Alternative CNDOL Fockians for fast and accurate description of molecular exciton properties.

CNDOL is an a priori, approximate Fockian for molecular wave functions. In this study, we employ several modes of singly excited configuration interaction (CIS) to model molecular excitation properties by using four combinations of the one electron operator terms. Those options are compared to the experimental and theoretical data for a carefully selected set of molecules. The resulting excitons are represented by CIS wave functions that encompass all valence electrons in the system for each excited state energy. The Coulomb-exchange term associated to the calculated excitation energies is rationalized to evaluate theoretical exciton binding energies. This property is shown to be useful for discriminating the charge donation ability of molecular and supermolecular systems. Multielectronic 3D maps of exciton formal charges are showcased, demonstrating the applicability of these approximate wave functions for modeling properties of large molecules and clusters at nanoscales. This modeling proves useful in designing molecular photovoltaic devices. Our methodology holds potential applications in systematic evaluations of such systems and the development of fundamental artificial intelligence databases for predicting related properties.

RCDPeaks: memory-efficient density peaks clustering of long molecular dynamics.

MOTIVATION: Density Peaks is a widely spread clustering algorithm that has been previously applied to Molecular Dynamics (MD) simulations. Its conception of cluster centers as elements displaying both a high density of neighbors and a large distance to other elements of high density, particularly fits the nature of a geometrical converged MD simulation. Despite its theoretical convenience, implementations of Density Peaks carry a quadratic memory complexity that only permits the analysis of relatively short trajectories. RESULTS: Here, we describe DP+, an exact novel implementation of Density Peaks that drastically reduces the RAM consumption in comparison to the scarcely available alternatives designed for MD. Based on DP+, we developed RCDPeaks, a refined variant of the original Density Peaks algorithm. Through the use of DP+, RCDPeaks was able to cluster a one-million frames trajectory using less than 4.5 GB of RAM, a task that would have taken more than 2 TB and about 3× more time with the fastest and less memory-hunger alternative currently available. Other key features of RCDPeaks include the automatic selection of parameters, the screening of center candidates and the geometrical refining of returned clusters. AVAILABILITY AND IMPLEMENTATION: The source code and documentation of RCDPeaks are free and publicly available on GitHub (https://github.com/LQCT/RCDPeaks.git). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MDSCAN: RMSD-based HDBSCAN clustering of long molecular dynamics.

MOTIVATION: The term clustering designates a comprehensive family of unsupervised learning methods allowing to group similar elements into sets called clusters. Geometrical clustering of molecular dynamics (MD) trajectories is a well-established analysis to gain insights into the conformational behavior of simulated systems. However, popular variants collapse when processing relatively long trajectories because of their quadratic memory or time complexity. From the arsenal of clustering algorithms, HDBSCAN stands out as a hierarchical density-based alternative that provides robust differentiation of intimately related elements from noise data. Although a very efficient implementation of this algorithm is available for programming-skilled users (HDBSCAN*), it cannot treat long trajectories under the de facto molecular similarity metric RMSD. RESULTS: Here, we propose MDSCAN, an HDBSCAN-inspired software specifically conceived for non-programmers users to perform memory-efficient RMSD-based clustering of long MD trajectories. Methodological improvements over the original version include the encoding of trajectories as a particular class of vantage-point tree (decreasing time complexity), and a dual-heap approach to construct a quasi-minimum spanning tree (reducing memory complexity). MDSCAN was able to process a trajectory of 1 million frames using the RMSD metric in about 21 h with <8 GB of RAM, a task that would have taken a similar time but more than 32 TB of RAM with the accelerated HDBSCAN* implementation generally used. AVAILABILITY AND IMPLEMENTATION: The source code and documentation of MDSCAN are free and publicly available on GitHub (https://github.com/LQCT/MDScan.git) and as a PyPI package (https://pypi.org/project/mdscan/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Temporal trend, spatial analysis and spatiotemporal clusters of infant mortality associated with congenital toxoplasmosis in Brazil: Time series from 2000 to 2020.

OBJECTIVE: To analyse the spatial, temporal and spatial-temporal patterns of infant mortality associated with congenital toxoplasmosis in Brazil between the years 2000 and 2020. METHODS: Ecological study of time series, with spatial analysis and spatiotemporal scan of infant mortality associated with congenital toxoplasmosis from the records of deaths of the Mortality Information System of the Brazilian Ministry of Health. The rates were smoothed by the Local Empirical Bayesian model. The Global Moran Index, Global Geary's Contiguity and Getis-Ord General statistics were calculated for spatial autocorrelation assessment. The trends were evaluated by the Joinpoint method. RESULTS: We identified 1183 infant deaths associated with congenital toxoplasmosis in Brazil between 2000 and 2020. The predominant characteristics were male sex (52.1%), post-neonatal age group (51.9%), white race/colour (45.7%), and Southeast region of residence (40.0%). The infant mortality rate associated with congenital toxoplasmosis showed an increasing trend in the country in the years analysed. The spatial analysis showed heterogeneous distribution of mortality in the Brazilian territory and found no evidence of spatial autocorrelation; but spatial-temporal analysis identified three risk clusters involving 703 municipalities. CONCLUSION: Infant mortality associated with congenital toxoplasmosis is a persistent public health problem in Brazil. The risk factors male sex, indigenous race/colour, early neonatal age, North and Northeast regions and risk clusters mapped in this study should be observed for future analysis and planning of health care policies in the control of infant deaths associated with congenital toxoplasmosis. Health surveillance strategies and public health policies need to be strengthened.

1,3 Dipolar Cycloaddition of Münchnones: Factors behind the Regioselectivity.

The 1,3 dipolar cycloaddition reactions of münchnones and alkenes provide an expedite synthetic way to substituted pyrroles, an exceedingly important structural motif in the pharmaceutical and material science fields of research. The factors governing their regioselectivity rationalization are not well understood. Using several approaches, we investigate a set of 14 reactions (featuring two münchnones, 12 different alkenes, and two alkynes). The Natural Bond Theory and the Non-Covalent Interaction Index analyses of the noncovalent interaction energies fail to predict the experimental major regioisomer. Employing global cDFT descriptors or local ones such as the Fukui function and dual descriptor yields similarly inaccurate predictions. Only the local softness pairing, within Pearson's Hard and Soft Acids and Bases principle, constitutes a reliable predictor for the major reaction product. By taking into account an estimator for the steric effects, the correct regioisomer is predicted. Steric effects play a major role in driving the regioselectivity, as was corroborated by energy decomposition analysis of the transition states.

Retrospective validation of parkland grading scale in a Latin-American high-volume center.

BACKGROUND: Increased complication rates following laparoscopic cholecystectomies have been described, likely related to surgical difficulty, anatomical variations, and gallbladder inflammation severity. Parkland Grading Scale (PGS) stratifies the severity of intraoperative findings to predict operative difficulty and complications. This study aims to validate PGS as a postoperative-outcome predictive tool, comparing its performance with Tokyo Guidelines Grading System (TGGS). METHODS: This is a single-center retrospective cohort study where PGS and TGGS performances were evaluated regarding intraoperative and postoperative outcomes. Both univariate and bivariate analyses were performed on each severity grading scale using STATA-SE 16.0 software. Additionally, we proposed a Logistic Regression Model for each scale. Their association with outcomes was compared between both scales by their Receiver Operating Characteristic Curve. RESULTS: 400 Patients were included. Grade 1 predominance was observed for both PGS and TGGS (47.36% and 25.3%, respectively). A positive association was observed between higher PGS grades and inpatient postoperative care, length of stay, ICU care, and antibiotic requirement. Based on the area under the ROC curve, better performance was observed for PGS over TGGS in the evaluated outcomes. CONCLUSION: PGS performed better than TGGS as a predictive tool for inpatient postoperative care, length of stay, ICU, and antibiotic requirement, especially in severe cases.

BitQT: a graph-based approach to the quality threshold clustering of molecular dynamics.

MOTIVATION: Classical Molecular Dynamics (MD) is a standard computational approach to model time-dependent processes at the atomic level. The inherent sparsity of increasingly huge generated trajectories demands clustering algorithms to reduce other post-simulation analysis complexity. The Quality Threshold (QT) variant is an appealing one from the vast number of available clustering methods. It guarantees that all members of a particular cluster will maintain a collective similarity established by a user-defined threshold. Unfortunately, its high computational cost for processing big data limits its application in the molecular simulation field. RESULTS: In this work, we propose a methodological parallel between QT clustering and another well-known algorithm in the field of Graph Theory, the Maximum Clique Problem. Molecular trajectories are represented as graphs whose nodes designate conformations, while unweighted edges indicate mutual similarity between nodes. The use of a binary-encoded RMSD matrix coupled to the exploitation of bitwise operations to extract clusters significantly contributes to reaching a very affordable algorithm compared to the few implementations of QT for MD available in the literature. Our alternative provides results in good agreement with the exact one while strictly preserving the collective similarity of clusters. AVAILABILITY AND IMPLEMENTATION: The source code and documentation of BitQT are free and publicly available on GitHub (https://github.com/LQCT/BitQT.git) and ReadTheDocs (https://bitqt.readthedocs.io/en/latest/), respectively. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Salamander-Eci: An optical clearing protocol for the three-dimensional exploration of regeneration.

BACKGROUND: Salamander limb regeneration is a complex biological process that entails the orchestration of multiple cellular and molecular mechanisms in a three-dimensional space. Hence, a comprehensive understanding of this process requires whole-structure level explorations. Recent advances in imaging and optical clearing methods have transformed the study of regenerative phenomena, allowing the three-dimensional visualization of structures and entire organisms. RESULTS: Here we introduce Salamander-Eci, a rapid and robust optical clearing protocol optimized for the widely used axolotl model, which allows simultaneous immunohistochemistry and Click-chemistry detection with minimal volume disruption. We provide examples of its application, from whole larva to adult limbs and organs, and complement it with an image analysis pipeline for volumetric cell quantification. Further, we offer a detailed 3D quantitation of cell proliferation throughout axolotl limb regeneration. CONCLUSIONS: Salamander-Eci enables the comprehensive volumetric analysis of regenerative phenomena at both local and systemic levels.

Cell-Free Circulating Tumor DNA Improves Standard Genotyping of Non-Small-Cell Lung Cancer and Increases Detection of Targetable Alterations in a Selected Hispanic Cohort.

BACKGROUND: Several studies have shown that the non-small-cell lung cancer (NSCLC) genomic background among Hispanics differs from other populations. The finding of low-frequency genomic alterations in cell-free DNA (cfDNA) can increase diagnostic accuracy and could improve treatment in NSCLC. METHODS: Data from 54 Hispanic patients with advanced NSCLC with high clinical suspicion for ALK, EGFR, and ROS1 mutations were collected (including young age, female sex, and non-smokers). cfDNA was extracted from plasma and analyzed using a commercial next-generation sequencing test (Guardant360) which detects genomic alterations in 74 genes. RESULTS: The median age was 56 years (range 31-83). Most patients were female (661.1%) and never smokers (72.3%). Among the patients included, 96% (52/54) had cfDNA detectable alterations with a mean number of 3.37 cfDNA alterations per test (range 1-10). cfDNA was able to detect some genomic alterations previously undetected by tissue biopsy. Among patients with insufficient or unavailable tissue to perform testing, mutations in EGFR and ALK which led to a change in therapy were determined using cfDNA in 28.8 and 3.8% of cases, respectively. Among patients with cfDNA alterations, 46.1% (n = 24) were switched to a targeted therapy with a median progression-free survival of 11.1 months (95% CI 7.6-14.6) and an overall survival of 40.3 months (95% CI 27.1-53.6). Concurrent genetic mutations with TP53 and KRAS negatively impacted the prognosis. CONCLUSIONS: In a selected population of NSCLC Hispanic patients, comprehensive cfDNA analysis allowed a treatment change in 46.1% of the cases. Guardant360 allows the identification of genomic alterations to improve treatment selection and increase prognosis.

Application of a temporal synchronization device for the study of laser-induced plasma spectroscopy in a multi-pulse regime.

The objective of this technical note is to present the results of employing a new, to the best of our knowledge, temporary synchronization device to the study of laser-induced plasma spectroscopy in a multi-pulse regime. By providing a means of controlling the time delay and the reading window of the spectrometer, this device allows the user to distinguish among the emissions from independent micro-pulses and groups of micro-pulses. Using this method, it is possible to optimize the reading of the spectra by choosing the most appropriate time delay and duration values of the spectral reading window.

[Phospholipase A2 receptor antigen antibodies in serum and renal biopsies of patients with membranous nephropathy]. / Prevalencia del anticuerpo anti receptor de fosfolipasa A2 sérico e histológico en pacientes con nefropatía membranosa en un Centro Universitario.

BACKGROUND: The discovery of the phospholipase A2 receptor antigen and its highly specific autoantibody (anti-PLA2R Ab) was useful for the diagnosis and follow-up of patients with membranous nephropathy (MN). Thus, some international guidelines recommend not performing renal biopsy in patients with positive serum anti-PLA2R Ab. AIM: To evaluate the prevalence of anti-PLA2R Ab in serum and renal tissue samples from Chilean patients with primary MN. MATERIAL AND METHODS: Twenty-eight patients aged 50 ± 14 years (20 males) with biopsy-proven primary MN plus a negative workup for secondary causes were included. Measurements of serum and renal histologic anti-PLA2R Ab were performed. The relationship between the findings of serum and tissue anti-PLA2R Ab was evaluated. RESULTS: Fifteen patients (54 %) had anti-PLA2R Ab presence in serum and 19 patients (68%) had positive anti-PLA2R Ab in the renal biopsy. All patients with positive serum anti-PLA2R Ab had positive antibodies on immunohistochemistry. CONCLUSIONS: Serum anti-PLA2R Ab is potentially useful in the diagnosis of patients with suspected primary MN in Chilean population.

Understanding the disrupting mechanism of the Tau aggregation motif "306 VQIVYK311 " by phenylthiazolyl-hydrazides inhibitors.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by the abnormal processing of the Tau and the amyloid precursor proteins. The unusual aggregation of Tau is based on the formation of intermolecular ß-sheets through two motifs: 275 VQIINK280 and 306 VQIVYK311 . Phenylthiazolyl-hydrazides (PTHs) are capable of inhibiting/disassembling Tau aggregates. However, the disaggregation mechanism of Tau oligomers by PTHs is still unknown. In this work, we studied the disruption of the oligomeric form of the Tau motif 306 VQIVYK311 by PTHs through molecular docking, molecular dynamics, and free energy calculations. We predicted hydrophobic interactions as the major driving forces for the stabilization of Tau oligomer, with V306 and I308 being the major contributors. Nonpolar component of the binding free energy is essential to stabilize Tau-PTH complexes. PTHs disrupted mainly the van der Waals interactions between the monomers, leading to oligomer destabilization. Destabilization of full Tau filament by PTHs and emodin was not observed in the sampled 20 ns; however, in all cases, the nonpolar component of the binding free energy is essential for the formation of Tau filament-PTH and Tau filament-emodin. These results provide useful clues for the design of more effective Tau-aggregation inhibitors.

Quality Threshold Clustering of Molecular Dynamics: A Word of Caution.

Clustering Molecular Dynamics trajectories is a common analysis that allows grouping together similar conformations. Several algorithms have been designed and optimized to perform this routine task, and among them, Quality Threshold stands as a very attractive option. This algorithm guarantees that in retrieved clusters no pair of frames will have a similarity value greater than a specified threshold, and hence, a set of strongly correlated frames are obtained for each cluster. In this work, it is shown that various commonly used software implementations are flawed by confusing Quality Threshold with another simplistic well-known clustering algorithm published by Daura et al. (Daura, X.; van Gunsteren, W. F.; Jaun, B.; Mark, A. E.; Gademann, K.; Seebach, D. Peptide Folding: When Simulation Meets Experiment. Angew. Chemie Int. Ed. 1999, 38 (1/2), 236-240). Daura's algorithm does not impose any quality threshold for the frames contained in retrieved clusters, bringing unrelated structural configurations altogether. The advantages of using Quality Threshold whenever possible to explore Molecular Dynamic trajectories is exemplified. An in-house implementation of the original Quality Threshold algorithm has been developed in order to illustrate our comments, and its code is freely available for further use by the scientific community.

BitClust: Fast Geometrical Clustering of Long Molecular Dynamics Simulations.

The growing computational capacity allows the investigation of large biomolecular systems by increasingly extensive molecular dynamics simulations. The resulting huge trajectories demand efficient partition methods to discern relevant structural dissimilarity. Clustering algorithms are available to address this task, but their implementations still need to be improved to gain in computational speed and to reduce the consumption of random access memory. We propose the BitClust code which, based on a combination of Python and C programming languages, performs fast structural clustering of long molecular trajectories. BitClust takes advantage of bitwise operations applied to a bit-encoded pairwise similarity matrix. Our approach allowed us to process a half-million frame trajectory in 6 h using less than 35 GB, a task that is not affordable with any of the similar alternatives.

Theoretical Evaluation of the Molecular Inclusion Process between Chlordecone and Cyclodextrins: A New Method for Mitigating the Basis Set Superposition Error in the Case of an Implicit Solvation Model.

The aim of this work is to describe the molecular inclusion of chlordecone with α-, ß-, and γ-cyclodextrin in aqueous solution using quantum mechanics. The guest-host complexes of chlordecone and cyclodextrins are modeled in aqueous solution using the multiple minima hypersurface methodology with a PM6-D3H4X semiempirical Hamiltonian, and the lowest energy minima obtained are reoptimized using the M06-2X density functional and the intermolecular interactions described using quantum theory of atoms in molecules (QTAIM). The studied complexes are classified according to the degree of inclusion, namely, total occlusion, partial occlusion, and external interaction. More stable complexes are obtained when γ-CD is used as the host molecule. The interactions characterized through QTAIM analysis are all of electrostatic nature, predominantly of dispersive type. In this work, a method based on the counterpoise correction is also discussed to mitigate the basis set superposition error in density functional theory calculations when using an implicit solvation model.

Role of Augmented Basis Sets and Quest for ab Initio Performance/Cost Alternative to Kohn-Sham Density Functional Theory.

Following a previous work, we have assessed the feasibility of MP2/CBS(d, t) as an alternative to state-of-the-art density functionals. The effect of using augmented basis sets is here tested on the 76 barrier heights and 10 isomerization reactions previously utilized. Moreover, calculations for 20 sets of the GMTKN24 database for thermochemistry, kinetics, and noncovalent interactions have been performed. For the density functional theory calculations, M06-2X and B3LYP-D3 functionals are utilized as two representative functionals, while MP2 and CCSD(T) methods are employed as the ab initio counterparts. The results show that MP2 calculations perform similarly to the ones obtained with M06-2X insofar as accuracy and computational cost are concerned. For all methods, the use of augmented basis sets yields enhanced results for anionic systems when compared with the ones from non-augmented bases. Otherwise, the basis-set change effect is found to be minimal. It is therefore concluded that the use of large basis sets is unjustified when facing the increase in computational cost.

Low intra-operative diagnostic accuracy does not affect postoperative treatment of acute appendicitis.

BACKGROUND: The intra-operative classification of appendicitis defines postoperative treatment. The correct designation can influence patient recovery, complications and hospital costs. Recent research has shown that intra-operative classification criteria varies among surgeons, and is not always the same as the pathologist's report. Classification accuracy can lower costs by preventing unnecessary treatment or sub-optimal interventions. METHODS: During a period of 4 months, N = 133 appendix specimens were received and evaluated by the pathology department of a single teaching hospital. Five surgeons extracted the specimens and one experienced pathologist drew the histopathology reports. A comparison between the surgeons' classifications and the pathologist's was made. Classification accuracy was determined and statistical analyses was performed using chi-square, and p values were obtained. A p < 0.05 was considered significant. RESULTS: A total of N = 133 specimens were obtained, 127 belonged to patients following emergency surgery due to acute abdominal pain; the other six were from elective hemi-colectomies for right colonic adenocarcinomas, and were not included. Of the 127 specimens analyzed, 14 (11%) were negative, 21 (16.5%) were edematous, 81 (63.7%) were phlegmonous and 11 (8.6%) were gangrenous. A total of 18 (14%) perforated appendices were also reported. Surgical accuracy was 60.6% (N = 67) with a statistically significant p < 0.001. Only five patients with incorrect intraoperative classifications received unnecessary or lacked treatment. CONCLUSIONS: An overall accuracy of 60.6% is seen when the surgical classification is compared to the pathological classification. Although the surgeons' accuracy is low when comparing intra-operative versus histopathological classification, this variation in designation does not affect postoperative treatment significantly.

Fiber pathways supporting early literacy development in 5-8-year-old children.

The development of fluent reading is an extended process that requires the recruitment of a comprehensive system of perisylvian brain regions connected by an extensive network of fiber pathways. In the present cross-sectional study, we focused on fiber pathways-the arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), and vertical occipital fasciculus (VOF)-proposed to support early literacy in typical 5-8-year-old children. We related quantitative metrics of fiber pathway microstructure in these pathways to early literacy measures of phonological awareness and decoding. We found that diffusion properties of the AF, ILF, and VOF not only show age-related differences, but also are predictive of early literacy skills after controlling for the effects of age, general white matter development, sex, IQ, and phonological skill. Perhaps most novel, we provide evidence supporting the involvement of the recently re-identified VOF in early literacy, and further, we provide evidence that a bilateral network of fiber pathways supports early literacy development.

Assessing How Correlated Molecular Orbital Calculations Can Perform versus Kohn-Sham DFT: Barrier Heights/Isomerizations.

To assess the title issue, 38 hydrogen transfer barrier heights and 38 non-hydrogen transfer barrier heights/isomerizations extracted from extensive databases have been considered, in addition to 4 2 p-isomerization reactions and 6 others for large organic molecules. All Kohn-Sham DFT calculations have employed the popular M06-2X functional, whereas the correlated molecular orbital (MO)-based ones are from single-reference MP2 and CCSD(T) methods. They have all utilized the same basis sets, with raw MO energies subsequently extrapolated to the complete basis set limit without additional cost. MP2 calculations are found to be as cost-effective as DFT ones and often slightly more, while showing a satisfactory accuracy when compared with the reference data. Although the focus is on barrier heights, the results may bear broader implications, in that one may see successes and difficulties of DFT when compared with traditional MO theories for the same data.

Integrating sampling techniques and inverse virtual screening: toward the discovery of artificial peptide-based receptors for ligands.

A novel heuristic using an iterative select-and-purge strategy is proposed. It combines statistical techniques for sampling and classification by rigid molecular docking through an inverse virtual screening scheme. This approach aims to the de novo discovery of short peptides that may act as docking receptors for small target molecules when there are no data available about known association complexes between them. The algorithm performs an unbiased stochastic exploration of the sample space, acting as a binary classifier when analyzing the entire peptides population. It uses a novel and effective criterion for weighting the likelihood of a given peptide to form an association complex with a particular ligand molecule based on amino acid sequences. The exploratory analysis relies on chemical information of peptides composition, sequence patterns, and association free energies (docking scores) in order to converge to those peptides forming the association complexes with higher affinities. Statistical estimations support these results providing an association probability by improving predictions accuracy even in cases where only a fraction of all possible combinations are sampled. False positives/false negatives ratio was also improved with this method. A simple rigid-body docking approach together with the proper information about amino acid sequences was used. The methodology was applied in a retrospective docking study to all 8000 possible tripeptide combinations using the 20 natural amino acids, screened against a training set of 77 different ligands with diverse functional groups. Afterward, all tripeptides were screened against a test set of 82 ligands, also containing different functional groups. Results show that our integrated methodology is capable of finding a representative group of the top-scoring tripeptides. The associated probability of identifying the best receptor or a group of the top-ranked receptors is more than double and about 10 times higher, respectively, when compared to classical random sampling methods.