bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simplified curcumin targets the membrane of Bacillus subtilis
Authors: Morão Luana G. , Polaquini Carlos R. , Kopacz Malgorzata , Torrezan Guilherme S. , Ayusso Gabriela M. , Dilarri Guilherme , Cavalca Lúcia B. , Zielińska Aleksandra , Scheffers Dirk‐Jan , Regasini Luis O. , Ferreira Henrique 
Published: July 2018

AbstractCurcumin is the main constituent of turmeric, a seasoning popularized around the world with Indian cuisine. Among the benefits attributed to curcumin are anti‐inflammatory, antimicrobial, antitumoral, and chemopreventive effects. Besides, curcumin inhibits the growth of the gram‐positive bacterium Bacillus subtilis. The anti‐B. subtilis action happens by interference with the division protein FtsZ, an ancestral tubulin widespread in Bacteria. FtsZ forms protofilaments in a GTP‐dependent manner, with the concomitant recruitment of essential factors to operate cell division. By stimulating the GTPase activity of FtsZ, curcumin destabilizes its function. Recently, curcumin was shown to promote membrane permeabilization in B. subtilis. Here, we used molecular simplification to dissect the functionalities of curcumin. A simplified form, in which a monocarbonyl group substituted the β‐diketone moiety, showed antibacterial action against gram‐positive and gram‐negative bacteria of clinical interest. The simplified curcumin also disrupted the divisional septum of B. subtilis; however, subsequent biochemical analysis did not support a direct action on FtsZ. Our results suggest that the simplified curcumin exerted its function mainly through membrane permeabilization, with disruption of the membrane potential necessary for FtsZ intra‐cellular localization. Finally, we show here experimental evidence for the requirement of the β‐diketone group of curcumin for its interaction with FtsZ.
Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking
Authors: Alagumuthu Manikandan , Muralidharan Vivek Panyam , Andrew Monic , Ahmed Mohammed Habeeb , Iyer Sathiyanarayanan Kulathu , Arumugam Sivakumar 
Published: July 2018

AbstractDeveloping a new antibacterial drug by using (Z/E)‐4‐(4‐substituted‐benzylidene)‐2‐isoquinoline‐1,3(2H,4H)‐diones (5a–h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a–h. DNA gyrase inhibitory potentials were further validated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a–h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram−ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC50 0.55±0.12 μM; 5d, IC50 0.65±0.075 μg/mL; 5e, IC50 0.45±0.035 μM; 5f, IC50 0.58±0.025 μM; 5h, IC50 0.25±0.015 μM while Clorobiocin (standard) showed IC50 0.5±0.05 μM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, pharmacokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)‐4‐(4‐substituted‐benzylidene)‐2‐isoquinoline‐1,3(2H,4H) ‐diones (5a–h).
Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches
Authors: Hoffer Laurent , Muller Christophe , Roche Philippe , Morelli Xavier 
Published: July 2018

AbstractFor several decades, hit identification for drug discovery has been facilitated by developments in both fragment‐based and high‐throughput screening technologies. However, a major bottleneck in drug discovery projects continues to be the optimization of primary hits from screening campaigns in order to derive lead compounds. Computational chemistry or molecular modeling can play an important role during this hit‐to‐lead (H2L) stage by both suggesting putative optimizations and decreasing the number of compounds to be experimentally synthesized and evaluated. However, it is also crucial to consider the feasibility of organically synthesizing these virtually designed compounds. Furthermore, the generated molecules should have reasonable physicochemical properties and be medicinally relevant. This review focuses on chemistry‐driven and structure‐based computational methods that can be used to tackle the difficult problem of H2L optimization, with emphasis being placed on the strategy developed in our laboratory.
Galactomannan More than Pectin Exacerbates Liver Injury in Mice Fed with High‐Fat, High‐Cholesterol Diet
Authors: Shtriker Miriam G. , Peri Irena , Taieb Elise , Nyska Abraham , Tirosh Oren , Madar Zecharia 
Published: July 2018

ScopeGalactomannan and citrus pectin are considered ‘super fibers’ known for altering gut microbiota composition and improving glucose and lipid metabolism. The study aims to investigate the fiber's effect on a nonalcoholic steatohepatitis (NASH) model.Methods and resultsTwo feeding experiments are carried out using groups of 7–8 week‐old male C57BL/6J mice. The diets used are based on a high cholesterol/cholate diet (HCD), such as a nutritional NASH model. Mice are fed a diet with or without 15% fiber‐citrus pectin (HCD‐CP) or galactomannan (HCD‐G) together with the HCD (first experiment), which commenced 3 weeks prior to the HCD (second experiment). Liver damage is evaluated by histological and biochemical parameters. Galactomannan leads to lesser weight gain and improved glucose tolerance, but increased liver damage. This is shown by elevated levels of liver enzymes compared to that with HCD alone. Fibers induce higher steatosis, as evaluated by liver histology. This intriguing result is linked to various changes in the gut microbiota, such as elevated Proteobacteria levels in the galactomannan group, which are correlated with disturbed metabolism and dysbiosis.ConclusionsIn a NASH mouse model, galactomannan increases liver damage but improves glucose metabolism. Changes in the microbiota composition may answer this enigmatic observation.
On the strength of transversely isotropic rocks
Authors: Zhao Yang , Semnani Shabnam J. , Yin Qing , Borja Ronaldo I. 
Published: July 2018

SummaryAccurate prediction of strength in rocks with distinct bedding planes requires knowledge of the bedding plane orientation relative to the load direction. Thermal softening adds complexity to the problem since it is known to have significant influence on the strength and strain localization properties of rocks. In this paper, we use a recently proposed thermoplastic constitutive model appropriate for rocks exhibiting transverse isotropy in both the elastic and plastic responses to predict their strength and strain localization properties. Recognizing that laboratory‐derived strengths can be influenced by material and geometric inhomogeneities of the rock samples, we consider both stress‐point and boundary‐value problem simulations of rock strength behavior. Both plane strain and 3D loading conditions are considered. Results of the simulations of the strength of a natural Tournemire shale and a synthetic transversely isotropic rock suggest that the mechanical model can reproduce the general U‐shaped variation of rock strength with bedding plane orientation quite well. We show that this variation could depend on many factors, including the stress loading condition (plane strain versus 3D), degree of anisotropy, temperature, shear‐induced dilation versus shear‐induced compaction, specimen imperfections, and boundary restraints.
Brain investigations of rodent disease models by chemical exchange saturation transfer at 21.1 T
Authors: Roussel Tangi , Rosenberg Jens T. , Grant Samuel C. , Frydman Lucio 
Published: July 2018

This study explores opportunities opened up by ultrahigh fields for in vivo saturation transfer brain magnetic resonance imaging experiments. Fast spin‐echo images weighted by chemical exchange saturation transfer (CEST) effects were collected on Sprague–Dawley rats at 21.1 T, focusing on two neurological models. One involved a middle cerebral artery occlusion emulating ischemic stroke; the other involved xenografted glioma cells that were followed over the course of several days as they developed into brain tumors. A remarkably strong saturation‐derived contrast was observed for the growing tumors when calculating magnetization transfer ratios atc. 3.8 ppm. This large contrast originated partially from an increase in the contribution of the amide CEST effect, but mostly from strong decreases in the Overhauser and magnetization transfer contributions to the upfield region, whose differential attenuations could be clearly discerned thanks to the ultrahigh field. The high spectral separation arising at 21.1 T also revealed numerous CEST signals usually overlapping at lower fields. Ischemic lesions were also investigated but, remarkably, magnetization and saturation transfer contrasts were nearly absent when computing transfer asymmetries using either high or low saturation power schemes. These behaviors were consistently observed at 24 hours post‐occlusion, regardless of the data processing approach assayed. Considerations related to how various parameters defining these experiments depend on the magnetic field, primarily chemical shifts andT1values, are discussed.
Provider bias as a function of patient genotype: polygenic score analysis among diabetics from the Health and Retirement Study
Authors: Huibregtse B. M. , Boardman J. D. 
Published: July 2018

SummaryObjectivePoor patient–provider interactions due to provider bias are associated with worse physiological and behavioural health outcomes for patients. Prior research has shown that patients with obesity perceive less favourable interactions compared with those with lower weights. This paper explores whether this association depends on patients' cumulative polygenic score with respect to genes linked to obesity (i.e. a single variable quantifying the individual's genome‐wide risk factors for high body mass index [BMI] or genetic liability) and whether providers react differentially to patients whose obesity is more genetic in nature compared with patients with diabetes caused by environmental factors.MethodsThe association between patients' BMI category, their polygenic score for high BMI and their interaction was assessed for two measures of the patient–provider interaction within a sample of 521 older patients with diabetes from the Health and Retirement Study.ResultsParticularly for patients with obesity, the quality of the patient–provider interaction depended on genetic liability for high BMI controlling for demographic and clinical covariates. Providers responded less favourably to patients with diabetes influenced by environmental factors compared with individuals with high genetic liability.ConclusionsResults of this study suggest that a patient's genotype may elicit particular responses from their healthcare provider. When a provider judges a patient's high BMI to be environmentally driven rather than genetically oriented, patients receive reduced quality of care.
Enthalpic stabilization of an SH3 domain by D2O
Authors: Stadmiller Samantha S. , Pielak Gary J. 
Published: July 2018

AbstractThe stability of a protein is vital for its biological function, and proper folding is partially driven by intermolecular interactions between protein and water. In many studies, H2O is replaced by D2O because H2O interferes with the protein signal. Even this small perturbation, however, affects protein stability. Studies in isotopic waters also might provide insight into the role of solvation and hydrogen bonding in protein folding. Here, we report a complete thermodynamic analysis of the reversible, two‐state, thermal unfolding of the metastable, 7‐kDa N‐terminal src‐homology 3 domain of the Drosophila signal transduction protein drk in H2O and D2O using one‐dimensional 19F NMR spectroscopy. The stabilizing effect of D2O compared with H2O is enthalpic and has a small to insignificant effect on the temperature of maximum stability, the entropy, and the heat capacity of unfolding. We also provide a concise summary of the literature about the effects of D2O on protein stability and integrate our results into this body of data.
A new structural class of bacterial thioester domains reveals a slipknot topology
Authors: Miller Ona K. , Banfield Mark J. , Schwarz‐Linek Ulrich 
Published: July 2018

AbstractAn increasing number of surface‐associated proteins identified in Gram‐positive bacteria are characterized by intramolecular cross‐links in structurally conserved thioester, isopeptide, and ester domains (TIE proteins). Two classes of thioester domains (TEDs) have been predicted based on sequence with, to date, only representatives of Class I structurally characterized. Here, we present crystal structures of three Class II TEDs from Bacillus anthracis, vancomycin‐resistant Staphylococcus aureus, and vancomycin‐resistant Enterococcus faecium. These proteins are structurally distinct from Class I TEDs due to a β‐sandwich domain that is inserted into the conserved TED fold to form a slipknot structure. Further, the B. anthracis TED domain is presented in the context of a full‐length sortase‐anchored protein structure (BaTIE). This provides insight into the three‐dimensional arrangement of TIE proteins, which emerge as very abundant putative adhesins of Gram‐positive bacteria.
A protein–protein host–guest complex: Thermostable ferritin encapsulating positively supercharged green fluorescent protein
Authors: Pulsipher Katherine W. , Bulos Joshua A. , Villegas José A. , Saven Jeffery G. , Dmochowski Ivan J. 
Published: July 2018

AbstractWe characterize the encapsulation of supercharged green fluorescent protein, GFP(+36), by thermophilic ferritin from Archaeoglobus fulgidus (AfFtn). The AfFtn–GFP(+36) assembly is rapid, nearly stoichiometric, and robust. Using a more stably assembled mutant AfFtn, we show that encapsulation can occur in the presence of mostly assembled cages, in addition to encapsulation starting from AfFtn individual subunits. Assembly and encapsulation do not occur with non‐supercharged GFP or the alternately supercharged GFP(−30), highlighting the role of complementary electrostatic interactions between the cargo and AfFtn cage interior. We also present a method for verifying protein–protein encapsulation, using nickel nitrilotriacetic acid agarose resin. AfFtn‐supercharged protein host‐guest complexes could find applications in enzyme studies, protein separations, and in vivo protein stabilization and targeted delivery.
Comparison of ERG and SPINK1 expression among incidental and metastatic prostate cancer in Japanese men
Authors: Koide Haruhisa , Kimura Takahiro , Inaba Hiroyuki , Sato Shun , Iwatani Kosuke , Yorozu Takashi , Furusato Bungo , Kamata Yuko , Miki Jun , Kiyota Hiroshi , Takahashi Hiroyuki , Egawa Shin 
Published: July 2018

BackgroundTMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal‐type 1 (SPINK1) was almost exclusively defined in ERG‐negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts.MethodsA total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients.ResultsThe overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre‐treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration‐resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71).ConclusionsERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration‐sensitive PCa.
The effects of Enterolobium contortisiliquum serine protease inhibitor on the survival of the termite Nasutitermes corniger, and its use as affinity adsorbent to purify termite proteases
Authors: da Silva Ferreira Rodrigo , Napoleão Thiago Henrique , Silva‐Lucca Rosemeire A , Silva Mariana Cristina Cabral , Paiva Patrícia Maria Guedes , Oliva Maria Luiza Vilela 
Published: July 2018

AbstractBACKGROUNDTermites are one of the main wood destroying insects. Nasutitermes corniger (Isoptera: Termitidae), can invade and attack urban wooden environments used in the structures of buildings. The use of synthetic pesticides is the traditional method used to prevent termite attack; however, these compounds generally cause harm to the environment. This paper describes the insecticidal activity of Enterolobium contortisiliquum protease inhibitor (EcTI) on Nasutitermes corniger workers and soldiers.RESULTSEcTI induced mortality in Nasutitermes corniger workers (LC50 0.242 mg mL−1 at 6 days of exposure). Gut extracts from workers and soldiers showed protease activity on the H‐D‐Pro‐Phe‐Arg‐pNan substrate. EcTI inhibited gut proteases in N. corniger at nM concentrations in vitro. The inhibitory activity towards termite enzymes was stable within the range of 25–65 °C. The inhibitor's unordered structure showed a high content of β‐sheets; its secondary structure and the thermal denaturation monitored by CD showed a two‐state transition and melting temperature (Tm) of approximately 73 °C.CONCLUSIONOur results contribute to the understanding of Nasutitermes corniger complexity and provide new clues to achieve a better comprehension of the molecular mechanism of action of insecticides to this pest. © 2018 Society of Chemical Industry
Higher use of techniques studied and performance in melee combat produce a higher psychophysiological stress response
Authors: Diaz‐Manzano Montaña , Fuentes Juan P. , Fernandez‐Lucas Jesús , Aznar‐Lain Susana , Clemente‐Suárez Vicente Javier 
Published: July 2018

AbstractWe aimed to analyse the effectiveness of an operative training in soldiers' psychophysiological and melee combat performance. Nineteen soldiers performed a 50‐hr training for 10 weeks. After training, they were divided into two groups: higher performance group (HPG) and lower performance group (LPG), then they conducted a realistic melee simulation where psychophysiological response, task performance, and the utilization of techniques learned were measured. HPG presented a significantly (p < 0.05) higher heart rate, blood lactate, and jump height; a lower blood oxygen saturation, task performance mark, use of studied techniques than LPG after the simulation; and a higher low frequency/high frequency ratio of heart rate variability previous the simulation than LPG. Independent of performance and the use of studied techniques by the participants, the melee simulation produced an increase in fight or flight response, increasing rated of stress and perceived exertion, sympathetic modulation, and physiological response. A specific melee combat training program induced different modifications in psychophysiological and task performance depending on the level of studied technique used. HPG presented a significantly higher cardiovascular response than LPG and time perception, and memory presented no differences between groups; also HPG presented a significantly higher use of studied techniques.
Ecosystem traps and where to find them
Authors: Bosch Jan , Olsson Helena Holmström 
Published: July 2018

AbstractToday, companies operate in business ecosystems where they collaborate, compete, share, and learn from others with benefits such as to present more attractive offerings and sharing innovation costs. With ecosystems being the new way of operating, the ability to strategically reposition oneself to increase or shift power balance is becoming key for competitive advantage. However, companies run into a number of traps when trying to realize strategical changes in their ecosystems. In this paper, we identify 5 traps that companies fall into. First, the “descriptive versus prescriptive trap” is when companies assume that current boundaries between partners are immutable. Second, the “assumptions trap” is when powerful ecosystem partners assume that they understand what others regard as value‐adding without validating their assumptions. Third, the “keeping it too simple trap” is when companies overlooks the effort required to align interests. Fourth, the “doing it all at once trap” is when companies disrupt an ecosystem assuming that all partners can change direction at the same time. Finally, the “planning trap” is when companies are unable to move forward without a complete plan. We provide empirical evidence for each trap, and we propose an ecosystem engagement process for how to avoid falling into these.
Shear Strength of Reactive Resistance Welded Ti6Al4V Parts with the Use of Ni(V)/Al Multilayers
Authors: Maj Łukasz , Morgiel Jerzy , Mars Krzysztof , Tarasek Anna , Godlewska Elżbieta 
Published: July 2018

Abstract
The Ti6Al4V/(Ni/Al)/Ti6Al4V joints were obtained through reactive resistance welding which takes advantage of electric current heating to initiate the rapid exothermic reaction of Ni(V)/Al multilayers and activate diffusion of elements across the Ni/Al-Ti6Al4V interfaces. Simulations of temperature distribution, carried out using COMSOL® software, showed temperature gradient in the joint being a result of differences in resistivity of the Ti6Al4V alloy and the (Ni/Al)/Ti6Al4V interface. Shear tests revealed that extending duration of the process from 2 to 6 minutes helped to improve the shear strength from ~ 240 to ~ 335 MPa. The microstructure observations of the samples after those tests showed that de-cohesion of the joint occurred along the filler material/base material interface. A microcrack network characteristic for reacted Ni/Al foil with small ridges was found on the flat surfaces of fractured samples.