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Background: Non-genetic factors like microbial dysbiosis may be contributing to the increasing incidence/progression of type 1 diabetes mellitus (T1DM). Objectives: To analyse the gut microbiota profile in Indian children with T1DM and its effect on glycaemic control. Methodology: Faecal samples of 29 children with T1DM were collected and faecal microbial DNA was extracted and subjected to 16S rRNA (ribosomal RNA) sequencing and further analysis. Results: The dominant phyla in children with T1DM were Firmicutes and Bacteroidetes. Butyrate-producing bacteria Blautia and Ruminococcus showed a significant negative correlation with the glycosylated haemoglobin (HbA1C) levels (p < 0.05). Coprococcus and Propionibacterium were important negative predictors of glycaemic control (p < 0.05). Conclusion: Our study suggests that Indian children with T1DM have a distinct gut microbiome taxonomic composition and that short-chain fatty acid-producing bacteria like Ruminococcus and Blautia (butyrate-producing) may play an important role in the glycaemic control of subjects with T1DM. [ABSTRACT FROM AUTHOR]

Ultra‐high performance concrete (UHPC) is an emerging class of cementitious materials with the strength and durability characteristics that far exceed those of normal‐strength concrete (NSC). While the use of UHPC in bridge structures has significantly advanced, the same cannot be stated for building structures. Among possible building applications, this study focuses on the use of UHPC in shear walls, where a significant loading demand is anticipated from the lateral loads due to wind and/or earthquake events. Upon validating a set of finite‐element models with the experimental test results, a holistic investigation has been performed in the current study to evaluate a variety of UHPC shear walls. In particular, the main structural response measures, including initial stiffness, force‐displacement relationship, and strength loss under cyclic lateral loads, have been extracted and compared. The study has been then extended to systematically investigate the effects of key design variables, such as wall thickness, aspect ratio, axial force, steel reinforcement, presence of boundary elements, and strength of embedded steel bars. The outcome of this study provides the building sector with firsthand information regarding the possibility of replacing NSC with UHPC in shear walls. This will be an important step forward to improve the safety and performance of building structures, especially where they are exposed to a high risk of wind and/or earthquake hazards. [ABSTRACT FROM AUTHOR]

In this letter, the effect of deadtime in a gallium nitride (GaN) based grid-connected differential-mode Ćuk converter with high-frequency (HF) transformer isolation is analyzed. It is shown that different levels of lower order harmonics appear in the grid current depending on the power factor of an operation. Utilizing the leakage inductance of the HF transformer, the deadtime is suitably eliminated to result in an improved grid-current total harmonic distortion (THD). Experimental results support the proposed solution. [ABSTRACT FROM AUTHOR]

Human gut microbiome studies are increasing at a rapid pace to understand contributions of the prokaryotic life to the innate workings of their eukaryotic host. Majority of studies focus on the pattern of gut microbial diversity in various diseases, however, understanding the core microbiota of healthy individuals presents a unique opportunity to study the microbial fingerprint in population specific studies. Present study was undertaken to determine the core microbiome of a healthy population and its imputed metabolic role. A total of 8990, clone library sequences (> 900 bp) of 16S rRNA gene from fecal samples of 43 individuals were used. The core gut microbiota was computed using QIIME pipeline. Our results show the distinctive predominance of genus Prevotella and the core composition of genera Prevotella, Bacteroides, Roseburia and Megasphaera in the Indian gut. PICRUSt analysis for functional imputation of the microbiome indicates a higher potential of the microbiota for carbohydrate metabolism. The presence of core microbiota may indicate key functions played by these microbes for the human host. [ABSTRACT FROM AUTHOR]

Microinverters for grid-connected photovoltaic (PV) power conversion systems often require voltage boost due to the low dc voltage of the PV panels. A high-frequency (HF) transformer-isolated differential-mode Ćuk inverter (DMCI) is an attractive topology due to its inherent voltage boost capability and high power density. One of the significant operational issue of the DMCI addressed in this paper is the presence of lower order harmonic distortion in the injected grid current. It is shown that lower order odd and even harmonic voltages are generated with this topology. This problem is accentuated due to the low damping offered by the grid to harmonic voltages. A systematic low-complexity control design is proposed to address this issue. It is shown experimentally that the DMCI operates stably with effective attenuation of the lower order harmonics using the proposed design. Practical operational issues of the DMCI with fast switching GaN field-effect transistor (FET) devices are analyzed and solutions are proposed. It is shown that there can be significant HF noise generation in the DMCI with a frequency range higher than the switching frequency. Practical solutions for resolving HF issues using a combination of circuit layout design and additional passive components are proposed and validated. All of the experimental results are demonstrated on a 500-W GaN-FET-based microinverter prototype. [ABSTRACT FROM PUBLISHER]

This observational study compares the ratio of serum anti-Mullerian hormone (AMH) to the total antral follicle count (AFC) (as a marker of AMH production per follicle) in the various phenotypes of women with polycystic ovary syndrome (PCOS) and isolated polycystic ovarian morphology (PCOM). Two hundred and sixty-two women were recruited. Women with PCOS were divided into four phenotypes based on the diagnostic inclusion criteria of oligo-anovulation (OA), hyperandrogenism (HA) and polycystic ovarian morphology (PCOM). These included Group A (OA + HA + PCOM), Group B (OA + HA), Group C (HA + PCOM) and Group D (OA + PCOM). A ratio of serum AMH to total AFC was calculated and expressed as the AMH/AFC ratio which was compared in the phenotypes of PCOS and isolated PCOM. The median AMH/AFC ratios in PCOS-A, PCOS-D, PCOS-C and PCOM were 1.5, 1.6, 1.2 and 1.1, respectively. There were significant differences in the groups compared [F(3, 238) = 6.14,p = 0.000)]. The ratios were significantly higher in the oligo-anovulatory phenotypes PCOS-A and PCOS-D than the PCOM (p = 0.004 and 0.002, respectively). There was no significant difference in the ratio between ovulatory phenotype PCOS-C and PCOM (p = 0.59). The role of androgens and LH in per-follicle AMH production remains limited. The findings support the hypothesis of a key role for AMH in the mechanism of anovulation in PCOS. [ABSTRACT FROM AUTHOR]

Grid-interactive power converters are normally synchronized with the grid using phase-locked loops (PLLs). The performance of the PLLs is affected by the non-ideal conditions in the sensed grid voltage such as harmonics, frequency deviations and the dc offsets in single-phase systems. In this paper, a single-phase PLL is presented to mitigate the effects of these non-idealities. This PLL is based on the popular second order generalized integrator (SOGI) structure. The SOGI structure is modified to eliminate the effects of input dc offsets. The resulting SOGI structure has a high-pass filtering property. Hence, this PLL is termed as a high-pass generalized integrator based PLL (HGI-PLL). It has fixed parameters which reduces the implementation complexity and aids in the implementation in low-end digital controllers. The HGI-PLL is shown to have the lowest resource utilization among the SOGI based PLLs with dc cancelling capability. Systematic design methods are evolved leading to a design that limits the unit vector THD to within 1% for given non-ideal input conditions in terms of frequency deviation and harmonic distortion. The proposed designs achieve the fastest transient response. The performance of this PLL has been verified experimentally. The results agree with the theoretical prediction. [ABSTRACT FROM AUTHOR]

Starting-up of photovoltaic (PV) inverters involves pre-charging of the input dc bus capacitance. Ideally, direct pre-charging of this capacitance from the PV modules is possible as the PV modules are current limited. Practically, the parasitic elements of the system such as the PV module capacitance, effective wire inductance and resistance determine the start-up transient. The start-up transient is also affected by the contactor connecting the PV modules to the inverter input dc bus. In this work, the start-up current and voltages are measured experimentally for different parallel and series connections of the PV modules. These measurements are used to estimate the stray elements, namely the PV module capacitance, effective inductance and resistance. The estimation is based on a linear small-signal model of the start-up conditions. The effect of different connections of the PV modules and the effect of varying irradiation on the scaling of the values of the stray elements are quantified. The System model is further refined by inclusion of connecting cable capacitance and contactor resistance. Dynamics of the resulting fifth-order model are seen to be consistent with those of the simplified third-order model. The analysis of this paper can be used to estimate the expected peak inrush current in PV inverters. It can also be used to arrive at a detailed modelling of PV modules to evaluate the transient behaviour. [ABSTRACT FROM AUTHOR]

Second-order generalized integrator (SOGI) based phase-locked loops (PLLs) are commonly used for grid voltage synchronization in single-phase grid-connected power converters. SOGI-PLLs are attractive because of their simple structure that makes them suitable for implementation even in low-end digital controllers. In this paper, an SOGI based fixed-parameter PLL structure with full dc offset rejection capability is presented. This PLL uses two cascaded SOGI structures and it is termed as cascaded generalized integrator PLL (CGI-PLL). A systematic design procedure is proposed for the CGI-PLL that minimizes the response time and unit vector harmonic distortion. This design achieves minimum settling time for any given worst-case frequency deviation in the grid voltage and ensures that the unit vector THD is less than 1%. The PLL designed using the proposed method has good harmonic attenuation capability. The steady-state and transient response of this PLL have been validated experimentally and are found to agree with the theoretical analysis. [ABSTRACT FROM AUTHOR]

We report a facile, microwave-accelerated, one-pot tandem synthesis of unsymmetrical ureas via a Curtius rearrangement. In this method, one-pot microwave irradiation of commercially available (hetero)aromatic acids and amines in the presence of diphenylphosphoryl azide enabled extremely rapid (1-5 min) construction of an array of unsymmetrical ureas in good to excellent yields. We demonstrate the utility of our method in the efficient, gram-scale synthesis of key biologically active compounds targeting the cannabinoid 1 and α7 nicotinic acetylcholine receptors. [ABSTRACT FROM AUTHOR]

Inverters are required to convert the dc power from photovoltaic panels to ac. In grid connected inverters, the ac output is directly fed into the electric grid. In this paper, a high-frequency transformer based inverter topology is presented. This leads to a very compact inverter. The modulation of this inverter with a lossless snubber circuit is proposed. Proposed modulation eliminates the over-voltage spikes due to transformer leakage inductance. Commutation of the leakage inductance energy with this modulation is also discussed. The performance of the inverter with the proposed modulation is validated using simulation and experimental results. [ABSTRACT FROM AUTHOR]

Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs. [ABSTRACT FROM AUTHOR]

Phase-locked loops (PLLs) are necessary in applications which require grid synchronization. Presence of unbalance or harmonics in the grid voltage creates errors in the estimated frequency and angle of a PLL. The error in estimated angle has the effect of distorting the unit vectors generated by the PLL. In this paper, analytical expressions are derived which determine the error in the phase angle estimated by a PLL when there is unbalance and harmonics in the grid voltage. By using the derived expressions, the total harmonic distortion (THD) and the fundamental phase error of the unit vectors can be determined for a given PLL topology and a given level of unbalance and distortion in the grid voltage. The accuracy of the results obtained from the analytical expressions is validated with the simulation and experimental results for synchronous reference frame PLL (SRF-PLL). Based on these expressions, a new tuning method for the SRF-PLL is proposed which quantifies the tradeoff between the unit vector THD and the bandwidth of the SRF-PLL. Using this method, the exact value of the bandwidth of the SRF-PLL can be obtained for a given worst case grid voltage unbalance and distortion to have an acceptable level of unit vector THD. The tuning method for SRF-PLL is also validated experimentally. [ABSTRACT FROM PUBLISHER]

Abstract: We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction time (10–15min) with high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The optimization process is reported and the results from the microwave route are compared with those of the conventional synthetic route. In almost all cases, the microwave acceleration consistently provided improved yields favoring the cis-diastereomer. [Copyright &y& Elsevier]

Anexpeditious microwave-assisted synthesis of 4BP-TQS, its enantiomericseparation, and their functional evaluation is reported. Electrophysiologicalcharacterization in Xenopusoocytesrevealed that activity exclusively resided in the (+)-enantiomer 1b(GAT107) and (−)-enantiomer 1adidnot affect its activity when coapplied. X-ray crystallography studiesrevealed the absolute stereochemistry of 1bto be 3aR,4S,9bS. 1brepresents the most potent ago-PAM of α7 nAChRs availableto date and is considered for further in vivo evaluation. [ABSTRACT FROM AUTHOR]

In this paper, a simple single-phase grid-connected photovoltaic (PV) inverter topology consisting of a boost section, a low-voltage single-phase inverter with an inductive filter, and a step-up transformer interfacing the grid is considered. Ideally, this topology will not inject any lower order harmonics into the grid due to high-frequency pulse width modulation operation. However, the nonideal factors in the system such as core saturation-induced distorted magnetizing current of the transformer and the dead time of the inverter, etc., contribute to a significant amount of lower order harmonics in the grid current. A novel design of inverter current control that mitigates lower order harmonics is presented in this paper. An adaptive harmonic compensation technique and its design are proposed for the lower order harmonic compensation. In addition, a proportional-resonant-integral (PRI) controller and its design are also proposed. This controller eliminates the dc component in the control system, which introduces even harmonics in the grid current in the topology considered. The dynamics of the system due to the interaction between the PRI controller and the adaptive compensation scheme is also analyzed. The complete design has been validated with experimental results and good agreement with theoretical analysis of the overall system is observed. [ABSTRACT FROM AUTHOR]

Identification of disordered regions in protein sequence(s) is a very important problem and a long standing puzzle to biologists. In many proteins, these structural disorders (an outcome of improper protein folding) inside an otherwise ordered structure exhibit many important biological functions. Classical approaches to identify these regions in a sequence rely mainly on the pattern recognition algorithms where amino acid residues are classified as ordered or disordered. In this work, we employ recurrence quantification analysis based approach to understand the complex dynamics underlying these regions. We hypothesize and demonstrate that proteins with disordered regions show a strong evidence of the order-chaos-order transition pattern by using windowed recurrence quantification analysis on a database of 476 proteins available from . [ABSTRACT FROM AUTHOR]

No abstract received. [ABSTRACT FROM AUTHOR]

Abstract: Xylanases are an industrially important class of hydrolytic enzymes that degrade xylans. Production of xylanase from a fungal culture by submerged fermentation and optimization of the operating conditions for maximum activity are the two aims of the present study. Penicillium janthinellum NCIM 1169 with Mandels–Weber medium, sugarcane bagassse (40#) as a carbon source and beef extract as a nitrogen source were used in the experiments. We did 41 experiments to see the effect of variations in carbon, nitrogen source, pH, and inoculum on xylanase activity. This data was then used to build an input/output model using multiple linear regression, back propagation neural network and lazy learning algorithm. It was found that lazy learning model correlated well in mapping input/output data. This model was then utilized as an objective function in genetic algorithm to find the optimal combination of the operating conditions to get the maximum xylanase activity. It was observed that with carbon source, 1.63%, nitrogen source, 0.16%, pH, 4.1, and inoculum, 5.5%, maximum xylanase activity of 28.98±1.73U/ml was achieved. [Copyright &y& Elsevier]

Abstract: A support vector machine with knowledge incorporation is applied to detect the faults in Tennessee Eastman Process, a benchmark problem in chemical engineering. The knowledge incorporated algorithm takes advantage of the information on horizontal translation invariance in tangent direction of the instances in dataset. This essentially changes the representation of the input data while training the algorithm. These local translations do not alter the class membership of the instances in the dataset. The results on binary as well as multiple fault detection justify the use of knowledge incorporation. [Copyright &y& Elsevier]

Head-related transfer functions (HRTFs) measured from human subjects were approximated using infinite-impulse-response (IIR) filter models. Models were restricted to rational transfer functions (plus simple delays) so that specific models are characterized by the locations of poles and zeros in the complex plane. The all-pole case (with no nontrivial zeros) is treated first using the theory of linear prediction. Then the general pole-zero model is derived using a weighted-least-squares (WLS) formulation of the modified least-squares problem proposed by Kalman (1958). Both estimation algorithms are based on solutions of sets of linear equations and result in efficient computational schemes to find low-order model HRTFs. The validity of each of these two low-order models was assessed in psychophysical experiments. Specifically, a four-interval, two-alternative, forced-choice paradigm was used to test the discriminability of virtual stimuli constructed from empirical and model HRTFs for corresponding locations. For these experiments, the stimuli were 80 ms, noise tokens generated from a wideband noise generator. Results show that sounds synthesized through model HRTFs were indistinguishable from sounds synthesized from original HRTF measurements for the majority of positions tested. The advantages of the techniques described here are the computational efficiencies achieved for low-order IIR models. Properties of the all-pole and pole-zero estimators are discussed in the context of low-order HRTF representations, and implications for basic and applied contexts are considered. [ABSTRACT FROM AUTHOR]

This paper describes a robust support vector machines (SVMs) classification methodology, which can offer superior classification performance for important process engineering problems. The method incorporates efficient tuning procedures based on minimization of radius/margin and span bound for leave-one-out errors. An agent-based asynchronous teams (A-teams) software framework, which combines Genetic-Quasi-Newton algorithms for the optimization is highly successful in obtaining the optimal SVM hyper-parameters. The algorithm has been applied for classification of binary as well as multi-class real world problems. [Copyright &y& Elsevier]

This work provides a methodology for the control of complex non-linear systems by compensating for the non-linear part using support vector machines (SVM) and subsequently developing simple linear feedback law for control. The method tested for the benchmark Ro¨ssler and Lorenz chaotic oscillators shows excellent performance. [Copyright &y& Elsevier]

Describes the synthesis of polycyclic aromatic chlorocarbon perchlorotriphenylene from tetrachlorophthalic anhydride. Stability of product; Molecular orbital calculations; X-ray structure of perchlorotriphenylene; Computational studies of the conformations of perchlorotriphenylene.

Presents research which studied how accurately the head-related transfer function (HRTF) must be reproduced to achieve three-dimensional perception of auditory signals in anechoic space. Perception of sounds heard over headphones compared with real sound sources; Location-dependent filtering in perception; Effect of smoothing HRTFs in frequency; Distinguishing real from virtual sources.

A two term composite nonlinear feedback (2TCNF) control technique is developed here for nonlinear time delay systems in presence of input saturation. The proposed controller consists of two terms that are conventional composite nonlinear feedback (CNF) control and delay state control. CNF control has advantage of fast transient response and delay state control improves damping characteristics. The proposed controller thus has both these advantages and it tracks the reference smoothly. The closed loop asymptotic stability is guaranteed via Lyapunov–Krasovskii analysis. The efficiency of the proposed controller is tested on exothermic chemical reactor and validated through simulation results. Its performance is compared with the conventional CNF control. The superiority of 2TCNF is established in terms of less overshoot, fast transient response and reduced steady state error. [ABSTRACT FROM AUTHOR]

Reports on the synthesis and crystallographic characterization of the aromatic hydrocarbon perchlorotriphenylene. Avoidance of chlorination in the final step of the synthesis; Trimerization of tetrachlorobenzene as an alternative synthesis; Enrichment of the product under vacuum conditions; X-ray structure.

An efficient microwave-assisted synthesis of cyclopentene ring-fused tetrahydroquinolines using a three-component Povarov reaction is reported. [ABSTRACT FROM AUTHOR]

Background and Purpose: Orthosteric agonists and positive allosteric modulators (PAMs) of the α7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function.Experimental Approach: Initial studies examined the α7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model.Key Results: Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through α7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test.Conclusions and Implications: Collectively, these results provide the first proof of principle that α7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain. [ABSTRACT FROM AUTHOR]

An abstract of the article "Cutaneous Tuberculosis Associated with Infliximab Treatment" by Sumir Patel, Abhijit Kulkarni, Rad Agrawal, and Arezo Shahwali is presented.

An abstract of the article "Monolobar Caroli's Disease: A Case Report" by Sumir Patel, Abhijit Kulkarni, Rad Agrawal, and Girija Nathan is presented.

The α7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetra-hydro-3H-cyclopenta[c]quinoline-8-sulfonamide) have the combined properties of agonists and PAMs (ago-PAM) and produce very effective channel activation (direct allosteric activation (DAA)) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solvent-accessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for theDAAsite, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for Asp-101. This hypothesis is supported with data from site-directed mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structural elements that can be mapped onto the receptor surface for an improved understanding of this novel way to target α7 nAChR therapeutically. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to investigate aneuploidy detection using an approach based on nuchal translucency (NT) and non-invasive prenatal testing (NIPT).Methods: This was a cohort study including 5,306 high-risk pregnancies with NT measurements and chorionic villus samples (CVS) tested for full karyotype.Results: The fetal karyotype was normal in 4,172 (78.6%) cases and abnormal in 1,134 (21.4%), including 1,009 with a likely clinically significant adverse outcome. Universal CVS with full karyotyping would lead to the diagnosis of all clinically significant abnormalities. A policy of relying solely on NIPT would have led to the diagnosis of 88.9% of clinically significant abnormalities. A strategy whereby NIPT is the main method, with CVS reserved for cases with NT ≥3.0 mm, would require CVS in 21.7% of cases, identify 94.8% of significant abnormalities and avoid miscarriage in 41 pregnancies compared to CVS for all.Conclusions: A policy of NIPT for increased-risk cases and CVS with full karyotype if the NT was ≥3.0 mm reduced the risk of miscarriage yet still identified 95% of clinically significant aneuploidy. [ABSTRACT FROM AUTHOR]

The α7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since α7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the α7 ion channel. However, the best α7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather “silent agonists”, which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of α7 nAChRs. There are two forms of α7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was α7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by α7 receptors in that conformation. [ABSTRACT FROM AUTHOR]

GAT107, the (+)-enantiomer of racemic 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, is a strong positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptor (nAChR) activation by orthosteric agonists with intrinsic allosteric agonist activities. The direct activation produced by GAT107 in electrophysiological studies is observed only as long as GAT107 is freely diffusible in solution, although the potentiating activity primed by GAT107 can persist for over 30min after drug washout. Direct activation is sensitive to α7 nAChR antagonistmethyllycaconitine, although the primed potentiation is not. The data are consistent with GAT107 activity arising from two different sites. We show that the coupling between PAMs and the binding of orthosteric ligands requires tryptophan 55 (Trp-55), which is located at the subunit interface on the complementary surface of the orthosteric binding site. Mutations of Trp-55 increase the direct activation produced by GAT107 and reduce or prevent the synergy between allosteric and orthosteric binding sites, so that thesemutants can also be directly activated by other PAMs such as PNU-120596 and TQS, which do not activate wild-type α7 in the absence of orthosteric agonists. We identify Tyr-93 as an essential element for orthosteric activation, because Y93C mutants are insensitive to orthosteric agonists but respond to GAT107. Our data show that both orthosteric and allosteric activation of α7 nAChR require cooperative activity at the interface between the subunits in the extracellular domain.These cooperative effects rely on key aromatic residues, and although muta-tions of Trp-55 reduce the restraints placed on the requirement for orthosteric agonists, Tyr-93 can conduct both orthosteric activation and desensitization among the subunits. [ABSTRACT FROM AUTHOR]

Abstract: In this article, we utilize the concept of partial Granger causality to study the penicillin production process under several operating conditions. We propose a graph-theoretic template (causal network) based method for intelligent process monitoring. We validate our results with the aid of existing knowledge and available literature. The proposed method is quite general and can be extended to analyze several physical, chemical or biological systems. [ABSTRACT FROM AUTHOR]

Study Question: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births?Summary Answer: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively.What Is Known Already: Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics.Study Design, Size, Duration: A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included.Participants/materials, Setting, Methods: A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation.Main Results and the Role Of Chance: During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births.Limitations, Reasons For Caution: Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected.Wider Implications Of the Findings: Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS.Study Funding/competing Interest(s): L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children's Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work.Trial Registration Number: NA. [ABSTRACT FROM AUTHOR]

In this paper, a modular control approach has been proposed for a single- and three-phase differential-mode Ćuk inverter (DMCI) operating with a recently proposed discontinuous-modulation scheme that offers tangible performance benefits over conventional continuous modulation scheme. The modular control scheme uses a combination of a transformation and adaptive control law to meet tracking requirements in the presence of converter nonlinearity. Experimental results for the single- and three-phase DMCI are provided for startup, steady state, load transition, and total harmonic distortion using different types of loads, which validate the efficacy of the implemented modular tracking controller. Further, detailed stability of the closed-loop DMCI module is provided. [ABSTRACT FROM AUTHOR]

We planned a systematic review and meta-analysis of randomized clinical trials (RCTs) to examine the best available evidence regarding the intrauterine instillation of embryo culture supernatant prior to embryo transfer in ART. The outcomes were: (i) live birth; (ii) clinical pregnancy; (iii) multiple pregnancy; and (iv) miscarriage rates. Five RCTs were considered eligible and available for qualitative synthesis. Due to clinical heterogeneity, results from only two trials were combined for the meta-analysis. The live birth rate (risk ratio [RR], 0.47; 95% confidence interval [CI] 0.22-0.98; one study, 60 participants, low-quality evidence) was found to be significantly lower with intrauterine instillation of embryo culture supernatant compared to no intervention. The clinical pregnancy rate was similar between the embryo culture supernatant group and the control group (RR 1.02 RR, 95% CI 0.77-1.36; two trials, 156 participants, I2 = 0%). To conclude, this review did not find any improvement in clinical pregnancy rate with the intrauterine instillation of embryo culture supernatant prior to embryo transfer compared to no intervention in women undergoing ART and we remain uncertain regarding its effect on live birth rate. [ABSTRACT FROM AUTHOR]

Background and Purpose: GAT107 ((3aR,4S,9bS)-4-(4-bromo-phenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta-[c]quinoline-8-sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.Experimental Approach: Voltage-clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.Key Results: Long-lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non-conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR-selective antagonist and in how effectively they promote current.Conclusions& Implications: Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM-inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non-conducting states have common activity on signal transduction.Linked Articles: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. [ABSTRACT FROM AUTHOR]

Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca 2 + -dependent manner. Here, we investigated potential crosstalk between α7 nAChR and PPAR-α, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full α7 agonist, attenuated formalin-induced nociceptive behavior in α7-dependent manner. Interestingly, the selective PPAR-α antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the α7 nAChR PAM PNU120596, ago-PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin-injected paw blocked PNU282987-induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR-α agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid CB 1 antagonist rimonabant and the CB 2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-α plays a key role in a putative antinociceptive α7 nicotinic signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To develop transferrin (Tf)-targeted delivery systems for the pro-apoptotic drug, NCL-240, and to evaluate the efficacy of this delivery system in ovarian cancer NCI/ADR-RES cells, grown in vitro in a 3D spheroid model. Methods: Tf-targeted PEG-PE-based micellar and ePC/CHOL-based liposomal delivery systems for NCL-240 were prepared. NCI/ADR-RES cells were used to generate spheroids by a non-adhesive liquid overlay technique. Spheroid growth and development were monitored by size (diameter) analysis and H&E staining. The targeted formulations were compared to untargeted ones in terms of their degree of spheroid association and penetration. A cell viability analysis with NCL-240-loaded micelles and liposomes was performed to assess the effectiveness of Tf-targeting. Results: Tf-targeted polymeric micelles and Tf-targeted liposomes loaded with NCL-240 were prepared. NCI/ADR-RES cells generated spheroids that demonstrated the presence of a distinct necrotic core along with proliferating cells in the spheroid periphery, partly mimicking in vivo tumors. The Tf-targeted micelles and liposomes had a deeper spheroid penetration as compared to the untargeted delivery systems. Cell viability studies using the spheroid model demonstrated that Tf-mediated targeting markedly improved the cytotoxicity profile of NCL-240. Conclusion: Transferrin targeting enhanced delivery and effectiveness of micelles and liposomes loaded with NCL-240 against NCI/ADR-RES cancer cells in a 3D spheroid model. [ABSTRACT FROM AUTHOR]

Blockade of cannabinoid type 1 (CB 1)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB 1 antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB 1 signaling by decreasing affinity and/or efficacy of CB 1 ligands. We hypothesized that a CB 1 -NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB 1 antagonists. GAT358, a CB 1 -NAM, failed to elicit cardinal signs of direct CB 1 activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB 1 agonist CP55,940, suggesting that a CB 1 -NAM blocked cardinal signs of CB 1 activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB 1 positive allosteric modulator (CB 1 -PAM), and absent in CB 1 -knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CB 1 -NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects. [Display omitted] • CB 1 negative allosteric modulator GAT358 does not produce cannabimimetic effects. • GAT358 decreases CB 1 agonist-induced catalepsy, hypothermia but not antinociception. • GAT358 eliminates morphine-induced phasic dopamine release in the NAc shell. • GAT358 blocks conditioned place preference to morphine via a CB 1 mechanism. • GAT358 reduces oral oxycodone but not water intake in a two-bottle choice assay. [ABSTRACT FROM AUTHOR]

Purpose: To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells. Methods: Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles. Results: NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines. Conclusion: These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines. [ABSTRACT FROM AUTHOR]

Background: Peroral endoscopic myotomy (POEM) has been performed as a novel endoscopic procedure to treat achalasia with favorable outcome. The objective of this study was to assess the outcome of POEM in our initial series and to assess the safety and efficacy of POEM in a variety of esophageal motility-related clinical problems.Methods: This is a retrospective cross-sectional study involving all patients with esophageal motility disorders defined by the Chicago classification, who had undergone consideration for POEM at our institution. Validated questionnaires such as gastroesophageal reflux disease health-related quality of life (GERD-HRQL), reflux symptom index (RSI) and achalasia disease-specific health-related quality of life were obtained pre- and postoperatively.Results: From January 2013 to October 2014, a total of 35 POEMs (achalasia n = 25, non-achalasia n = 10) were performed on 33 patients (female n = 20, male n = 13, mean age 56.9 years). There was no mortality. The rate of inadvertent mucosotomy was 17.1%. The rate of complications requiring interventions was 5.7%. During a mean follow-up period of 7 months (range 0.5-17), 92% of patients with achalasia and 75% of those with non-achalasia motility disorders had a symptomatic improvement in dysphagia. Chest pain was completely resolved in all patients with achalasia (8/8) and 80% of patients with non-achalasia (4/5). The GERD-HRQL, RSI and dysphagia scores significantly improved after POEM in patients with achalasia. There was a significant improvement in GERD-HRQL and RSI scores, and a trend toward lower dysphagia score in patients with non-achalasia.Conclusions: The outcome of POEM to treat achalasia and non-achalasia motility disorders is consistent with previous studies. Potential benefit of POEM includes not only its flexibility to adjust the length and location of myotomy but also the ability to extend myotomy proximally without thoracoscopy or thoracotomy. POEM can be combined with laparoscopic procedures and used as "salvage" for localized esophageal dysmotility. [ABSTRACT FROM AUTHOR]

Background and Objective Surgical treatment of ossified posterior longitudinal ligament (OPLL) continues to be wrought with confusion, debate, and arguments. We report our experience with an alternative form of treatment that involves only fixation of the involved spinal segments. We report and put on record our remarkably gratifying clinical experience in 13 of 14 patients having OPLL after surgery that involved only facetal fixation and aimed at arthrodesis of involved spinal segments. No direct bone, ligament, or disc resection was done for decompression of the spinal dural tube or root canal. The OPLL was not directly handled during the surgical procedure. The rationale of the proposed treatment is discussed. Methods During the period June 2012 to August 2014, 14 patients having OPLL were treated by facetal transarticular screw fixation technique. The Japanese Orthopaedic Association score, visual analogue scale, and Odom's criteria were used as indices to monitor the clinical status. Results The procedure resulted in firm stabilization and fixation of the spinal segments and provided a ground for arthrodesis. During an average follow-up period of 17 months, there was immediate postoperative and progressive recovery in symptoms in 13 patients. There were no surgery or implant-related mechanical or infective complications. Conclusions Instability could be the defining phenomenon in pathogenesis of clinical symptoms related to OPLL. The clinical outcome in our patients suggests that only fixation of the spinal segments can be a simple, safe, and rationale form of treatment for the complex pathology of OPLL. [ABSTRACT FROM AUTHOR]

Endoscopic retrograde cholangiopancreatography (ERCP) has become an important tool in the diagnosis and treatment of pancreaticobiliary pathology. ERCP in patients that have undergone Roux-en-Y gastric bypass (RYGB) is particularly challenging because traditional transoral endoscopy may be limited. We present our experience with ERCP after RYGB and review the literature. In 2007 eight patients underwent ERCP after RYGB using open or laparoscopic transgastric access. After introduction of pneumoperitoneum, a total of four ports were placed. A purse-string was placed around a gastrotomy 4 to 6cm proximal to the pylorus. The endoscope was introduced through a 15 mm left-upper-quadrant port and the gastrotomy. Endoscopy was then performed. Laparoscopic gastrotomy was used in all patients that underwent a previous laparoscopic Rouxen- Y gastric bypass (LRYGB) (n = 6) and open gastrotomy was used for patients with a previous open RYGB (n = 2). Cannulation and interventions in the pancreaticobiliary tree were successful in all cases. There were no postoperative complications. Laparoscopic transgastric ERCP after LRYGB is feasible, highly successful, may be performed expeditiously, and does not seem to add significant morbidity to the procedure. The ability to perform ERCP in this patient population is critical due to their tendency to have preexisting biliary disease and to develop gallstones and the associated complications. [ABSTRACT FROM AUTHOR]

• Expression of RIC3 is dynamically regulated following immune activation. • Similar expression dynamics suggest similar function for RIC3 and α7 nAChR. • RIC3 is required for the cholinergic anti-inflammatory pathway. • RIC3 and α7 nAChR expression increases in some MS patients. • Expression of RIC3 and of the α7 nAChR encoding gene is correlated in MS patients. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels having many functions including inflammation control, as part of the cholinergic anti-inflammatory pathway. Genome wide association studies implicated RIC3, a chaperone of nAChRs, in multiple sclerosis (MS), a neuroinflammatory disease. To understand the involvement of RIC3 in inflammatory diseases we examined its expression, regulation, and function in activated immune cells. Our results show that immune activation leads to dynamic changes in RIC3 expression, in a mouse model of MS and in human lymphocytes and macrophages. We also show similarities in the expression dynamics of RIC3 and CHRNA7, encoding for the α7 nAChR subunit. Homomeric α7 nAChRs were shown to mediate the anti-inflammatory effects of cholinergic agonists. Thus, similarity in expression dynamics between RIC3 and CHRNA7 is suggestive of functional concordance. Indeed, siRNA mediated silencing of RIC3 in a mouse macrophage cell line eliminates the anti-inflammatory effects of cholinergic agonists. Furthermore, we show increased average expression of RIC3 and CHRNA7 in lymphocytes from MS patients, and a strong correlation between expression levels of these two genes in MS patients but not in healthy donors. Together, our results are consistent with a role for RIC3 and for the mechanisms regulating its expression in inflammatory processes and in neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Various antitumor drugs, including paclitaxel, frequently cause chemotherapy-induced peripheral neuropathy (CIPN) that can be sustained even after therapy has been completed. The current work was designed to evaluate R-47, an α7 nAChR silent agonist, in our mouse model of CIPN. R-47 was administered to male C57BL/6J mice prior to and during paclitaxel treatment. Additionally, we tested if R-47 would alter nicotine's reward and withdrawal effects. The H460 and A549 non-small cell lung cancer (NSCLC) cell lines were exposed to R-47 for 24–72 h, and tumor-bearing NSG mice received R-47 prior to and during paclitaxel treatment. R-47 prevents and reverses paclitaxel-induced mechanical hypersensitivity in mice in an α7 nAChR-dependent manner. No tolerance develops following repeated administration of R-47, and the drug lacks intrinsic rewarding effects. Additionally, R-47 neither changes the rewarding effect of nicotine in the Conditioned Place Preference test nor enhances mecamylamine-precipitated withdrawal. Furthermore, R-47 prevents paclitaxel-mediated loss of intraepidermal nerve fibers and morphological alterations of microglia in the spinal cord. Moreover, R-47 does not increase NSCLC cell viability, colony formation, or proliferation, and does not interfere with paclitaxel-induced growth arrest, DNA fragmentation, or apoptosis. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These studies suggest that R-47 could be a viable and efficacious approach for the prevention and treatment of CIPN that would not interfere with the antitumor activity of paclitaxel or promote lung tumor growth. • α7 silent agonist R-47 is antinociceptive in mice. • R-47 suppresses paclitaxel-induced changes in spinal microglia morphology. • R-47 lacks rewarding effects but produces spontaneous pain relief in the CPP test. • R-47 does not precipitate nicotine physical and affective-like withdrawal symptoms. • R-47 does not enhance tumor growth nor impair paclitaxel's antitumor effects. [ABSTRACT FROM AUTHOR]