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Cancer resistance to chemotherapy and radiation therapies presents significant challenges, necessitating the exploration of alternative approaches. Targeting specific proteins at the molecular level, particularly their active sites, holds promise in addressing this issue. We investigated the potential of 4′-methoxy-2-nitrochalcone (MNC) as an MCL-1 inhibitor, examining its chemical and structural characteristics to elucidate its biological activity and guide the selection of potential candidates. We conducted a docking study, followed by synthesis, structural characterization, theoretical calculations, and in vitro experiments to comprehensively evaluate MNC. The docking results revealed MNC’s excellent binding within the active site of MCL-1. At 50 µM, MNC demonstrated 99% inhibition of HCT116 cell proliferation, with an IC50 value of 15.18 µM after 24 h. Treatment with MNC at 30.36 and 15.18 µM resulted in reduced cell density. Notably, MNC exhibited marked cytotoxicity at concentrations of 15.58 µM and 7.79 µM, inducing high frequencies of plasma membrane rupture and apoptosis, respectively. Our findings highlight the significant biological potential of MNC as an MCL-1 inhibitor. Furthermore, we propose exploring chalcones with hydrogen bond acceptor substituents as promising candidates for studying inhibitors targeting this protein. In conclusion, our study addresses the challenge of cancer resistance by investigating MNC as an MCL-1 inhibitor. Through detailed characterization and experimental validation, we establish the efficacof MNC in inhibiting cell proliferation and inducing cytotoxic effects. These results underscore the potential of MNC as a valuable therapeutic agent and suggest the use of chalcones with hydrogen bond acceptor substituents as a basis for developing novel MCL-1 inhibitors.

We present a minimal extension of the left-right symmetric model based on the gauge group $SU(3)_{c} \times SU(2)_{L} \times SU(2)_{R} \times U(1)_{B-L} \times U(1)_{X}$, in which a vector-like fermion pair ($\zeta_L$ and $\zeta_R$) charged under the $U(1)_{B-L} \times U(1)_X$ symmetry is introduced. Associated with the symmetry breaking of the gauge group $SU(2)_{R} \times U(1)_{B-L} \times U(1)_{X}$ down to the Standard Model (SM) hypercharge $U(1)_Y$, Majorana masses for $\zeta_{L, R}$ are generated and the lightest mass eigenstate plays a role of the dark matter (DM) in our universe by its communication with the SM particles through a new neutral gauge boson "$X$". We consider various phenomenological constraints of this DM scenario, such as the observed DM relic density, the LHC Run-2 constraints from the search for a narrow resonance, and the perturbativity of the gauge couplings below the Planck scale. Combining all constraints, we identify the allowed parameter region which turns out to be very narrow. A significant portion of the currently allowed parameter region will be tested by the High-Luminosity LHC experiments., Comment: 23 pages, 6 figures

In this contribution, we re-assess some aspects of axionic electrodynamics by coupling non-linear electromagnetic effects to axion physics. We present a number of motivations to justify the coupling of the axion to the photon in terms of a general non-linear extension of the electromagnetic sector. Our emphasis in the paper relies on the investigation of the constitutive permittivity and permeability tensors, for which the axion contributes by introducing dependence on the frequency and wave vector of the propagating radiation. Also, we point out how the axion mass and the axion-photon-photon coupling constant contribute to a dispersive behavior of the electromagnetic waves, in contrast to what happens in the case of non-linear extensions, when effective refractive indices appear which depend only on the direction of the propagation with respect to the external fields. The axion changes this picture by yielding refractive indices with dependence on the wavelength. We apply our results to the special case of the Born-Infeld Electrodynamics and we show that it becomes birefringent whenever the axion is coupled. The paper is supplemented by an Appendix, where we approach the recent discussion on the controversy in defining the Poynting vector of axionic electrodynamics. We present our path to tackle the question and give the expressions we work out for both the Poynting vector and the momentum density transported by the waves., 30 pages, no figures

Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation - a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design. publishersversion published

Entomopathogenic nematodes (EPNs) from Heterorhabditidae and Steinernematidae families are extensively used to control insect pests. In Brazil, however, relatively few studies have identified and characterized these entomopathogens. The objective of this study was to identify and characterize an EPN isolate obtained from soil samples collected in the state of Paraná, Brazil. An isolate (UEL 08) of Heterorhabditis was detected in a soil sample collected from a pasture area cultivated with Brachiaria grass in Londrina, state of Paraná, Brazil (23°34ʹ311ʹʹS, 050°58ʹ298ʹʹW), using the insect-baiting technique with Galleria mellonella larvae as hosts. The nematode was identified through morphometric studies and molecular analyses based on amplification of the rDNA ITS region. Although we identified certain morphometric differences compared with the original description, the molecular data indicated that the ITS sequence obtained for the UEL 08 isolate is identical to the reference sequence of H. amazonensis (DQ665222) and presented 100% similarity. Thus, the findings of our morphological and molecular studies confirmed that the isolated nematode is H. amazonensis, which is the first time this species has been registered in Paraná. Study of the biological characteristics of H. amazonensis (UEL 08) revealed that the isolate has two distinct life cycles – one short (216 h) and the other long (288 h) – and produces two generations in both cycles. We observed that H. amazonensis (UEL 8) was pathogenic and virulent to the three evaluated hosts, although with different virulence against these hosts. The larvae of G. mellonella and Alphitobius diaperinus were more susceptible than adult Dichelops (Diacereus) melacanthus, with 100%, 85%, and 46% mortality, respectively. Furthermore, an in vivo production assay revealed a mean daily yield of 3.4 × 103 infective juveniles/g host larvae. Resumo Nematoides entomopatogênicos (NEP) das famílias Heterorhabditidae e Steinernematidae são amplamente utilizados no controle de insetos-pragas. No Brasil, os estudos relacionados a caracterização e identificação destes entomopatógenos são recentes e escassos. Nesse sentido, o objetivo deste estudo foi isolar NEP de amostras de solos coletadas em diferentes áreas no estado do Paraná, Brasil. Um isolado Heterorhabditis (UEL 08) detectado em amostra de solo em área de pastagem cultivada com braquiária, localizada em Londrina, Paraná, Brasil (23º34´311´´S, 050º58´298´´W), utilizando o método de “inseto-isca” com lagartas de Galleria mellonella. Para a identificação foram realizados estudos de morfometria e identificação molecular a partir da amplificação da região ITS. Algumas diferenças foram encontradas em termos de morfometria em comparação com a descrição original, entretanto, os dados moleculares demonstraram que a sequência obtida para o isolado UEL 08 é idêntica à sequência de referência de H. amazonensis (DQ665222), com a qual apresentou 100% de similaridade. Os estudos das características biológicas de H. amazonensis (UEL 08) revelaram que o isolado tem dois ciclos de vida distintos, um curto (216 h) e outro longo (288 h), sendo que ocorrem duas gerações em ambos os ciclos. O isolado UEL 08 H. amazonensis foi patogénico e virulento sobre os três hospedeiros avaliados. Notadamente, as larvas de G. mellonella e Alphitobius diaperinus foram consideradas mais susceptíveis do que os adultos do percevejo Dichelops (Diacereus) melacanthus, com percentagens de mortalidade de 100%, 85% e 46% de mortalidade, respectivamente. O ensaio de produção in vivo revelou um rendimento médio diário de 3,4 × 103 juvenis infectantes/g de larva hospedeira.

Honey bee abdominal pigmentation is one of the most recognisable traits and it is often used by beekeepers as an indicator of M-lineage subspecies purity. However, this approach may negatively impact population diversity and is futile if there is no association between tergite colour patterns and the genetic background. To assess whether this trait can be used as a proxy for introgression proportions in M-lineage subspecies, we genotyped, with highly informative SNP assays, A. m. mellifera and A. m. iberiensis individuals displaying four different colour phenotypes. The SNP data detected highly introgressed bees exhibiting a black phenotype and, at the same time, pure or marginally introgressed bees with yellow banding patterns, in both subspecies. Despite these observations, contrary to A. m. iberiensis , in A. m. mellifera , introgression proportions revealed to be a significant predictor of abdominal pigmentation. Therefore, abdominal pigmentation could be used by A. m. mellifera conservationists to guide colony selection when genetic tools are unavailable. KAB was funded by Dr. Tony Ryan research scholarship and an Irish Research Council scholarship. This work was financed by the Native Irish Honeybee Society (NIHBS), Federation of Irish Beekeeping Associations (FIBKA) and FEDER (Fundo Europeu de Desenvolvimento Regional) through the program COMPETE 2020–POCI (Programa Operacional para a Competividade e Internacionalização) and by the Portuguese funds through FCT (Fundação para a Ciência e a Tecnologia) in the framework of the project BeeHappy (POCI-01-0145-FEDER-029871). info:eu-repo/semantics/publishedVersion

Chalcones exhibit a broad spectrum of biological activities, mainly due to α,β-unsaturated ketone, and are precursors of the biosynthesis of flavonoids present in plants. These compounds have been shown to be useful in the biological approach, proven by the broad spectrum of biological activities reported, and also in the technological approach, considering their potential as nonlinear optic (NLO) material. In this context, this work aimed to examine the crystallization and characterization of fluorinated chalcone (E)-1-(4-fluorophenyl)-3-(4-isopropylphenyl)prop-2-en-1-one (DFC). A comprehensive structural study of DFC was carried out to understand the process of stabilizing the crystalline lattice through X-ray diffraction, infrared spectroscopy, and molecular modeling studies. Finally, the electrical properties of DFC were calculated by using the supermolecule method (SM). DFC molecules are connected by means of CH···O and CH···F intermolecular contacts, forming dimers which play an important role in the stabilization of crystal packing. Molecular modeling studies indicated that this compound could act as an anti-tuberculosis ligand because of its high binding affinity with the M. tuberculosis enoyl-acyl carrier protein, InhA. On the other hand, theoretical calculations were performed to evaluate the NLO properties of DFC and indicated that it showed good potential. Keywords: Molecular modeling, NLO properties, Fluorinated chalcone

We propose a model of Majorana fermions with quartic self-couplings. These Majorana fermions acquire masses via a type II seesaw mechanism in which the physical eigenstates are identified as a light Majorana fermion and another heavy Majorana fermion. On a physical basis, the quartic self-couplings involve axial currents of these Majorana fermions, and also the interaction of the axial current for the light particle with the heavy particle one. We introduce two auxiliaries gauge fields in this model, and we study the stability conditions of the correspondent effective potential of the model. The ground state of the effective potential introduces two 4-vectors as scales of vacuum expected values, and consequently, the dynamical Lorentz symmetry breaking (DLSB) emerges in the model. We use the expansion of the effective action to calculate the effective Lagrangian up to second order in the auxiliary fields as fluctuations around the ground state. This mechanism generates dynamics for the auxiliary gauge fields, mixed mass terms, longitudinal propagation, and Chern-Simons term through radiative corrections. After the diagonalization, the two gauge fields gain masses through an analogous type II seesaw mechanism in which a gauge boson has a light mass, and the other one acquires a heavy mass. In this scenario of Lorentz symmetry breaking, we obtain the correspondent dispersion relations for the Majorana fermions and the gauge boson fields. Posteriorly, we analyze the neutrino's oscillations in the presence of a DLSB parameter, in the transition $\nu_{e} \rightarrow \nu_{\mu}$. We discuss the parameter space of this transition and show that the DLSB can conciliate the LSND and super-Kamiokande results., Comment: 13 pages, 6 figures, published version in the Physical Review D

The properties of the modified Maxwell electrodynamics (ModMax) are investigated in presence of external and uniform electric and magnetic fields. We expand the non-linear theory around an electromagnetic background up to second order in the propagating fields to obtain the permittivity and permeability tensors, dispersion relations, group velocity and refractive indices as functions of external fields. The case with perpendicular background fields is contemplated. The phenomenon of birefringence is discussed and the fundamental role of the ModMax parameter becomes clear. We calculate the difference of the refractive indices in terms of this parameter and the external fields. Finally, we set up a scenario where the axion is present and compute the interaction energy for the coupled axion-ModMax electrodynamics if a magnetic background field is considered. This calculation is carried out in the framework of the gauge-invariant, but path-dependent variables formalism. Our results show that the interaction energy contains a linear component, leading to the confinement of static probe charges where the interference between the ModMax parameter, the axion mass and the axion-photon coupling constant is pointed out., Comment: 12 pages, 2 figures, published version in Physical Review D

Paracoccidioidomycosis (PCM) is a systemic mycosis, endemic in Latin America, caused by fungi of the genus Paracoccidioides. The treatment of PCM is complex, requiring a long treatment period, which often results in serious side effects. The aim of this study was to screen for inhibitors of a specific target of the fungus that is absent in humans. Methylcitrate synthase (MCS) is a unique enzyme of microorganisms and is responsible for the synthesis of methylcitrate at the beginning of the propionate degradation pathway. This pathway is essential for several microorganisms, since the accumulation of propionyl-CoA can impair virulence and prevent the development of the pathogen. We performed the modeling and molecular dynamics of the structure of Paracoccidioides lutzii MCS (PlMCS) and performed a virtual screening on 89,415 compounds against the active site of the enzyme. The compounds were selected according to the affinity and efficiency criteria of in vitro tests. Six compounds were able to inhibit the enzymatic activity of recombinant PlMCS but only the compound ZINC08964784 showed fungistatic and fungicidal activity against Paracoccidioides spp. cells. The analysis of the interaction profile of this compound with PlMCS showed its effectiveness in terms of specificity and stability when compared to the substrate (propionyl-CoA) of the enzyme. In addition, this compound did not show cytotoxicity in mammalian cells, with an excellent selectivity index. Our results suggest that the compound ZINC08964784 may become a promising alternative antifungal against Paracoccidioides spp. Communicated by Ramaswamy H. Sarma

The stinkbug Euschistus heros is an important pest of Brazilian agricultural production with increasing importance in the Neotropical region. High reproductive potential and increased risk of resistance to insecticides are determining factors influencing its pest status. This work evaluated the effects of pyriproxyfen on the reproduction and morphological development of the reproductive system of E. heros. Pyriproxyfen was utilized at sublethal concentrations (LC30) in fourth-instar nymphs (N4). Sublethal pyriproxyfen resulted in a reduction in fertility and fecundity of 2 and 12% when only the males were treated, 47 and 53% when only the females were treated, and 32 and 46% when females and males were treated. Basal oocytes were larger and more previtellogenic in newly emerged pyriproxyfen-treated females. The nuclear area of testicular accessory cells shrunk after 10 and 15 days of age in treated insects. Similarly, testicular shape was altered, changing from an ellipsoid to an obpyriform pattern, characterized by hypertrophy of the basal region over time. The apparent area of the organ grew until ten days of age, then shrunk at 15 days of age. In summary, pyriproxyfen treatments disrupted the normal development of N4 of E. heros and diminished the reproductive potential of female and male adults.

The Neotropical brown stink bug, Euschistus heros, is the most important sucking pest of soybean crops, quantitatively and qualitatively affecting grain and seed. This study aimed to determine mouthpart deformities, feeding inhibition, and E. heros nymphs’ mortality when in contact with insect growth disruptors (IGDs). The effects of two insecticides of the chitin biosynthesis inhibitor group (CBIs), lufenuron and diflubenzuron, and the juvenile hormone analog pyriproxyfen were tested in the laboratory. CBI application promoted mouthpart deformities, feeding inhibition, alteration of metamorphosis, and mortality of E. heros nymphs. Although pyriproxyfen did not cause mouthpart deformation, it caused certain mortality for nymphs, possibly due to physiological disorders. Lufenuron caused feed inhibition and mortality in less time when compared with diflubenzuron and pyriproxyfen. It was also more toxic to 4th instar nymphs. The insecticides, when used in higher concentrations, increased nymph’s mortality in less time. Nymphs with deformed mouthparts were unable to feed and died. All IGDs in the tested concentrations caused 100% mortality and prevented adult formation.

Chemically induced toxicity is the leading cause of recent extinction of honey bees. In this regard, we developed an innovative artificial intelligence-based web app (BeeToxAI) for assessing the acute toxicity of chemicals to Apis mellifera. Initially, we developed and externally validated QSAR models for classification (external set accuracy ∼91%) through the combination of Random Forest and molecular fingerprints to predict the potential for chemicals to cause acute contact toxicity and acute oral toxicity to honey bees. Then, we developed and externally validated regression QSAR models ( R 2 = 0.75) using Feedforward Neural Networks (FNNs). Afterward, the best models were implemented in the publicly available BeeToxAI web app ( http://beetoxai.labmol.com.br/ ) . The outputs of BeeToxAI are: toxicity predictions with estimated confidence, applicability domain estimation, and color-coded maps of relative structure fragment contributions to toxicity. As an additional assessment of BeeToxAI performance, we collected an external set of pesticides with known bee toxicity that were not included in our modeling dataset. BeeToxAI classification models were able to predict four out of five pesticides correctly. The acute contact toxicity model correctly predicted all of the eight pesticides. Here we demonstrate that BeeToxAI can be used as a rapid new approach methodology for predicting acute toxicity of chemicals in honey bees.

Objetivo: Verificar a associação entre a ocorrência de discrepâncias medicamentosas na admissão hospitalar e o tempo de internação em pacientes cirúrgicos em um hospital de ensino. Método: Trata-se de estudo de coorte retrospectivo, realizado com todos os pacientes internos na clínica cirúrgica no período compreendido entre os anos de 2014 a 2018. As discrepâncias foram avaliadas comparando os medicamentos da primeira prescrição médica em ambiente hospitalar e os medicamentos constantes na melhor história possível da medicação, document este constituinte do prontuário farmacêutico que detalha o uso dos medicamentos em domicílio na semana que antecede a internação. Essas informações foram obtidas através de entrevista estruturada com o paciente, aplicada por farmacêutico clínico nas primeiras 24h de entrada do paciente no hospital. Estes pacientes foram avaliados em dois grupos: (a) expostos a discrepâncias medicamentosas e (b) não expostos. As fontes de dados foram os prontuários farmacoterapêutico e eletrônico do paciente. O nível de significancia estatística foi estabelecido em p

Background Endoscopic remission (ER) is currently endorsed as one of the main treatment targets in Crohn’s Disease (CD). In a previous study, we have shown that transmural remission (TR) is associated with better clinical outcomes up to 1-year. It is unknown if these results still hold over a longer follow-up Methods This was a multicenter study, including 333 CD patients with magnetic resonance enterography (MRE) and colonoscopy evaluation performed within a 6-month interval and at least 5-years of follow-up. Patients were classified as having TR (inactive MRE and colonoscopy), ER (active MRE and inactive colonoscopy), and no remission (NR) (active colonoscopy). The need for surgery, hospitalization, steroids, and biologics was evaluated at 5-years of follow-up. Results Patients with TR presented lower rates of surgery (1.9% vs 17.9% vs 23.7%, P Conclusion TR was associated with improved clinical outcomes over 5-years of follow-up. Going beyond ER appears to provide significant clinical benefits in the short and long-term.

Aim: Computer-aided drug design approaches were applied to identify chalcones with antiplasmodial activity. Methodology: The virtual screening was performed as follows: structural standardization of in-house database of chalcones; identification of potential Plasmodium falciparum protein targets for the chalcones; homology modeling of the predicted P. falciparum targets; molecular docking studies; and in vitro experimental validation. Results: Using these models, we prioritized 16 chalcones with potential antiplasmodial activity, for further experimental evaluation. Among them, LabMol-86 and LabMol-87 showed potent in vitro antiplasmodial activity against P. falciparum, while LabMol-63 and LabMol-73 were potent inhibitors of Plasmodium berghei progression into mosquito stages. Conclusion: Our results encourage the exploration of chalcones in hit-to-lead optimization studies for tackling malaria.

Using magnetic measurements structural irregularities in electrodeposited nanotubes are inferred. The correlation between morphology and magnetic properties is very useful for studying materials. Through the use of the magnetic switching field distribution, the association with the surface irregularities imperfections of the magnetic nanotubes was performed. The distribution of magnetic switching field presents well behaved in smooth-surface nanotubes and, for nanotubes with irregularities, the distribution of switching fields has a noisy behavior, added to that smoothed signal. This noise is due to the superficial irregularities on the tubes surface because the magnetic barriers occurring in imperfect structures. Pinning centers due to irregularities are the principal aspect to observe in this situation. Magnetic measurements were associated directly to the morphology obtained by scanning electron microscopy.

Os produtos químicos perigosos, especialmente os agrotóxicos e produtos químicos industriais, vem sendo considerados responsáveis por uma queda dramática no número das abelhas. Consequentemente, a avaliação de risco ecológico de novos produtos químicos é vital e necessária. Uma vez que os ensaios experimentais em abelhas são caros, demorados e apresentam um problema ético, existe uma necessidade muito urgente de desenvolver métodos alternativos para avaliar a ecotoxicidade em abelhas. Na presente revisão, nós apresentamos os principais avanços tecnológicos utilizados para identificar e filtrar com segurança, compostos potencialmente tóxicos para abelhas. Em seguida, nós destacamos os principais esforços e armadilhas na integração, preparo e padronização de dados necessários para construção de modelos computacionais e sugerimos roteiros que possam contribuir para otimizar os resultados da pesquisa e conduzir a construção de modelos computacionais mais eficientes e preditivos.

Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and affects over 200 million people worldwide. The control and treatment of this neglected tropical disease is based on a single drug, praziquantel, which raises concerns about the development of drug resistance. This, and the lack of efficacy of praziquantel against juvenile worms, highlights the urgency for new antischistosomal therapies. In this review we focus on innovative approaches to the identification of antischistosomal drug candidates, including the use of automated assays, fragment-based screening, computer-aided and artificial intelligence-based computational methods. We highlight the current developments that may contribute to optimizing research outputs and lead to more effective drugs for this highly prevalent disease, in a more cost-effective drug discovery endeavor.

The increasing availability of extensive collections of chemical compounds associated with experimental data provides an opportunity to build predictive quantitative structure-activity relationship (QSAR) models using machine learning (ML) algorithms. These models can promote data-driven decisions and have the potential to speed up the drug discovery process and reduce their failure rates. However, many essential aspects of data preparation and modeling are not available in any standalone program. Here, we developed an automated framework for the curation of chemogenomics data and to develop QSAR models for virtual screening using the open-source KoNstanz Information MinEr (KNIME) program. The workflow includes four modules: (i) dataset preparation and curation; (ii) chemical space analysis and structure-activity relationships (SAR) rules; (iii) modeling; and (iv) virtual screening (VS). As case studies, we applied these workflows to four datasets associated with different endpoints. The implemented protocol can efficiently curate chemical and biological data in public databases and generates robust QSAR models. We provide scientists a simple and guided cheminformatics workbench following the best practices widely accepted by the community, in which scientists can adapt to solve their research problems. The workflows are freely available for download at GitHub and LabMol web portals.

Non-linear electrodynamic models are re-assessed in this paper to pursue an investigation of the kinematics of the Compton effect in a magnetic background. Before considering specific models, we start off by presenting a general non-linear Lagrangian built up in terms of the most general Lorentz- and gauge-invariant combinations of the electric and magnetic fields. The extended Maxwell-like equations and the energy-momentum tensor conservation are presented and discussed in their generality. We next expand the fields around a uniform and time-independent electric and magnetic backgrounds up to second order in the propagating wave, and compute dispersion relations which account for the effect of the external fields. We obtain thereby the refraction index and the group velocity for the propagating radiation in different situations. In particular, we focus on the kinematics of the Compton effect in presence of external magnetic fields. This yields constraints that relate the derivatives of the general Lagrangian with respect to the field invariants and the magnetic background under consideration. We carry out our inspection by focusing on some specific non-linear electrodynamic effective models: Hoffmann-Infeld, Euler-Heisenberg, generalized Born-Infeld and Logarithmic., Comment: 13 pages, 9 figures, accepted version in Physical Review D

The increasing availability of extensive collections of chemical compounds associated with experimental data provides an opportunity to build predictive quantitative structure-activity relationship (QSAR) models using machine learning (ML) algorithms. These models can promote data-driven decisions and have the potential to speed up the drug discovery process and reduce their failure rates. However, many essential aspects of data preparation and modeling are not available in any standalone program. Here, we developed an automated framework for the curation of chemogenomics data and to develop QSAR models for virtual screening using the open-source KoNstanz Information MinEr (KNIME) program. The workflow includes four modules: (i) dataset preparation and curation; (ii) chemical space analysis and structure-activity relationships (SAR) rules; (iii) modeling; and (iv) virtual screening (VS). As case studies, we applied these workflows to four datasets associated with different endpoints. The implemented protocol can efficiently curate chemical and biological data in public databases and generates robust QSAR models. We provide scientists a simple and guided cheminformatics workbench following the best practices widely accepted by the community, in which scientists can adapt to solve their research problems. The workflows are freely available for download at GitHub and LabMol web portals.

We study CPT-odd non-minimal Lorentz-symmetry violating couplings in the electroweak sector modifying the interactions between leptons, gauge mediators and the Higgs boson. The tree-level (differential) cross sections for three important electroweak processes are discussed: $e^+ \, e^- \rightarrow Z \, H$, $e^+ \, e^- \rightarrow Z \, Z$ and $\gamma \, \gamma \rightarrow W^+ \, W^-$. By considering next-generation $e^+ \, e^-$ colliders reaching center-of-mass energies at the TeV scale and the estimated improved precision for the measurements of the respective cross sections, we are able to project upper bounds on the purely time-like background 4-vector as strict as $\lesssim 10^{-5} \, \mbox{GeV}^{-1}$, in agreement with previous work on similar Lorentz-violating couplings., Comment: 15 pages, published in NPB

The foot is key to sport [1] and is part of a set of mechanisms responsible for absorbing impacts, maintaining balance and distribution of forces. Therefore, special attention to the distribution o...

Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity., Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

In this paper, we study the thermodynamics of short-range central potentials, namely, the Lee-Wick potential, and the Plasma potential. In the first part of the paper we obtain the numerical solution for the orbits equation for these potentials. Posteriorly, we introduce the thermodynamics through the microcanonical and canonical ensembles formalism defined on the phase space of the system. We calculate the density of states associated with the Lee-Wick and the Plasma potentials. From density of states, we obtain the thermodynamical physical quantities like entropy and temperature as functions of the energy. We also use the Boltzmann-Gibbs formalism to obtain the partition functions, the mean energy and the thermal capacity for these short-range potentials., 25 pages, 14 figures

Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii Transmission-blocking activity was observed for epirubicin in vitro and in vivo Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

Resumen: Anualmente acontecen millones de accidentes y miles de fallecimientos derivados de la actividad laboral, siendo el 30% de estos siniestros aportados por la construcción civil. Debido a que este sector es uno de los motores de la economía iberoamericana, se torna relevante identificar el comportamiento de la siniestralidad laboral de dicha industria en la región. Por tal motivo, este artículo presenta como objetivo principal el desarrollo de un análisis sobre la accidentalidad laboral iberoamericana en el sector de la construcción, con base en resultados obtenidos de fuentes estadísticas oficiales para el periodo 2013-2017. El estudio en mención se llevó a cabo mediante investigaciones cuantitativas, observaciones estadísticas, determinación de correlaciones y uso de los métodos multicriterio AHP y TOPSIS. Los principales resultados de esta investigación se obtuvieron: la caracterización de la accidentalidad, un ranking Iberoamericano de siniestralidad y el análisis de aspectos básicos exigidos a empleadores de cada país involucrado. Asimismo, se consiguió identificar que en el periodo de análisis la región tuvo una mejoría en la lucha contra esta problemática, ya que se registró una reducción sucesiva en las cifras de accidentalidad a través del tiempo.

In the past decade we have seen two major Ebola virus outbreaks in Africa, the Zika virus in Brazil and the current outbreak of coronavirus disease which has been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). There is a strong sense of Déjà vu as the world is caught flat footed without effective treatments to administer to patients. Our team has been actively involved in several small molecule drug discovery efforts for the preceding virus outbreaks. In 2014 we used machine learning to identify 3 new molecules to test for the Ebola virus and these were subsequently shown to be active in vitro and in vivo. We have also been involved in open science approaches that leverage the community to help. In 2016 we launched the OpenZika project as an IBM World Community Grid Project that used distributed computing power of volunteers to dock large numbers of compounds into Zika and related flavivirus targets. This led us into several collaborations in which we validated computational predictions in vitro. With both of these initiatives there was some knowledge of the virus, many compounds had already been tested in the case of Ebola, whereas for Zika initially all we had was the virus RNA sequence. In the current SARS-CoV-2 outbreak, this was a completely new virus and the scientists in China and elsewhere have started from scratch. In the space of a few weeks since the outbreak is acknowledged to have started, there are now compounds suggested as active in vitro and molecules repurposed in clinical trials. While this has been impressive, we propose there may still be gaps in our approach to drug discovery for such outbreaks. There is an opportunity to repurpose additional approved drugs for this virus and we now suggest how these might be identified leveraging prior work on MERS-CoV, SARS-CoV and other viruses. We also describe some of the immense challenges and limitations of the open antiviral drug discovery approaches we have been involved in.

The Doplicher, Fredenhagen and Roberts (DFR) noncommutative (NC) formalism is propose in a curved space-time. In DFR approach, the NC parameter is promoted to the set of coordinates of the space-time. As consequence, the field theory defined on this space contains extra dimensions. We propose a metric containing the new coordinates to explain the length measurements of this extended space. We promote the Minkowski part of this extended metric to a metric defined in a curved manifold. Thus, we can build up a NC gravitation model with extra-dimensions. Based on the curved metric, we propose an Einstein-Hilbert action to describe the NC gravitation model on the DFR space. We present the NC version for the gravitational field equations. The weak field approximation is considered in the field equations to obtain the wave equations for the graviton propagation on the DFR space., 6 pages

Let $G$ be a simple graph and $I(X_G)=\varphi^{-1}(x_i^2-x_j^2 : i,j\in V_G)$, where $\varphi \colon K[E_G]\to K[V_G]$ is the homomorphism that sends an edge to the product of its vertices. The ideal $I(X_G)$ is Cohen--Macaulay, one-dimensional and binomial. If $G$ is bipartite, it is known that the Castelnuovo--Mumford regularity of $I(X_G)$ is equal to the maximum cardinality of a set of edges having no more than half of the edges of any Eulerian subgraph of $G$. Here, with respect to the grevlex order associated to an ordering of the edge set of $G$, we describe a Gr\"obner basis for $I(X_G)$, and we characterize the standard monomials of the ideal $(I(X_G),t_e)$ in terms of even sets of vertices marked with a parity. Using these results, we give a combinatorial interpretation of the degree of $I(X_G)$, via the set of even sets of vertices of $G$; and we show that the Castelnuovo--Mumford regularity of $I(X_G)$, for any graph, is the maximum cardinality of a set of edges having no more than half of the edges of any \emph{even} Eulerian subgraph of $G$ or, equivalently, the maximum cardinality of a minimum fixed parity $T$-join.

Studies evaluating the occurrence of enteropathogenic bacteria in urban rats (Rattus spp.) are scarce worldwide, specifically in the urban environments of tropical countries. This study aims to estimate the prevalence of diarrhoeagenic Escherichia coli (DEC) and Salmonella spp. with zoonotic potential in urban slum environments. We trapped rats between April and June 2018 in Salvador, Brazil. We collected rectal swabs from Rattus spp., and cultured for E. coli and Salmonella spp., and screened E. coli isolates by polymerase chain reaction to identify pathotypes. E. coli were found in 70% of Rattus norvegicus and were found in four Rattus rattus. DEC were isolated in 31.3% of the 67 brown rats (R. norvegicus). The pathotypes detected more frequently were shiga toxin E. coli in 11.9%, followed by atypical enteropathogenic E. coli in 10.4% and enteroinvasive E. coli in 4.5%. From the five black rats (R. rattus), two presented DEC. Salmonella enterica was found in only one (1.4%) of 67 R. norvegicus. Our findings indicate that both R. norvegicus and R. rattus are host of DEC and, at lower prevalence, S. enterica, highlighting the importance of rodents as potential sources of pathogenic agents for humans.