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Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC 50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Efforts to tackle malaria must continue for a disease that threatens half of the global population. Parasite resistance to current therapies requires new chemotypes that are able to demonstrate effectiveness and safety. Previously, we developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, was made freely available to the scientific community and offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization. Here, we experimentally validate MAIP and demonstrate how the approach was used in combination with a robust compound selection workflow and a recently introduced innovative high-throughput screening (HTS) cascade to select and purchase compounds from a public library for subsequent experimental screening. We observed a 12-fold enrichment compared with a randomly selected set of molecules, and the eight hits we ultimately selected exhibit good potency and absorption, distribution, metabolism, and excretion (ADME) profiles., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7- N -substituted-3-oxadiazole quinolone hit class. We established the structure-activity relationship and optimized the antimalarial potency. The optimized analog WJM228 ( 17 ) showed robust metabolic stability in vitro , although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Q o site of cytochrome b (cyt b ), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Q o site but not Q i site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b . Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Q o site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

Our goal is data-driven discovery of features for text simplification. In this paper, we investigate three types of lexical chains: exact, synonymous, and semantic. A lexical chain links semantically related words in a document. We examine their potential with a document-level corpus statistics study (914 texts) to estimate their overall capacity to differentiate between easy and difficult text and a classification task (11 000 sentences) to determine usefulness of features at sentence-level for simplification. For the corpus statistics study we tested five document-level features for each chain type: total number of chains, average chain length, average chain span, number of crossing chains, and the number of chains longer than half the document length. We found significant differences between easy and difficult text for average chain length and the average number of cross chains. For the sentence classification study, we compared the lexical chain features to standard bag-of-words features on a range of classifiers: logistic regression, naïve Bayes, decision trees, linear and RBF kernel SVM, and random forest. The lexical chain features performed significantly better than the bag-of-words baseline across all classifiers with the best classifier achieving an accuracy of ∼90% (compared to 78% for bag-of-words). Overall, we find several lexical chain features provide specific information useful for identifying difficult sentences of text, beyond what is available from standard lexical features.

Lithium-ion batteries are the most popular used portable energy storage technology due to the relatively high energy density. While thermal instability induced safety concerns impede the pace of developing large scale applications, the practical applications have no tolerance for the catastrophic failure. To learn more about the characteristics of battery failure, the criticality of battery thermal runaway is studied in this paper. Semenov and Thomas models are employed to analyze the criticality of battery thermal runaway in uniform and nonuniform temperature distribution situations. In order to improve accuracy of prediction, the critical parameters of overall reaction are taken as a weighted average of four exothermic reactions and the critical criteria are revised by the consumption of reactants. Results from revised model are consistence with oven model. According to the revised thermal abuse models, the critical criterion (ψ cr ,δ cr ) and critical temperature distribution (θ cr ) are analyzed in different composite materials, convective heat transfer coefficients and cell deformations. Results give the variation of critical criteria and critical temperature with these factors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Simplifying medical texts facilitates readability and comprehension. While most simplification work focuses on English, we investigate whether features important for simplifying English text are similarly helpful for simplifying Spanish text. We conducted a user study on 15 Spanish medical texts using Amazon Mechanical Turk and measured perceived and actual difficulty. Using the median of the difficulty scores, we split the texts into easy and difficult groups and extracted 10 surface, 2 semantic and 4 grammatical features. Using t-tests, we identified those features that significantly distinguish easy text from difficult text in Spanish and compare with prior work in English. We found that easy Spanish texts use more repeated words and adverbs, less negations and more familiar words, similar to English. Also like English, difficult Spanish texts use more nouns and adjectives. However in contrast to English, easier Spanish texts contained longer sentences and used grammatical structures that were more varied.

The electrochemical performance of anodes made of transition metal oxides (TMOs) in lithium-ion batteries (LIBs) often suffers from their chemical and mechanical instability. In this research, a novel electrode with a hierarchical current collector for TMO active materials is successfully fabricated. It consists of porous nickel as current collector on a copper substrate. The copper has vertically aligned microchannels. Anatase titanium dioxide (TiO 2 ) nanoparticles of ∼100 nm are directly synthesized and cast on the porous Ni using a one-step process. Characterization indicates that this electrode exhibits excellent performance in terms of capacity, reliable rate, and long cyclic stability. The maximum insertion coefficient for the reaction product of Li x TiO 2 is ∼0.85, a desirable value as an anode of LIBs. Cross-sectional SEM and EDS analysis confirmed the uniform and stable distribution of nanosized TiO 2 nanoparticles inside the Ni microchannels during cycling. This is due to the synergistic effect of nano-TiO 2 and the hierarchical Cu/Ni current collector. The advantages of the Cu/Ni/TiO 2 anode include enhanced activity of electrochemical reactions, shortened lithium ion diffusion pathways, ultrahigh specific surface area, effective accommodation of volume changes of TiO 2 nanoparticles, and optimized routes for electrons transport.

Many different text features influence text readability and content comprehension. Negation is commonly suggested as one such feature, but few general-purpose tools exist to discover negation and studies of the impact of negation on text readability are rare. In this paper, we introduce a new negation parser (NegAIT) for detecting morphological, sentential, and double negation. We evaluated the parser using a human annotated gold standard containing 500 Wikipedia sentences and achieved 95%, 89% and 67% precision with 100%, 80%, and 67% recall, respectively. We also investigate two applications of this new negation parser. First, we performed a corpus statistics study to demonstrate different negation usage in easy and difficult text. Negation usage was compared in six corpora: patient blogs (4K sentences), Cochrane reviews (91K sentences), PubMed abstracts (20K sentences), clinical trial texts (48K sentences), and English and Simple English Wikipedia articles for different medical topics (60K and 6K sentences). The most difficult text contained the least negation. However, when comparing negation types, difficult texts (i.e., Cochrane, PubMed, English Wikipedia and clinical trials) contained significantly (p<0.01) more morphological negations. Second, we conducted a predictive analytics study to show the importance of negation in distinguishing between easy and difficulty text. Five binary classifiers (Naïve Bayes, SVM, decision tree, logistic regression and linear regression) were trained using only negation information. All classifiers achieved better performance than the majority baseline. The Naïve Bayes' classifier achieved the highest accuracy at 77% (9% higher than the majority baseline)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Escalating health care expenses pose a new challenge to the health care environment of becoming more cost-effective. There is an urgent need for more accurate data on the costs of health care procedures. Demographic changes, changing morbidity profile, and the rising impact of noncommunicable diseases are emphasizing the role of nuclear medicine (NM) in the future health care environment. However, the impact of emerging disease load and stagnant resource availability needs to be balanced by a strategic drive towards optimal utilization of available healthcare resources., Aim: The aim was to ascertain the cost of diagnostic procedures conducted at the NM Department of a tertiary health care facility by employing activity based costing (ABC) method., Materials and Methods: A descriptive cross-sectional study was carried out over a period of 1 year. ABC methodology was utilized for ascertaining unit cost of different diagnostic procedures and such costs were compared with prevalent market rates for estimating cost effectiveness of the department being studied., Results: The cost per unit procedure for various procedures varied from Rs. 869 (USD 14.48) for a thyroid scan to Rs. 11230 (USD 187.16) for a meta-iodo-benzyl-guanidine (MIBG) scan, the most cost-effective investigations being the stress thallium, technetium-99 m myocardial perfusion imaging (MPI) and MIBG scan. The costs obtained from this study were observed to be competitive when compared to prevalent market rates., Conclusion: ABC methodology provides precise costing inputs and should be used for all future costing studies in NM Departments.

Several bacterial species possess the ability to attach to surfaces and colonize them in the form of thin films called biofilms. Biofilms that grow in porous media are relevant to several industrial and environmental processes such as wastewater treatment and CO2 sequestration. We used Pseudomonas fluorescens, a Gram-negative aerobic bacterium, to investigate biofilm formation in a microfluidic device that mimics porous media. The microfluidic device consists of an array of micro-posts, which were fabricated using soft-lithography. Subsequently, biofilm formation in these devices with flow was investigated and we demonstrate the formation of filamentous biofilms known as streamers in our device. The detailed protocols for fabrication and assembly of microfluidic device are provided here along with the bacterial culture protocols. Detailed procedures for experimentation with the microfluidic device are also presented along with representative results.

The present paper highlights the UV-Vis and fluorescence spectroscopic studies on spontaneous non-covalent interaction between a designed monoporphyrin, namely, 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrin (1) and fullerenes (C(60) and C(70)) in toluene medium. While UV-Vis studies reveal considerable amount of fullerene/1 interaction in ground state, steady state fluorescence study establishes remarkable quenching of fluorescence intensity of 1 in the presence of fullerenes C(60) and C(70). Stoichiometry of both the fullerene complexes of 1 is determined to be 1:1. The magnitude of average binding constant (K) values for C(70)/1 and C(60)/1 systems is estimated to be 8705 and 3440 dm(3) mol(-1), respectively, which also prove that moderate value of selectivity in binding between C(70) and C(60) complexes of 1 is resulted in our present work. The genetics of the photo-physical characteristics of fullerene/1 complexes get tremendous support from lifetime experiment, which signifies the importance of static quenching phenomenon for our presently investigated supramolecules. Life time experiment yields larger magnitude of charge separated rate constant for the fullerene/1 species in toluene. Theoretical calculations at molecular mechanics level evoke the single projection geometric structures for the C(60)/1 and C(70)/1 systems in vacuo which also proves that interaction between C(70) and 1 is governed by the dispersive forces associated with π-π interaction rather than electrostatic mechanism associated with charge transfer mechanism., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: We designed this study to focus on women with mobile uteri benign no larger than 14 weeks, who would ordinarily be considered candidates for vaginal hysterectomy and compare the outcomes when abdominal routes were chosen. We also compared the intra and post operative complications, requirement for blood transfusion, length of hospital stay, between abdominal and vaginal route of hysterectomy., Method: In a simple randomized prospective comparative study 200 consecutive patients requiring hysterectomy for benign uterine conditions were analysed over a period of 2 years. (June 2006-May 2008). Group A (n = 100) underwent vaginal hysterectomy (non descent vaginal hysterectomy, NDVH) which was compared with group B (n = 100) who had abdominal hysterectomy., Results: As far as duration of operation, duration of i.v. drip, mobilization in post operative ward, duration of hospital stay, P value was significant. Regarding blood loss P value was insignificant., Conclusion: The accessibility of the vaginal passage, disease confined to the uterus and the surgeons experience are the major determining factors for the choice of the route of hysterectomy.

Phase diagrams of pseudoternary systems of Tween-80, butanol, hexane and water were constructed by a visual titration method. The cloud points (CPs) at various compositions were determined and the variations in the cloud points were analyzed on the basis of changes in the composition of the different components in the microemulsions. A quantitative model was established by using multiple regression analysis considering weight percent of emulsifier (surfactant+cosurfactant) and oil as independent variables. A lowering in the CP with increase in emulsifier content and decrease in oil content was observed. Addition of sodium chloride also depressed the CP significantly. Further, with the increase in temperature the turbid phase started separating to three different transparent zones. The upper layer was recognized as the oil-rich phase, middle layer was due to microemulsion and the lower layer was found to be a micellar system. Metal ions and colored organic substrates partitioned into these different phases, which provides scope for applications in metal ion preconcentration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A study on the phenomenon of clouding and the applications of cloud point technology has been thoroughly discussed. The phase behaviour of clouding and various methods adopted for the determination of cloud point of various surfactant systems have been elucidated. The systems containing anionic, cationic, nonionic surfactants as well as microemulsions have been reviewed with respect to their clouding phenomena and the effects of structural variation in the surfactant systems have been incorporated. Additives of various natures control the clouding of surfactants. Electrolytes, nonelectrolytes, organic substances as well as ionic surfactants, when present in the surfactant solutions, play a major role in the clouding phenomena. The review includes the morphological study of clouds and their applications in the extraction of trace inorganic, organic materials as well as pesticides and protein substrates from different sources., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Central to the response of Mycobacterium tuberculosis to environmental stress is the regulation of genes under the control of alternative sigma factors. Sigma E of M. tuberculosis plays an important role in the intracellular life of the bacterium and regulates several genes which are important for maintaining the integrity of the cell envelope stress. This makes it important to understand how SigE is activated under stress. Here we elucidate the mechanisms regulating interaction of SigE with its cognate anti-sigma factor RseA. Cysteines 70 and 73 are required for redox-dependent interaction of RseA with SigE. Under surface stress, PknB-dependent phosphorylation of RseA on T39 is required for its cleavage by ClpC1P2 thereby activating the SigE regulon. Rv2745c (MSMEG&#95;2694), a transcriptional regulator, activates the clp regulon in response to vancomycin-induced stress. Taken together with the previous report that Rv2745c is activated by SigE, our study uncovers a positive feedback loop that activates the sigE regulon under envelope stress.

The bacterial divisome is a multiprotein complex. Specific protein-protein interactions specify whether cell division occurs optimally, or whether division is arrested. Little is known about these protein-protein interactions and their regulation in mycobacteria. We have investigated the interrelationship between the products of the Mycobacterium tuberculosis gene cluster Rv0014c-Rv0019c, namely PknA (encoded by Rv0014c) and FtsZ-interacting protein A, FipA (encoded by Rv0019c) and the products of the division cell wall (dcw) cluster, namely FtsZ and FtsQ. M. smegmatis strains depleted in components of the two gene clusters have been complemented with orthologs of the respective genes of M. tuberculosis. Here we identify FipA as an interacting partner of FtsZ and FtsQ and establish that PknA-dependent phosphorylation of FipA on T77 and FtsZ on T343 is required for cell division under oxidative stress. A fipA knockout strain of M. smegmatis is less capable of withstanding oxidative stress than the wild type and showed elongation of cells due to a defect in septum formation. Localization of FtsQ, FtsZ and FipA at mid-cell was also compromised. Growth and survival defects under oxidative stress could be functionally complemented by fipA of M. tuberculosis but not its T77A mutant. Merodiploid strains of M. smegmatis expressing the FtsZ(T343A) showed inhibition of FtsZ-FipA interaction and Z ring formation under oxidative stress. Knockdown of FipA led to elongation of M. tuberculosis cells grown in macrophages and reduced intramacrophage growth. These data reveal a novel role of phosphorylation-dependent protein-protein interactions involving FipA, in the sustenance of mycobacterial cell division under oxidative stress.

Wag31 of Mycobacterium tuberculosis belongs to the DivIVA family of proteins known to regulate cell morphology in Gram-positive bacteria. Here we demonstrate an unrecognized, novel role of Wag31 in oxidatively stressed mycobacteria. We report the cleavage of penicillin-binding protein 3 (PBP3) by the intramembrane metalloprotease Rv2869c (MSMEG&#95;2579) in oxidatively stressed cells. Amino acids (102)A and (103)A of PBP3 are required for Rv2869c-mediated cleavage. Wag31(MTB), by virtue of its interaction with PBP3 through amino acid residues (46)NSD(48), protects it from oxidative stress-induced cleavage. PBP3 undergoes cleavage in Mycobacterium smegmatis (strain PM2) harbouring wag31(Delta(46)NSD(48)) instead of the wild type, with concomitant reduction in ability to withstand oxidative stress. Overexpression of Wag31(Delta(46)NSD(48)) attenuates the survival of M. tuberculosis in macrophages with concomitant cleavage of PBP3, and renders the organism more susceptible towards hydrogen peroxide as well as drugs which generate reactive oxygen species, namely isoniazid and ofloxacin. We propose that targeting Wag31 could enhance the activity of mycobactericidal drugs which are known to generate reactive oxygen species.

The performance of 2.7 microm superficially porous particles at 600 bar and sub-2 microm fully porous particles at 1000 bar were compared by the Poppe plot method. Theoretical Poppe plots were first constructed for each stationary phase to compare their kinetic performance at different analysis times. The theory was then verified by experiments under the optimized conditions identified from the Poppe plot calculation. We found that the 2.7 microm superficially porous particles at 600 bar can provide similar performance compared to the sub-2 microm fully porous particles at ultra-high pressure (1000 bar) when analysis times are very short (e.g. sub-minute). As analysis time increases, the superficially porous particles start to outperform the sub-2 microm particles and can give much higher efficiencies (e.g. > 2 times higher plate count) at very long analysis times (>3h). The comparison was extended to gradient elution of a mixture of pharmaceutical interest by constructing gradient peak capacity Poppe plots and similar behavior was observed.

In bacteria, biogenesis of cell wall at the division site requires penicillin-binding protein 3 (PBP3) (or Ftsl). Using pull-down, bacterial two-hybrid, and peptide-based interaction assays, we provide evidence that FtsW of Mycobacterium tuberculosis (FtsWMTB) interacts with PBP3 through two extracytoplasmic loops. Pro306 in the larger loop and Pro386 in the smaller loop of FtsW are crucial for these interactions. Fluorescence microscopy shows that conditional silencing of ftsW in Mycobacterium smegmatis prevents cell septation and positioning of PBP3 at mid-cell. Pull-down assays and conditional depletion of FtsW in M. smegmatis provide evidence that FtsZ, FtsW and PBP3 of mycobacteria are capable of forming a ternary complex, with FtsW acting as a bridging molecule. Bacterial three-hybrid analysis suggests that in M. tuberculosis, the interaction (unique to mycobacteria) of FtsZ with the cytosolic C-tail of FtsW strengthens the interaction of FtsW with PBP3. ftsW of M. smegmatis could be replaced by ftsW of M. tuberculosis. FtsWMTB could support formation of the FtsZ-FtsW-PBP3 ternary complex in M. smegmatis. Our findings raise the possibility that in the genus Mycobacterium binding of FtsZ to the C-tail of FtsW may modulate its interactions with PBP3, thereby potentially regulating septal peptidoglycan biogenesis.

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans.

Despite the importance of accurately determining inorganic arsenic speciation in natural waters to predicting bioavailability and environmental and health impacts, there remains considerable debate about the most appropriate species preservation strategies to adopt. In particular, the high-iron, low-Eh (redox potential) shallow groundwaters in West Bengal, Bangladesh and SE Asia, the use of which for drinking and irrigation purposes has led to massive international concerns for human health, are particularly prone to changes in arsenic speciation after sampling. The effectiveness of HCl and EDTA preservation strategies has been compared and used on variably arsenic-rich West Bengali groundwater samples, analysed by ion chromatography-inductively coupled plasma-mass spectrometry (IC-ICP-MS). Immediate filtration and acidification with HCl followed by refrigerated storage was found to be the most effective strategy for minimizing the oxidation of inorganic As(III) during storage. The use of a PRP-X100 (Hamilton) column with a 20 mmol L(-1) NH4H2PO4 as mobile phase enabled the separation of Cl- from As(III), monomethylarsonic acid, dimethylarsinic acid and As(V), thereby eliminating any isobaric interference between 40Ar35Cl+ and 75As+. The use of EDTA as a preservative, whose action is impaired by the high calcium concentrations typical of these types of groundwater, resulted in marked oxidation during storage. The use of HCl is therefore indicated for analytical methods in which chloride-rich matrices are not problematical. The groundwaters analysed by IC-ICP-MS were found to contain between 5 and 770 ng As mL(-1) exclusively as inorganic arsenic species. As(III)/total-As varied between 0 and 0.94.