Publications by authors named "Partha Mitra"

103 Publications

Comparative study on organic effluent degradation capabilities and electrical transport properties of polygonal ZnCoO spinels fabricated using different green fuels.

Mater Sci Eng C Mater Biol Appl 2020 Dec 28;117:111304. Epub 2020 Jul 28.

Dept. of Physics, The University of Burdwan, Burdwan 713104, India. Electronic address:

The present work highlights biosynthesis of nano-sized heterometalic spinel ZnCoO particles using different green extracts as capping agent. In this work we have fabricated polygonal ZnCoO with Punica granatum peel extract, Camellia sinensis extract, Moringa oleifera leaf extract and green coffee beans extract in an effortless green pathway. Phase pure material synthesis was confirmed using XRD. Microstructural, morphological, compositional and optical characterisations has been carried out using TEM, FESEM, EDX, FTIR, photoluminescence and UV-Vis spectroscopy. Punica granatum peel extract assisted ZnCoO sample shows superior catalytic efficiency of ~84.96% for Rhodamine B pollutant. ZnCoO sample synthesized using pomegranate peel extract shows highest conductivity of ~8.074 × 10 Ω cm with activation energy of 2.099 eV at 503 K. Synthesized nanoparticles also show antibacterial activity for B. megaterium, B. subtilis and B. cereus. To the best of our knowledge, synthesis of ZnCoO using these four green extracts and their comparative degradation capability, electrical properties and antibacterial study is explained for the first time in this work.
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http://dx.doi.org/10.1016/j.msec.2020.111304DOI Listing
December 2020

Rapid Emergence of SARS-CoV-2 in the Greater New York Metropolitan Area: Geolocation, Demographics, Positivity Rates, and Hospitalization for 46 793 Persons Tested by Northwell Health.

Clin Infect Dis 2020 12;71(12):3204-3213

Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Hempstead, New York, USA.

Background: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized.

Methods: Northwell Health Laboratories tested 46 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization.

Results: From 8 March through 10 April, a total of 26 735 of 46 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income.

Conclusions: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.
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http://dx.doi.org/10.1093/cid/ciaa922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454448PMC
December 2020

Multimodal cross-registration and quantification of metric distortions in marmoset whole brain histology using diffeomorphic mappings.

J Comp Neurol 2021 Feb 1;529(2):281-295. Epub 2020 Jun 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

Whole brain neuroanatomy using tera-voxel light-microscopic data sets is of much current interest. A fundamental problem in this field is the mapping of individual brain data sets to a reference space. Previous work has not rigorously quantified in-vivo to ex-vivo distortions in brain geometry from tissue processing. Further, existing approaches focus on registering unimodal volumetric data; however, given the increasing interest in the marmoset model for neuroscience research and the importance of addressing individual brain architecture variations, new algorithms are necessary to cross-register multimodal data sets including MRIs and multiple histological series. Here we present a computational approach for same-subject multimodal MRI-guided reconstruction of a series of consecutive histological sections, jointly with diffeomorphic mapping to a reference atlas. We quantify the scale change during different stages of brain histological processing using the Jacobian determinant of the diffeomorphic transformations involved. By mapping the final image stacks to the ex-vivo post-fixation MRI, we show that (a) tape-transfer assisted histological sections can be reassembled accurately into 3D volumes with a local scale change of 2.0 ± 0.4% per axis dimension; in contrast, (b) tissue perfusion/fixation as assessed by mapping the in-vivo MRIs to the ex-vivo post fixation MRIs shows a larger median absolute scale change of 6.9 ± 2.1% per axis dimension. This is the first systematic quantification of local metric distortions associated with whole-brain histological processing, and we expect that the results will generalize to other species. These local scale changes will be important for computing local properties to create reference brain maps.
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http://dx.doi.org/10.1002/cne.24946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666050PMC
February 2021

Open access resource for cellular-resolution analyses of corticocortical connectivity in the marmoset monkey.

Nat Commun 2020 02 28;11(1):1133. Epub 2020 Feb 28.

Australian Research Council, Centre of Excellence for Integrative Brain Function, Monash University Node, Clayton, VIC, 3800, Australia.

Understanding the principles of neuronal connectivity requires tools for efficient quantification and visualization of large datasets. The primate cortex is particularly challenging due to its complex mosaic of areas, which in many cases lack clear boundaries. Here, we introduce a resource that allows exploration of results of 143 retrograde tracer injections in the marmoset neocortex. Data obtained in different animals are registered to a common stereotaxic space using an algorithm guided by expert delineation of histological borders, allowing accurate assignment of connections to areas despite interindividual variability. The resource incorporates tools for analyses relative to cytoarchitectural areas, including statistical properties such as the fraction of labeled neurons and the percentage of supragranular neurons. It also provides purely spatial (parcellation-free) data, based on the stereotaxic coordinates of 2 million labeled neurons. This resource helps bridge the gap between high-density cellular connectivity studies in rodents and imaging-based analyses of human brains.
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http://dx.doi.org/10.1038/s41467-020-14858-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048793PMC
February 2020

ZEBrA: Zebra finch Expression Brain Atlas-A resource for comparative molecular neuroanatomy and brain evolution studies.

J Comp Neurol 2020 08 19;528(12):2099-2131. Epub 2020 Feb 19.

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon.

An in-depth understanding of the genetics and evolution of brain function and behavior requires a detailed mapping of gene expression in functional brain circuits across major vertebrate clades. Here we present the Zebra finch Expression Brain Atlas (ZEBrA; www.zebrafinchatlas.org, RRID: SCR_012988), a web-based resource that maps the expression of genes linked to a broad range of functions onto the brain of zebra finches. ZEBrA is a first of its kind gene expression brain atlas for a bird species and a first for any sauropsid. ZEBrA's >3,200 high-resolution digital images of in situ hybridized sections for ~650 genes (as of June 2019) are presented in alignment with an annotated histological atlas and can be browsed down to cellular resolution. An extensive relational database connects expression patterns to information about gene function, mouse expression patterns and phenotypes, and gene involvement in human diseases and communication disorders. By enabling brain-wide gene expression assessments in a bird, ZEBrA provides important substrates for comparative neuroanatomy and molecular brain evolution studies. ZEBrA also provides unique opportunities for linking genetic pathways to vocal learning and motor control circuits, as well as for novel insights into the molecular basis of sex steroids actions, brain dimorphisms, reproductive and social behaviors, sleep function, and adult neurogenesis, among many fundamental themes.
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http://dx.doi.org/10.1002/cne.24879DOI Listing
August 2020

The mechanism of MYB transcriptional regulation by MLL-AF9 oncoprotein.

Sci Rep 2019 12 27;9(1):20084. Epub 2019 Dec 27.

School of Pharmacy, University of Queensland, Brisbane, QLD, Australia.

Acute leukaemias express high levels of MYB which are required for the initiation and maintenance of the disease. Inhibition of MYB expression or activity has been shown to suppress MLL-fusion oncoprotein-induced acute myeloid leukaemias (AML), which are among the most aggressive forms of AML, and indeed MYB transcription has been reported to be regulated by the MLL-AF9 oncoprotein. This highlights the importance of understanding the mechanism of MYB transcriptional regulation in these leukaemias. Here we have demonstrated that the MLL-AF9 fusion protein regulates MYB transcription directly at the promoter region, in part by recruiting the transcriptional regulator kinase CDK9, and CDK9 inhibition effectively suppresses MYB expression as well as cell proliferation. However, MYB regulation by MLL-AF9 does not require H3K79 methylation mediated by the methyltransferase DOT1L, which has also been shown to be a key mediator of MLL-AF9 leukemogenicity. The identification of specific, essential and druggable transcriptional regulators may enable effective targeting of MYB expression, which in turn could potentially lead to new therapeutic approaches for acute myeloid leukaemia with MLL-AF9.
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http://dx.doi.org/10.1038/s41598-019-56426-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934848PMC
December 2019

ESTIMATING DIFFEOMORPHIC MAPPINGS BETWEEN TEMPLATES AND NOISY DATA: VARIANCE BOUNDS ON THE ESTIMATED CANONICAL VOLUME FORM.

Q Appl Math 2019 20;77:467-488. Epub 2018 Nov 20.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218.

Anatomy is undergoing a renaissance driven by the availability of large digital data sets generated by light microscopy. A central computational task is to map individual data volumes to standardized templates. This is accomplished by regularized estimation of a diffeomorphic transformation between the coordinate systems of the individual data and the template, building the transformation incrementally by integrating a smooth flow field. The canonical volume form of this transformation is used to quantify local growth, atrophy, or cell density. While multiple implementations exist for this estimation, less attention has been paid to the variance of the estimated diffeomorphism for noisy data. Notably, there is an infinite dimensional unobservable space defined by those diffeomorphisms which leave the template invariant. These form the stabilizer subgroup of the diffeomorphic group acting on the template. The corresponding flat directions in the energy landscape are expected to lead to increased estimation variance. Here we show that a least-action principle used to generate geodesics in the space of diffeomor-phisms connecting the subject brain to the template removes the stabilizer. This provides reduced-variance estimates of the volume form. Using simulations we demonstrate that the asymmetric large deformation diffeomorphic mapping methods (LDDMM), which explicitly incorporate the asymmetry between idealized template images and noisy empirical images, provide lower variance estimators than their symmetrized counterparts (cf. ANTs). We derive Cramer-Rao bounds for the variances in the limit of small deformations. Analytical results are shown for the Jacobian in terms of perturbations of the vector fields and divergence of the vector field.
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http://dx.doi.org/10.1090/qam/1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924927PMC
November 2018

Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury.

Brain 2019 11;142(11):3550-3564

Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland, USA.

Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.
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http://dx.doi.org/10.1093/brain/awz290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821371PMC
November 2019

Can One Concurrently Record Electrical Spikes from Every Neuron in a Mammalian Brain?

Neuron 2019 09 5;103(6):1005-1015. Epub 2019 Sep 5.

Howard Hughes Medical Institutes, Janelia Research Campus, Ashburn, VA, USA; Department of Bioengineering, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

The classic approach to measure the spiking response of neurons involves the use of metal electrodes to record extracellular potentials. Starting over 60 years ago with a single recording site, this technology now extends to ever larger numbers and densities of sites. We argue, based on the mechanical and electrical properties of existing materials, estimates of signal-to-noise ratios, assumptions regarding extracellular space in the brain, and estimates of heat generation by the electronic interface, that it should be possible to fabricate rigid electrodes to concurrently record from essentially every neuron in the cortical mantle. This will involve fabrication with existing yet nontraditional materials and procedures. We further emphasize the need to advance materials for improved flexible electrodes as an essential advance to record from neurons in brainstem and spinal cord in moving animals.
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http://dx.doi.org/10.1016/j.neuron.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763354PMC
September 2019

Relation of koniocellular layers of dorsal lateral geniculate to inferior pulvinar nuclei in common marmosets.

Eur J Neurosci 2019 12 16;50(12):4004-4017. Epub 2019 Aug 16.

Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.

Traditionally, the dorsal lateral geniculate nucleus (LGN) and the inferior pulvinar (IPul) nucleus are considered as anatomically and functionally distinct thalamic nuclei. However, in several primate species it has also been established that the koniocellular (K) layers of LGN and parts of the IPul have a shared pattern of immunoreactivity for the calcium-binding protein calbindin. These calbindin-rich cells constitute a thalamic matrix system which is implicated in thalamocortical synchronisation. Further, the K layers and IPul are both involved in visual processing and have similar connections with retina and superior colliculus. Here, we confirmed the continuity between calbindin-rich cells in LGN K layers and the central lateral division of IPul (IPulCL) in marmoset monkeys. By employing a high-throughput neuronal tracing method, we found that both the K layers and IPulCL form comparable patterns of connections with striate and extrastriate cortices; these connections are largely different to those of the parvocellular and magnocellular laminae of LGN. Retrograde tracer-labelled cells and anterograde tracer-labelled axon terminals merged seamlessly from IPulCL into LGN K layers. These results support continuity between LGN K layers and IPulCL, providing an anatomical basis for functional congruity of this region of the dorsal thalamic matrix and calling into question the traditional segregation between LGN and the inferior pulvinar nucleus.
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http://dx.doi.org/10.1111/ejn.14529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928438PMC
December 2019

MYB regulates the DNA damage response and components of the homology-directed repair pathway in human estrogen receptor-positive breast cancer cells.

Oncogene 2019 06 10;38(26):5239-5249. Epub 2019 Apr 10.

School of Pharmacy, University of Queensland, Brisbane, QLD, 4102, Australia.

Over 70% of human breast cancers are estrogen receptor-positive (ER), most of which express MYB. In these and other cell types, the MYB transcription factor regulates the expression of many genes involved in cell proliferation, differentiation, tumorigenesis, and apoptosis. So far, no clear link has been established between MYB and the DNA damage response in breast cancer. Here, we found that silencing MYB in the ER breast cancer cell line MCF-7 led to increased DNA damage accumulation, as marked by increased γ-H2AX foci following induction of double-stranded breaks. We further found that this was likely mediated by decreased homologous recombination-mediated repair (HRR), since silencing MYB impaired the formation of RAD51 foci in response to DNA damage. Moreover, cells depleted for MYB exhibited reduced expression of several key genes involved in HRR including BRCA1, PALB2, and TOPBP1. Taken together, these data imply that MYB and its targets play an important role in the response of ER breast cancer cells to DNA damage, and suggest that induction of DNA damage along with inhibition of MYB activity could offer therapeutic benefits for ER breast cancer and possibly other cancer types.
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http://dx.doi.org/10.1038/s41388-019-0789-3DOI Listing
June 2019

Genetic Single Neuron Anatomy Reveals Fine Granularity of Cortical Axo-Axonic Cells.

Cell Rep 2019 03;26(11):3145-3159.e5

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Parsing diverse nerve cells into biological types is necessary for understanding neural circuit organization. Morphology is an intuitive criterion for neuronal classification and a proxy of connectivity, but morphological diversity and variability often preclude resolving the granularity of neuron types. Combining genetic labeling with high-resolution, large-volume light microscopy, we established a single neuron anatomy platform that resolves, registers, and quantifies complete neuron morphologies in the mouse brain. We discovered that cortical axo-axonic cells (AACs), a cardinal GABAergic interneuron type that controls pyramidal neuron (PyN) spiking at axon initial segments, consist of multiple subtypes distinguished by highly laminar-specific soma position and dendritic and axonal arborization patterns. Whereas the laminar arrangements of AAC dendrites reflect differential recruitment by input streams, the laminar distribution and local geometry of AAC axons enable differential innervation of PyN ensembles. This platform will facilitate genetically targeted, high-resolution, and scalable single neuron anatomy in the mouse brain.
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http://dx.doi.org/10.1016/j.celrep.2019.02.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863572PMC
March 2019

An active texture-based digital atlas enables automated mapping of structures and markers across brains.

Nat Methods 2019 04 11;16(4):341-350. Epub 2019 Mar 11.

Department of Physics, University of California, San Diego, CA, USA.

Brain atlases enable the mapping of labeled cells and projections from different brains onto a standard coordinate system. We address two issues in the construction and use of atlases. First, expert neuroanatomists ascertain the fine-scale pattern of brain tissue, the 'texture' formed by cellular organization, to define cytoarchitectural borders. We automate the processes of localizing landmark structures and alignment of brains to a reference atlas using machine learning and training data derived from expert annotations. Second, we construct an atlas that is active; that is, augmented with each use. We show that the alignment of new brains to a reference atlas can continuously refine the coordinate system and associated variance. We apply this approach to the adult murine brainstem and achieve a precise alignment of projections in cytoarchitecturally ill-defined regions across brains from different animals.
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http://dx.doi.org/10.1038/s41592-019-0328-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736610PMC
April 2019

Comparative Principles for Next-Generation Neuroscience.

Front Behav Neurosci 2019 5;13:12. Epub 2019 Feb 5.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States.

Neuroscience is enjoying a renaissance of discovery due in large part to the implementation of next-generation molecular technologies. The advent of genetically encoded tools has complemented existing methods and provided researchers the opportunity to examine the nervous system with unprecedented precision and to reveal facets of neural function at multiple scales. The weight of these discoveries, however, has been technique-driven from a small number of species amenable to the most advanced gene-editing technologies. To deepen interpretation and build on these breakthroughs, an understanding of nervous system evolution and diversity are critical. Evolutionary change integrates advantageous variants of features into lineages, but is also constrained by pre-existing organization and function. Ultimately, each species' neural architecture comprises both properties that are species-specific and those that are retained and shared. Understanding the evolutionary history of a nervous system provides interpretive power when examining relationships between brain structure and function. The exceptional diversity of nervous systems and their unique or unusual features can also be leveraged to advance research by providing opportunities to ask new questions and interpret findings that are not accessible in individual species. As new genetic and molecular technologies are added to the experimental toolkits utilized in diverse taxa, the field is at a key juncture to revisit the significance of evolutionary and comparative approaches for next-generation neuroscience as a foundational framework for understanding fundamental principles of neural function.
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http://dx.doi.org/10.3389/fnbeh.2019.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373779PMC
February 2019

A high-throughput neurohistological pipeline for brain-wide mesoscale connectivity mapping of the common marmoset.

Elife 2019 02 5;8. Epub 2019 Feb 5.

Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.

Understanding the connectivity architecture of entire vertebrate brains is a fundamental but difficult task. Here we present an integrated neuro-histological pipeline as well as a grid-based tracer injection strategy for systematic mesoscale connectivity mapping in the common marmoset (). Individual brains are sectioned into ~1700 20 µm sections using the tape transfer technique, permitting high quality 3D reconstruction of a series of histochemical stains (Nissl, myelin) interleaved with tracer labeled sections. Systematic in-vivo MRI of the individual animals facilitates injection placement into reference-atlas defined anatomical compartments. Further, by combining the resulting 3D volumes, containing informative cytoarchitectonic markers, with in-vivo and ex-vivo MRI, and using an integrated computational pipeline, we are able to accurately map individual brains into a common reference atlas despite the significant individual variation. This approach will facilitate the systematic assembly of a mesoscale connectivity matrix together with unprecedented 3D reconstructions of brain-wide projection patterns in a primate brain.
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http://dx.doi.org/10.7554/eLife.40042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384052PMC
February 2019

Transcription regulation of : a potential and novel therapeutic target in cancer.

Authors:
Partha Mitra

Ann Transl Med 2018 Nov;6(22):443

Pre-clinical Division, Vaxxas Pty. Ltd. Translational Research Institute, Woolloongabba QLD 4102, Australia.

Basal transcription factors have never been considered as a priority target in the field of drug discovery. However, their unparalleled roles in decoding the genetic information in response to the appropriate signal and their association with the disease progression are very well-established phenomena. Instead of considering transcription factors as such a target, in this review, we discuss about the potential of the regulatory mechanisms that control their gene expression. Based on our recent understanding about the critical roles of at the cellular and molecular level in several types of cancers, we discuss here how MLL-fusion protein centred SEC in leukaemia, ligand-estrogen receptor (ER) complex in breast cancer (BC) and NF-κB and associated factors in colorectal cancer regulate the transcription of this gene. We further discuss plausible strategies, specific to each cancer type, to target those bona fide activators/co-activators, which control the regulation of this gene and therefore to shed fresh light in targeting the transcriptional regulation as a novel approach to the future drug discovery in cancer.
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http://dx.doi.org/10.21037/atm.2018.09.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281535PMC
November 2018

On variational solutions for whole brain serial-section histology using a Sobolev prior in the computational anatomy random orbit model.

PLoS Comput Biol 2018 12 26;14(12):e1006610. Epub 2018 Dec 26.

Center for Imaging Science, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

This paper presents a variational framework for dense diffeomorphic atlas-mapping onto high-throughput histology stacks at the 20 μm meso-scale. The observed sections are modelled as Gaussian random fields conditioned on a sequence of unknown section by section rigid motions and unknown diffeomorphic transformation of a three-dimensional atlas. To regularize over the high-dimensionality of our parameter space (which is a product space of the rigid motion dimensions and the diffeomorphism dimensions), the histology stacks are modelled as arising from a first order Sobolev space smoothness prior. We show that the joint maximum a-posteriori, penalized-likelihood estimator of our high dimensional parameter space emerges as a joint optimization interleaving rigid motion estimation for histology restacking and large deformation diffeomorphic metric mapping to atlas coordinates. We show that joint optimization in this parameter space solves the classical curvature non-identifiability of the histology stacking problem. The algorithms are demonstrated on a collection of whole-brain histological image stacks from the Mouse Brain Architecture Project.
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http://dx.doi.org/10.1371/journal.pcbi.1006610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324828PMC
December 2018

Unidirectional monosynaptic connections from auditory areas to the primary visual cortex in the marmoset monkey.

Brain Struct Funct 2019 Jan 4;224(1):111-131. Epub 2018 Oct 4.

Monash University Node, Australian Research Council, Centre of Excellence for Integrative Brain Function, Clayton, VIC, 3800, Australia.

Until the late twentieth century, it was believed that different sensory modalities were processed by largely independent pathways in the primate cortex, with cross-modal integration only occurring in specialized polysensory areas. This model was challenged by the finding that the peripheral representation of the primary visual cortex (V1) receives monosynaptic connections from areas of the auditory cortex in the macaque. However, auditory projections to V1 have not been reported in other primates. We investigated the existence of direct interconnections between V1 and auditory areas in the marmoset, a New World monkey. Labelled neurons in auditory cortex were observed following 4 out of 10 retrograde tracer injections involving V1. These projections to V1 originated in the caudal subdivisions of auditory cortex (primary auditory cortex, caudal belt and parabelt areas), and targeted parts of V1 that represent parafoveal and peripheral vision. Injections near the representation of the vertical meridian of the visual field labelled few or no cells in auditory cortex. We also placed 8 retrograde tracer injections involving core, belt and parabelt auditory areas, none of which revealed direct projections from V1. These results confirm the existence of a direct, nonreciprocal projection from auditory areas to V1 in a different primate species, which has evolved separately from the macaque for over 30 million years. The essential similarity of these observations between marmoset and macaque indicate that early-stage audiovisual integration is a shared characteristic of primate sensory processing.
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http://dx.doi.org/10.1007/s00429-018-1764-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373361PMC
January 2019

Multi-drug therapy in breast cancer: are there any alternatives?

Authors:
Partha Mitra

Ann Transl Med 2018 Jun;6(11):221

School of Medicine, University of Queensland, Brisbane, QLD, Australia.

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http://dx.doi.org/10.21037/atm.2018.04.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036005PMC
June 2018

Flavopiridol Inhibits TGF--Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2.

J Pharmacol Exp Ther 2018 04 9;365(1):156-164. Epub 2018 Feb 9.

Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, Kuantan, Pahang, Malaysia (M.A.R.); School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia (A.S., T.J.P., R.G., N.O., P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (D.K., P.M., P.J.L.); Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe, Guangzhou, China (Y.C., P.J.L.); Faculty of Health Sciences, University of Macau, Taipa, Macau, China (W.Z.); and Monash University, Departments of Medicine and Immunology, Central and Eastern Clinical School, Alfred Health, Melbourne, Victoria, Australia (N.O.)

Transforming growth factor- (TGF-) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF--stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF--stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF--mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF--stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.
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http://dx.doi.org/10.1124/jpet.117.244483DOI Listing
April 2018

PCB exposure and potential future cancer incidence in Slovak children: an assessment from molecular finger printing by Ingenuity Pathway Analysis (IPA®) derived from experimental and epidemiological investigations.

Environ Sci Pollut Res Int 2018 Jun 15;25(17):16493-16507. Epub 2017 Nov 15.

Molecular Genetics Laboratory, Department of Biology, Howard University, 415 College Street, NW, Room 408, EE Just Hall, Washington, DC, 20059, USA.

The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA®) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71). TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin's disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases.
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http://dx.doi.org/10.1007/s11356-017-0149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953777PMC
June 2018

Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

Cell 2017 Oct;171(2):456-469.e22

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA. Electronic address:

The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions.
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http://dx.doi.org/10.1016/j.cell.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870827PMC
October 2017

A new strongly paramagnetic cerium-containing microporous MOF for CO fixation under ambient conditions.

Dalton Trans 2017 Oct;46(40):13783-13792

Department of Materials Science, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India.

Metal organic frameworks (MOFs) bearing multicarboxylate linkers are in great demand for designing robust heterogeneous catalysts. A new microporous Ce(iii)-based metal organic framework (CeNDC) has been synthesized under solvothermal conditions, which showed strong paramagnetism and a CO uptake capacity of 1.64 mmol g (7.23 weight%) at 273 K. The CeNDC showed high catalytic activity in CO fixation for the synthesis of cyclic carbonates with a maximum yield of 92% at ambient temperature and pressure. This rare earth metal-based MOF has been well characterized by single crystal X-ray diffraction, PXRD, N adsorption/desorption, UHR-TEM, FESEM, FTIR, C MAS NMR and TGA. Here, we have carried out magnetic analysis, which revealed that the Ce(iii) in this MOF exhibited F magnetism in the ground state. The CeNDC catalyst showed high recycling efficiency in CO fixation reactions, together with retention of the MOF structure after several rounds of reuse. Presumably, the presence of acidic Ce(iii) metal ions and microporosity in the coordinated polymer network is responsible for the high catalytic activity.
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http://dx.doi.org/10.1039/c7dt02040fDOI Listing
October 2017

Metrics for comparing neuronal tree shapes based on persistent homology.

PLoS One 2017 15;12(8):e0182184. Epub 2017 Aug 15.

Computer Science and Engineering Department, The Ohio State University, Columbus, OH 43221, United States of America.

As more and more neuroanatomical data are made available through efforts such as NeuroMorpho.Org and FlyCircuit.org, the need to develop computational tools to facilitate automatic knowledge discovery from such large datasets becomes more urgent. One fundamental question is how best to compare neuron structures, for instance to organize and classify large collection of neurons. We aim to develop a flexible yet powerful framework to support comparison and classification of large collection of neuron structures efficiently. Specifically we propose to use a topological persistence-based feature vectorization framework. Existing methods to vectorize a neuron (i.e, convert a neuron to a feature vector so as to support efficient comparison and/or searching) typically rely on statistics or summaries of morphometric information, such as the average or maximum local torque angle or partition asymmetry. These simple summaries have limited power in encoding global tree structures. Based on the concept of topological persistence recently developed in the field of computational topology, we vectorize each neuron structure into a simple yet informative summary. In particular, each type of information of interest can be represented as a descriptor function defined on the neuron tree, which is then mapped to a simple persistence-signature. Our framework can encode both local and global tree structure, as well as other information of interest (electrophysiological or dynamical measures), by considering multiple descriptor functions on the neuron. The resulting persistence-based signature is potentially more informative than simple statistical summaries (such as average/mean/max) of morphometric quantities-Indeed, we show that using a certain descriptor function will give a persistence-based signature containing strictly more information than the classical Sholl analysis. At the same time, our framework retains the efficiency associated with treating neurons as points in a simple Euclidean feature space, which would be important for constructing efficient searching or indexing structures over them. We present preliminary experimental results to demonstrate the effectiveness of our persistence-based neuronal feature vectorization framework.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182184PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557505PMC
October 2017

Polarization-Tailored Fano Interference in Plasmonic Crystals: A Mueller Matrix Model of Anisotropic Fano Resonance.

ACS Nano 2017 02 15;11(2):1641-1648. Epub 2017 Feb 15.

Department of Physical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata , Mohanpur 741246, India.

Fano resonance is observed in a wide range of micro- and nano-optical systems and has been a subject of intensive investigations due to its numerous potential applications. Methods that can control or modulate Fano resonance by tuning some experimentally accessible parameters are highly desirable for realistic applications. Here we present a simple yet elegant approach using the Mueller matrix formalism for controlling the Fano interference effect and engineering the resulting asymmetric spectral line shape in an anisotropic optical system. The approach is founded on a generalized model of anisotropic Fano resonance, which relates the spectral asymmetry to physically meaningful and experimentally accessible parameters of interference, namely, the Fano phase shift and the relative amplitudes of the interfering modes. The differences in these parameters between orthogonal linear polarizations in an anisotropic system are exploited to desirably tune the Fano spectral asymmetry using pre- and postselection of optimized polarization states. The concept is demonstrated on waveguided plasmonic crystals using Mueller matrix-based polarization analysis. The approach enabled tailoring of several exotic regimes of Fano resonance in a single device, including the complete reversal of the spectral asymmetry, and shows potential for applications involving control and manipulation of electromagnetic waves at the nanoscale.
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http://dx.doi.org/10.1021/acsnano.6b07406DOI Listing
February 2017

Ga proteins: molecular pharmacology and therapeutic potential.

Cell Mol Life Sci 2017 04 4;74(8):1379-1390. Epub 2016 Nov 4.

School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.

Seven transmembrane G protein-coupled receptors (GPCRs) have gained much interest in recent years as it is the largest class among cell surface receptors. G proteins lie in the heart of GPCRs signalling and therefore can be therapeutically targeted to overcome complexities in GPCR responses and signalling. G proteins are classified into four families (G, G, G and G); G is further subdivided into four classes. Among them G and G isoforms are most crucial and ubiquitously expressed; these isoforms are almost 88% similar at their amino acid sequence but may exhibit functional divergences. However, uncertainties often arise about G and G inhibitors, these G proteins might also have suitability to the invention of novel-specific inhibitors for each isoforms. YM-254890 and UBO-QIC are discovered as potent inhibitors of G functions and also investigated in thrombin protease-activated receptor (PAR)-1 inhibitors and platelet aggregation inhibition. The most likely G protein involved in PAR-1 stimulates responses is one of the G family isoforms. In this review, we highlight the molecular structures and pharmacological responses of G family which may reflect the biochemical and molecular role of G and G. The advanced understanding of G and G role in GPCR signalling may shed light on our understanding on cell biology, cellular physiology and pathophysiology and also lead to the development of novel therapeutic agents for a number of diseases.
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http://dx.doi.org/10.1007/s00018-016-2405-9DOI Listing
April 2017

Towards a comprehensive atlas of cortical connections in a primate brain: Mapping tracer injection studies of the common marmoset into a reference digital template.

J Comp Neurol 2016 08;524(11):2161-81

Neuroscience Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

The marmoset is an emerging animal model for large-scale attempts to understand primate brain connectivity, but achieving this aim requires the development and validation of procedures for normalization and integration of results from many neuroanatomical experiments. Here we describe a computational pipeline for coregistration of retrograde tracing data on connections of cortical areas into a 3D marmoset brain template, generated from Nissl-stained sections. The procedure results in a series of spatial transformations that are applied to the coordinates of labeled neurons in the different cases, bringing them into common stereotaxic space. We applied this procedure to 17 injections, placed in the frontal lobe of nine marmosets as part of earlier studies. Visualizations of cortical patterns of connections revealed by these injections are supplied as Supplementary Materials. Comparison between the results of the automated and human-based processing of these cases reveals that the centers of injection sites can be reconstructed, on average, to within 0.6 mm of coordinates estimated by an experienced neuroanatomist. Moreover, cell counts obtained in different areas by the automated approach are highly correlated (r = 0.83) with those obtained by an expert, who examined in detail histological sections for each individual. The present procedure enables comparison and visualization of large datasets, which in turn opens the way for integration and analysis of results from many animals. Its versatility, including applicability to archival materials, may reduce the number of additional experiments required to produce the first detailed cortical connectome of a primate brain. J. Comp. Neurol. 524:2161-2181, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cne.24023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892968PMC
August 2016

Comparative three-dimensional connectome map of motor cortical projections in the mouse brain.

Sci Rep 2016 Feb 2;6:20072. Epub 2016 Feb 2.

Department of Biological Sciences, Korea Advanced Institute of Science &Technology, Daejeon, Korea, 305-338.

The motor cortex orchestrates simple to complex motor behaviors through its output projections to target areas. The primary (MOp) and secondary (MOs) motor cortices are known to produce specific output projections that are targeted to both similar and different target areas. These projections are further divided into layer 5 and 6 neuronal outputs, thereby producing four cortical outputs that may target other areas in a combinatorial manner. However, the precise network structure that integrates these four projections remains poorly understood. Here, we constructed a whole-brain, three-dimensional (3D) map showing the tract pathways and targeting locations of these four motor cortical outputs in mice. Remarkably, these motor cortical projections showed unique and separate tract pathways despite targeting similar areas. Within target areas, various combinations of these four projections were defined based on specific 3D spatial patterns, reflecting anterior-posterior, dorsal-ventral, and core-capsular relationships. This 3D topographic map ultimately provides evidence for the relevance of comparative connectomics: motor cortical projections known to be convergent are actually segregated in many target areas with unique targeting patterns, a finding that has anatomical value for revealing functional subdomains that have not been classified by conventional methods.
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http://dx.doi.org/10.1038/srep20072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735720PMC
February 2016

CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.

Oncotarget 2016 Feb;7(8):9069-83

School of Pharmacy, University of Queensland, Brisbane, QLD, Australia.

Our previous studies showed that MYB is required for proliferation of, and confers protection against apoptosis on, estrogen receptor-positive (ER(+ve)) breast cancer cells, which are almost invariably also MYB(+ve). We have also shown that MYB expression in ER(+ve) breast cancer cells is regulated at the level of transcriptional elongation and as such, is suppressed by CDK9i. Here we examined the effects of CDK9i on breast cancer cells and the involvement of MYB in these effects. ER(+ve) breast cancer cell lines including MCF-7 were much more sensitive (> 10 times) to killing by CDK9i than ER(-ve)/MYB(-ve) cells. Moreover, surviving cells showed a block at the G2/M phase of the cell cycle. Importantly, ectopic MYB expression conferred resistance to apoptosis induction, cell killing and G2/M accumulation. Expression of relevant MYB target genes including BCL2 and CCNB1 was suppressed by CDK9 inhibition, and this too was reversed by ectopic MYB expression. Nevertheless, inhibition of BCL2 alone either by MYB knockdown or by ABT-199 treatment was insufficient for significant induction of apoptosis. Further studies implied that suppression of MCL-1, a well-documented target of CDK9 inhibition, was additionally required for apoptosis induction, while maximal levels of apoptosis induced by CDK9i are likely to also involve inhibition of BCL2L1 expression. Taken together these data suggest that MYB regulation of BCL2 underlies the heightened sensitivity of ER(+ve) compared to ER(-ve) breast cancer cells to CDK9 inhibition, and that these compounds represent a potential therapeutic for ER(+ve) breast cancers and possibly other MYB-dependent cancers.
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http://dx.doi.org/10.18632/oncotarget.6997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891027PMC
February 2016

CT-guided aspiration cytology of advanced silicosis and confirmation of the deposited zeolite nano particles through X ray diffraction: A novel approach.

Diagn Cytopathol 2016 Mar 9;44(3):246-9. Epub 2016 Jan 9.

Department of Radiology, Burdwan Scan Centre, Burdwan, India.

Silicosis is a common occupational lung disease, resulting in fibrotic nodular lesions in the upper lobes of the lung parenchyma. Most of the pneumoconioses are diagnosed on the basis of relevant history and clinico-radiological correlation. Image-guided aspiration cytology appears to be poorly yielding and is not usually considered as a diagnostic modality. However, silicosis may sometimes offer a diagnostic challenge because of its radiological resemblance and clinical overlap with pulmonary tuberculosis and neoplastic lesions. We present a unique situation where image-guided fine needle aspiration cytology (FNAC) has been advised on the basis of nodular upper lobe opacities. The cytology smears revealed hypocellular granular material, while phase contrast and polarized light microscopy highlighted crystalline particles. History of silica dust exposure long back was available after the cytological evaluation, suggesting the diagnosis of pulmonary silicosis. X ray diffraction (XRD) crystallography was also possible on cytology smears, confirming zeolite nano particles of size as small as 40 - 50 nm as the concerned agent for the first time. Cytological evaluation by phase contrast and polarized light microscopy may be useful for the confirmation of silicosis, supplemented by clinical history and radiological evaluation. XRD on smears may help in determination of chemical nature and particle size.
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http://dx.doi.org/10.1002/dc.23415DOI Listing
March 2016