Miracle-dz/UniFAR-FTUs huggingface dataset:
Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease

Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms. A major challenge of the approach is the identification of the cellular targets. Here we report GNF7686, a small molecule inhibitor of Trypanosoma cruzi, the causative agent of Chagas disease, and identification of cytochrome b as its target. Following discovery of GNF7686 in a parasite growth inhibition high throughput screen, we were able to evolve a GNF7686-resistant culture of T. cruzi epimastigotes. Clones from this culture bore a mutation coding for a substitution of leucine by phenylalanine at amino acid position 197 in cytochrome b. Cytochrome b is a component of complex III (cytochrome bc1) in the mitochondrial electron transport chain and catalyzes the transfer of electrons from ubiquinol to cytochrome c by a mechanism that utilizes two distinct catalytic sites, QN and QP. The L197F mutation is located in the QN site and confers resistance to GNF7686 in both parasite cell growth and biochemical cytochrome b assays. Additionally, the mutant cytochrome b confers resistance to antimycin A, another QN site inhibitor, but not to strobilurin or myxothiazol, which target the QP site. GNF7686 represents a promising starting point for Chagas disease drug discovery as it potently inhibits growth of intracellular T. cruzi amastigotes with a half maximal effective concentration (EC50) of 0.15 µM, and is highly specific for T. cruzi cytochrome b. No effect on the mammalian respiratory chain or mammalian cell proliferation was observed with up to 25 µM of GNF7686. Our approach, which combines T. cruzi chemical genetics with biochemical target validation, can be broadly applied to the discovery of additional novel drug targets and drug leads for Chagas disease.
Novel Index of Maladaptive Myocardial Remodeling in Hypertension

Background— Hypertensive left ventricular hypertrophy (HTN-LVH) is a leading cause of heart failure. Conventional patterns of cardiac geometry do not adequately risk-stratify patients with HTN-LVH. Using cardiovascular magnetic resonance, we developed a novel Remodeling Index (RI) that was designed to detect an exaggerated hypertrophic response to hypertension and tested its potential to risk-stratify hypertensive patients. Methods and Results— The RI was derived using LaPlace’s Law ( ), and normal RI ranges were established in 180 healthy volunteers. The utility of the RI was examined in 256 asymptomatic hypertensive patients and 10 patients with heart failure with preserved ejection fraction. Hypertensive patients underwent multimodal cardiac assessment: contrast-enhanced cardiovascular magnetic resonance, echocardiograms, 24-hour blood pressure monitoring, and cardiac biomarkers (high-sensitivity cardiac troponins, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and galectin-3). Blood pressure accounted for only 20% of the variance observed in LV mass. Although there was no association between blood pressure and myocardial fibrosis, LV mass was independently associated with fibrosis. Compared with hypertensive patients without LVH (n=191; 74.6%) and those with HTN-LVH and normal RI (n=50; 19.5%), patients with HTN-LVH and low RI (HTN-LVH/low RI; n=15, 5.9%) had an amplified myocardial response: elevated indexed LV masses (83±24 g/m2), more fibrosis (73%), and higher biomarkers of myocardial injury and dysfunction (P<0.05 for all). RI was similar in HTN-LVH/low RI and heart failure with preserved ejection fraction (4.1 [3.4–4.5] versus 3.7 [3.4–4.0], respectively; P=0.15). Conclusions— We suggest that RI provides an approach for stratifying hypertensive patients and is suitable for testing in other disease cohorts to assess its clinical utility. Clinical Trial Registration— URL: https://clinicaltrials.gov. Unique identifier: NCT02670031.
Restoration of Sensitivity in Chemo — Resistant Glioma Cells by Cold Atmospheric Plasma

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite multimodal treatments including surgery, chemotherapy and radiotherapy the prognosis remains poor and relapse occurs regularly. The alkylating agent temozolomide (TMZ) has been shown to improve the overall survival in patients with malignant gliomas, especially in tumors with methylated promoter of the O6-methylguanine-DNA-methyltransferase (MGMT) gene. However, intrinsic and acquired resistance towards TMZ makes it crucial to find new therapeutic strategies aimed at improving the prognosis of patients suffering from malignant gliomas. Cold atmospheric plasma is a new auspicious candidate in cancer treatment. In the present study we demonstrate the anti-cancer properties of different dosages of cold atmospheric plasma (CAP) both in TMZ-sensitive and TMZ-resistant cells by proliferation assay, immunoblotting, cell cycle analysis, and clonogenicity assay. Importantly, CAP treatment restored the responsiveness of resistant glioma cells towards TMZ therapy. Concomitant treatment with CAP and TMZ led to inhibition of cell growth and cell cycle arrest, thus CAP might be a promising candidate for combination therapy especially for patients suffering from GBMs showing an unfavorable MGMT status and TMZ resistance.
Entamoeba histolytica-secreted cysteine proteases induce IL-8 production in human mast cells via a PAR2-independent mechanism

Entamoeba histolytica is an extracellular tissue parasite causing colitis and occasional liver abscess in humans. E. histolytica-derived secretory products (SPs) contain large amounts of cysteine proteases (CPs), one of the important amoebic virulence factors. Although tissue-residing mast cells play an important role in the mucosal inflammatory response to this pathogen, it is not known whether the SPs induce mast cell activation. In this study, when human mast cells (HMC-1 cells) were stimulated with SPs collected from pathogenic wild-type amoebae, interleukin IL-8 mRNA expression and production were significantly increased compared with cells incubated with medium alone. Inhibition of CP activity in the SPs with heat or the CP inhibitor E64 resulted in significant reduction of IL-8 production. Moreover, SPs obtained from inhibitors of cysteine protease (ICP)-overexpressing amoebae with low CP activity showed weaker stimulatory effects on IL-8 production than the wild-type control. Preincubation of HMC-1 cells with antibodies to human protease-activated receptor 2 (PAR2) did not affect the SP-induced IL-8 production. These results suggest that cysteine proteases in E. histolytica-derived secretory products stimulate mast cells to produce IL-8 via a PAR2-independent mechanism, which contributes to IL-8-mediated tissue inflammatory responses during the early phase of human amoebiasis.
Serum antibody and ocular responses to murine corneal infection caused by Pseudomonas aeruginosa

The serum antibody response and differential corneal response to primary and secondary infections by Pseudomonas aeruginosa were investigated in DBA/2J (resistant) and C57BL/6J (susceptible) mice, since they respond differently to intracorneal challenge. Using an enzyme-linked immunosorbent assay, we found that naturally resistant DBA/2J mice mounted a significant immunoglobulin M (IgM) and IgG response to P. aeruginosa within 7 days postinfection of one eye; this was subsequently followed by a drop in the IgM response. Of 31 mice, 30 were able to restore corneal clarity within 3 to 4 weeks. However, when C57BL/6J mice were infected intracorneally, their levels of serum antibody developed more slowly than did those of the DBA/2J mice, and they were unable to restore corneal clarity within 8 to 12 weeks. None of the mice from either test strain mounted a detectable serum IgA response to P. aeruginosa over a 90-day holding period. However, infection of the contralateral, normal cornea of mice of both test strains resulted in a heightened IgG response to P. aeruginosa within 30 days after the secondary infection. Many (50%) of the susceptible C57BL/6J mice recovered or exhibited less severe corneal damage within the 30-day holding period. If the C57BL/6J mice were reinfected 60 days after the primary infection instead of after 30 days, most (89%) of the mice had restored corneal clarity within 3 to 6 days. Passive transfer of immune serum from either recovered DBA/2J or C57BL/6J mice to naive C57BL/6J mice resulted in the restoration of corneal clarity in many of the recipients following infection.
Pareto-based Hybrid Multi-Objective Evolutionary Algorithm for Flexible Job-shop Scheduling Problem

In this paper, flexible job-shop scheduling problem (FJSP) is studied in the case of optimizing different contradictory objectives consisting of: (1) minimizing makespan, (2) minimizing total workload, and (3) minimizing workload of the most loaded machine. As the problem belongs to the class of NP-Hard problems, a new hybrid evolutionary algorithm is proposed to obtain a large set of Pareto-optimal solutions in a reasonable run time. The algorithm utilizes from a local search heuristic for improving the chance of obtaining more number of global Pareto-optimal solutions. The solution method uses from a perturbed global criterion function for guiding the search direction of the hybrid algorithm. Computational experiences show that the hybrid algorithm has superior performance in contrast to previous studies.
Systemic α-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release.

Systemically administered α-melanocyte-stimulating hormone (α-MSH) inhibits endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered α-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic α-MSH suppresses the LPS-induced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 μg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0-8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0-2 h) and IL-6 bioassay (0-8 h). α-MSH (100 μg/kg ip) completely prevented the onset of LPS-induced fever during the first 3-4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal α-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal α-MSH during the first 4 h after LPS but had no effect on α-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered α-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal α-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.
Eigenvectors in the superintegrable model I: generators

In order to calculate correlation functions of the chiral Potts model, one only needs to study the eigenvectors of the superintegrable model. Here we start this study by looking for eigenvectors of the transfer matrix of the periodic τ2(tq) model which commutes with the chiral Potts transfer matrix. We show that the degeneracy of the eigenspace of τ2(tq) in the Q = 0 sector is 2r, with r = (N − 1)L/N when the size of the transfer matrix L is a multiple of N. We introduce chiral Potts model operators, different from the more commonly used generators of quantum group . From these we can form the generators of a loop algebra . For this algebra, we then use the roots of the Drinfeld polynomial to give new explicit expressions for the generators representing the loop algebra as the direct sum of r copies of the simple algebra .
Sulfated Galactofucan from the Brown Alga Saccharina latissima—Variability of Yield, Structural Composition and Bioactivity

The fucose-containing sulfated polysaccharides (SP) from brown algae exhibit a wide range of bioactivities and are, therefore, considered promising candidates for health-supporting and medicinal applications. A critical issue is their availability in high, reproducible quality. The aim of the present study was to fractionate and characterize the SP extracted from Saccharina latissima (S.l.-SP) harvested from two marine habitats, the Baltic Sea and North Atlantic Ocean, in May, June and September. The fractionation of crude S.l. -SP by anion exchange chromatography including analytical investigations revealed that S.l. -SP is composed of a homogeneous fraction of sulfated galactofucan (SGF) and a mixture of low-sulfated, uronic acid and protein containing heteropolysaccharides. Furthermore, the results indicated that S.l. growing at an intertidal zone with high salinity harvested at the end of the growing period delivered the highest yield of S.l. -SP with SGF as the main fraction (67%). Its SGF had the highest degree of sulfation (0.81), fucose content (86.1%) and fucose/galactose ratio (7.8) and was most active (e.g., elastase inhibition: IC50 0.21 μg/mL). Thus, S.l. from the North Atlantic harvested in autumn proved to be more appropriate for the isolation of S.l. -SP than S.l. from the Baltic Sea and S.l. harvested in spring, respectively. In conclusion, this study demonstrated that habitat and harvest time of brown algae should be considered as factors influencing the yield as well as the composition and thus also the bioactivity of their SP.
Analysis and Optimization of Caching and Multicasting in Large-Scale Cache-Enabled Wireless Networks

Caching and multicasting at base stations are two promising approaches to supporting massive content delivery over wireless networks. However, existing analysis and designs do not fully explore and exploit the potential advantages of the two approaches. In this paper, we consider the analysis and optimization of caching and multicasting in a large-scale cache-enabled wireless network. We propose a random caching and multicasting design. By carefully handling different types of interferers and adopting appropriate approximations, we derive a tractable expression for the successful transmission probability in the general region, utilizing tools from stochastic geometry. We also obtain a closed-form expression for the successful transmission probability in the high signal-to-noise ratio (SNR) and user density region. Then, we consider the successful transmission probability maximization, which is a very complex nonconvex problem in general. Using optimization techniques, we develop an iterative numerical algorithm to obtain a local optimal caching and multicasting design in the general region. To reduce complexity and maintain superior performance, we also derive an asymptotically optimal caching and multicasting design in the asymptotic region, based on a two-stage optimization framework. Finally, numerical simulations show that the asymptotically optimal design achieves a significant gain in successful transmission probability over some baseline schemes in the general region.
A Two Stages Invasive Weed Optimization via a New Clustering Strategy

Invasive weed optimization (IWO), which is inspired from the invasive behavior of weeds growing in nature, has high explorative power and can converge to the optimal solution of a problem efficiently. However, the key parameter values are hard to set. Then competitive exclusion operator selects better solutions only based on fitness value, which may lead to premature convergence. In order to alleviate the two problems, this paper proposes a two stages IWO technique. In the first stage IWO mainly focuses on explorative search to find the promising solutions. With these obtained solutions picked out in the first stage, a new clustering strategy which is first proposed by this paper is adopted to capture different promising solution regions. In the second stage a modified IWO is utilized to search each promising regions carefully. Based on the results of clustering, the value of key parameter is determined by statistic information but not artificial setting. In this way parameter problem is solved and a balance between exploration and exploitation is achieved. Experimental results indicate that the proposed technique is an effective and efficient algorithm which can not only explores and exploits the promising regions in the search space effectively but also obtain the result superior to the standard invasive weed optimization.
Inductive Phase Shift Spectroscopy for Volumetric Brain Edema Detection: An Experimental Simulation

This study evaluates experimentally an induction based non-invasive technique for detection of changes of fluid volume through phase shift measurements as a possible method for volumetric brain edema monitoring. An induction coil - spherical head model was build and tested. The model involves two different diameter coils coaxially centered on a two- compartment glass sphere head model centrally placed with respect to the coils. Three different fluid volumes of physiological saline in 20 ml increments were used to simulate different edema levels. Phase shift of the impedance coils as a function of relative fluid volume was measured at five frequencies (40, 50, 100, 200 and 300 MHz) by a commercial vector network analyzer. The results show significant phase shift increase as a function of frequency and fluid volume. The experiments with the coil- spherical head system suggest that the tested technique has the potential to become a practical configuration for non-invasive volumetric brain edema monitoring.
Wide-Field Motion Integration in Fly VS Cells: Insights from an Inverse Approach

Fly lobula plate tangential cells are known to perform wide-field motion integration. It is assumed that the shape of these neurons, and in particular the shape of the subclass of VS cells, is responsible for this type of computation. We employed an inverse approach to investigate the morphology-function relationship underlying wide-field motion integration in VS cells. In the inverse approach detailed, model neurons are optimized to perform a predefined computation: here, wide-field motion integration. We embedded the model neurons to be optimized in a biologically plausible model of fly motion detection to provide realistic inputs, and subsequently optimized model neuron with and without active conductances (gNa, gK, gK(Na)) along their dendrites to perform this computation. We found that both passive and active optimized model neurons perform well as wide-field motion integrators. In addition, all optimized morphologies share the same blueprint as real VS cells. In addition, we also found a recurring blueprint for the distribution of gK and gNa in the active models. Moreover, we demonstrate how this morphology and distribution of conductances contribute to wide-field motion integration. As such, by using the inverse approach we can predict the still unknown distribution of gK and gNa and their role in motion integration in VS cells.
Stable Extracellular RNA Fragments of Mycobacterium tuberculosis Induce Early Apoptosis in Human Monocytes via a Caspase-8 Dependent Mechanism

The molecular basis of pathogen-induced host cell apoptosis is well characterized for a number of microorganisms. Mycobacterium tuberculosis is known to induce apoptosis and it was shown that live but not heat killed M. tuberculosis stimulates this biological pathway in monocytes. The dependence of this activity on live bacilli led us to hypothesize that products released or secreted by M. tuberculosis are the primary apoptotic factors for human monocytes. Thus, the culture filtrate of in vitro grown M. tuberculosis strain H37Rv was fractioned by conventional chromatography and the apoptosis-inducing activity of individual fractions was measured on human monocytes. The tests employed included measurement of cell membrane damage, caspase activation, and cytokine release. Small molecular weight RNAs of M. tuberculosis were recognized as the predominant apoptosis inducing factors. The RNA was comprised primarily of tRNA and rRNA fragments that stably accumulate in the culture filtrate during early log-phase growth. The RNA fragments signaled through a caspase-8 dependent, caspase-1 and TNF-α independent pathway that ultimately compromised the human monocytes' ability to control M. tuberculosis infection. These studies provide the first report of bacterial RNA inducing apoptosis. They also provide a foundation to pursue pathways for secretion or release of nucleic acids from M. tuberculosis and the impact of secreted RNA fragments on pathogenesis.
Analysis of the LKB1-STRAD-MO25 complex

Mutations in the LKB1 tumour suppressor threonine kinase cause the inherited Peutz-Jeghers cancer syndrome and are also observed in some sporadic cancers. Recent work indicates that LKB1 exerts effects on metabolism, polarity and proliferation by phosphorylating and activating protein kinases belonging to the AMPK subfamily. In vivo, LKB1 forms a complex with STRAD, an inactive pseudokinase, and MO25, an armadillo repeat scaffolding-like protein. Binding of LKB1 to STRAD-MO25 activates LKB1 and re-localises it from the nucleus to the cytoplasm. To learn more about the inherent properties of the LKB1-STRAD-MO25 complex, we first investigated the activity of 34 point mutants of LKB1 found in human cancers and their ability to interact with STRAD and MO25. Interestingly, 12 of these mutants failed to interact with STRAD-MO25. Performing mutagenesis analysis, we defined two binding sites located on opposite surfaces of MO25α, which are required for the assembly of MO25α into a complex with STRADα and LKB1. In addition, we demonstrate that LKB1 does not require phosphorylation of its own T-loop to be activated by STRADα-MO25α, and discuss the possibility that this unusual mechanism of regulation arises from LKB1 functioning as an upstream kinase. Finally, we establish that STRADα, despite being catalytically inactive, is still capable of binding ATP with high affinity, but that this is not required for activation of LKB1. Taken together, our findings reinforce the functional importance of the binding of LKB1 to STRAD, and provide a greater understanding of the mechanism by which LKB1 is regulated and activated through its interaction with STRAD and MO25.