Publications by authors named "Saikat Ghosh"

72 Publications

COBRA PzF™ coronary stent in clinical and preclinical studies: setting the stage for new antithrombotic strategies?

Future Cardiol 2021 Sep 15. Epub 2021 Sep 15.

CVPath Institute, 19 Firstfield Road, Gaithersburg, MD 20878, USA.

Major advances have been made in coronary artery stent technology over the last decades. Drug-eluting stents reduced in-stent restenosis and have shown better outcomes compared with bare metal stents, yet some limitations still exist to their use. Because they delay healing of the vessel wall, longer dual antiplatelet therapy is mandatory to mitigate against stent thrombosis and this limitation is most concerning in subjects at high risk for bleeding. The COBRA PzF nanocoated coronary stent has been associated with accelerated endothelialization relative to drug-eluting stents, reduced inflammation and thromboresistance in preclinical studies, suggesting more flexible dual antiplatelet therapy requirement with potential benefits especially in those at high bleeding risk. Here, we discuss the significance of COBRA PzF in light of recent experimental and clinical studies.
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http://dx.doi.org/10.2217/fca-2021-0057DOI Listing
September 2021

Development of a dry powder for inhalation of nanoparticles codelivering cisplatin and siRNA in lung cancer.

Ther Deliv 2021 09 10;12(9):651-670. Epub 2021 Aug 10.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.

The current study sought to formulate a dry powder inhalant (DPI) for pulmonary delivery of lipopolymeric nanoparticles (LPNs) consisting of cisplatin and siRNA for multidrug-resistant lung cancer. siRNA against ABCC3 gene was used to silence drug efflux promoter. The formulation was optimized through the quality by design system by nanoparticle size and cisplatin entrapment. The lipid concentration, polymer concentration and lipid molar ratio were selected as variables. The DPI was characterized by deposition study using the Anderson cascade impactor. DPI formulation showed improved pulmonary pharmacokinetic parameters of cisplatin with higher residence time in lungs. Local delivery of siRNA and cisplatin to the lung tissue resulted into an enhanced therapeutic effectiveness in combating drug resistance.
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http://dx.doi.org/10.4155/tde-2020-0117DOI Listing
September 2021

Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches.

J Control Release 2021 Sep 14;337:27-58. Epub 2021 Jul 14.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390001, India; Formulation Research & Development, Novel Drug Delivery Systems, Sun Pharmaceutical Industries Ltd, Vadodara, Gujarat 390012, India. Electronic address:

Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are amongst the most aggressive forms of solid tumors. TNBC is highlighted by absence of genetic components of progesterone receptor, HER2/neu and estrogen receptor in breast cancer. NSCLC is characterized by integration of malignant carcinoma into respiratory system. Both cancers are associated with poor median and overall survival rates with low progression free survival with high incidences of relapse. These cancers are characterized by tumor heterogeneity, genetic mutations, generation of cancer-stem cells, immune-resistance and chemoresistance. Further, these neoplasms have been reported for tumor cross-talk into second primary cancers for each other. Current chemotherapeutic regimens include usage of multiple agents in tandem to affect tumor cells through multiple mechanisms with various such combinations being clinically tested. However, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Consequently, passive targeted albumin bound paclitaxel and PEGylated liposomal doxorubicin have been clinically used and tested with newer drugs for improved therapeutic efficacy in these cancers. Active targeting of nanocarriers against surface overexpressed proteins in both neoplasms have been explored. However, use of single agent nanoparticulate formulations against both cancers have failed to elicit desired outcomes. This review aims to identify clinical unmet need in these cancers while establishing a correlation with tested nano-formulation approaches and issues with preclinical to clinical translation. Lipid and polymer-based drug-drug and drug-gene combinatorial nanocarriers delivering multiple chemotherapeutics simultaneously to desired site of action have been detailed. Finally, emerging opportunities such as pharmacological targets (immune check point and epigentic modulators) as well as gene-based modulation (siRNA/CRISPR/Cas9) and the nano-formulation challenges for effective treatment of both cancers have been explored.
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http://dx.doi.org/10.1016/j.jconrel.2021.07.014DOI Listing
September 2021

Efficacy and safety of cerebral embolic protection systems during transcatheter aortic valve replacement: a review of current clinical findings.

Expert Rev Cardiovasc Ther 2021 Aug 21;19(8):725-737. Epub 2021 Jul 21.

CVPath Institute, Gaithersburg, MD, USA.

Introduction: Cerebrovascular events are one of the most serious consequences after transcatheter aortic valve replacement (TAVR). More than half of the cerebrovascular events following TAVR are due to procedure-related emboli. Embolic protection devices (EPDs) have the potential to decrease cerebrovascular events during TAVR procedure. However, randomized controlled trials (RCTs) have not conclusively determined if EPDs are effective, likely because of small number of patients enrolled. However, meta-analyses and propensity-matched analyses from large registries have shown efficacy and suggest the importance of EPDs in prevention of stroke during TAVR and perhaps other structural heart procedures.

Areas Covered: This review will focus on clinical and histopathologic studies examining the efficacy, safety, and histopathologic device capture findings in the presence and absence of EPDs during TAVR procedures.

Expert Opinion: Clinical studies have not conclusively determined the efficacy of EPDs. Current ongoing large-scale RCT (PROTECTED TAVR [NCT04149535]) has the potential to prove their efficacy. Histopathological evaluation of debris captured by EPDs contributes to our understanding of the mechanisms of TAVR procedure-related embolic events and suggests the importance of preventing cerebral embolization of debris released during this and other structural heart procedures.
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http://dx.doi.org/10.1080/14779072.2021.1955346DOI Listing
August 2021

Huntington's Chorea-a Rare Neurodegenerative Autosomal Dominant Disease: Insight into Molecular Genetics, Prognosis and Diagnosis.

Appl Biochem Biotechnol 2021 Aug 7;193(8):2634-2648. Epub 2021 Jul 7.

Department of Biotechnology, University of Engineering and Management, Kolkata, University Area, Plot, Street Number 03, Action Area III, B/5, Newtown, Kolkata, West Bengal, 700156, India.

Huntington's disease is a neurodegenerative autosomal disease results due to expansion of polymorphic CAG repeats in the huntingtin gene. Phosphorylation of the translation initiation factor 4E-BP results in the alteration of the translation control leading to unwanted protein synthesis and neuronal function. Consequences of mutant huntington (mhtt) gene transcription are not well known. Variability of age of onset is an important factor of Huntington's disease separating adult and juvenile types. The factors which are taken into account are-genetic modifiers, maternal protection i.e excessive paternal transmission, superior ageing genes and environmental threshold. A major focus has been given to the molecular pathogenesis which includes-motor disturbance, cognitive disturbance and neuropsychiatric disturbance. The diagnosis part has also been taken care of. This includes genetic testing and both primary and secondary symptoms. The present review also focuses on the genetics and pathology of Huntington's disease.
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http://dx.doi.org/10.1007/s12010-021-03523-xDOI Listing
August 2021

Acute thrombogenicity of fluoropolymer coated stents versus competitive drug-eluting stents under single antiplatelet therapy.

Int J Cardiol 2021 09 23;338:42-49. Epub 2021 Jun 23.

CVPath Institute, Inc., Gaithersburg, MD, USA; University of Maryland, Baltimore, MD, USA. Electronic address:

Background: Recent clinical studies have suggested the feasibility of 1-month dual antiplatelet therapy (DAPT) for patients receiving drug-eluting stent (DES). Although our previous ex-vivo swine arteriovenous (AV) shunt studies under low dose heparin treatment suggested superior thromboresistance of fluoropolymer-coated everolimus-eluting stent (FP-EES) when compared to other polymer-based DESs, the relative thromboresistance of different DESs under single antiplatelet therapy (SAPT) has never been examined. This study aimed to evaluate platelet adhesion under SAPT in competitive DESs in the in vitro flow loop model and ex vivo swine AV shunt model.

Methods: The thrombogenicity of FP-EES, BioLinx polymer zotarolimus-eluting stent (BL-ZES), and biodegradable polymer everolimus-eluting stent (BP-EES) was assessed acutely using the swine AV shunt model under aspirin or clopidogrel SAPT. Stents were immunostained using antibodies against platelets and inflammatory markers and evaluated by confocal microscopy. Also, the adhesion of platelet and albumin on the three DESs was assessed by an in-vitro flow loop model using human platelets under aspirin SAPT and fluorescent albumin, respectively.

Results: In the shunt model, FP-EES showed significantly less platelet and inflammatory cell adhesion than BL-ZES and BP-EES. In the flow loop model, FP-EES showed significantly less platelet coverage and more albumin adsorption than BL-ZES and BP-EES.

Conclusions: These results suggest FP-EES may have particular advantage for short-term DAPT compared to other DESs.
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http://dx.doi.org/10.1016/j.ijcard.2021.06.034DOI Listing
September 2021

Formulation and clinical perspectives of inhalation-based nanocarrier delivery: a new archetype in lung cancer treatment.

Ther Deliv 2021 05 27;12(5):397-418. Epub 2021 Apr 27.

Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India.

Despite tremendous research in targeted delivery and specific molecular inhibitors (gene delivery), cytotoxic drug delivery through inhalation has been seen as a core part in the treatment of the lung cancer. Inhalation delivery provides a high dose of the drug directly to the lungs without affecting other body organs, increasing the therapeutic ratio. This article reviews the research performed over the last several decades regarding inhalation delivery of various cancer therapeutics for the treatment of lung cancer. Nevertheless, pulmonary administration of nanocarrier-based cancer therapeutics for lung cancer therapy is still in its infancy and faces greater than expected challenges. This article focuses on the current inhalable nanocarrier-based drugs for lung cancer treatment.
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http://dx.doi.org/10.4155/tde-2020-0101DOI Listing
May 2021

Small organic molecules act as a trigger in an "unzippering" mechanism to facilitate carbon nanotube dispersion.

Sci Total Environ 2021 Mar 12;758:143620. Epub 2020 Nov 12.

Yunnan Key Lab of Soil Carbon Sequestration and Pollution Control, Faculty of Environmental Science & Engineering, Kunming University of Science & Technology, Kunming 650500, China.

In binary dispersing agents system, the contribution and roles of different sized molecules to carbon nanotubes (CNTs) dispersion remain unclear, which hinders the understanding of the environmental behaviour and risks of CNTs. This study compared the dispersion of CNTs by m-nitrobenzoic acid (NBA), trans-cinnamic acid (TCA), tannic acid (TA), and their mixtures. The dispersion efficiency of CNTs significantly reduced with the increased solid-phase concentration (Q) of TA due to the adsorption of TA on newly exposed CNTs surfaces. However, the CNTs dispersion efficiency by NBA or TCA was independent of Q because the dispersed CNTs surface was completely occupied by NBA or TCA without new exposed sites available for subsequent adsorption. The mixture of NBA or TCA with TA significantly enhanced the dispersion efficiency of CNTs, indicating a synergistic effect of CNTs dispersion. The addition of NBA or TCA decreased the hydrodynamic diameter of CNTs dispersed by TA, which indicated that NBA or TCA facilitated TA wedging into CNTs bundles for more complete separation of CNTs. This study highlighted the triggering effect of small molecules in the "unzippering" mechanism for improving the dispersing efficiency of CNTs by large molecules.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143620DOI Listing
March 2021

Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer.

Drug Deliv Transl Res 2021 Oct 11;11(5):2052-2071. Epub 2020 Nov 11.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390001, India.

The resistance of cancer cells to chemotherapy has presented a formidable challenge. The current research aims at evaluating whether silencing of the cisplatin efflux promoter gene ABCC3 using siRNA co-loaded with the drug in a nanocarrier improves its efficacy in non-small cell lung cancer (NSCLC). Hybrid nanocarriers (HNCs) comprising lipids and poly(lactic acid-polyethylene glycol) di-block copolymer (PEG-PLA) were prepared for achieving the simultaneous delivery of cisplatin caprylate and ABCC3-siRNA to the cancer cells. PEGylation of the formulated HNCs was carried out using post-insertion technique for imparting long circulation characteristics to the carrier. The optimized formulation exhibited an entrapment efficiency of 71.9 ± 2.2% and 95.83 ± 0.39% for cisplatin caprylate and siRNA respectively. Further, the HNC was found to have hydrodynamic diameter of 153.2 ± 1.76 nm and + 25.39 ± 0.49 mV zeta potential. Morphological evaluation using cryo transmission electron microscopy confirmed the presence of lipid bilayer surrounding the polymeric core in HNCs. The in vitro cellular uptake studies showed improved uptake, while cell viability studies of the co-loaded formulation in A549 cell-line indicated significantly improved cytotoxic potential when compared with drug solution and drug-loaded HNCs; cell cycle analysis indicated increased percentage of cell arrest in G2-M phase compared with drug-loaded HNCs. Further, the gene knock-down study showed that silencing of ABCC3 mRNA might be improved in vitro efficacy of the formulation. The optimized cisplatin and ABCC3 siRNA co-loaded formulation presented significantly increased half-life and tumour regression in A549 xenograft model in BALB/c nude mice. In conclusion, siRNA co-loaded formulation presented reduced drug resistance and increased efficacy, which might be promising for the current cisplatin-based treatments in NSCLC.
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http://dx.doi.org/10.1007/s13346-020-00867-5DOI Listing
October 2021

Optimization and efficacy study of synergistic vincristine coloaded liposomal doxorubicin against breast and lung cancer.

Nanomedicine (Lond) 2020 11 22;15(26):2585-2607. Epub 2020 Oct 22.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat - 390001, India.

To improve the efficacy of poly-ethylene glycol (PEG)ylated liposomes coloaded with doxorubicin and vincristine against triple-negative breast cancer (TNBC) and non-small-cell lung cancer (NSCLC). The combinatorial index of the drugs was established using the Chou-Talalay method in MDA-MB-231 and A549 cell lines. The most effective ratio was co-encapsulated in factorial design optimized nanoliposomes which were characterized for similarity to clinical standard and evaluated and for therapeutic efficacy. The formulation exhibited more than 95% co-encapsulation, a size of 95.74 ± 2.65 nm and zeta potential of -9.17 ± 1.19 mV while having no significant differences in physicochemical and biochemical characteristics as compared with the clinical standard. Efficacy evaluation studies showed significantly improved cytotoxicity and tumor regression compared with liposomal doxorubicin indicating improvement in efficacy against TNBC and NSCLC.
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http://dx.doi.org/10.2217/nnm-2020-0169DOI Listing
November 2020

Synergistic co-loading of vincristine improved chemotherapeutic potential of pegylated liposomal doxorubicin against triple negative breast cancer and non-small cell lung cancer.

Nanomedicine 2021 01 16;31:102320. Epub 2020 Oct 16.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India; Pharmaceutical Research, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS University, Mumbai, Maharashtra, India. Electronic address:

The current work aims to explore the biological characteristics of vincristine synergistic co-loading into pegylated liposomal doxorubicin in non-indicated modalities of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). The combinatorial liposome prepared by active co-loading of the drugs against modified ammonium ion gradient exhibited 95% encapsulation of both drugs. The cellular uptake studies using confocal microscopy and flow cytometry showed significantly increased uptake of dual drug formulation as against liposomal doxorubicin. The co-loaded liposome formulation had significantly increased cell cycle arrest in G/M phase with subsequent apoptosis and reduced cell viability in both tumor cell lines than doxorubicin liposome. This carrier exhibited similar acute toxicity, pharmacokinetic and tissue distribution profiles with significant increase in tumor regression as compared to liposomal doxorubicin. These results indicate that co-encapsulation of vincristine into clinically used pegylated liposomal doxorubicin significantly improved in-vitro and in-vivo therapeutic efficacy against NSCLC and TNBC.
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http://dx.doi.org/10.1016/j.nano.2020.102320DOI Listing
January 2021

A fully sustainable, self-poled, bio-waste based piezoelectric nanogenerator: electricity generation from pomelo fruit membrane.

Sci Rep 2020 07 21;10(1):12121. Epub 2020 Jul 21.

Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, 110016, India.

A self-powered system is very much essential aspect in the recent trend to improve the working efficiency of the portable and wearable devices. Here, we have reported a fully sustainable, self-poled, bio-compatible, and bio-waste based piezoelectric energy harvester which has been made of Pomelo Fruit Membrane (PFM). PFM based piezoelectric generator (PFMBPEG) could generate ~ 6.4 V output voltage and ~ 7.44 μA output current directly, only by finger tapping on the device and registers a power density of ~ 12 μW cm whereas, the same piezoelectric generator can generate ~ 15 V output voltage, 130 μA output current, and power density of ~ 487.5 μW cm by using a full wave rectifier. The sensitivity and energy harvesting competence of the generator have also been assessed by attaching this nanogenerator into various parts of human body (as energy sources) such as wrist, elbow, finger, throat, jaws, leg and putting the device into ultrasonic bath and in every case, it could successfully generate voltage. Therefore, this bio-waste based energy harvester can be used as a power source for the different potable and wearable electronic goods where a small amount of energy is required, specifically in the biomedical applications (i.e., health monitoring, power source for the implantable devices and so on). Finally, mechanical stability the developed piezoelectric generator has been evaluated by cyclic bending test and it has been observed that there is no significant deformation of the PFM film even after 100 cycles.
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http://dx.doi.org/10.1038/s41598-020-68751-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374593PMC
July 2020

Observation of Quantum Phase Synchronization in Spin-1 Atoms.

Phys Rev Lett 2020 Jul;125(1):013601

Department of Physics, Indian Institute of Technology-Kanpur, Uttar Pradesh 208016, India.

With growing interest in quantum technologies, possibilities of synchronizing quantum systems have garnered significant recent attention. In experiments with dilute ensemble of laser cooled spin-1 ^{87}Rb atoms, we observe phase difference of spin coherences to synchronize with phases of external classical fields. An initial limit-cycle state of a spin-1 atom localizes in phase space due to dark-state polaritons generated by classical two-photon tone fields. In particular, when the two couplings fields are out of phase, the limit-cycle state synchronizes only with two artificially engineered, anisotropic decay rates. Furthermore, we observe a blockade of synchronization due to quantum interference and emergence of Arnold-tongue-like features. Such anisotropic decay induced synchronization of spin-1 systems with no classical analog can provide insights in open quantum systems and find applications in synchronized quantum networks.
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http://dx.doi.org/10.1103/PhysRevLett.125.013601DOI Listing
July 2020

Drosophila metamorphosis involves hemocyte mediated macroendocytosis and efferocytosis.

Int J Dev Biol 2020 ;64(4-5-6):319-329

Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Punjab, India.

Drosophila hemocytes are majorly associated with immune responses, but they also undertake several non-immune functions that are crucial during various stages of development. The activity and behaviour of hemocytes are least documented during the metamorphic phase of fly development. Here we describe the activity, form and behaviour of the most abundant type of hemocyte in Drosophila melanogaster, the "plasmatocyte," throughout pupal development. Our study reveals different forms of plasmatocytes laden with varying degrees of histolyzing debris (muscle and fat) which extend beyond the size of the cell itself, highlighting the phagocytic capacity of these plasmatocytes. Interestingly, the engulfment of apoptotic debris by plasmatocytes is an actin-dependent process, and by the end of metamorphosis, clearance is achieved. The uptake of apoptotic debris consisting of muscles and lipids by the plasmatocytes provides us a model that can be employed to dissect out the relevant components of macroendocytosis and lipid-loaded phagocytosis. This understanding, by itself, is crucial for addressing the emerging role of phagocytes in physiology and pathophysiology.
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http://dx.doi.org/10.1387/ijdb.190215lmDOI Listing
January 2020

Giant Tunable Mechanical Nonlinearity in Graphene-Silicon Nitride Hybrid Resonator.

Nano Lett 2020 Jun 1;20(6):4659-4666. Epub 2020 Jun 1.

Department of Physics, Indian Institute of Technology, Kanpur UP-208016, India.

High quality factor mechanical resonators have shown great promise in the development of classical and quantum technologies. Simultaneously, progress has been made in developing controlled mechanical nonlinearity. Here, we combine these two directions of progress in a single platform consisting of coupled silicon nitride (SiNx) and graphene mechanical resonators. We show that nonlinear response can be induced on a large area SiNx resonator mode and can be efficiently controlled by coupling it to a gate-tunable, freely suspended graphene mode. The induced nonlinear response of the hybrid modes, as measured on the SiNx resonator surface is giant, with one of the highest measured Duffing constants. We observe a novel phononic frequency comb which we use as an alternate validation of the measured values, along with numerical simulations which are in overall agreement with the measurements.
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http://dx.doi.org/10.1021/acs.nanolett.0c01586DOI Listing
June 2020

Cabbage looper (Trichoplusia ni Hübner) labial glands contain unique bacterial flora in contrast with their alimentary canal, mandibular glands, and Malpighian tubules.

Microbiologyopen 2020 04 28;9(4):e994. Epub 2020 Jan 28.

Invasive Insect Biocontrol and Behavior Lab, USDA-ARS, Beltsville, Maryland.

In recent years, several studies have examined the gut microbiome of lepidopteran larvae and how factors such as host plant affect it, and in turn, how gut bacteria affect host plant responses to herbivory. In addition, other studies have detailed how secretions of the labial (salivary) glands can alter host plant defense responses. We examined the gut microbiome of the cabbage looper (Trichoplusia ni) feeding on collards (Brassica oleracea) and separately analyzed the microbiomes of various organs that open directly into the alimentary canal, including the labial glands, mandibular glands, and the Malpighian tubules. In this study, the gut microbiome of T. ni was found to be generally consistent with those of other lepidopteran larvae in prior studies. The greatest diversity of bacteria appeared in the Firmicutes, Actinobacteria, Proteobacteria, and Bacteriodetes. Well-represented genera included Staphylococcus, Streptococcus, Corynebacterium, Pseudomonas, Diaphorobacter, Methylobacterium, Flavobacterium, and Cloacibacterium. Across all organs, two amplicon sequence variants (ASVs) associated with the genera Diaphorobacter and Cloacibacterium appeared to be most abundant. In terms of the most prevalent ASVs, the alimentary canal, Malpighian tubules, and mandibular glands appeared to have similar complements of bacteria, with relatively few significant differences evident. However, aside from the Diaphorobacter and Cloacibacterium ASVs common to all the organs, the labial glands appeared to possess a distinctive complement of bacteria which was absent or poorly represented in the other organs. Among these were representatives of the Pseudomonas, Flavobacterium, Caulobacterium, Anaerococcus, and Methylobacterium. These results suggest that the labial glands present bacteria with different selective pressures than those occurring in the mandibular gland, Malpighian tubules and the alimentary canal. Given the documented effects that labial gland secretions and the gut microbiome can exert on host plant defenses, the effects exerted by the bacteria inhabiting the labial glands themselves deserve further study.
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http://dx.doi.org/10.1002/mbo3.994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142365PMC
April 2020

Biomedical Application of Doxorubicin Coated Hydroxyapatite-Poly(lactide-co-glycolide) Nanocomposite for Controlling Osteosarcoma Therapeutics.

J Nanosci Nanotechnol 2020 07;20(7):3994-4004

Department of Chemistry, National Institute of Technology, 791112, Arunachal Pradesh, India.

Nano drug delivery systems are widely used in cancer treatment nowadays. It is used to accomplish a remarkable drug therapeutic index to increase the efficacy of nanocomposites against cancer cells without affecting the other cells. Ceramic nanoparticles are well-known to carry chemotherapeutic drugs to the infected sites. Interest in them is aroused by their potential for application as promising biomaterials, especially in various orthopaedic applications. In the current study, Hydroxyapatite (HAp) was prepared by a simple precipitation method and coated with a potent anticancer drug doxorubicin (DOX) using poly(lactide-co-glycolide) (PLGA) polymer. The interfacial strength of the composite is enhanced by the use of polymer in the nanocomposite preparation. An interaction between HAp particle and PLGA matrix has been noticed, which leads to improve the physicochemical properties of the prepared composites. Such a novel nanocomposite is further physicochemically characterized using Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Transmission Electron Spectroscopy (TEM) and Particle Size Distribution (PSD). In addition, the biocompatibility and the anticancer activity of the nanocomposite were evaluated by a colorimetric assay (MTT assay). The synthesized DOX-HAp-PLGA nanocomposite shows a significant cytotoxicity towards osteosarcoma cells, which may be potentially used as an anticancer agent against osteosarcoma diseases.
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http://dx.doi.org/10.1166/jnn.2020.17689DOI Listing
July 2020

Suspended state heteroaggregation kinetics of kaolinite and fullerene (nC) in the presence of tannic acid: Effect of π-π interactions.

Sci Total Environ 2020 Apr 7;713:136559. Epub 2020 Jan 7.

Stockbridge School of Agriculture, University of Massachusetts, Amherst, MA 01003, United States of America.

The colloidal heteroassociation between natural mineral colloids and engineered nanoparticles (ENPs) can reduce the bioavailability and toxicity of the ENPs. However, the efficacy of this heteroassociation-based entrapment of ENPs depends on the intrinsic material properties of the particles and the physicochemical parameters of the aquatic environment. Natural organic matter (NOM)-induced surface modifications of clay colloids, functionalization of ENPs, and efficiency of counterions as effective coagulants profoundly affect the effectiveness of heteroaggregation-based attenuation of anthropogenic colloids. In this study, tannic acid (TA), a surrogate of NOM, prevented the edge-to-face self-association of sodium-saturated kaolinite (Na-kaolinite) at acidic pH, as evaluated from the transverse proton spin-spin relaxation data (T). Likewise, fullerene water suspension (FWS) adhesion to Na-kaolinite prevented the self-association of Na-kaolinite and enhanced the colloidal stability. At pH 4 and diffusion-limited aggregation regime salt concentrations, the Na-kaolinite and FWS heteroaggregation rates were lower than the Na-kaolinite homoaggregation rates, and eventually reached a plateau. The higher colloidal stability of the Na-kaolinite and FWS binary mixture than that of Na-kaolinite, regardless of stronger charge screening by Ca reflects steric stabilization. However, at pH 7, the increased electrostatic barrier reduces the feasibility of colloidal heteroassociation between Na-kaolinite and FWS; thus, higher salt concentrations are required to initiate aggregation. Weak adsorption of TA on Na-kaolinite at pH 7 facilitated stronger π-π interactions with FWS. All suspensions exhibited faster aggregate growth at pH 7 than pH 4, possibly due to the stronger cation response at pH 7. In situ atomic force microscopy imaging and line profile plots of Na-kaolinite, TA, and FWS mixture in CaCl further corroborated the difference in the heteroaggregation rates observed at the two different pH values. Thus, TA-induced surface functionalization of FWS and the consequent increased electrostatic barrier to heteroassociation with Na-kaolinite may facilitate the environmental mobility of FWS in aquatic media.
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http://dx.doi.org/10.1016/j.scitotenv.2020.136559DOI Listing
April 2020

Prion-like p53 Amyloids in Cancer.

Biochemistry 2020 01 21;59(2):146-155. Epub 2019 Oct 21.

Department of Biosciences and Bioengineering , IIT Bombay, Powai , Mumbai , India 400076.

The global transcription factor, p53, is a master regulator of gene expression in cells. Mutations in the gene promote unregulated cell growth through the inactivation of downstream effectors of the p53 pathway. In fact, mutant p53 is highly prone to misfolding and frequently resides inside the cell as large aggregates, causing loss of physiological function of the tumor-suppressor protein. Here, we review the plausible reasons for functional loss of p53, including amyloid formation leading to unhindered cancer progression. We discuss previous as well as recent findings regarding the amyloid formation of p53 and . We elaborate on prion-like properties of p53 amyloids and their possible involvement in cancer progression. Because the p53 pathway is historically most targeted for the development of anticancer therapeutics, we have also summarized some of the recent approaches and advances in reviving the antiproliferative activities of wild-type p53. In this Perspective, we provide insight into understanding p53 as a prion-like protein and propose cancer to be recognized as an amyloid or prion-like disease.
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http://dx.doi.org/10.1021/acs.biochem.9b00796DOI Listing
January 2020

Surface engineered liposomal delivery of therapeutics across the blood brain barrier: recent advances, challenges and opportunities.

Expert Opin Drug Deliv 2019 12;16(12):1287-1311

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, India.

: The delivery of drug payload to treat various brain diseases are met with various hindrances owing to the presence of the homeostasis regulatory gate, Blood-Brain Barrier (BBB). Although, pathogenesis and progression of the brain diseases alter the permeability of this barrier, effective delivery of agents is not achieved for the attainment of desired treatment outcomes. Liposomes with their salient properties have proven to be exciting options to navigate therapeutics across this barrier.: This review tends to establish a correlation between the pathophysiology of disease affected barrier, with liposome-based passive and active delivery approaches for therapeutic agents, permitting their transport across the BBB. The potential of these carriers to present therapeutically effective agents' concentrations to the desired site of action have also been explored. Further, assessment of physicochemical, biopharmaceutical, and biological properties required for efficient translation of such carriers from bench to bedside has been made.: The encapsulation of the therapeutics in these structures enables suitable pro-brain delivery modifications of inherent pharmacokinetic-pharmacodynamic profiles along with appropriate surface engineering opportunities to deliver the drug cargo to the intended locations in the brain. However, a careful balance between the use of these surface-modified structures and toxicity potential needs to be ascertained for clinical safety and effectiveness.
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http://dx.doi.org/10.1080/17425247.2019.1676721DOI Listing
December 2019

Tannic acid- and cation-mediated interfacial self-assembly and epitaxial growth of fullerene (nC) and kaolinite binary graphitic aggregates.

J Colloid Interface Sci 2019 Nov 29;556:717-725. Epub 2019 Aug 29.

Stockbridge School of Agriculture, University of Massachusetts, Amherst, MA 01003, United States.

In this study, we investigated the tannic acid (TA)-, Ca-, and mica-enabled interfacial assembly of nC fullerene (FWS) and Na-saturated kaolinite (Na-Kl) with in and ex situ atomic force microscopy (AFM). The epitaxial growth of herringbone motif, two dimensional (2D) chiral clusters and 3D mounds were detected. π-π electron donor-acceptor (EDA) interactions drove the transformation of the FWS, and the symmetry of the muscovite substrate directed the epitaxial ordering of self-assembled herringbone motifs. A ternary mixture of Na-Kl/FWS/TA in the presence of Ca produced double-stranded (ds) helices and 2D platelets of chiral clusters with a nano-porous monolayer on K-treated muscovite surfaces. The weak hydration of exchangeable K and stronger electric fields possibly contributed to the 1D and 2D propagation of aggregates. However, the local increment in carbon content due to the nucleation of functionalized FWS on mica diminished the K-induced electric field effect and facilitated the 3D growth of helical mounds. The diffusion limited mass-transfer of particulates across the Ehrlich-Schwoebel barrier (ESB) and screw dislocation assisted motion of particulates specifically at higher steps aided mound growth. Thus, the structural incorporation of FWS can substantially impede its interfacial transport and produce hierarchical hybrid mineral-enriched graphitic aggregates.
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http://dx.doi.org/10.1016/j.jcis.2019.08.106DOI Listing
November 2019

Cell Adhesion-Mediated Actomyosin Assembly Regulates the Activity of Cubitus Interruptus for Hematopoietic Progenitor Maintenance in .

Genetics 2019 08 28;212(4):1279-1300. Epub 2019 May 28.

Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Mohali 140306, India

The actomyosin network is involved in crucial cellular processes including morphogenesis, cell adhesion, apoptosis, proliferation, differentiation, and collective cell migration in , , and mammals. Here, we demonstrate that larval blood stem-like progenitors require actomyosin activity for their maintenance. Genetic loss of the actomyosin network from progenitors caused a decline in their number. Likewise, the progenitor population increased upon sustained actomyosin activation via phosphorylation by Rho-associated kinase. We show that actomyosin positively regulates larval blood progenitors by controlling the maintenance factor Cubitus interruptus (Ci). Overexpression of the maintenance signal via a constitutively activated construct (ci.HA) failed to sustain Ci-155 in the absence of actomyosin components like Zipper (zip) and Squash (sqh), thus favoring protein kinase A (PKA)-independent regulation of Ci activity. Furthermore, we demonstrate that a change in cortical actomyosin assembly mediated by DE-cadherin modulates Ci activity, thereby determining progenitor status. Thus, loss of cell adhesion and downstream actomyosin activity results in desensitization of the progenitors to Hh signaling, leading to their differentiation. Our data reveal how cell adhesion and the actomyosin network cooperate to influence patterning, morphogenesis, and maintenance of the hematopoietic stem-like progenitor pool in the developing hematopoietic organ.
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http://dx.doi.org/10.1534/genetics.119.302209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707476PMC
August 2019

Nanocarriers in effective pulmonary delivery of siRNA: current approaches and challenges.

Ther Deliv 2019 05;10(5):311-332

Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India.

Research on siRNA is increasing due to its wide applicability as a therapeutic agent in irreversible medical conditions. siRNA inhibits expression of the specific gene after its delivery from formulation to cytosol region of a cell. RNAi (RNA interference) is a mechanism by which siRNA is silencing gene expression for a particular disease. Numerous studies revealed that naked siRNA delivery is not preferred due to instability and poor pharmacokinetic performance. Nanocarriers based delivery of siRNA has the advantage to overcome physiological barriers and protect the integrity of siRNA from degradation by RNAase. Various diseases like lung cancer, cystic fibrosis, asthma, etc can be treated effectively by local lung delivery. The selective targeted therapeutic action in diseased organ and least off targeted cytotoxicity are the key benefits of pulmonary delivery. The current review highlights recent developments in pulmonary delivery of siRNA with novel nanosized formulation approach with the proven applications.
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http://dx.doi.org/10.4155/tde-2019-0012DOI Listing
May 2019

Combinatorial nanocarriers against drug resistance in hematological cancers: Opportunities and emerging strategies.

J Control Release 2019 02 18;296:114-139. Epub 2019 Jan 18.

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390001, India. Electronic address:

Hematological cancers are a group of malignancies affecting human hematopoietic and lymphoid tissues. Although the patients respond to treatment regimen during initial phases, the hematoma tumor heterogeneity results in the presence of some minimal disease residue thereby exhibiting remission, relapses or refractoriness in disease conditions leading to poor overall survival period. The current therapeutic standard practices involve blending of conventional agents with novel targeting agents or immune-therapeutics in a cocktail to effectively reap the benefits of drugs acting through multiple signaling pathways. Considerable evaluation of the risk benefit ratio on part of clinicians is necessitated to select the best optimum therapy considering the high incidences of drug resistance. This drug resistance may be attributed to faulty upregulation or mutation of multiple drug resistance regulating genes, increased tumor cell immune system cross talk, increased expression of drug efflux pump inducers and inhibition of apoptosis among others. Conventional single drug nanotherapeutics as modulators of drug resistance have already clinically exhibited their potential by passively delivering the active cargo to desired targets in hematological neoplasms. However, with the ever-growing clinical failures of such therapies, the landscape of hematological cancer treatment has seen a plethora of changes in the last few years. The two towering changes in the treatment has been the approval of combinatorial drug nanocarrier Vyxeos™ and chimeric antigen receptor T cell (CAR-T) therapy Kymriah™ as well as Yescarta™. The approval of CAR-T therapy not only resulted in a paradigm shift in the avenues of blood cancer treatment towards personalized approaches but also saddled it with questions of economic viability and effectiveness in the entire spectrum of such neoplasms. Under such conditions, combinatorial drug nanocarriers encompassing synergistic ratios of clinically effective drug combinations affording temporal and spatial control present an exciting approach to overcome these drug resistance modalities. This platform provides increased chances of therapeutic in-vitro in-vivo correlation along with minimization of drug resistance and associated disease relapse conditions. The present review intends to present the current preclinical and clinical advances in combinatorial nanocarrier mediated management of drug resistance in hematological cancers.
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http://dx.doi.org/10.1016/j.jconrel.2019.01.011DOI Listing
February 2019

Motion Transduction with Thermo-mechanically Squeezed Graphene Resonator Modes.

Nano Lett 2018 11 29;18(11):6719-6724. Epub 2018 Oct 29.

Department of Physics , Indian Institute of Technology , Kanpur , Uttar Pradesh 208016 , India.

There is a recent surge of interest in amplification and detection of tiny motion in the growing field of opto- and electromechanics. Here, we demonstrate widely tunable, broad bandwidth, and high gain all-mechanical motion amplifiers based on graphene/silicon nitride (SiNx) hybrids. In these devices, a tiny motion of a large-area SiNx membrane is transduced to a much larger motion in a graphene drum resonator coupled to SiNx. Furthermore, the thermal noise of graphene is reduced (squeezed) through parametric tension modulation. The parameters of the amplifier are measured by photothermally actuating SiNx and interferometrically detecting graphene displacement. We obtain a displacement power gain of 38 dB and demonstrate 4.7 dB of squeezing, resulting in a detection sensitivity of 3.8 [Formula: see text], close to the thermal noise limit of SiNx.
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http://dx.doi.org/10.1021/acs.nanolett.8b02293DOI Listing
November 2018

Lipid-Based Oral Formulation Strategies for Lipophilic Drugs.

AAPS PharmSciTech 2018 Nov 25;19(8):3609-3630. Epub 2018 Sep 25.

Department of Pharmaceutics, Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Kalabhavan Campus, Vadodara, Gujarat, 390001, India.

Partition coefficient (log P) is a key physicochemical characteristic of lipophilic drugs which plays a significant role in formulation development for oral administration. Lipid-based formulation strategies can increase lymphatic transport of these drugs and can enhance bioavailability many folds. The number of lipophilic drugs in pharmacopoeias and under discovery are continuously increasing and making the job of the formulation scientist difficult to develop suitable formulation of these drugs due to potent nature and water insolubility of these drugs. Recently, many natural and synthetic lipids are appearing in the market which are helpful in the development of lipid-based formulations of these types of drugs having enhanced solubility and bioavailability. One such reason for this enhanced bioavailability is the accessibility of the lymphatic transport as well as avoidance of first-pass effect. This review discusses the impact of lipophilicity in enhancing the intestinal lymphatic drug transport thereby reducing first-pass metabolism. The most appropriate strategy for developing a lipid-based formulation depending upon the degree of lipophilicity has been critically discussed and provides information on how to develop optimum formulation. Various formulation strategies are discussed in-depth by classifying lipid-based oral drug delivery systems with case studies of few marketed formulations with challenges and opportunities for the future of the formulations.
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http://dx.doi.org/10.1208/s12249-018-1188-8DOI Listing
November 2018

De novo formation of an aggregation pheromone precursor by an isoprenyl diphosphate synthase-related terpene synthase in the harlequin bug.

Proc Natl Acad Sci U S A 2018 09 23;115(37):E8634-E8641. Epub 2018 Aug 23.

Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061;

Insects use a diverse array of specialized terpene metabolites as pheromones in intraspecific interactions. In contrast to plants and microbes, which employ enzymes called terpene synthases (TPSs) to synthesize terpene metabolites, limited information from few species is available about the enzymatic mechanisms underlying terpene pheromone biosynthesis in insects. Several stink bugs (Hemiptera: Pentatomidae), among them severe agricultural pests, release 15-carbon sesquiterpenes with a bisabolene skeleton as sex or aggregation pheromones. The harlequin bug, , a specialist pest of crucifers, uses two stereoisomers of 10,11-epoxy-1-bisabolen-3-ol as a male-released aggregation pheromone called murgantiol. We show that TPS (IDS-1), an enzyme unrelated to plant and microbial TPSs but with similarity to -isoprenyl diphosphate synthases (IDS) of the core terpene biosynthetic pathway, catalyzes the formation of (1,6,7)-1,10-bisaboladien-1-ol (sesquipiperitol) as a terpene intermediate in murgantiol biosynthesis. Sesquipiperitol, a so-far-unknown compound in animals, also occurs in plants, indicating convergent evolution in the biosynthesis of this sesquiterpene. RNAi-mediated knockdown of mRNA confirmed the role of in murgantiol biosynthesis. TPS expression is highly specific to tissues lining the cuticle of the abdominal sternites of mature males. Phylogenetic analysis suggests that TPS is derived from a -IDS progenitor and diverged from bona fide -IDS proteins including IDS-2, which functions as an (,)-farnesyl diphosphate (FPP) synthase. Structure-guided mutagenesis revealed several residues critical to TPS and FPPS activity. The emergence of an IDS-like protein with TPS activity in demonstrates that de novo terpene biosynthesis evolved in the Hemiptera in an adaptation for intraspecific communication.
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http://dx.doi.org/10.1073/pnas.1800008115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140472PMC
September 2018

Detecting proliferation of adult hemocytes in by BrdU incorporation.

Wellcome Open Res 2018 24;3:47. Epub 2018 Apr 24.

Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research-Mohali, Manauli, Punjab, 140306, India.

and mammalian hematopoiesis share several similarities that ranges from phases to the battery of transcription factors and signaling molecules that execute this process. These resounding similarities along with the rich genetic tools available in fruitfly makes it a popular invertebrate model to study blood cell development both during normal and aberrant conditions. The larval system is the most extensively studied to date. Several studies have shown that these hemocytes just like mammalian counterpart proliferate and get routinely regenerated upon infection. However, employing the same protocol it was concluded that blood cell proliferation although abundant in larval stages is absent in adult fruitfly. The current protocol describes the strategies that can be employed to document the hemocyte proliferation in adulthood. The fact that a subset of blood cells tucked away in the hematopoietic hub are not locked in senescence, rather they still harbour the proliferative capacity to tide over challenges was successfully demonstrated by this method.  Although we have adopted bacterial infection as a bait to evoke this proliferative capacity of the hemocytes, we envision that it can also efficiently characterize the proliferative responses of hemocytes in tumorigenic conditions as well as scenarios of environmental and metabolic stresses during adulthood.
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http://dx.doi.org/10.12688/wellcomeopenres.14560.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989151PMC
April 2018

Double-stranded RNA Oral Delivery Methods to Induce RNA Interference in Phloem and Plant-sap-feeding Hemipteran Insects.

J Vis Exp 2018 05 4(135). Epub 2018 May 4.

Invasive Insect Biocontrol and Behavior Laboratory, Agricultural Research Service, United States Department of Agriculture;

Phloem and plant sap feeding insects invade the integrity of crops and fruits to retrieve nutrients, in the process damaging food crops. Hemipteran insects account for a number of economically substantial pests of plants that cause damage to crops by feeding on phloem sap. The brown marmorated stink bug (BMSB), Halyomorpha halys (Heteroptera: Pentatomidae) and the Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Liviidae) are hemipteran insect pests introduced in North America, where they are an invasive agricultural pest of high-value specialty, row, and staple crops and citrus fruits, as well as a nuisance pest when they aggregate indoors. Insecticide resistance in many species has led to the development of alternate methods of pest management strategies. Double-stranded RNA (dsRNA)-mediated RNA interference (RNAi) is a gene silencing mechanism for functional genomic studies that has potential applications as a tool for the management of insect pests. Exogenously synthesized dsRNA or small interfering RNA (siRNA) can trigger highly efficient gene silencing through the degradation of endogenous RNA, which is homologous to that presented. Effective and environmental use of RNAi as molecular biopesticides for biocontrol of hemipteran insects requires the in vivo delivery of dsRNAs through feeding. Here we demonstrate methods for delivery of dsRNA to insects: loading of dsRNA into green beans by immersion, and absorbing of gene-specific dsRNA with oral delivery through ingestion. We have also outlined non-transgenic plant delivery approaches using foliar sprays, root drench, trunk injections as well as clay granules, all of which may be essential for sustained release of dsRNA. Efficient delivery by orally ingested dsRNA was confirmed as an effective dosage to induce a significant decrease in expression of targeted genes, such as juvenile hormone acid O-methyltransferase (JHAMT) and vitellogenin (Vg). These innovative methods represent strategies for delivery of dsRNA to use in crop protection and overcome environmental challenges for pest management.
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http://dx.doi.org/10.3791/57390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101104PMC
May 2018
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