Draft genome sequencing data of multidrug-resistant Staphylococcus haemolyticus from Bangladeshi hospitals.

Here, we report the draft genome sequence data of two multidrug-resistant (MDR) Staphylococcus haemolyticus strains, SAC2 and SAC7, isolated from clinical samples from Dhaka, Bangladesh. The sequence raw read files were generated using Ion Torrent Sequencing Technology using the genomic DNA from the pure culture of the strains. These two Bangladeshi S. haemolyticus strains had an average genome size of 2.49 million base pairs with a GC content of 32.6 % and an average of 1783 coding sequences. We conducted genomic studies using bioinformatics tools focusing on resistance genes, virulence factors, and toxin-antitoxin systems. A phylogenomic study with S. haemolyticus strains isolated worldwide revealed that these two Bangladeshi strains are in different nodes but clustered together. The data can be used as a starting point for understanding the genomic content, epidemiology, and evolution of S. haemolyticus in Bangladesh. The genome sequence data of SAC2 and SAC7 strains have been deposited in the NCBI database under BioSample accession numbers SAMN35731443 and SAMN35731649, respectively.

Challenges of Protein-Protein Docking of the Membrane Proteins.

Despite the recent advances in the determination of high-resolution membrane protein (MP) structures, the structural and functional characterization of MPs remains extremely challenging, mainly due to the hydrophobic nature, low abundance, poor expression, purification, and crystallization difficulties associated with MPs. Whereby the major challenges/hurdles for MP structure determination are associated with the expression, purification, and crystallization procedures. Although there have been significant advances in the experimental determination of MP structures, only a limited number of MP structures (approximately less than 1% of all) are available in the Protein Data Bank (PDB). Therefore, the structures of a large number of MPs still remain unresolved, which leads to the availability of widely unplumbed structural and functional information related to MPs. As a result, recent developments in the drug discovery realm and the significant biological contemplation have led to the development of several novel, low-cost, and time-efficient computational methods that overcome the limitations of experimental approaches, supplement experiments, and provide alternatives for the characterization of MPs. Whereby the fine tuning and optimizations of these computational approaches remains an ongoing endeavor.Computational methods offer a potential way for the elucidation of structural features and the augmentation of currently available MP information. However, the use of computational modeling can be extremely challenging for MPs mainly due to insufficient knowledge of (or gaps in) atomic structures of MPs. Despite the availability of numerous in silico methods for 3D structure determination the applicability of these methods to MPs remains relatively low since all methods are not well-suited or adequate for MPs. However, sophisticated methods for MP structure predictions are constantly being developed and updated to integrate the modifications required for MPs. Currently, different computational methods for (1) MP structure prediction, (2) stability analysis of MPs through molecular dynamics simulations, (3) modeling of MP complexes through docking, (4) prediction of interactions between MPs, and (5) MP interactions with its soluble partner are extensively used. Towards this end, MP docking is widely used. It is notable that the MP docking methods yet few in number might show greater potential in terms of filling the knowledge gap. In this chapter, MP docking methods and associated challenges have been reviewed to improve the applicability, accuracy, and the ability to model macromolecular complexes.

Biological regulatory network analysis for targeting the mitochondrial calcium uniporter (MCU) mediated calcium (Ca2+) transport in neurodegenerative disorders.

Calcium (Ca2+) has been observed as the most important ion involved in a series of cellular processes and its homeostasis is critical for normal cellular functions. Mitochondrial calcium uniporter (MCU) complex has been recognized as the most important calcium-specific channel located in the inner mitochondrial membrane and is one of the major players in maintaining the Ca2+ homeostasis by transporting Ca2+ across the mitochondrial membrane. Furthermore, dysregulation of the mitochondrial Ca2+ homeostasis has been orchestrated to neurodegenerative response. This necessitates quantitative evaluation of the MCU-dependent mROS production and subsequent cellular responses for more specific therapeutic interventions against neurodegenerative disorders. Towards this goal, here we present a biological regulatory network of MCU to dynamically simulate the MCU-mediated ROS production and its response in neurodegeneration. Previously, ruthenium complex RuRed and its derivatives have been reported to show low nM to high µM potency against MCU to maintain cytosolic Ca2+ (cCa2+) homeostasis by modulating mitochondrial Ca2+ (mCa2+) uptake. Therefore, structural modeling and dynamic simulation of MCU pore-forming subunit is performed to probe the interaction profiling of previously reported Ru265 and its derivatives compounds with MCU. The current study highlighted MCU as a potential drug target in neurodegenerative disorders. Furthermore, ASP261 and GLU264 amino acid residues in DIME motif of MCU pore-forming subunits are identified as crucial for modulating the activity of MCU in neurodegenerative disorders.

Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1.

The expression of drug efflux pump ABCB1/P-glycoprotein (P-gp), a transmembrane protein belonging to the ATP-binding cassette superfamily, is a leading cause of multidrug resistance (MDR). We previously curated a dataset of structurally diverse and selective inhibitors of ABCB1 to develop a pharmacophore model that was used to identify four novel compounds, which we showed to be potent and efficacious inhibitors of ABCB1. Here, we dock the inhibitors into a model structure of the human transporter and use molecular dynamics (MD) simulations to report the conformational dynamics of human ABCB1 induced by the binding of the inhibitors. The binding hypotheses are compared to the wider curated dataset and those previously reported in the literature. Protein-ligand interactions and MD simulations are in good agreement and, combined with LipE profiling, statistical and pharmacokinetic analyses, are indicative of potent and selective inhibition of ABCB1.

Structural and functional insight into a new emerging target IP3R in cancer.

Calcium signaling has been identified as an important phenomenon in a plethora of cellular processes. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER-residing intracellular calcium (Ca2+) release channels responsible for cell bioenergetics by transferring calcium from the ER to the mitochondria. The recent availability of full-length IP3R channel structure has enabled the researchers to design the IP3 competitive ligands and reveal the channel gating mechanism by elucidating the conformational changes induced by ligands. However, limited knowledge is available for IP3R antagonists and the exact mechanism of action of these antagonists within a tumorigenic environment of a cell. Here in this review a summarized information about the role of IP3R in cell proliferation and apoptosis has been discussed. Moreover, structure and gating mechanism of IP3R in the presence of antagonists have been provided in this review. Additionally, compelling information about ligand-based studies (both agonists and antagonists) has been discussed. The shortcomings of these studies and the challenges toward the design of potent IP3R modulators have also been provided in this review. However, the conformational changes induced by antagonists for channel gating mechanism still display some major drawbacks that need to be addressed. However, the design, synthesis and availability of isoform-specific antagonists is a rather challenging one due to intra-structural similarity within the binding domain of each isoform. HighlightsThe intricate complexity of IP3R's in cellular processes declares them an important target whereby, the recently solved structure depicts the receptor's potential involvement in a complex network of processes spanning from cell proliferation to cell death.Pharmacological inhibition of IP3R attenuates the proliferation or invasiveness of cancers, thus inducing necrotic cell death.Despite significant advancements, there is a tremendous need to design new potential hits to target IP3R, based upon 3D structural features and pharmacophoric patterns.Communicated by Ramaswamy H. Sarma.

Smart Wireless Sensor Technology for Healthcare Monitoring System Using Cognitive Radio Networks.

Programmable Object Interfaces are increasingly intriguing researchers because of their broader applications, especially in the medical field. In a Wireless Body Area Network (WBAN), for example, patients' health can be monitored using clinical nano sensors. Exchanging such sensitive data requires a high level of security and protection against attacks. To that end, the literature is rich with security schemes that include the advanced encryption standard, secure hashing algorithm, and digital signatures that aim to secure the data exchange. However, such schemes elevate the time complexity, rendering the data transmission slower. Cognitive radio technology with a medical body area network system involves communication links between WBAN gateways, server and nano sensors, which renders the entire system vulnerable to security attacks. In this paper, a novel DNA-based encryption technique is proposed to secure medical data sharing between sensing devices and central repositories. It has less computational time throughout authentication, encryption, and decryption. Our analysis of experimental attack scenarios shows that our technique is better than its counterparts.

Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma.

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm-1) and carbonyl groups (1662.38 cm-1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein.

An Intelligent Healthcare System Using IoT in Wireless Sensor Network.

The Internet of Things (IoT) uses wireless networks without infrastructure to install a huge number of wireless sensors that track system, physical, and environmental factors. There are a variety of WSN uses, and some well-known application factors include energy consumption and lifespan duration for routing purposes. The sensors have detecting, processing, and communication capabilities. In this paper, an intelligent healthcare system is proposed which consists of nano sensors that collect real-time health status and transfer it to the doctor's server. Time consumption and various attacks are major concerns, and some existing techniques contain stumbling blocks. Therefore, in this research, a genetic-based encryption method is advocated to protect data transmitted over a wireless channel using sensors to avoid an uncomfortable data transmission environment. An authentication procedure is also proposed for legitimate users to access the data channel. Results show that the proposed algorithm is lightweight and energy efficient, and time consumption is 90% lower with a higher security ratio.

Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1).

The expression of the drug efflux pump ABCB1 correlates negatively with cancer survival, making the transporter an attractive target for therapeutic inhibition. In order to identify new inhibitors of ABCB1, we have exploited the cryo-EM structure of the protein to develop a pharmacophore model derived from the best docked conformations of a structurally diverse range of known inhibitors. The pharmacophore model was used to screen the Chembridge compound library. We identified six new potential inhibitors with distinct chemistry compared to the third-generation inhibitor tariquidar and with favourable lipophilic efficiency (LipE) and lipophilicity (CLogP) characteristics, suggesting oral bioavailability. These were evaluated experimentally for efficacy and potency using a fluorescent drug transport assay in live cells. The half-maximal inhibitory concentrations (IC50) of four of the compounds were in the low nanomolar range (1.35 to 26.4 nM). The two most promising compounds were also able to resensitise ABCB1-expressing cells to taxol. This study demonstrates the utility of cryo-electron microscopy structure determination for drug identification and design.

Characterization and whole-genome sequencing of an extreme arsenic-tolerant Citrobacter freundii SRS1 strain isolated from Savar area in Bangladesh.

Citrobacter freundii SRS1, gram-negative bacteria, were isolated from Savar, Bangladesh. The strain could tolerate up to 80 mmol L-1 sodium arsenite, 400 mmol L-1 sodium arsenate, 5 mmol L-1 manganese sulfate, 3 mmol L-1 lead nitrate, 2.5 mmol L-1 cobalt chloride, 2.5 mmol L-1 cadmium acetate, and 2.5 mmol L-1 chromium chloride. The whole-genome sequencing revealed that the genome size of C. freundii SRS1 is estimated to be 5.4 Mb long, and the G + C content is 51.7%. The genome of C. freundii SRS1 contains arsA, arsB, arsC, arsD, arsH, arsR, and acr3 genes for arsenic resistance; czcA, czcD, cbiN, and cbiM genes for cobalt resistance; chrA and chrB genes for chromium resistance; mntH, sitA, sitB, sitC, and sitD genes for manganese resistance; and zntA gene for lead and cadmium resistance. This novel acr3 gene has never previously been reported in any C. freundii strain except SRS1. A set of 130 completely sequenced strains of C. freundii was selected for phylogenomic analysis. The phylogenetic tree showed that the SRS1 strain is closely related to the C. freundii 62 strain. Further analyses of the genes involved in metal and metalloid resistance might facilitate identifying the mechanisms and pathways involved in high metal resistance in the C. freundii SRS1 strain.

Myxovirus resistance (Mx) Gene Diversity in Avian Influenza Virus Infections.

Avian influenza viruses (AIVs) pose threats to animal and human health. Outbreaks from the highly pathogenic avian influenza virus (HPAIV) in indigenous chickens in Bangladesh are infrequent. This could be attributed to the Myxovirus resistance (Mx) gene. To determine the impact of Mx gene diversity on AIV infections in chicken, we assessed the Mx genes, AIVs, and anti-AIV antibodies. DNA from blood cells, serum, and cloacal swab samples was isolated from non-vaccinated indigenous chickens and vaccinated commercial chickens. Possible relationships were assessed using the general linear model (GLM) procedure. Three genotypes of the Mx gene were detected (the resistant AA type, the sensitive GG type, and the heterozygous AG type). The AA genotype (0.48) was more prevalent than the GG (0.19) and the AG (0.33) genotypes. The AA genotype was more prevalent in indigenous than in commercial chickens. A total of 17 hemagglutinating viruses were isolated from the 512 swab samples. AIVs were detected in two samples (2/512; 0.39%) and subtyped as H1N1, whereas Newcastle disease virus (NDV) was detected in the remaining samples. The viral infections did not lead to apparent symptoms. Anti-AIV antibodies were detected in 44.92% of the samples with levels ranging from 27.37% to 67.65% in indigenous chickens and from 26% to 87.5% in commercial chickens. The anti-AIV antibody was detected in 40.16%, 65.98%, and 39.77% of chickens with resistant, sensitive, and heterozygous genotypes, respectively. The genotypes showed significant association (p < 0.001) with the anti-AIV antibodies. The low AIV isolation rates and high antibody prevalence rates could indicate seroconversion resulting from exposure to the virus as it circulates. Results indicate that the resistant genotype of the Mx gene might not offer anti-AIV protection for chickens.

Barriers to breastfeeding are shaped by sociocultural context: an exploratory qualitative study in Bangladesh.

BACKGROUND: Breastfeeding practice is still not optimum in Bangladesh. Understanding barriers to breastfeeding is needed to prevent harmful practices. This study aimed to understand barriers to breastfeeding among infants and young children in Bangladesh. METHODS: This qualitative study was conducted in five rural sub-districts and one urban slum in Bangladesh. We conceptualized that barriers to breastfeeding can be broadly grouped into individual, society, and system level barriers. We conducted in-depth interviews with 33 breastfeeding mothers and 13 grandmothers of breastfed children (total n = 46 interviews). We observed 23 of these infants and young children being breastfed. These data were supplemented by 3 focus group discussions held with the children's fathers. We managed the data using Atlas.ti software and analyzed the data thematically using an inductive approach. RESULTS: Important individual-level barriers perceived to influence breastfeeding included misconceptions about the adverse effects of breastfeeding on maternal health, nutrition and physical appearance, and lack of awareness of the value of breastfeeding among family members. Perceived society-level barriers included sociocultural norms, beliefs, and practices such as mother obliged to give more attention on household chores than breastfeeding to become a good housewife and feeding formula milk perceived as a symbol of parents' financial solvency in the society. System-level barriers included attractive advertisements of breastmilk substitutes, and inadequate facilities and support processes in mothers' work environments. CONCLUSION: A range of barriers at individual, society and system level have important implications for infant and young children's breastfeeding practices in Bangladesh. Development of interventions that address the range of barriers that many mothers face is essential to support breastfeeding practices. Potential interventions include strengthening information-giving during interaction between mothers and health workers on breastfeeding techniques, and engaging fathers and other "significant others" in counseling on breastfeeding.

Whole-genome sequencing and comparative analysis of heavy metals tolerant Bacillus anthracis FHq strain isolated from tannery effluents in Bangladesh.

Heavy metal contamination of the environment is a primary concern in Bangladesh. This study aims to characterize a novel heavy metal tolerant strain, Bacillus anthracis FHq, isolated from the tannery effluents of Savar, Bangladesh. The strain could tolerate up to 5 mM of lead nitrate, 2.5 mM of sodium arsenate, chromium chloride, cobalt chloride, 1.5 mM cadmium acetate, and 1 mM of sodium arsenite. Whole-genome sequencing analysis revealed that the genome of the strain is around 5.2 Mbp long, and the G + C content is 35.4%. Besides, FHq has genes cadC, zntA, arsCR, czcD, and chrA, which confer lead, arsenic, cobalt, and chromium resistance, respectively. A total of nineteen other closely related and completely sequenced B. anthracis strains were selected based on average nucleotide identity along with the FHq strain for phylogenomic and pan-genome analysis. The phylogenomic analysis predicted the inter-genomic evolutionary relationship of the strain isolated from Bangladesh, and it was closely related to a strain isolated from China. Pan-genome analysis revealed that the FHq strain possesses 6045 pan genes, 3802 core genes, and 152 unique genes in its genomic content. Hence, the genetic information and comparative analysis of the FHq strain might facilitate identifying the mechanisms conferring high resistance to lead in B. anthracis strains isolated from Bangladesh.

Decoding the Role of Epigenetics in Breast Cancer Using Formal Modeling and Machine-Learning Methods.

Breast carcinogenesis is known to be instigated by genetic and epigenetic modifications impacting multiple cellular signaling cascades, thus making its prevention and treatments a challenging endeavor. However, epigenetic modification, particularly DNA methylation-mediated silencing of key TSGs, is a hallmark of cancer progression. One such tumor suppressor gene (TSG) RUNX3 (Runt-related transcription factor 3) has been a new insight in breast cancer known to be suppressed due to local promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1). However, the precise mechanism of epigenetic-influenced silencing of the RUNX3 signaling resulting in cancer invasion and metastasis remains inadequately characterized. In this study, a biological regulatory network (BRN) has been designed to model the dynamics of the DNMT1-RUNX3 network augmented by other regulators such as p21, c-myc, and p53. For this purpose, the René Thomas qualitative modeling was applied to compute the unknown parameters and the subsequent trajectories signified important behaviors of the DNMT1-RUNX3 network (i.e., recovery cycle, homeostasis, and bifurcation state). As a result, the biological system was observed to invade cancer metastasis due to persistent activation of oncogene c-myc accompanied by consistent downregulation of TSG RUNX3. Conversely, homeostasis was achieved in the absence of c-myc and activated TSG RUNX3. Furthermore, DNMT1 was endorsed as a potential epigenetic drug target to be subjected to the implementation of machine-learning techniques for the classification of the active and inactive DNMT1 modulators. The best-performing ML model successfully classified the active and least-active DNMT1 inhibitors exhibiting 97% classification accuracy. Collectively, this study reveals the underlined epigenetic events responsible for RUNX3-implicated breast cancer metastasis along with the classification of DNMT1 modulators that can potentially drive the perception of epigenetic-based tumor therapy.

Combined Machine Learning and GRID-Independent Molecular Descriptor (GRIND) Models to Probe the Activity Profiles of 5-Lipoxygenase Activating Protein Inhibitors.

Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA), and their high production has been reported in multiple allergic, autoimmune, and cardiovascular disorders. The biological synthesis of leukotrienes is instigated by transfer of AA to 5-lipoxygenase (5-LO) via the 5-lipoxygenase-activating protein (FLAP). Suppression of FLAP can inhibit LT production at the earliest level, providing relief to patients requiring anti-leukotriene therapy. Over the last 3 decades, several FLAP modulators have been synthesized and pharmacologically tested, but none of them could be able to reach the market. Therefore, it is highly desirable to unveil the structural requirement of FLAP modulators. Here, in this study, supervised machine learning techniques and molecular modeling strategies are adapted to vaticinate the important 2D and 3D anti-inflammatory properties of structurally diverse FLAP inhibitors, respectively. For this purpose, multiple machine learning classification models have been developed to reveal the most relevant 2D features. Furthermore, to probe the 3D molecular basis of interaction of diverse anti-inflammatory compounds with FLAP, molecular docking studies were executed. By using the most probable binding poses from docking studies, the GRIND model was developed, which indicated the positive contribution of four hydrophobic, two hydrogen bond acceptor, and two shape-based features at certain distances from each other towards the inhibitory potency of FLAP modulators. Collectively, this study sheds light on important two-dimensional and three-dimensional structural requirements of FLAP modulators that can potentially guide the development of more potent chemotypes for the treatment of inflammatory disorders.

Barriers to seeking timely treatment for severe childhood pneumonia in rural Bangladesh.

OBJECTIVE: Delays in seeking medical attention for childhood pneumonia may lead to increased morbidity and mortality. This study aimed at identifying the drivers of delayed seeking of treatment for severe childhood pneumonia in rural Bangladesh. METHODS: We conducted a formative study from June to September 2015 in one northern district of Bangladesh. In-depth interviews were conducted with 20 rural mothers of children under 5 years with moderate or severe pneumonia. We analysed the data thematically. RESULTS: We found that mothers often failed to assess severity of pneumonia accurately due to lack of knowledge or misperception about symptoms of pneumonia. Several factors delayed timely steps that could lead to initiation of appropriate treatment. They included time lost in consultation with non-formal practitioners, social norms that required mothers to seek permission from male household heads (eg, husbands) before they could seek healthcare for their children, avoiding community-based public health centres due to their irregular schedules, lack of medical supplies, shortage of hospital beds and long distance of secondary or tertiary hospitals from households. Financial hardships and inability to identify a substitute caregiver for other children at home while the mother accompanied the sick child in hospital were other factors. CONCLUSIONS: This study identified key social, economic and infrastructural factors that lead to delayed treatment for childhood pneumonia in the study district in rural Bangladesh. Interventions that inform mothers and empower women in the decision to seek healthcare, as well as improvement of infrastructure at the facility level could lead to improved behaviour in seeking and getting treatment of childhood pneumonia in rural Bangladesh.

Molecular docking and pharmacophore models to probe binding hypothesis of inhibitors of hypoxia inducible factor-1.

Hypoxia inducible factor-1 is a heterodimeric transcription factor that regulates cellular responses to hypoxia and is involved in tumor progression and resistance to chemotherapy. Dimerization between HIF-1α and ß subunits has been recognized crucial for DNA binding and transcriptional activity of HIF-1. Therefore, inhibitors of α and ß dimerization subunits of HIF-1 may potentially evade HIF-1-mediated chemotherapy resistance. In the current study, ligand-based pharmacophore model was developed to determine 3 D binding features of HIF-1 inhibitors. The selected pharmacophore model comprises of one hydrogen bond donor, one hydrogen bond acceptor and one hydrophobic feature. The selected model was used for virtual screening of publically available data base by ChemBridge Corporation. Overall, six potential hits against HIF-1α and ß dimerization have been identified. These include, Hit 1 (4-(4-chlorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid), 3 (2-[2-(2-hydroxybenzoyl)carbonohydrazonoyl]benzoic acid) and 5 (3-(4-methoxyphenyl)-2,4-quinolinedicarboxylic acid) nicotonic acid derivatives, Hit 2 (3-[(1-adamantylamino)sulfonyl]benzoic acid), 4 (5-{[(2-fluorophenyl)amino]sulfonyl}-2-methylbenzoic acid), and 6 (4-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)benzoic acid) sulfonamide derivatives. Additionally, adamantyl moiety of compound 2 shows interactions with the experimentally known hydrophobic amino acid residues (V336, C334, E245) of HIF-1α and ß dimerization site. The identified hits showed lower to higher µM biological activity (IC50) values and thus, after further structure optimization may serve as potential inhibitor of HIF-1 dimerization in cancer chemotherapy.Communicated by Ramaswamy H. Sarma.

Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP3R) Inhibitors in Cancer.

Inositol 1, 4, 5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca2+ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP3-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP3R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC50) of a compound for IP3R inhibition. Moreover, our GRIND model (PLS: Q2 = 0.70 and R2 = 0.72) further strengthens the identified pharmacophore features of IP3R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6-8.0 Å and 6.8-7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP3R modulators were used to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP3R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer.

Molecular Dynamic Simulations to Probe Stereoselectivity of Tiagabine Binding with Human GAT1.

The human gamma aminobutyric acid transporter subtype 1 (hGAT1) located in the nerve terminals is known to catalyze the neuronal function by the electrogenic reuptake of γ-aminobutyric acid (GABA) with the co-transport of Na+ and Cl- ions. In the past, there has been a major research drive focused on the dysfunction of hGAT1 in several neurological disorders. Thus, hGAT1 of the GABAergic system has been well established as an attractive target for such diseased conditions. Till date, there are various reports about stereo selectivity of -COOH group of tiagabine, a Food and Drug Administration (FDA)-approved hGAT1-selective antiepileptic drug. However, the effect of the stereochemistry of the protonated -NH group of tiagabine has never been scrutinized. Therefore, in this study, tiagabine has been used to explore the binding hypothesis of different enantiomers of tiagabine. In addition, the impact of axial and equatorial configuration of the-COOH group attached at the meta position of the piperidine ring of tiagabine enantiomers was also investigated. Further, the stability of the finally selected four hGAT1-tiagabine enantiomers namely entries 3, 4, 6, and 9 was evaluated through 100 ns molecular dynamics (MD) simulations for the selection of the best probable tiagabine enantiomer. The results indicate that the protonated -NH group in the R-conformation and the -COOH group of Tiagabine in the equatorial configuration of entry 4 provide maximum strength in terms of interaction within the hGAT1 binding pocket to prevent the change in hGAT1 conformational state, i.e., from open-to-out to open-to-in as compared to other selected tiagabine enantiomers 3, 6, and 9.

Performance of volunteer community health workers in implementing home-fortification interventions in Bangladesh: A qualitative investigation.

INTRODUCTION: BRAC, an international development organisation based in Bangladesh, uses female volunteer community health workers called Shasthya Shebika (SS), who receive small incentives to implement its home-fortification interventions at the community level. This paper examines the individual, community and BRAC work environment factors that exert an influence on the performance of SS. METHODS: This qualitative study was conducted between the period of June 2014 to December 2016 as part of a larger evaluation of BRAC's home-fortification programme. Data were collected through in-depth interviews, focus group discussions, and key informant interviews and analysed thematically. The participants were SS and their supervisors working for BRAC, caregivers of children aged 6-59 months, husbands of SS, village doctors, and Upazila Health and Family Planning Officers. RESULTS: Younger, better educated and more experienced SS with positive self-efficacy were perceived to have performed better than their peers. Social and community factors, such as community recognition of the SS's services, social and religious norms, family support, and household distance, also affected the performance of the SS. There were several challenges at the programme and organisational level that needed to be addressed, including appropriate recruitment, timely basic training and income-generation guidance for the SS. CONCLUSION: BRAC's volunteer SS model faces challenges at individual, community, programme and organisational level. Importantly, BRAC's SS require a living wage to earn essential income for their family. Considering the current socio-cultural and economic context of Bangladesh, BRAC may need to revise the existing volunteer SS model to ensure that SS receive an adequate income so that they can devote themselves to implementing its home-fortification intervention.