihood of being an INHD patient (P = 0.01), and the negative association with ambulatory assistance needs approached statistical significance (P = 0.056). No other psychosocial factors included in this main regression analysis were statistically significantly associated with INHD patient status. Discussion: Researchers comparing the outcomes of patients undergoing INHD versus other treatment modalities will need to account for differences in employment status—and other factors like requiring ambulatory assistance and age which may predict the ability to work—between INHD users and comparison patients to avoid bias in estimates.