Integrating multiscale and machine learning approaches towards the SAMPL9 log P challenge.

The partition coefficient (log P) is an important physicochemical property that provides information regarding a molecule's pharmacokinetics, toxicity, and bioavailability. Methods to accurately predict the partition coefficient have the potential to accelerate drug design. In an effort to test current methods and explore new computational techniques, the statistical assessment of the modeling of proteins and ligands (SAMPL) has established a blind prediction challenge. The ninth iteration challenge was to predict the toluene-water partition coefficient (log Ptol/w) of sixteen drug molecules. Herein, three approaches are reported broadly under the categories of quantum mechanics (QM), molecular mechanics (MM), and data-driven machine learning (ML). The three blind submissions yield mean unsigned errors (MUE) ranging from 1.53-2.93 log Ptol/w units. The MUEs were reduced to 1.00 log Ptol/w for the QM methods. While MM and ML methods outperformed DFT approaches for challenge molecules with fewer rotational degrees of freedom, they suffered for the larger molecules in this dataset. Overall, DFT functionals paired with a triple-ζ basis set were the simplest and most effective tool to obtain quantitatively accurate partition coefficients.

Potential energy surfaces and dynamic properties via ab initio composite and density functional approaches.

Vibrational spectroscopy enables critical insight into the structural and dynamic properties of molecules. Presently, the majority of theoretical approaches to spectroscopy employ wavefunction-based ab initio or density functional methods that rely on the harmonic approximation. This approximation breaks down for large molecules with strongly anharmonic bonds or for molecules with large internuclear separations. An alternative to these methods involves generating molecular anharmonic potential energy surfaces (potentials) and using them to extrapolate the vibrational frequencies. This study examines the efficacy of density functional theory (DFT) and the correlation consistent Composite Approach (ccCA) in generating anharmonic frequencies from potentials of small main group molecules. Vibrational self-consistent field Theory (VSCF) and post-VSCF methods were used to calculate the fundamental frequencies of these molecules from their potentials. Functional choice, basis set selection, and mode-coupling are also examined as factors in influencing accuracy. The absolute deviations for the calculated frequencies using potentials at the ccCA level of theory were lower than the potentials at the DFT level. With DFT resulting in bending modes that are better described than those of ccCA, a multilevel DFT:ccCA approach where DFT potentials are used for single vibrational mode potentials and ccCA is used for vibrational mode-mode couplings can be utilized for larger polyatomic systems. The frequencies obtained with this multilevel approach using VCIPSI-PT2 were closer to experimental frequencies than the scaled harmonic frequencies, indicating the success of utilizing post-VSCF methods to generate more accurate representations of computed infrared spectra.

No-boundary thinking for artificial intelligence in bioinformatics and education.

No-boundary thinking enables the scientific community to reflect in a thoughtful manner and discover new opportunities, create innovative solutions, and break through barriers that might have otherwise constrained their progress. This concept encourages thinking without being confined by traditional rules, limitations, or established norms, and a mindset that is not limited by previous work, leading to fresh perspectives and innovative outcomes. So, where do we see the field of artificial intelligence (AI) in bioinformatics going in the next 30 years? That was the theme of a "No-Boundary Thinking" Session as part of the Mid-South Computational Bioinformatics Society's (MCBIOS) 19th annual meeting in Irving, Texas. This session addressed various areas of AI in an open discussion and raised some perspectives on how popular tools like ChatGPT can be integrated into bioinformatics, communicating with scientists in different fields to properly utilize the potential of these algorithms, and how to continue educational outreach to further interest of data science and informatics to the next-generation of scientists.

Tale of Three Molecular Nitrides: Mononuclear Vanadium (V) and (IV) Nitrides As Well As a Mixed-Valence Trivanadium Nitride Having a V3N4 Double-Diamond Core.

Transmetallation of [VCl3(THF)3] and [TlTptBu,Me] afforded [(TptBu,Me)VCl2] (1, TptBu,Me = hydro-tris(3-tert-butyl-5-methylpyrazol-1-yl)borate), which was reduced with KC8 to form a C3v symmetric VII complex, [(TptBu,Me)VCl] (2). Complex 1 has a high-spin (S = 1) ground state and displays rhombic high-frequency and -field electron paramagnetic resonance (HFEPR) spectra, while complex 2 has an S = 3/2 4A2 ground state observable by conventional EPR spectroscopy. Complex 1 reacts with NaN3 to form the VV nitride-azide complex [(TptBu,Me)V≡N(N3)] (3). A likely VIII azide intermediate en route to 3, [(TptBu,Me)VCl(N3)] (4), was isolated by reacting 1 with N3SiMe3. Complex 4 is thermally stable but reacts with NaN3 to form 3, implying a bis-azide intermediate, [(TptBu,Me)V(N3)2] (A), leading to 3. Reduction of 3 with KC8 furnishes a trinuclear and mixed-valent nitride, [{(TptBu,Me)V}2(µ4-VN4)] (5), conforming to a Robin-Day class I description. Complex 5 features a central vanadium ion supported only by bridging nitride ligands. Contrary to 1, complex 2 reacts with NaN3 to produce an azide-bridged dimer, [{(TptBu,Me)V}2(1,3-µ2-N3)2] (6), with two antiferromagnetically coupled high-spin VII ions. Complex 5 could be independently produced along with [(κ2-TptBu,Me)2V] upon photolysis of 6 in arene solvents. The putative {VIV≡N} intermediate, [(TptBu,Me)V≡N] (B), was intercepted by photolyzing 6 in a coordinating solvent, such as tetrahydrofuran (THF), yielding [(TptBu,Me)V≡N(THF)] (B-THF). In arene solvents, B-THF expels THF to afford 5 and [(κ2-TptBu,Me)2V]. A more stable adduct (B-OPPh3) was prepared by reacting B-THF with OPPh3. These adducts of B are the first neutral and mononuclear VIV nitride complexes to be isolated.

Computational Aspects of Single-Molecule Kinetics for Coupled Catalytic Cycles: A Spectral Analysis.

Catalysis from single active sites is analyzed using methods developed from single-molecule kinetics. Using a stochastic Markov-state description, the observable properties of general catalytic networks of reactions are expressed using an eigenvalue decomposition of the transition matrix for the Markov process. By the use of a sensitivity analysis, the necessary eigenvalues and eigenvectors are related to the energies of controlling barriers and wells located along the reaction routes. A generalization of the energetic span theory allows the eigenvalues to be computed from several activation energies corresponding to distinct barrier-well pairings. The formalism is demonstrated for model problems and for a physically realistic mechanism for an alkene hydrogenation reaction on a single-atom catalyst. The spectral analysis permits a hierarchy of timescales to be identified from the single-molecule signal, which correspond to specific relaxation modes in the network.

Gastrectomy mortality in Australia.

BACKGROUND: Despite advances in medical management and endoscopic therapy, gastrectomy remains an important yet high-risk procedure for a range of benign and malignant upper gastrointestinal pathologies. No study has previously analysed Australian gastrectomy perioperative mortality rate (POMR). This retrospective, population-based cohort study was conducted to determine the Australian national gastrectomy POMR, allowing state-based and regional trends and outcomes to be assessed. METHODS: Logistic regression models were compared using de-identified procedural data between 1 July 2005 and 30 June 2017 from the Australian Institute of Health and Welfare. Codes relating to total and subtotal gastrectomy contained in the Australian Classification of Health Interventions were used to extract patient data. Mortality rates were risk adjusted for age and gender. Temporal trends and differences between states/territories and regions were investigated. RESULTS: The national average POMR throughout the study period was 2.1%. For subtotal gastrectomy, the national mean POMR was 1.1%, decreasing from 2.7% (2005) to 1.3% (2017). For total gastrectomy, the national mean POMR was 2.8%, decreasing from 3.3% (2005) to 1.7% (2017). POMR significantly reduced over time without variation between states or regions. Procedure volume steadily reduced in rural centres with a concomitant increase in metropolitan centres over time. CONCLUSION: Pleasingly, the Australian gastrectomy POMR is favourable when compared to international cohorts. Improved outcomes were consistent between states and territories, and metropolitan and regional centres. Progressive metropolitan centralization of gastrectomy was demonstrated without evidence of improved outcomes.

Re-fractures of the paediatric radius and/or ulna: A systematic review.

BACKGROUND: Fractures of the radius and/or ulna are one of the most common injuries in children. Evidence identifying risk factors for refracture, however, has not been summarised in a systematic review. Guidance for counselling patients and parents to minimise the risk of refracture is limited. The aims of this study are to 1) to determine if casting time 6 weeks or less is a risk factor for refracture after paediatric radius and/or ulna fractures, 2) to identify other risk factors for refracture after paediatric radius and/or ulna fractures and 3) to develop more accurate guidelines for counselling parents after a radius and/or ulna fracture in their child. METHODS: A thorough search was performed in accordance with the Joanna Briggs Institute (JBI) guidelines for systematic review. JBI Critical Appraisal checklists were used for risk of bias assessment. RESULTS: Diaphyseal both-bone fractures treated non-surgically should be casted for longer than 6 weeks. Surgically treated patients can be casted for less than 6 weeks. Diaphyseal and greenstick fractures have a higher risk of refracture. Residual angulation and incomplete healing in greenstick fractures may lead to a higher risk of refracture. Gender does not affect refracture risk. Falls, use of wheeled vehicles, playground activities and trampolining confer high-risk of refracture. Refracture risk is greatest up to 9 months from initial fracture. CONCLUSION: Further case-controlled studies with sub-group analysis are required to further investigate risk factors for refracture after radius and/or ulna fractures in children.

Screening for Carpal Tunnel Syndrome in Patients With Mucopolysaccharidosis.

Mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage diseases with multisystem manifestations, including carpal tunnel syndrome (CTS). This study comprised a systematic review of literature and hospital guidelines addressing the method and frequency of screening for carpal tunnel syndrome in mucopolysaccharidosis patients and a review of carpal tunnel syndrome in patients seen in the multidisciplinary mucopolysaccharidosis clinic of a pediatric hospital, in order to develop screening recommendations. The literature reported the importance of routine carpal tunnel syndrome screening from early childhood in patients with mucopolysaccharidosis I, II, IV, and VI. Screening methods included physical examination, nerve conduction studies, electromyography, and ultrasonography. Ten of 20 mucopolysaccharidosis patients in our series underwent carpal tunnel syndrome surgery. Given the high incidence of carpal tunnel syndrome at a young age in mucopolysaccharidosis, the authors recommend performing physical examination and obtaining patient and caregiver history for carpal tunnel syndrome every 6 months from the time of mucopolysaccharidosis diagnosis, supplemented by annual nerve conduction studies in cases with poor history or equivocal examination.

SAMPL6 logP challenge: machine learning and quantum mechanical approaches.

Two different types of approaches: (a) approaches that combine quantitative structure activity relationships, quantum mechanical electronic structure methods, and machine-learning and, (b) electronic structure vertical solvation approaches, were used to predict the logP coefficients of 11 molecules as part of the SAMPL6 logP blind prediction challenge. Using electronic structures optimized with density functional theory (DFT), several molecular descriptors were calculated for each molecule, including van der Waals areas and volumes, HOMO/LUMO energies, dipole moments, polarizabilities, and electrophilic and nucleophilic superdelocalizabilities. A multilinear regression model and a partial least squares model were used to train a set of 97 molecules. As well, descriptors were generated using the molecular operating environment and used to create additional machine learning models. Electronic structure vertical solvation approaches considered include DFT and the domain-based local pair natural orbital methods combined with the solvated variant of the correlation consistent composite approach.

Domain-based local pair natural orbital methods within the correlation consistent composite approach.

Ab initio composite approaches have been utilized to model and predict main group thermochemistry within 1 kcal mol-1 , on average, from well-established reliable experiments, primarily for molecules with less than 30 atoms. For molecules of increasing size and complexity, such as biomolecular complexes, composite methodologies have been limited in their application. Therefore, the domain-based local pair natural orbital (DLPNO) methods have been implemented within the correlation consistent composite approach (ccCA) framework, namely DLPNO-ccCA, to reduce the computational cost (disk space, CPU (central processing unit) time, memory) and predict energetic properties such as enthalpies of formation, noncovalent interactions, and conformation energies for organic biomolecular complexes including one of the largest molecules examined via composite strategies, within 1 kcal mol-1 , after calibration with 119 molecules and a set of linear alkanes. © 2019 Wiley Periodicals, Inc.

Prediction of pKa s of Late Transition-Metal Hydrides via a QM/QM Approach.

Three implicit solvation models, the conductor-like polarizable continuum model (C-PCM), the conductor-like screening model (COSMO), and universal implicit solvent model (SMD), combined with a hybrid two layer QM/QM approach (ONIOM), were utilized to calculate the pKa values, using a direct thermodynamic scheme, of a set of Group 10 transition metal (TM) hydrides in acetonitrile. To obtain the optimal combination of quantum methods for ONIOM calculations with implicit solvation models, the influence of factors, such as the choice of density functional and basis set, the atomic radii used to build a cavity in the solvent, and the size of the model system in an ONIOM scheme, was examined. Additionally, the impact of Grimme's empirical dispersion correction and exact exchange was also investigated. The results were calibrated by experimental data. This investigation provides insight about effective models for the prediction of thermodynamic properties of TM-containing complexes with bulky ligands. © 2019 Wiley Periodicals, Inc.

Communication and management of incidental pathology in 1,214 consecutive appendicectomies; a cohort study.

BACKGROUND: Important incidental pathology requiring further action is commonly found during appendicectomy, macro- and microscopically. We aimed to determine whether the acute surgical unit (ASU) model improved the management and disclosure of these findings. METHODS: An ASU model was introduced at our institution on 01/08/2012. In this retrospective cohort study, all patients undergoing appendicectomy 2.5 years before (Traditional group) or after (ASU group) this date were compared. The primary outcomes were rates of appropriate management of the incidental findings, and communication of the findings to the patient and to their general practitioner (GP). RESULTS: 1,214 patients underwent emergency appendicectomy; 465 in the Traditional group and 749 in the ASU group. 80 (6.6%) patients (25 and 55 in each respective period) had important incidental findings. There were 24 patients with benign polyps, 15 with neuro-endocrine tumour, 11 with endometriosis, 8 with pelvic inflammatory disease, 8 Enterobius vermicularis infection, 7 with low grade mucinous cystadenoma, 3 with inflammatory bowel disease, 2 with diverticulitis, 2 with tubo-ovarian mass, 1 with secondary appendiceal malignancy and none with primary appendiceal adenocarcinoma. One patient had dual pathologies. There was no difference between the Traditional and ASU group with regards to communication of the findings to the patient (p = 0.44) and their GP (p = 0.27), and there was no difference in the rates of appropriate management (p = 0.21). CONCLUSION: The introduction of an ASU model did not change rates of surgeon-to-patient and surgeon-to-GP communication nor affect rates of appropriate management of important incidental pathology during appendectomy.

Acute surgical unit improves outcomes in appendicectomy.

BACKGROUND: Few large Australian studies have explored the impact of acute surgical unit (ASU) model in appendicitis. METHODS: An ASU model commenced practice at our institution on 1 August 2012. In this retrospective cohort study, patients undergoing appendicectomy 2.5 years before (Traditional group) or after (ASU group) this date were compared. Primary outcomes were median length of stay, median time from emergency department referral to theatre start and proportion of cases performed in-hours. Secondary outcomes were rates of complications, open appendicectomy, consultant scrubbed for procedure, intensive care unit admission and re-presentation to emergency department within 30 days. RESULTS: After removing those with incomplete data, 1214 patients were enrolled; 465 in the Traditional group and 749 in the ASU group. There were no significant baseline differences between groups. Compared with the Traditional group, ASU patients had similar length of stay (1.81 versus 1.81 days; P = 0.54) and time to theatre (0.59 versus 0.56 days; P = 0.14), but a greater proportion of in-hours operation (72% versus 79%; P = 0.014). The ASU group also experienced fewer complications (9% versus 6%; P = 0.031), fewer primary open (4% versus 1%; P < 0.0001) or conversion-to-open appendicectomies (6% versus 2%; P < 0.0005) and had superior rates of consultant scrubbed in theatre (21% versus 56%; P < 0.00001). Rates of intensive care unit admission (1% versus 1%; P = 0.72) and re-presentation were unchanged (5% versus 5%; P = 0.46). CONCLUSION: In our institution, the introduction of an ASU model was associated with more in-hours operations and safer care for patients undergoing appendicectomy.

SAMPL6 host-guest challenge: binding free energies via a multistep approach.

In this effort in the SAMPL6 host-guest binding challenge, a combination of molecular dynamics and quantum mechanical methods were used to blindly predict the host-guest binding free energies of a series of cucurbit[8]uril (CB8), octa-acid (OA), and tetramethyl octa-acid (TEMOA) hosts bound to various guest molecules in aqueous solution. Poses for host-guest systems were generated via molecular dynamics (MD) simulations and clustering analyses. The binding free energies for the structures obtained via cluster analyses of MD trajectories were calculated using the MMPBSA method and density functional theory (DFT) with the inclusion of Grimme's dispersion correction, an implicit solvation model to model the aqueous solution, and the resolution-of-the-identity (RI) approximation (MMPBSA, RI-B3PW91-D3, and RI-B3PW91, respectively). Among these three methods tested, the results for OA and TEMOA systems showed MMPBSA and RI-B3PW91-D3 methods can be used to qualitatively rank binding energies of small molecules with an overbinding by 7 and 37 kcal/mol respectively, and RI-B3PW91 gave the poorest quality results, indicating the importance of dispersion correction for the binding free energy calculations. Due to the complexity of the CB8 systems, all of the methods tested show poor correlation with the experimental results. Other quantum mechanical approaches used for the calculation of binding free energies included DFT without the RI approximation, utilizing truncated basis sets to reduce the computational cost (memory, disk space, CPU time), and a corrected dielectric constant to account for ionic strength within the implicit solvation model.