Phenothiazine Embedded Dithiasmaragdyrins.

Two different types of novel phenothiazine-embedded dithiasmaragdyrins containing one phenothiazine ring, two thiophene rings and two pyrrole rings connected via three meso carbons and two direct bonds in the macrocyclic framework were synthesized over the sequence of synthetic steps starting with phenothiazine. Three examples of phenothiazine-embedded dithiasmaragdyrins were synthesized by condensing appropriate phenothiazine-based pentapyrrane with pentafluorobenzaldehyde and two examples of phenothiazine sulfone embedded dithiasmaragdyrins were synthesized by condensing phenothiazine-based diol with appropriate meso-aryl dipyrromethane under mild acid-catalysed conditions. 1D&2D NMR studies revealed that the thiophene rings adopted inverted orientation in phenothiazine sulfone embedded dithiasmaragdyrins whereas in phenothiazine-embedded dithiasmaragdyrins, the thiophene rings were in normal orientation. Both types of macrocycles exhibit nonaromatic absorption features and showed panchochromic absorption features in its neutral and protonated forms. The electrochemical studies indicated that the phenothiazine-embedded dithiasmaragdyrins were more electron-rich compared to phenothiazine sulfone embedded dithiasmaragdyrins. DFT studies revealed that both types of dithiasmaragdyrins exhibit significantly distorted structures and TD-DFT studies support the experimental observations.

Synthesis of Phenothiazine Embedded Heteroporphyrins.

A series of phenothiazine embedded heteroporphyrins containing one phenothiazine unit, two pyrrole rings and one heterocycle such as furan, thiophene, selenophene and tellurophene connected via four meso carbons were synthesized. The macrocycles were synthesized by condensing the phenothiazine based tripyrrane with corresponding 2,5-bis(hydroxymethyl)heterocycle under BF3 ⋅ OEt2 catalyzed conditions and compared the structural, spectral, and electrochemical properties with the reported phenothiazinophyrins. The studies showed that the phenothiazine embedded heteroporphyrins were nonaromatic and electronic properties were significantly altered by replacing the pyrrole ring from phenothiazinophyrin with different heterocycles. The X-ray structure of phenothiazine embedded thiaporphyrin revealed that the macrocycle was distorted with an inverted thiophene ring. Both mono-protonated and diprotonated derivatives of macrocycles were generated by the controlled addition of trifluoroacetic acid to the macrocycles. The macrocyclic protons experienced upfield/downfield shifts in protonated derivatives compared to their corresponding neutral phenothiazine embedded heteroporphyrins. However, the heterocyclic ring in both mono- and diprotonated derivatives retained its inverted conformation. The macrocycles in their neutral and protonated form exhibit nonaromatic absorption features. The studies indicated the electron rich nature of macrocycles and DFT/TD-DFT studies were carried out to justify the experimental observations.

Synthesis of stable nonaromatic phenothiazinophyrins.

Stable and nonaromatic phenothiazinophyrins which resulted from the replacement of one of the pyrrole rings of porphyrin with a phenothiazine unit were synthesized by condensing phenothiazine based tripyrrane with aryl aldehyde and pyrrole under acid catalysed conditions. NMR studies revealed that the pyrrole ring that is across the phenothiazine unit is inverted and DFT studies also supported that the pyrrole ring inverted phenothiazinophyrins were more stable. Phenothiazinophyrins and their protonated derivatives showed panchromatic absorption features and absorbed in the visible to NIR region.

Biofouling in Membrane Bioreactors: Mechanism, Interactions and Possible Mitigation Using Biosurfactants.

Biofouling roots damage to membrane bioreactors (MBRs), such as physical, functional and organisational changes and even therefore clogging of the membrane pores and successive microbial degradation. Further, it blocks the pores, results into a biomass cake and in due course reduces the membrane flux and leads to an increase in the operational costs. MBR fouling contributed to the rise in transmembrane pressure (TMP) and decrease in permeate flux (in case of constant pressure operation mode). Chemical surfactants adopted for the cleaning of membrane surfaces have certain disadvantages such as toxicity manifestations, damage to the membranes and high CMC concentrations. Biosurfactant surfactants have attained increasing interest due to their low toxicity, biodegradability, stability to extreme environmental conditions such as temperatures, pH and tolerance to salinity. The biosurfactants trapped the foulants via micelle formation, which distresses hydrophobic interactions amongst bacteria and the surface. Rhamnolipids as an anionic biosurfactant pose a significant interfacial potential and have affinity to bind organic matter. The present review discusses the problem of biofouling in MBRs, type and interactions of foulants involved and also highlights the mechanisms of biosurfactant cleaning, effect of different parameters, effect of concentration, TMP, flux recovery, permeability, mitigation practices and challenges.

Structural insights into the catalytic mechanism of granzyme B upon substrate and inhibitor binding.

Human granzyme B (hGzmB), which is present in various immune cells, has attracted much attention due to its role in various pathophysiological conditions. The hGzmB activity is triggered at a catalytic triad (His59, Asp103, Ser198), cleaving its specific substrates. To date, the drug design strategy against hGzmB mainly targets the catalytic triad, which causes the non-specificity problem of inhibitors due to the highly conserved active site in serine proteases. In the present work, microsecond classical molecular dynamics simulations are devoted to exploring the structural dynamics of the hGzmB catalytic cycle in the presence of Ac-IEPD-AMC, a known substrate (active hGzmB), and Ac-IEPD-CHO, a known inhibitor (inactive hGzmB). By comparing active and inactive forms of hGzmB in the six different stages of the hGzmB catalytic cycle, we revealed, for the very first time, an additional network of interactions involving Arg216, a residue located outside the conventional binding site. Upon activation, the His59∙∙∙Asp103 hydrogen bond is broken due to the formation of the Asp103∙∙∙Arg216 salt bridge, expanding the active site to facilitate the substrate-binding. On the contrary, the binding of inhibitor Ac-IEPD-CHO to hGzmB prevents the Arg216-mediated interactions within the catalytic triad, thus preventing hGzmB activity. In silico Arg216Ala mutation confirms the role of Arg216 in enzyme activity, as the substrate Ac-IEPD-AMC failed to bind to the mutated hGzmB. Importantly, as Arg216 is not conserved amongst the various granzymes, the current findings can be a major step to guide the design of hGzmB specific therapeutics.

The lived experiences of health science graduate students with anxiety and depression.

Health science graduate programs are intensive experiences in students' lives which can contribute to perceived symptoms of anxiety and/or depression. The consequent impact of these symptoms can have an overall effect on the graduate students' ability to participate in their daily lives, along with their program of study. The purpose of this study was to understand the lived experiences of health science graduate students who experience perceived signs and symptoms of anxiety and/or depression. An open-ended, qualitative phenomenological survey was used to understand the experiences of 56 Doctor of Occupational Therapy, Doctor of Physical Therapy, and Doctor of Pharmacy students at a university in the southeastern United States. Three themes were identified from the data: the cyclic effect of symptoms and triggers; the importance of support systems; and the benefit of coping skill utilization. Future research is needed to understand the effects of preventive and rehabilitative measures to address health science graduate students' mental health.

Temporal dynamics of justice climate and team innovation.

Team innovation-exploration and exploitation of useful and novel ideas by a team has been a topic of great importance for organizations in today's dynamic, complex, and competitive environment. Grounded in the social contagion theory of justice, we theorize a justice-to-innovation processual model based on within-team justice climate occurrences that change over time. We posit that collective and shared justice perceptions of team members construct dynamically based on justice-related work events. Within teams, state justice climate level and strength (represented by the Mean and the low-SD scores of individual team members in the moment or an episode) are important precursors of team innovation. The proposed theoretical model explicates an emotional contagion process arguing that positive and negative team affect states mediate the relationship between state justice climate and team innovation. Positive/negative team affect states result in collective actions and team interactions that foster/hinder team innovation. The present article significantly contributes to the development of the dynamical models of justice and innovation for teams where most research is confined to static models of justice climate.

Reverse the Lens, Set Focus on the Followers: A Theoretical Framework of Resource Dependence, Upward Influence, and Leadership.

Leadership theories predominantly focus on the top-down managerial influence on employees. Recent theoretical developments, however, have accentuated the call for scholarly attention on holistic models comprising both leadership and followership. In the present study, the author developed a theoretical framework of upward influence and leadership construction by drawing on resource dependence theory. Specifically, the author proposed a novel outlook illuminating upward influence in hierarchical relationships whereby employees, as the hosts of tacit resources, inculcate interdependent relationships with their managers. Considering the dependence of employees and managers on each other for tangible and intangible resources, relationships with a (a) power imbalance and (b) joint or embedded dependence emerge. The author further explained the role of leadership construction in power-imbalanced and embedded relationships and elaborated on organizational and team structural boundary conditions. By revitalizing upward influence, the proposed theoretical framework offered new insights into leadership and followership literature, with the potential to change the conversation from a foundational thesis assuming the managerial capacity to lead and bestow resources on their subordinates to a two-way resource-dependence perspective, which has been scarcely considered in contemporary management research.

Generic Paradoxical Tensions, Appraisals, Work Motivation, and Performance: Insights From a Weekly Repeated-Measures Study.

Drawing on the paradox theory, the author developed a theoretical model of appraisal-motivational responses to generic paradoxical tensions. The author postulated that paradoxical tensions are appraised both as a challenge and as a threat, in turn prompting mixed effects, positive and negative, on performance. The dual effects of paradoxical tensions are explained by the intermittent role of motivation toward work and a dispositional boundary condition-individual' adaptability-cross-situation variability of behaviors. The results from an eight-wave weekly repeated measures study spanning a period of 2 months (N = 178, total observations = 1,355) provided support for the proposed theoretical model. By illuminating the nuanced intraindividual psychological process, the present study brings forward novel insights on cognitive appraisals and motivations of paradoxical tensions advancing microfoundation of the paradox research.

An App-Based Workplace Mindfulness Intervention, and Its Effects Over Time.

We investigated the week-to-week effects of a mindfulness intervention on emotional exhaustion, work engagement, and job satisfaction in a field study involving 218 participants who participated and reported their weekly outcomes during the 8-week program. To examine how mindfulness impacted work outcomes, we used intraindividual modeling of the 8-week data. Mindfulness increased over time, and time also had indirect effects on emotional exhaustion, work engagement, and job satisfaction, through mindfulness. Supplementary growth curve analyses on the improvement of mindfulness over time showed a slight decrease in the positive effect of time on mindfulness.

Structure-based identification of inhibitors disrupting the CD2-CD58 interactions.

The immune system has very intricate mechanisms of fighting against the invading infections which are accomplished by a sequential event of molecular interactions in the body. One of the crucial phenomena in this process is the recognition of T-cells by the antigen-presenting cells (APCs), which is initiated by the rapid interaction between both cell surface receptors, i.e., CD2 located on T-cells and CD58 located on APCs. Under various pathological conditions, which involve undesired immune response, inhibiting the CD2-CD58 interactions becomes a therapeutically relevant opportunity. Herein we present an extensive work to identify novel inhibiting agents of the CD2-CD58 interactions. Classical molecular dynamics (MD) simulations of the CD2-CD58 complex highlighted a series of crucial CD58 residues responsible for the interactions with CD2. Based on such results, a pharmacophore map, complementary to the CD2-binding site of CD58, was created and employed for virtual screening of ~ 300,000 available compounds. On the ~ 6000 compounds filtered from pharmacophore mapping, ADME screening leads to ~ 350 molecules. Molecular docking was then performed on these molecules, and fifteen compounds emerged with significant binding energy (< - 50 kcal/mol) for CD58. Finally, short MD simulations were performed in triplicate on each complex (i) to provide a microscopic view of the ligand binding and (ii) to rule out possibly weak binders of CD58 from the identified hits. At last, we suggest eight compounds for in vitro testing that were identified as promising hits to bind CD58 with a high binding affinity.

Structural exploration of glutamine synthetase from Leishmania donovani: Insights from in silico and in vitro analysis.

Glutamine synthetase from L. donovani (LdGS) has been identified as a potential antileishmanial target in our previous report based on biochemical and inhibition studies. With the aim to structurally explore LdGS, systematic in silico and in vitro studies have been employed in the present study to identify amino acids crucial for LdGS mediated catalysis. A comparative analysis with human GS (HsGS) was performed which revealed significant differences in the active site pocket of human and parasite GS enzyme. The important amino acids identified from the in silico analysis of the optimized complexes, were subjected to in silico and in vitro alanine scanning by site directed mutagenesis. The results indicated crucial conserved and non conserved residues required for GS activity. The role of these residues in maintenance of secondary and tertiary structure of GS enzyme was also explored. In silico virtual screening was performed which resulted in the identification of five hits i.e. ZINC83236243, ZINC77319454, ZINC83236244, ZINC83236734 and ZINC83236736, as potential LdGS selective inhibitors. The illustrated structural and functional details of enzyme provides a better understanding of the structural integrity of LdGS and can be further utilized for the development of parasite specific GS inhibitors for treatment of visceral leishmaniasis infections.

Quinacrine and curcumin synergistically increased the breast cancer stem cells death by inhibiting ABCG2 and modulating DNA damage repair pathway.

Cancer stem cell like cells (CSCs) present a challenge in the management of cancers due to their involvement in the development of resistance against various chemotherapeutic agents. Over expression of ABCG2 transporter gene is one of the factors responsible for drug resistance in CSCs, which causes efflux of therapeutic drugs from these cells. The development of inhibitors against CSCs has not achieved any significant success, till date. In this work, we have evaluated the anti-proliferative activity of curcumin (Cur) and quinacrine (QC) against CSCs using in vitro model system. Cur and QC synergistically inhibited the proliferation, migration and invasion of CSCs enriched side population (SP) cells of cigarette smoke condensate induced breast epithelial transformed (MCF-10A-Tr) generated metastatic cells. Cur + QC combination increased the DNA damage and inhibited the DNA repair pathways in SP cells. Uptake of QC increased in Cur pre-treated SP cells and this combination inhibited the ABCG2 activity by the reduction of ATP hydrolysis in cells. In vitro DNA binding reconstitution system suggests that QC specifically binds to DNA and caused DNA damage inside the cell. Decreased level of ABCG2, representative cell survival and DNA repair proteins were noted after Cur + QC treatment in SP cells. The molecular docking studies were performed to examine the binding behaviour of these drugs with ABCG2, which showed that QC (-53.99 kcal/mol) and Cur (-45.90 kcal/mol) occupy a highly overlapping interaction domain. This suggested that in Cur pre-treated cells, the Cur occupied the ligand-binding site in ABCG2, thus making the ligand binding site unavailable for the QC. This causes an increase in the intracellular concentration of QC. The results indicate that Cur + QC combination causes CSCs death by increasing the concentration of QC in the cells and thus causing the DNA damage and inhibiting the DNA repair pathways through modulating the ABCG2 activity.

Intraindividual variability in identity centrality: Examining the dynamics of perceived role progress and state identity centrality.

Conventionally, identity centrality has been conceived of as a stable and transsituational construct, with situational variability in identity centrality treated as being of little informational value. In contrast to past research, we develop a theoretical model arguing that a portion of within-person variability in identity centrality is systematic and meaningful. Drawing on identity control theory, we examine the within-person relationship flowing from perceived role progress to state identity centrality, which is conventionally viewed as reverse causal at the between-person level. We further explain the intermittent effect of an intense positive emotion-passion for the role-and investigate the contingent effect of in-role effort. The results from 2 repeated-measures studies showed that a significant proportion of total variance in identity centrality occurred at the within-person level and perceived role progress influenced state identity centrality by engendering passion for the role contingent on in-role effort. We discuss the theoretical and practical implications of our findings for management and organizations to inspire new intellectual debate and novel viewpoints to advance the microfoundation of identity theory. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Multiple Splenic Infarcts Complicating Plasmodium vivax Malaria.

Splenic infarct is a rare complication in Plasmodium vivax malaria. We report a case of splenic infarction with acute kidney injury in a case of P. vivax malaria in a 13-year-old male child who presented to the emergency department with severe pain in the left hypochondrium. The patient was managed with intravenous artesunate and oral primaquine. Pain in left hypochondrium in children with P. vivax malaria due to splenic infarction needs to be evaluated for any surgical emergency like rupture or abscess. A review of literature of the unusual but serious complication is presented along with the case report.

Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors.

The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLCγ1 and its known binding partners. Indeed, molecular modeling of PLCγ1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLCγ1 and a comparable or higher binding affinity to ritonavir (∆Gbind < -25 kcal/mol), one of the most potent inhibitor reported till now.

HToPred: A Tool for Human Topoisomerase II Inhibitor Prediction.

The enzyme human topoisomerase IIα (hTopoIIα) is an important anticancer drug target. Due to the availability of multiple inhibitor-binding sites in this enzyme, the anti-hTopoII agents possess high chemical diversity. Chemoinformatics methods can be used to identify lead compounds from large databases for hTopoII inhibitory activity and classify them. In this work, we report the use of machine learning methods to develop classification models for the identification of possible anti-hTopoIIα agents and to classify them as catalytic inhibitors vs. poisons. Initially, an extensive dataset of small molecules which are reported to be evaluated towards hTopoIIα inhibition was collected from ChEMBL database and literature. Using this dataset, predictive models for classifying small molecules into hTopoIIα inhibitors and non-inhibitors were developed. Additionally, the model development was taken up for the prediction of the type of hTopoIIα inactivation. Several molecular fingerprints and physicochemical descriptors of the molecules in the dataset were calculated using the chemoinformatics tool RDKit. Various classifiers were evaluated to establish suitable protocol. Further, ensemble models were developed by bagging of homogenous classifier and selective fusion of heterogeneous classifiers. The models were thoroughly validated with 5-fold cross validation and external validation. The best performing models were incorporated into a tool christened as Human Topoisomerase IIα Inhibitor Prediction (HToPred, http://14.139.57.41/HToPred). A molecular docking based validation for the successful application of HToPred in predicting the mode of enzyme inhibition was performed, which further established the acceptability of this tool. This tool can serve as an important platform to prescreen compounds for anti-hTopoIIα potential.

Pharmacoinformatics analysis of merbarone binding site in human topoisomerase IIα.

Merbarone is a derivative of thiobarbituric acid, possessing catalytic inhibitory potential against human topoisomerase IIα (hTopoIIα). Merbarone was reported to inhibit DNA cleavage by hTopoIIα. It is important to understand the molecular mechanism of hTopoIIα inhibition by merbarone, as these details guide the rational design of new ligands. In this work, a systematic pharmacoinformatics analysis has been reported to analyze the merbarone-hTopoIIα interactions and to identify merbarone analogs as potential hTopoIIα inhibitors. The reported crystal structure of hTopoIIα-DNA complex (PDB ID: 4FM9) is not suitable for analyzing the merbarone-binding domain, because it is a biological assembly of hTopoIIα in C-gate open conformation. Therefore, 3D structure of hTopoIIα-DNA complex suitable for molecular modeling analysis at merbarone binding site was first generated. Using this generated complex, molecular docking analysis and molecular dynamics simulations were performed to explore the effect of merbarone on hTopoIIα-DNA complex. The binding energy for the enol form of merbarone with hTopoIIα-DNA was estimated to be -51.28 kcal/mol. The explored binding site and identified molecular recognition interactions were in accordance with the previously reported interference in the DNA-cleavage by merbarone. Virtual screening was performed using drug likeness filters, toxicity filters and ADMET descriptor based filters followed by molecular docking (ZINC database). Sixteen compounds were identified as merbarone-functional analogs suitable for hTopoIIα inhibition. These identified molecules can be considered for further evaluation of their anti-hTopoIIα activity.

Does N-terminal huntingtin function as a 'holdase' for inhibiting cellular protein aggregation?

Proteolytic cleavage of huntingtin gives rise to N-terminal fragments. While the role of truncated mutant huntingtin is described in Huntington's disease (HD) pathogenesis, the function of N-terminal wild-type protein is less studied. The yeast model of HD is generated by the presence of FLAG tag and absence of polyproline tract as flanking sequences of the elongated polyglutamine stretch. We show that the same sequence derived from wild-type huntingtin exon1 is able to inhibit the aggregation of proteins in vitro and in yeast cells. It is able to stabilize client proteins as varied as luciferase, α-synuclein, and p53 in a soluble but non-native state. This is somewhat similar to the 'holdase' function of small heat shock proteins and 'nonchaperone proteins' which are able to stabilize partially unfolded client proteins in a nonspecific manner, slowing down their aggregation. Mutagenesis studies show this property to be localized at the N17 domain preceding the polyglutamine tract. Distortion of this ordered segment, either by deletion of this segment or mutation of a single residue (L4A), leads to decreased stability and increased aggregation of client proteins. It is interesting to note that the helical conformation of the N17 domain is also essential for aggregation of the N-terminal mutant protein. Our results provide evidence for a novel function for the amphipathic helix derived from exon1 of wild-type huntingtin.

Etoposide and doxorubicin enhance the sensitivity of triple negative breast cancers through modulation of TRAIL-DR5 axis.

Death receptor 5 (DR5) is an important target for development of anticancer agents against triple-negative breast cancer (TNBC). Recently, we reported the molecular level details for the modulation of TRAIL-DR5 axis by quinacrine (QC) in breast cancer cells. In this work, the DR5 mediated anticancer potential of topoisomerase inhibitor etoposide (ET) and doxorubicin (DOX) against TNBC has been evaluated. ET and DOX enhanced the DR5 expression in TNBC cells, whereas non-topoisomerase inhibitors pifithrin-α (PIF) and dexamethasone (DEX) failed to do so. In the TRAIL pre-treated cells, ET and DOX induced higher apoptosis, indicating their synergistic effect with TRAIL. The molecular docking and molecular dynamics studies showed their ability to stabilize the TRAIL-DR5 complex, whereas PIF and DEX failed to do so. The binding energy for TRAIL-DR5 complexation in the ternary complexes containing ET (-111.08 kcal/mol) and DOX (-76.35 kcal/mol) were higher than reported binding energy of binary complex (-53.70 kcal/mol). The in silico and in vitro mutational studies highlighted the importance of DR5 residue SerB68 in mediating the receptor-drug interaction. ET and DOX failed to enhance apoptosis in DR5 knockdown (DR5-KD) cells. On the other hand, TRAIL+ET exhibited induction of DR5 and subsequent apoptosis in WT-DR5 overexpressed DR5-KD cells, by modulating the mitochondrial intrinsic apoptosis cascade. An induction of apoptosis and DR5 expression was noticed in xenograft mice and in TNBC patient-derived metastatic cells after TRAIL+ET treatment. Thus, data suggests ET and DOX act as DR5 agonistic ligands and enhance the cellular apoptosis in TNBC.