Multimodal Interrogation of Ventral Pallidum Projections Reveals Projection-Specific Signatures and Effects on Cocaine Reward.

The ventral pallidum (VP) is a central hub in the reward circuitry with diverse projections that have different behavioral roles attributed mostly to the connectivity with the downstream target. However, different VP projections may represent, as in the striatum, separate neuronal populations that differ in more than just connectivity. In this study, we performed in mice of both sexes a multimodal dissection of four major projections of the VP-to the lateral hypothalamus (VP→LH), ventral tegmental area (VP→VTA), lateral habenula (VP→LHb), and mediodorsal thalamus (VP→MDT)-with physiological, anatomical, genetic, and behavioral tools. We also tested for physiological differences between VP neurons receiving input from nucleus accumbens medium spiny neurons (MSNs) that express either the D1 (D1-MSNs) or the D2 (D2-MSNs) dopamine receptor. We show that each VP projection (1) when inhibited during a cocaine conditioned place preference (CPP) test affects performance differently, (2) receives a different pattern of inputs using rabies retrograde labeling, (3) shows differentially expressed genes using RNA sequencing, and (4) has projection-specific characteristics in excitability and synaptic input characteristics using whole-cell patch clamp. VP→LH and VP→VTA projections have different effects on CPP and show low overlap in circuit tracing experiments, as VP→VTA neurons receive more striatal input, while VP→LH neurons receive more olfactory input. Additionally, VP→VTA neurons are less excitable, while VP→LH neurons are more excitable than the average VP neuron, a difference driven mainly by D2-MSN-responding neurons. Thus, VP→VTA and VP→LH neurons may represent largely distinct populations of VP neurons.

PdNPs/NiNWs as a welding tool for the synthesis of polyfluorene derivatives by Suzuki polycondensation under microwave radiation.

Conjugated polymers are promising tools to differentiate various types of semiconducting single-walled carbon nanotubes (s-SWCNTs). However, their synthesis is challenging. Insufficient control over molecular weights, and unpredictive/unrepeatable batches hinder possible applications and scale-up. Furthermore, commercial homogeneous catalysts often require inert conditions and are almost impossible to recycle. To overcome these problems, we present a nanocatalyst consisting of magnetic nickel nanowires decorated with highly active palladium nanoparticles. A two-step wet chemical reduction protocol with the assistance of sonochemistry was employed to obtain a heterogeneous catalyst capable of conducting step-growth Suzuki polycondensation of a fluorene-based monomer. Additionally, we enhanced the performance of our catalytic system via controlled microwave irradiation, which significantly shortened the reaction time from 3 d to only 1 h. We studied the influence of the main process parameters on the yield and polymer chain length to gain insight into phenomena occurring in the presence of metallic species under microwave irradiation. Finally, the produced polymers were used to extract specific s-SWCNTs by conjugated polymer extraction to validate their utility.

Li Salt Assisted Highly Flexible Carbonaceous Ni3N@polyimide Electrode for an Efficient Asymmetric Supercapacitor.

This work used a highly flexible, sustainable polyimide tape as a substrate to deposit ductile-natured carbonaceous Ni3N (C/Ni3N@polyimide) material for supercapacitor application. C/Ni3N was prepared using a co-sputtering technique, and this method also provided better adhesion of the electrode material over the substrate, which is helpful in improving bending performance. The ductile behavior of the sputter-grown electrode and the high flexibility of the polyimide tape provide ultimate flexibility to the C/Ni3N@polyimide-based supercapacitor. To achieve optimum electrochemical performance, a series of electrochemical tests were done in the presence of various electrolytes. Further, a flexible asymmetric supercapacitor (NC-FSC) (C/Ni3N//carbon@polyimide) was assembled by using C/Ni3N as a cathode and a carbon thin film as an anode, separated by a GF/C-glass microfiber soaked in optimized 1 M Li2SO4 aqueous electrolyte. The NC-FSC offers a capacitance of 324 mF cm-2 with a high areal energy density of 115.26 µWh cm-2 and a power density of 811 µW cm-2, with ideal bending performance.

Synthesis and characterization of Fe3O4@SiO2@PDA@Ag core-shell nanoparticles and biological application on human lung cancer cell line and antibacterial strains.

Novel magnetic and metallic nanoparticles garner much attention of researchers due to their biological, chemical and catalytic properties in many chemical reactions. In this study, we have successfully prepared a core-shell Fe3O4@SiO2@PDA nanocomposite wrapped with Ag using a simple synthesis method, characterised and tested on small cell lung cancer and antibacterial strains. Incorporating Ag in Fe3O4@SiO2@PDA provides promising advantages in biomedical applications. The magnetic Fe3O4 nanoparticles were coated with SiO2 to obtain negatively charged surface which is then coated with polydopamine (PDA). Then silver nanoparticles were assembled on Fe3O4@SiO2@PDA surface, which results in the formation core-shell nanocomposite. The synthesised nanocomposite were characterized using SEM-EDAX, dynamic light scattering, XRD, FT-IR and TEM. In this work, we report the anticancer activity of silver nanoparticles against H1299 lung cancer cell line using MTT assay. The cytotoxicity data revealed that the IC50 of Fe3O4@SiO2@PDA@Ag against H1299 lung cancer nanocomposites cells was 21.52 µg/mL. Furthermore, the biological data of nanocomposites against Gram-negative 'Pseudomonas aeruginosa' and Gram-positive 'Staphylococcus aureus' were carried out. The range of minimum inhibitory concentration was found to be 115 µg/mL where gentamicin was used as a standard drug. The synthesized AgNPs proves its supremacy as an efficient biomedical agent and AgNPs may act as potential beneficial molecule in lung cancer chemoprevention and antibacterial strains.

In the present study, we have successfully prepared a core-shell Fe₃O₄@SiO₂@PDA@Ag nanocomposite.We have investigated the dose-dependent cellular toxicity of silver nanocomposite in the nonsmall cell lung cancer cell line H1299 using MTT assay.Also, we have evaluated the mode of cell death using apoptosis.We have also evaluated the bioactivity of AgNPs on both Gram-positive and Gram-negative bacterial cells with highly efficient antibacterial potency.

Nanodot zirconium trisulfide modified conducting thread: A smart substrate for fabrication of next generation biosensor.

In present work, we report an eco-friendly, flexible and highly conducting cotton thread (CT) as a smart substrate for the development of biosensing platform towards ultrasensitive detection of swine flu serum amyloid A (SAA) biomarker. The biosensor was fabricated by optimized coating of CT with poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) conductive ink followed by incorporation of nanodot zirconium trisulfide (nZrS3) which helped in enhancing the electrochemical properties and improving stability of PEDOT:PSS polymeric film. The fabricated nZrS3/PEDOT:PSS/CT electrode was then used for sequential immobilization of monoclonal antibodies of SAA (anti-SAA) and bovine serum albumin (BSA). The synthesized nanomaterials and fabricated electrodes were characterized through X-ray diffraction, Fourier-transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy and contact angle analyser techniques. The electrochemical response of the fabricated smart thread based biosensor (BSA/anti-SAA/ZrS3/PEDOT:PSS/CT) was recorded against SAA using chronoamperometry technique which revealed superior sensitivity {30.2 µA [log (µg mL-1)]-1 cm-2}, excellent lower detection limit (0.72 ng mL-1) and prolonged shelf life up to 48 days. The response of the biosensor was also validated by analysing the electrochemical response of SAA spiked serum samples and the obtained results showed good correlation with that of standard samples.

Interface Engineering-Driven Room-Temperature Ultralow Gas Sensors with Elucidating Sensing Performance of Heterostructure Transition Metal Dichalcogenide Thin Films.

In this report, we investigate the room-temperature gas sensing performance of heterostructure transition metal dichalcogenide (MoSe2/MoS2, WS2/MoS2, and WSe2/MoS2) thin films grown over a silicon substrate using a pulse laser deposition technique. The sensing response of the aforementioned sensors to a low concentration range of NO2, NH3, H2, CO, and H2S gases in air has been assessed at room temperature. The obtained results reveal that the heterojunctions of metal dichalcogenide show a drastic change in gas sensing performance compared to the monolayer thin films at room temperature. Nevertheless, the WSe2/MoS2-based sensor was found to have an excellent selectivity toward NO2 gas with a particularly high sensitivity of 10 ppb. The sensing behavior is explained on the basis of a change in electrical resistance as well as carrier localization prospects. Favorably, by developing a heterojunction of diselenide and disulfide nanomaterials, one may find a simple way of improving the sensing capabilities of gas sensors at room temperature.

Visible Light-Prompted Regioselective Synthesis of Novel 5-Aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazoles as DNA- and BSA-Targeting Agents.

Organic transformations mediated by visible light have gained popularity in recent years as they are green, renewable, inexpensive, and clean and yield excellent products. The present study describes cyclo-condensation of 2-methylthiazole-4-carbothioamide with differently substituted α-bromo-1,3-diketones achieved by utilizing a white light-emitting diode (LED) (9W) to accomplish the regioselective synthesis of novel 5-aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazole derivatives as DNA/bovine serum albumin (BSA)-targeting agents. The structure characterization of the exact regioisomer was achieved unequivocally by heteronuclear two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy [1H-13C] HMBC; [1H-13C] HMQC; and [1H-15N] HMBC. In silico toxicity studies indicated that the synthesized compounds exhibit low toxicity risks and adhere to the rules of oral bioavailability without any exception. Computational molecular modeling of the bithiazole derivatives with the dodecamer sequence of the DNA duplex and BSA identified 5-(4-chlorobenzoyl)-2',4-dimethyl-2,4'-bithiazole 7g as the most suitable derivative that can interact effectively with these biomolecules. Furthermore, theoretical results concurred with the ex vivo binding mode of the 7g with calf thymus DNA (ct-DNA) and BSA through a variety of spectroscopic techniques, viz., ultraviolet-visible (UV-visible), circular dichroism (CD), steady-state fluorescence, and competitive displacement assay, along with viscosity measurements.

Advancement in biomarker based effective diagnosis of neonatal sepsis.

Neonatal sepsis is considered as alarming medical emergency and becomes the common global reason of neonatal mortality. Non-specific symptoms and limitations of conventional diagnostic methods for neonatal sepsis mandate fast and reliable method to diagnose disease for point of care application. Recently, disease specific biomarkers have gained interest for rapid diagnosis that led to the development of electrochemical biosensor with enhanced specificity, sensitivity, cost-effectiveness and user-friendliness. Other than conventional biomarker C-reactive protein to diagnose neonatal sepsis, several potential biomarkers including Procalcitonin (PCT), Serum amyloid A (SAA) and other candidates are extensively investigated. The present review provides insights on advancements and diagnostic abilities of protein and nucleotide based biomarkers with their incorporation in developing electrochemical biosensors by employing novel fabrication strategies. This review provides an overview of most promising biomarker and its capability for neonatal sepsis diagnosis to fulfil future demand to develop electrochemical biosensor for point-of-care applications.

Designing of a unique bioreceptor and fabrication of an efficient genosensing platform for neonatal sepsis detection.

We report the results of studies related to the fabrication of a nanostructured graphene oxide (GO)-based electrochemical genosensor for neonatal sepsis detection. Initially, we selected the fimA gene of E. coli for nenonatal sepsis detection and further designed a 20-mer long amine-terminated oligonucleotide. This designed oligonucleotide will work as a bioreceptor for the detection of the virulent fimA gene. An electrochemical genosensor was further developed where GO was used as an immobilization matrix. For the formation of a thin film of GO on an indium tin oxide (ITO)-coated glass electrode, an optimized DC potential of 10 V for 90 s was applied via an electrophoretic deposition unit. Thereafter, the designed oligonucleotides were immobilized through EDC-NHS chemistry. The nanomaterial and fabricated electrodes were characterized via X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy and cyclic voltammetry techniques. The fabricated genosensor (BSA/pDNA/GO/ITO) has the ability to detect the target fimA gene with a linear detection range of 10-12 M to 10-6 M, a lower detection limit of 10-12 M and a sensitivity of 114.7 µA M-1 cm-2. We also investigated the biosensing ability of the developed genosensor in an artificial serum sample and the obtained electrochemical results were within the acceptable percentage relative standard deviation (% RSD), indicating that the fabricated genosensor can be used for the detection of neonatal sepsis by using a serum sample.

Nanoengineered phosphorus doped graphitic carbon nitride based ultrasensitive biosensing platform for Swine flu detection.

In the present study, we developed an amino-polyindole modified phosphorus doped graphitic carbon nitride nanomaterial (APIN/P-g-C3N4) based immunosensing biochip for Serum amyloid A (SAA) biomarker towards early diagnosis of Swine flu. The P-g-C3N4 was synthesis via polycondensation and functionalized with APIN. Further, the biochip was fabricated by modifying the working area of SPE with APIN/P-g-C3N4 using drop cast method, APIN introduced the larger loading of -NH2 group moieties onto P-g-C3N4 matrix and benefitted to reinforced the biomolecules via covalent linkages. The monoclonal anti-SAA was conjugated onto APIN/P-g-C3N4/SPE using EDC-NHS chemistry and BSA was added for non-specific site blocking. The structural, chemical, composition and morphological characteristics of the synthesized, functionalized nanomaterial and fabricated biochips were investigated by XRD, XPS, FT-IR spectroscopy, SEM, FE-SEM and TEM techniques. Further, the electrochemical characterization and response studies of fabricated biochip were analyzed using the CV and DPV techniques. Based on the analytical performance of the proposed immunosensing biochip i.e. BSA/anti-SAA/APIN/P-g-C3N4/SPE, it is capable to detect SAA protein with ultra sensitivity of 79.5 µA log (mL ng-1) cm-2, ultralow limit of detection of 5 ng mL-1 and wider linear detection range of 5 ng mL-1-500 µg mL-1 with quick response time of 10 min. Moreover, the fabricated immunosensing biochips was used to analyse SAA protein in spiked serum samples and the achieved results demonstrated the good agreement with the electrochemical response observed in standard SAA protein samples in analytical solution. The proposed biochip can provide insights for developing a wide range of clinical screening tools for detecting various contagious diseases.

Application of a Negative Intrauterine Pressure Suction Device for Prophylactic Management of Atonic Postpartum Hemorrhage: A Quality Improvement Study.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. PPH-preventing interventions need to be prioritized and can be integrated with conventional methods of PPH prevention. The introduction of negative intrauterine pressure using a suction cannula can be one of the cheapest modalities to decrease PPH secondary to uterine atonicity. This method has brought a renaissance to practical obstetrics in low-middle income countries (LMIC), where the cost and availability of uterotonics are major health issues. METHODS: It was a prospective quality improvement (QI) study conducted in the labor and delivery wards of a tertiary care medical institute and teaching center over the duration of one year. We aimed to assess the decrease in the incidence of atonic PPH with a negative intrauterine pressure suction device (NIPSD) integrated with active management of the third stage of labor (AMTSL) in the prevention of atonic PPH following normal vaginal delivery in low-risk antenatal women. In the initial six months, routine AMTSL was instituted for all consenting women (group 1). In the next six months, NIPSD was integrated with AMTSL (group 2). Data pertaining to the amount of blood loss, the incidence of primary PPH, uterine tone, fall in hemoglobin and hematocrit levels post-delivery, need for blood transfusion, and doctor and patient satisfaction were tabulated for all patients. RESULTS: A total of 1324 consenting women were eligible for enrollment during the study time frame. In the initial six months (baseline period, group 1), 715 participants were subjected to routine AMTSL in the third stage of labor. During the intervention phase (group 2), 609 parturient women were recruited. There was no significant difference in baseline parameters between the two groups. With the introduction of NIPSD to routine AMTSL, there was a significant decrease in the average volume of blood loss during vaginal delivery (group 1 = 389.45+65.42 ml, group 2 = 216.66+34.27 ml; p-value = 0.012). The incidence of atonic PPH was reduced by more than 75% (group 1 = 13 women, group 2 = 3 women; p-value = 0.001) after the introduction of NIPSD complementing routine AMTSL. The introduction of NIPSD has also been instrumental in reducing the cost burden on patient and hospital expenditures. The net benefit of its introduction resulted in a reduction of the overall cost burden of blood transfusions by around 70%. CONCLUSION: PPH is a public health problem, and measures to reduce PPH must be implemented to decrease this health burden. In countries with low resources, complementing routine AMTSL with NIPSD can be instrumental in decreasing the incidence of PPH. Considering its cost-effectiveness and reusability, LMIC can adopt NIPSD as a routine measure in all vaginal deliveries.

Comparative assessment of 9-bromo noscapine ionic liquid and noscapine: Synthesis, in-vitro studies plus computational & biophysical evaluation with human hemoglobin.

Noscapine is a proficient anticancer drug active against wide variety of tumors including lung cancer. Over time, several noscapine analogues have been assessed to maximize the efficiency of the drug, amongst which 9-bromo noscapine remains one of the most potent analogues till date. In the present work, we have synthesized 9-bromo noscapine ionic liquid [9-Br-Nos]IBr2, an active pharmaceutical ingredient based ionic liquid (API-IL) to address the existing issues of solubility and targeted drug delivery in the parent alkaloid as well as the synthesized analogues. We have devised a novel two-step synthesis route (first-ever ionic to ionic bromination) to obtain the desired [9-Br-Nos]IBr2 which is advantageous to its organic analogue in terms of increased solubility, lesser reaction time and better yield. Furthermore, we have compared 9-bromo noscapine ionic liquid with noscapine based on its binding interaction with human hemoglobin (Hb) studied via computational along with spectroscopic studies, and bioactivity against non-small cell lung cancer. We inferred formation of a complex between [9-Br-Nos]IBr2 and Hb in the stoichiometric ratio of 1:1, similar to noscapine. At 298 K, [9-Br-Nos]IBr2-Hb binding was found to exhibit Kb and ∆G of 36,307 M-1 and -11.5 KJmol-1, respectively, as compared to 159 M-1 and -12.5 KJmol-1 during Noscapine-Hb binding. This indicates a more stronger and viable interaction between [9-Br-Nos]IBr2 and Hb than the parent compound. From computational studies, the observed higher stability of [9-Br-Nos]I and better binding affinity with Hb with a binding energy of -91.75 kcalmol-1 supported the experimental observations. In the same light, novel [9-Br-Nos]IBr2 was found to exhibit an IC50 = 95.02 ± 6.32 µM compared to IC50 = 128.82 ± 2.87 µM for noscapine on A549 (non-small lung cancer) cell line at 48 h. Also, the desired ionic liquid proved to be more cytotoxic inducing a mortality rate of 87 % relative to 66 % evoked by noscapine at concentrations of 200 µM after 72 h.

Assessment of Fertility Outcomes Following Combined Clomiphene and Letrozole Versus Letrozole Therapy for the Treatment of Polycystic Ovarian Syndrome Subfertility.

BACKGROUND: Poly Cystic Ovarian Syndrome (PCOS) affects 8-13% of women in their reproductive age and is one of the foremost causes of female subfertility. Traditionally, clomiphene citrate has been the first-line treatment for ovulation induction in PCOS. However, the European Society of Human Reproduction and Embryology (ESHRE) international evidence-based guidelines in 2018 recommended the use of letrozole as first-line therapy for ovulation induction in anovulatory PCOS women, due to better pregnancy and live birth rates. Here we aimed to evaluate the effect of combined - clomiphene and letrozole versus letrozole for the treatment of PCOS subfertility. METHODS: It was a retrospective cohort study conducted on reproductive-age women fulfilling Rotterdam Criteria for PCOS with a history of subfertility. All participants receiving at least one cycle of letrozole and clomiphene combination were recruited as cases. However, women receiving letrozole only for ovulation induction were taken as controls. Hospital records were abstracted for data on baseline characteristics such as age, duration of infertility, PCOS phenotype, body mass index (BMI), past medical and fertility history, treatment with ovulation induction agents, and metformin use. The mean size of the largest follicle, number of dominant follicles of size greater than 15 mm and endometrial thickness on Days 12-14 or on the day of the luteinizing hormone (LH) surge were recorded. A cycle was termed ovulatory if serum progesterone levels were > 5.0 ng/ml on the seventh day after the LH surge or day 22 in the absence of the LH surge. Data pertaining to therapy-associated side effects were also abstracted from the clinical records. RESULTS: Amongst the ovulatory cycles in both groups, there was no significant difference in the day of the LH surge. Serum progesterone levels on the seventh day post-ovulation were higher with combination therapy (19.35 v/s 26.71, p=0.004). The number of ovulatory cycles was also greater with combination therapy, but the difference was just short of significant (25 vs 18, p=0.08). The mean diameter of the largest follicle, incidence of multi-follicular ovulation, and thin endometrium were similar in both groups. The adverse effect profile was similar in both groups. CONCLUSION: Combination treatment of clomiphene citrate with letrozole may potentially improve fertility outcomes in PCOS subfertility in terms of the likelihood of ovulation and higher post-ovulatory progesterone levels, however, larger studies are required.

Hemocompatible Functionalized Hydrogen Substituted Graphdiyne Based Highly Durable Biosensor for Liver Cancer Detection.

Present work focuses on the development of a highly durable biosensor for liver cancer (LC) biomarker (Annexin A2; ANXA2) detection. In this work, we have modified hydrogen substituted graphdiyne (HsGDY) using an organofunctional silane [3-(aminopropyl)triethoxysilane (APTES)], leveraging the opposite surface polarities on HsGDY and APTES to fabricate a highly hemocompatible functionalized nanomaterial matrix. The high hemocompatibility of APTES functionalized HsGDY (APTES/HsGDY) allows long-term stabilized immobilization of antibodies in their native state, hence increasing the durability of the biosensor. The biosensor was fabricated using electrophoretic deposition (EPD) of APTES/HsGDY onto an indium tin oxide (ITO)-coated glass substrate at 40% lower DC potential than nonfunctionalized HsGDY with successive immobilization of monoclonal antibodies of ANXA2 (anti-ANXA2) and bovine serum albumin (BSA). The synthesized nanomaterials and fabricated electrodes were investigated using a zetasizer and spectroscopic, microscopic, and electrochemical (cyclic voltammetry and differential pulse voltammetry) techniques. The developed immunosensor (BSA/anti-ANXA2/APTES/HsGDY/ITO) could detect ANXA2 in a linear detection range from 100 fg mL-1 to 100 ng mL-1 with a lower detection limit of 100 fg mL-1. The biosensor demonstrated excellent storage stability of 63 days along with high accuracy toward detection of ANXA2 in serum samples of LC patients as validated via enzyme-linked immunosorbent assay technique.

Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents.

In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC50 of 0.60, 0.88, 0.97 and 0.96 µM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 µM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents.

Biochemical interaction of human hemoglobin with ionic liquids of noscapinoids: Spectroscopic and computational approach.

In this work, we have developed noscapine based ionic liquids i.e., Noscapine (MeNOS) and 9-Bromonoscapine (MeBrNOS) as cation supported with bis(trifluoromethylsulfonyl)amide (NTf2-) as anion. We have reported the mechanism of binding interaction between noscapine based ILs and human hemoglobin (Hb) using various spectroscopic and computational techniques. The corresponding thermodynamics studies showed that the binding is exothermic in nature and major forces responsible for binding are Van der waals and hydrogen bonding interaction. The fluorescence spectra showed that the intensity of Hb decreases in the presence of [MeNOS]NTf2 and [MeBrNOS]NTf2 both shows static quenching. The secondary structural changes in Hb were observed and calculated by using CD spectroscopy. Molecular docking studies revealed that both the ILs show strong binding in ß1 fragment of the tetrameric structure of Hb, but the binding of [MeNOS]NTf2 is relatively stronger than [MeBrNOS]NTf2 and the results are supported by MD simulations.

Exploring the untapped catalytic application of a ZnO/CuI/PPy nanocomposite for the green synthesis of biologically active 2,4,5-trisubstituted imidazole scaffolds.

This work is focused on designing an innovative, efficient, and reusable heterogeneous ZnO/CuI/PPy nanocomposite via the self-assembly approach where pyrrole is oxidized into polypyrrole (PPy) and pyrrole also behaves as a reductant in the presence of KI. This so-obtained material was characterized by XRD, FTIR, FESEM, EDX, TEM, XPS, and ICP. TEM clearly shows a spherical morphology with the particle size ranging between 18 and 42 nm. The fabricated nanomaterial was tested for one-pot catalytic synthesis of biologically active 2,4,5-trisubstituted imidazoles under solvent-free conditions. The present work includes the benefits of an easy work-up procedure, higher product yield, shorter reaction duration, and no additional additive requirement under green and sustainable conditions. Moreover, the catalyst exhibited reusability for six runs with no considerable reduction in the respective yields and reactivity (confirmed by XRD, SEM, and TEM of the recycled catalyst). The ICP study shows very low leaching of copper (2.08 ppm) and zinc (0.12 ppm) metals. The approach also presented better values of green metrics like the E-factor, process mass intensity, carbon efficiency and reaction mass efficiency.

An expeditious on-water regioselective synthesis of novel arylidene-hydrazinyl-thiazoles as DNA targeting agents.

A series of twenty novel (E)-arylidene-hydrazinyl-thiazole derivatives has been synthesized employing α-bromo-ß-diketones, thiosemicarbazide, and aromatic/heteroaromatic aldehydes with a simple and facile one-pot multicomponent reaction passageway. This organic transformation proceeds efficiently in aqueous media and demonstrated a large functional group tolerance. The structures and stereochemistry of the regioisomeric product were rigorously characterized using heteronuclear 2D NMR experiments. The binding potential of the synthesized analogs with B-DNA dodecamer d(CGCGAATTCGCG)2 was primarily screened using molecular modeling tools and further, mechanistic investigations (either groove or intercalation) were performed using various spectroscopic techniques such as UV-Visible, Fluorescence, and Circular dichroism. The absorption spectra showed a hyperchromic shift in the absorption maxima of ctDNA with successive addition of thiazole derivatives, implying groove binding mode of interactions, further supported by displacement assay and circular dichroism analysis. Furthermore, steady-state fluorescence analysis revealed the static mode of quenching and moderate bindings between the ligand and DNA biomolecule. The competitive studies showed that the derivatives having a pyridinyl (heteroaromatic) group in their structure, bind with the nucleic acid of calf-thymus (ctDNA) more effectively in the minor groove region as compared with the aromatic substitutions.

Development of bioactive 2-substituted benzimidazole derivatives using an MnOx/HT nanocomposite catalyst.

Benzimidazole is a vital moiety found in a wide range of naturally and pharmacologically active molecules. We prepared a proficient and facile manganese oxide-supported magnesium and aluminium-based nanocomposite catalytic framework using the deposition-precipitation method and characterised it with XRD, XPS, SEM, TEM, and TGA techniques. Following that, the catalyst was used in the green synthesis of highly functional 2-substituted benzimidazole derivatives in an ethanol-water solvent system at room temperature using various assorted benzaldehydes and o-phenylenediamine as substituents. The synthesised catalyst operates efficiently and is applicable to a wide range of electron-withdrawing and electron-donating substrates, resulting in good to excellent yields. The advantages of this process include the use of a greener solvent, high yield, high conversions, no use of additives or bases, a good TOF, and a shorter reaction time.

Inducible CRISPR Epigenome Systems Mimic Cocaine Induced Bidirectional Regulation of Nab2 and Egr3.

Substance use disorder is a chronic disease and a leading cause of disability around the world. The NAc is a major brain hub mediating reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. We previously reported repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, and reduced it in D2-MSNs. Here, we report our findings of repeated cocaine exposure in male mice inducing MSN subtype-specific bidirectional expression of the Egr3 corepressor NGFI-A-binding protein 2 (Nab2). Using CRISPR activation and interference (CRISPRa and CRISPRi) tools combined with Nab2 or Egr3-targeted sgRNAs, we mimicked these bidirectional changes in Neuro2a cells. Furthermore, we investigated D1-MSN- and D2-MSN-specific expressional changes of histone lysine demethylases Kdm1a, Kdm6a, and Kdm5c in NAc after repeated cocaine exposure in male mice. Since Kdm1a showed bidirectional expression patterns in D1-MSNs and D2-MSNs, like Egr3, we developed a light-inducible Opto-CRISPR-KDM1a system. We were able to downregulate Egr3 and Nab2 transcripts in Neuro2A cells and cause similar bidirectional expression changes we observed in D1-MSNs and D2-MSNs of mouse repeated cocaine exposure model. Contrastingly, our Opto-CRISPR-p300 activation system induced the Egr3 and Nab2 transcripts and caused opposite bidirectional transcription regulations. Our study sheds light on the expression patterns of Nab2 and Egr3 in specific NAc MSNs in cocaine action and uses CRISPR tools to further mimic these expression patterns.SIGNIFICANCE STATEMENT Substance use disorder is a major societal issue. The lack of medication to treat cocaine addiction desperately calls for a treatment development based on precise understanding of molecular mechanisms underlying cocaine addiction. In this study, we show that Egr3 and Nab2 are bidirectionally regulated in mouse NAc D1-MSNs and D2-MSNs after repeated exposure to cocaine. Furthermore, histone lysine demethylations enzymes with putative EGR3 binding sites showed bidirectional regulation in D1- and D2-MSNs after repeated exposure to cocaine. Using Cre- and light-inducible CRISPR tools, we show that we can mimic this bidirectional regulation of Egr3 and Nab2 in Neuro2a cells.