Publications by authors named "Mitra J"

284 Publications

A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson's disease: Emerging concepts and challenges.

Prog Neurobiol 2020 02 18;185:101729. Epub 2019 Dec 18.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, 77030, USA; Center for Neuroregeneration, Department of Neurosurgery, Methodist Neurological Institute, Institute of Academic Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA; Weill Cornell Medical College of Cornell University, New York, 10065, USA. Electronic address:

α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present in dopaminergic neurons affected by Parkinson's disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a "double whammy" in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein's DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098698PMC
February 2020

RT PCR array screening reveals distinct perturbations in DNA damage response signaling in FUS-associated motor neuron disease.

Mol Brain 2019 12 4;12(1):103. Epub 2019 Dec 4.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has been linked to defective DNA repair. Many familial ALS patients harbor autosomal dominant mutations in the gene encoding the RNA/DNA binding protein 'fused in sarcoma' (FUS) commonly inducing its cytoplasmic mislocalization. Recent reports from our group and others demonstrate a role of FUS in maintaining genome integrity and the DNA damage response (DDR). FUS interacts with many DDR proteins and may regulate their recruitment at damage sites. Given the role of FUS in RNA transactions, here we explore whether FUS also regulates the expression of DDR factors. We performed RT PCR arrays for DNA repair and DDR signaling pathways in CRISPR/Cas9 FUS knockout (KO) and shRNA mediated FUS knockdown (KD) cells, which revealed significant (> 2-fold) downregulation of BRCA1, DNA ligase 4, MSH complex and RAD23B. Importantly, similar perturbations in these factors were also consistent in motor neurons differentiated from an ALS patient-derived induced pluripotent stem cell (iPSC) line with a FUS-P525L mutation, as well as in postmortem spinal cord tissue of sporadic ALS patients with FUS pathology. BRCA1 depletion has been linked to neuronal DNA double-strand breaks (DSBs) accumulation and cognitive defects. The ubiquitin receptor RAD23 functions both in nucleotide excision repair and proteasomal protein clearance pathway and is thus linked to neurodegeneration. Together, our study suggests that the FUS pathology perturbs DDR signaling via both its direct role and the effect on the expression of DDR genes. This underscors an intricate connections between FUS, genome instability, and neurodegeneration.
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http://dx.doi.org/10.1186/s13041-019-0526-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894127PMC
December 2019

Antimicrobial Peptides: Vestiges of Past or Modern Therapeutics?

Mini Rev Med Chem 2020 ;20(3):183-195

Radiopharmaceuticals Division, Anushaktinagar, Mumbai- 400094, India.

The ubiquitous occurrence of Antimicrobial Peptides (AMPs) in all domains of life emphasizes their crucial role as ancient mediators of host defense. Despite their antiquity and prolonged history of exposure to pathogens, endogenous AMPs continue to serve as effective antibiotics. An "evolutionary arms race" between host and pathogen resulted in structural diversity of AMPs, leading these molecules to retain activity against a wide range of pathogens, including antibiotic-resistant microbes. As the menace of antibiotic resistance continues to render most antibiotics ineffective against pathogens, the search for novel drug candidates has taken the center stage. The ability of AMPs to combat antibiotic-resistant microbes gave rise to a remarkable surge of interest in AMPs as potential therapeutics. Apart from being effective antimicrobials, AMPs have also found application as probes suitable for in-situ diagnosis of infection. Here, we review the evolutionary history of AMPs, their structural diversity, and mechanism of interaction with microbial membranes. We also summarize the role of AMPs as modern pharmaceuticals and challenges to this development.
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http://dx.doi.org/10.2174/1389557519666191125121407DOI Listing
November 2020

A Commentary on TDP-43 and DNA Damage Response in Amyotrophic Lateral Sclerosis.

J Exp Neurosci 2019 10;13:1179069519880166. Epub 2019 Oct 10.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston Methodist, Houston, TX, USA.

Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.
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http://dx.doi.org/10.1177/1179069519880166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791036PMC
October 2019

Streamlining effects of extra telomeric repeat on telomeric DNA folding revealed by fluorescence-force spectroscopy.

Nucleic Acids Res 2019 12;47(21):11044-11056

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD 21205, USA.

A human telomere ends in a single-stranded 3' tail, composed of repeats of T2AG3. G-quadruplexes (GQs) formed from four consecutive repeats have been shown to possess high-structural and mechanical diversity. In principle, a GQ can form from any four repeats that are not necessarily consecutive. To understand the dynamics of GQs with positional multiplicity, we studied five and six repeats human telomeric sequence using a combination of single molecule FRET and optical tweezers. Our results suggest preferential formation of GQs at the 3' end both in K+ and Na+ solutions, with minor populations of 5'-GQ or long-loop GQs. A vectorial folding assay which mimics the directional nature of telomere extension showed that the 3' preference holds even when folding is allowed to begin from the 5' side. In 100 mM K+, the unassociated T2AG3 segment has a streamlining effect in that one or two mechanically distinct species was observed at a single position instead of six or more observed without an unassociated repeat. We did not observe such streamlining effect in 100 mM Na+. Location of GQ and reduction in conformational diversity in the presence of extra repeats have implications in telomerase inhibition, T-loop formation and telomere end protection.
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http://dx.doi.org/10.1093/nar/gkz906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868435PMC
December 2019

Nanomechanics and co-transcriptional folding of Spinach and Mango.

Nat Commun 2019 09 20;10(1):4318. Epub 2019 Sep 20.

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA.

Recent advances in fluorogen-binding "light-up" RNA aptamers have enabled protein-free detection of RNA in cells. Detailed biophysical characterization of folding of G-Quadruplex (GQ)-based light-up aptamers such as Spinach, Mango and Corn is still lacking despite the potential implications on their folding and function. In this work we employ single-molecule fluorescence-force spectroscopy to examine mechanical responses of Spinach2, iMangoIII and MangoIV. Spinach2 unfolds in four discrete steps as force is increased to 7 pN and refolds in reciprocal steps upon force relaxation. In contrast, GQ-core unfolding in iMangoIII and MangoIV occurs in one discrete step at forces >10 pN and refolding occurred at lower forces showing hysteresis. Co-transcriptional folding using superhelicases shows reduced misfolding propensity and allowed a folding pathway different from refolding. Under physiologically relevant pico-Newton levels of force, these aptamers may unfold in vivo and subsequently misfold. Understanding of the dynamics of RNA aptamers will aid engineering of improved fluorogenic modules for cellular applications.
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http://dx.doi.org/10.1038/s41467-019-12299-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754394PMC
September 2019

A rapid, early detection of oral squamous cell carcinoma: Real time PCR based detection of tetranectin.

Mol Biol Res Commun 2019 Mar;8(1):33-40

Credora Life Sciences, Horamavu, Bangalore, Karnataka-560043, India.

The current study is focused on determining the mRNA expression levels of tetranectin, to detect oral squamous cell carcinoma (OSCC) and thus aiding in its classification at an early stage. RNA was isolated and cDNA synthesis was performed from the saliva samples of the patients and healthy individuals. A semiquantitative PCR based analysis was performed prior to quantitative and expression based analysis using Real time PCR. The study showed that the mRNA levels are much lesser in patients suffering from dysplastic and metastatic tumors as compared to healthy individuals (P≤0.05). This study can be a breakthrough in medical and dentistry studies. One of the most common malignant carcinomas, OSCC is a type of cancer of the mouth. Though surgical methods have been quite effective in delaying the metastasis, the detection methods using histology parameters are not very efficient and the disease is diagnosed generally in the last stages of the cancer. Tetranectin is a protein biomarker which has been used for detection of several cancers including oral cancer where the protein quantity is calculated.
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http://dx.doi.org/10.22099/mbrc.2019.31544.1365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510212PMC
March 2019

Electrocatalysis on Edge-Rich Spiral WS for Hydrogen Evolution.

ACS Nano 2019 Sep 23;13(9):10448-10455. Epub 2019 Aug 23.

School of Physics , Indian Institute of Science Education and Research Thiruvananthapuram , Maruthamala PO, Thiruvananthapuram , Kerala 695551 , India.

Transition metal dichalcogenides (TMDs) exhibit promising catalytic properties for hydrogen generation, and several approaches including defect engineering have been shown to increase the active catalytic sites. Despite preliminary understandings in defect engineering, insights on the role of various types of defects in TMDs for hydrogen evolution catalysis are limited. Screw dislocation-driven (SDD) growth is a line defect and yields fascinating spiral and pyramidal morphologies for TMDs with a large number of edge sites, resulting in very interesting electronic and catalytic properties. The role of dislocation lines and edge sites of these spiral structures on their hydrogen evolution catalytic properties is unexplored. Here we show that the large number of active edge sites connected together by dislocation lines in the vertical direction for a spiral WS domain results in exceptional catalytic properties toward hydrogen evolution reaction. A micro-electrochemical cell fabricated by photo- and electron beam-lithography processes is used to study the electrocatalytic activity of a single spiral WS domain, controllably grown by chemical vapor deposition. Conductive atomic force microscopy studies show improved vertical conduction for the spiral domain, which is compared with monolayer and mechanically exfoliated thick WS flakes. The obtained results are interesting and shed light on the role of SDD line defects, which contribute to large number of edge sites without compromising the vertical electrical conduction, on the electrocatalytic properties of TMDs for hydrogen evolution.
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http://dx.doi.org/10.1021/acsnano.9b04250DOI Listing
September 2019

Loss of endosomal recycling factor RAB11 coupled with complex regulation of MAPK/ERK/AKT signaling in postmortem spinal cord specimens of sporadic amyotrophic lateral sclerosis patients.

Mol Brain 2019 06 13;12(1):55. Epub 2019 Jun 13.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Synaptic abnormalities, perturbed endosomal recycling mediated by loss of the small GTPase RAB11, and neuroinflammatory signaling have been associated with multiple neurodegenerative diseases including the motor neuron disease, amyotrophic lateral sclerosis (ALS). This is consistent with the neuroprotective effect of RAB11 overexpression as well as of anti-inflammatory compounds. However, most studies were in animal models, and this phenomenon has not been demonstrated in human patients. Moreover, crosstalk between endosomal trafficking and inflammatory signaling pathways in ALS remains enigmatic. Here, we investigated RAB11 expression and MAPK/ERK/AKT signaling in 10 post-mortem spinal cord specimens from patients with sporadic ALS and age-matched controls. All 10 ALS patients showed TDP-43 pathology, whereas two specimens showed an overlapping FUS pathology and one had an acquired Q331K mutation in TDP-43. There was consistent RAB11 downregulation in all ALS cases, while p-AKT and phospho-ribosomal S6 kinase (p-p90RSK) were upregulated. Furthermore, competition between AKT and ERK pathways was observed in ALS, suggesting subtle differences among the TDP-43-ALS subtypes, which may influence patient therapeutic responses. Our findings demonstrate a complex regulation/perturbation pattern of signaling cascades involving MAPK/AKT/RAB11 in spinal cord tissue from ALS patients. These results underscore the relationships between ALS pathology, altered neuronal trafficking, and inflammation.
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http://dx.doi.org/10.1186/s13041-019-0475-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567394PMC
June 2019

Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis.

Hum Mol Genet 2019 08 1;28(15):2459-2476. Epub 2019 Apr 1.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA.

Dominant mutations in the RNA/DNA-binding protein TDP-43 have been linked to amyotrophic lateral sclerosis (ALS). Here, we screened genomic DNA extracted from spinal cord specimens of sporadic ALS patients for mutations in the TARDBP gene and identified a patient specimen with previously reported Q331K mutation. The patient spinal cord tissue with Q331K mutation showed accumulation of higher levels of DNA strand breaks and the DNA double-strand break (DSB) marker γH2AX, compared to age-matched controls, suggesting a role of the Q331K mutation in genome-damage accumulation. Using conditional SH-SY5Y lines ectopically expressing wild-type (WT) or Q331K-mutant TDP-43, we confirmed the increased cytosolic sequestration of the poly-ubiquitinated and aggregated form of mutant TDP-43, which correlated with increased genomic DNA strand breaks, activation of the DNA damage response factors phospho-ataxia-telangiectasia mutated (ATM), phospho-53BP1, γH2AX and neuronal apoptosis. We recently reported the involvement of WT TDP-43 in non-homologous end joining (NHEJ)-mediated DSB repair, where it acts as a scaffold for the recruitment of XRCC4-DNA ligase 4 complex. Here, the mutant TDP-43, due to its reduced interaction and enhanced cytosolic mislocalization, prevented the nuclear translocation of XRCC4-DNA ligase 4. Consistently, the mutant cells showed significantly reduced DNA strand break sealing activity and were sensitized to DNA-damaging drugs. In addition, the mutant cells showed elevated levels of reactive oxygen species, suggesting both dominant negative and loss-of-function effects of the mutation. Together, our study uncovered an association of sporadic Q331K mutation with persistent genome damage accumulation due to both damage induction and repair defects.
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http://dx.doi.org/10.1093/hmg/ddz062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659010PMC
August 2019

Genomic insights into HSFs as candidate genes for high-temperature stress adaptation and gene editing with minimal off-target effects in flax.

Sci Rep 2019 04 3;9(1):5581. Epub 2019 Apr 3.

Division of Crop Improvement, ICAR-Central Research Institute for Jute and Allied Fibres, Kolkata, West Bengal, 700121, India.

Flax (Linum usitatissimum) is a cool season crop commercially cultivated for seed oil and stem fibre production. A comprehensive characterization of the heat shock factor (HSF) candidate genes in flax can accelerate genetic improvement and adaptive breeding for high temperature stress tolerance. We report the genome-wide identification of 34 putative HSF genes from the flax genome, which we mapped on 14 of the 15 chromosomes. Through comparative homology analysis, we classified these genes into three broad groups, and sub-groups. The arrangement of HSF-specific protein motifs, DNA-binding domain (DBD) and hydrophobic heptad repeat (HR-A/B), and exon-intron boundaries substantiated the phylogenetic separation of these genes. Orthologous relationships and evolutionary analysis revealed that the co-evolution of the LusHSF genes was due to recent genome duplication events. Digital and RT-qPCR analyses provided significant evidence of the differential expression of the LusHSF genes in various tissues, at various developmental stages, and in response to high-temperature stress. The co-localization of diverse cis-acting elements in the promoters of the LusHSF genes further emphasized their regulatory roles in the abiotic stress response. We further confirmed DNA-binding sites on the LusHSF proteins and designed guide RNA sequences for gene editing with minimal off-target effects. These results will hasten functional investigations of LusHSFs or assist in devising genome engineering strategies to develop high-temperature stress tolerant flax cultivars.
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http://dx.doi.org/10.1038/s41598-019-41936-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447620PMC
April 2019

Extreme mechanical diversity of human telomeric DNA revealed by fluorescence-force spectroscopy.

Proc Natl Acad Sci U S A 2019 04 3;116(17):8350-8359. Epub 2019 Apr 3.

Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801;

G-quadruplexes (GQs) can adopt diverse structures and are functionally implicated in transcription, replication, translation, and maintenance of telomere. Their conformational diversity under physiological levels of mechanical stress, however, is poorly understood. We used single-molecule fluorescence-force spectroscopy that combines fluorescence resonance energy transfer with optical tweezers to measure human telomeric sequences under tension. Abrupt GQ unfolding with K in solution occurred at as many as four discrete levels of force. Added to an ultrastable state and a gradually unfolding state, there were six mechanically distinct structures. Extreme mechanical diversity was also observed with Na, although GQs were mechanically weaker. Our ability to detect small conformational changes at low forces enabled the determination of refolding forces of about 2 pN. Refolding was rapid and stochastically redistributed molecules to mechanically distinct states. A single guanine-to-thymine substitution mutant required much higher ion concentrations to display GQ-like unfolding and refolded via intermediates, contrary to the wild type. Contradicting an earlier proposal, truncation to three hexanucleotide repeats resulted in a single-stranded DNA-like mechanical behavior under all conditions, indicating that at least four repeats are required to form mechanically stable structures.
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http://dx.doi.org/10.1073/pnas.1815162116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486787PMC
April 2019

Azimuthal Anisotropy of Heavy-Flavor Decay Electrons in p-Pb Collisions at sqrt[s_{NN}]=5.02  TeV.

Phys Rev Lett 2019 Feb;122(7):072301

European Organization for Nuclear Research (CERN), Geneva, Switzerland.

Angular correlations between heavy-flavor decay electrons and charged particles at midrapidity (|η|<0.8) are measured in p-Pb collisions at sqrt[s_{NN}]=5.02  TeV. The analysis is carried out for the 0%-20% (high) and 60%-100% (low) multiplicity ranges. The jet contribution in the correlation distribution from high-multiplicity events is removed by subtracting the distribution from low-multiplicity events. An azimuthal modulation remains after removing the jet contribution, similar to previous observations in two-particle angular correlation measurements for light-flavor hadrons. A Fourier decomposition of the modulation results in a positive second-order coefficient (v_{2}) for heavy-flavor decay electrons in the transverse momentum interval 1.5
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http://dx.doi.org/10.1103/PhysRevLett.122.072301DOI Listing
February 2019

Functional instability allows access to DNA in longer transcription Activator-Like effector (TALE) arrays.

Elife 2019 02 27;8. Epub 2019 Feb 27.

T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States.

Transcription activator-like effectors (TALEs) bind DNA through an array of tandem 34-residue repeats. How TALE repeat domains wrap around DNA, often extending more than 1.5 helical turns, without using external energy is not well understood. Here, we examine the kinetics of DNA binding of TALE arrays with varying numbers of identical repeats. Single molecule fluorescence analysis and deterministic modeling reveal conformational heterogeneity in both the free- and DNA-bound TALE arrays. Our findings, combined with previously identified partly folded states, indicate a TALE instability that is functionally important for DNA binding. For TALEs forming less than one superhelical turn around DNA, partly folded states inhibit DNA binding. In contrast, for TALEs forming more than one turn, partly folded states facilitate DNA binding, demonstrating a mode of 'functional instability' that facilitates macromolecular assembly. Increasing repeat number slows down interconversion between the various DNA-free and DNA-bound states.
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http://dx.doi.org/10.7554/eLife.38298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461438PMC
February 2019

Multistimuli-Responsive Self-Healable and Moldable Nickel(II)-Based Gels for Reversible Gas Adsorption and Palladium Sequestration via Gel-to-Gel Transformation.

ACS Appl Mater Interfaces 2019 Mar 8;11(11):10718-10728. Epub 2019 Mar 8.

CSIR-Central Salt & Marine Chemicals Research Institute , Gijubhai Badheka Marg , Bhavnagar 364002 , Gujarat , India.

We report the in situ formation of Ni-based supramolecular organogel and organic-aqueous gels using amine appended triazole ligand, having varying morphology and rheological properties. These gels are self-healable and moldable or injectable respectively depending on the absence or presence of water in the gelation medium. Our studies reveal that the formation and rupture of hydrogen bonds assisted by the solvent movement is responsible for the self-healing nature of the gels. The porous structure of the gel has been observed from the migration of dye molecules on the self-healed gel. In addition, the gels show dual function of reversible adsorption of toxic gases and sequestration of heavy metal ions, especially palladium via  gel-to-gel transformation. It is imperative to stress that such transformation is extremely rare for small molecule based metallogels. The dynamic nature of Ni-N interactions has been utilized in achieving the reversible gas/vapor responsive behavior of the metallogels, which could be suitable in developing colorimetric probes for the detection of toxic gases and heavy metal ions. Such multifunctional gels are exceptional in contemporary literature and are expected to find utility in fabricating smart multistimuli-responsive gel-based materials in the future.
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http://dx.doi.org/10.1021/acsami.8b21606DOI Listing
March 2019

Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.

Proc Natl Acad Sci U S A 2019 03 15;116(10):4696-4705. Epub 2019 Feb 15.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
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http://dx.doi.org/10.1073/pnas.1818415116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410842PMC
March 2019

Mass Effect Deformation Heterogeneity (MEDH) on Gadolinium-contrast T1-weighted MRI is associated with decreased survival in patients with right cerebral hemisphere Glioblastoma: A feasibility study.

Sci Rep 2019 02 4;9(1):1145. Epub 2019 Feb 4.

Case Western Reserve University, Department of Biomedical Engineering, Cleveland, USA.

Subtle tissue deformations caused by mass-effect in Glioblastoma (GBM) are often not visually evident, and may cause neurological deficits, impacting survival. Radiomic features provide sub-visual quantitative measures to uncover disease characteristics. We present a new radiomic feature to capture mass effect-induced deformations in the brain on Gadolinium-contrast (Gd-C) T1w-MRI, and their impact on survival. Our rationale is that larger variations in deformation within functionally eloquent areas of the contralateral hemisphere are likely related to decreased survival. Displacements in the cortical and subcortical structures were measured by aligning the Gd-C T1w-MRI to a healthy atlas. The variance of deformation magnitudes was measured and defined as Mass Effect Deformation Heterogeneity (MEDH) within the brain structures. MEDH values were then correlated with overall-survival of 89 subjects on the discovery cohort, with tumors on the right (n = 41) and left (n = 48) cerebral hemispheres, and evaluated on a hold-out cohort (n = 49 subjects). On both cohorts, decreased survival time was found to be associated with increased MEDH in areas of language comprehension, social cognition, visual perception, emotion, somato-sensory, cognitive and motor-control functions, particularly in the memory areas in the left-hemisphere. Our results suggest that higher MEDH in functionally eloquent areas of the left-hemisphere due to GBM in the right-hemisphere may be associated with poor-survival.
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http://dx.doi.org/10.1038/s41598-018-37615-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362117PMC
February 2019

Resolving population structure and genetic differentiation associated with RAD-SNP loci under selection in tossa jute (Corchorus olitorius L.).

Mol Genet Genomics 2019 Apr 2;294(2):479-492. Epub 2019 Jan 2.

Rice Genome Lab, ICAR-National Research Centre on Plant Biotechnology (NRCPB), Pusa, New Delhi, 110 012, India.

The genetic basis of selection for geographic adaptation and how it has contributed to population structure are unknown in tossa jute (Corchorus olitorius), an important bast fibre crop. We performed restriction site-associated DNA (RAD) sequencing-based (1115 RAD-SNPs) population genomic analyses to investigate genetic differentiation and population structure within a collection of 221 fibre-type lines from across nine geographic regions of the world. Indian populations, with relatively higher overall diversity, were significantly differentiated (based on F and PCA) from the African and the other Asian populations. There is strong evidence that African C. olitorius was first introduced in peninsular India that could perhaps be its secondary centre of origin. However, multiple later introductions have occurred in central, eastern and northern India. Based on four assignment tests with different statistical bases, we infer that two ancestral subpopulations (African and Indian) structure the C. olitorius populations, but not in accordance with their geographic origins and patterns of diversity. Our results advocate recent migration of C. olitorius through introduction and germplasm exchange across geographical boundaries. We argue that high intraspecific genetic admixture could be associated with increased genetic variance within Indian populations. Employing both subpopulation (F/G-outlier) and individual-based (PCAdapt) tests, we detected putative RAD-SNP loci under selection and demonstrated that bast fibre production was an artificial, while abiotic and biotic stresses were natural selection pressures in C. olitorius adaptation. By reinferring the population structure without outlier loci, we propose ad interim that C. olitorius was possibly domesticated as a fibre crop in the Indian subcontinent.
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http://dx.doi.org/10.1007/s00438-018-1526-2DOI Listing
April 2019

Genome-wide regulatory gene-derived SSRs reveal genetic differentiation and population structure in fiber flax genotypes.

J Appl Genet 2019 Feb 27;60(1):13-25. Epub 2018 Oct 27.

Morden Research and Development Centre, Agriculture and Agri-Food Canada, 101 Route 100, Morden, MB, R6M 1Y5, Canada.

We designed a set of 580 simple sequence repeat markers; 506 from transcription factor-coding genes, and 74 from long non-coding RNAs and designated them as regulatory gene-derived simple sequence repeat (ReG-SSR) markers. From this set, we could anchor 559 ReG-SSR markers on 15 flax chromosomes with an average marker distance of 0.56 Mb. Thirty-one polymorphic ReG-SSR primers, amplifying SSR loci length of at least 20 bp were chosen from 134 screened primers. This primer set was used to characterize a diversity panel of 93 flax accessions. The panel included 33 accessions from India, including released varieties, dual-purpose lines and landraces, and 60 fiber flax accessions from the global core collection. Thirty-one ReG-SSR markers generated 76 alleles, with an average of 2.5 alleles per primer and a mean allele frequency of 0.77. These markers recorded 0.32 average gene diversity, 0.26 polymorphism information content and 1.35% null alleles. All the 31 ReG-SSR loci were found selectively neutral and showed no evidence of population reduction. A model-based clustering analysis separated the flax accessions into two sub-populations-Indian and global, with some accessions showing admixtures. The distinct clustering pattern of the Indian accessions compared to the global accessions, conforms to the principal coordinate analysis, genetic dissimilarity-based unweighted neighbor-joining tree and analysis of molecular variance. Fourteen flax accessions with 99.3% allelic richness were found optimum to adopt in breeding programs. In summary, the genome-wide ReG-SSR markers will serve as a functional marker resource for genetic and phenotypic relationship studies, marker-assisted selections, and provide a basis for selection of accessions from the Indian and global gene pool in fiber flax breeding programs.
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http://dx.doi.org/10.1007/s13353-018-0476-zDOI Listing
February 2019

Perceptions of an Obstetric Clinical Rotation by Nursing Students Who Are Men.

MCN Am J Matern Child Nurs 2018 Nov/Dec;43(6):330-333

Jose Mari Lawrence Mitra is a Staff Nurse, Cardiovascular Progressive Care Unit, Johnson City Medical Center, Johnson City, TN. The author can be reached via e-mail at Kenneth D. Phillips is a Professor, Associate Dean for Research, East Tennessee State University College of Nursing, Johnson City, TN. Joy E. Wachs is a Professor Emeritus, East Tennessee State University, Johnson City, TN.

Background: Maternity nursing is perceived as an unwelcoming specialty to many nursing students who are men. The purpose of this qualitative study was to describe the experiences of nursing students who are men at a Southeastern university before, during, and after their obstetric clinical rotations.

Methods: Students were interviewed individually. The sessions were recorded and transcribed. The transcripts were analyzed individually and collectively by a three-person study team using existential phenomenology.

Results: Seven nursing students who are men participated. Four major themes were discovered: preconceptions, welcoming, perceived rejection (of and by participants), and maternity unit culture. Students' perceptions appeared to be grounded in their level of comfort with maternity nursing.

Conclusions: This study adds to the scant amount of information available about experiences of nursing students who are men during their clinical maternity nursing rotation and may help to explain why some men may feel unwelcome in women's health nursing.
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http://dx.doi.org/10.1097/NMC.0000000000000481DOI Listing
March 2019

An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1.

J Alzheimers Dis 2018 ;66(2):453-460

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA.

Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.
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http://dx.doi.org/10.3233/JAD-180610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221916PMC
October 2019

Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis.

Nat Commun 2018 09 11;9(1):3683. Epub 2018 Sep 11.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 77030, TX, USA.

Genome damage and defective repair are etiologically linked to neurodegeneration. However, the specific mechanisms involved remain enigmatic. Here, we identify defects in DNA nick ligation and oxidative damage repair in a subset of amyotrophic lateral sclerosis (ALS) patients. These defects are caused by mutations in the RNA/DNA-binding protein FUS. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. We discover that loss of nuclear FUS caused DNA nick ligation defects in motor neurons due to reduced recruitment of XRCC1/LigIII to DNA strand breaks. Moreover, DNA ligation defects in ALS patient-derived iPSC lines carrying FUS mutations and in motor neurons generated therefrom are rescued by CRISPR/Cas9-mediated correction of mutation. Our findings uncovered a pathway of defective DNA ligation in FUS-linked ALS and suggest that LigIII-targeted therapies may prevent or slow down disease progression.
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http://dx.doi.org/10.1038/s41467-018-06111-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134028PMC
September 2018

Transcriptome profiling uncovers β-galactosidases of diverse domain classes influencing hypocotyl development in jute (Corchorus capsularis L.).

Phytochemistry 2018 Dec 30;156:20-32. Epub 2018 Aug 30.

ICAR-National Research Centre on Plant Biotechnology, Pusa Campus, New Delhi, 110 012, India.

Enzyme β-galactosidase (EC 3.2.1.23) is known to influence vascular differentiation during early vegetative growth of plants, but its role in hypocotyl development is not yet fully understood. We generated the hypocotyl transcriptome data of a hypocotyl-defect jute (Corchorus capsularis L.) mutant (52,393 unigenes) and its wild-type (WT) cv. JRC-212 (44,720 unigenes) by paired-end RNA-seq and identified 11 isoforms of β-galactosidase, using a combination of sequence annotation, domain identification and structural-homology modeling. Phylogenetic analysis classified the jute β-galactosidases into six subfamilies of glycoside hydrolase-35 family, which are closely related to homologs from Malvaceous species. We also report here the expression of a β-galactosidase of glycoside hydrolase-2 family that was earlier considered to be absent in higher plants. Comparative analysis of domain structure allowed us to propose a domain-centric evolution of the five classes of plant β-galactosidases. Further, we observed 1.8-12.2-fold higher expression of nine β-galactosidase isoforms in the mutant hypocotyl, which was characterized by slower growth, undulated shape and deformed cell wall. In vitro and in vivo β-galactosidase activities were also higher in the mutant hypocotyl. Phenotypic analysis supported a significant (P ≤ 0.01) positive correlation between enzyme activity and undulated hypocotyl. Taken together, our study identifies the complete set of β-galactosidases expressed in the jute hypocotyl, and provides compelling evidence that they may be involved in cell wall degradation during hypocotyl development.
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http://dx.doi.org/10.1016/j.phytochem.2018.08.017DOI Listing
December 2018

Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs.

Mol Nutr Food Res 2018 09 19;62(18):e1800228. Epub 2018 Jul 19.

Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030.

Scope: DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC.

Methods And Results: In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long-chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell-based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole-containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C-terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP-associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non-homologous end joining (NHEJ) repair activities in colon cancer cells.

Conclusion: Novel tetrazole-containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways.
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http://dx.doi.org/10.1002/mnfr.201800228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553464PMC
September 2018

Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress.

DNA Repair (Amst) 2018 Jun - Jul;66-67:1-10. Epub 2018 Apr 17.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address:

Posttranslational modifications of DNA repair proteins have been linked to their function. However, it is not clear if posttranslational acetylation affects subcellular localization of these enzymes. Here, we show that the human DNA glycosylase NEIL1, which is involved in repair of both endo- and exogenously generated oxidized bases via the base excision repair (BER) pathway, is acetylated by histone acetyltransferase p300. Acetylation occurs predominantly at Lys residues 296, 297 and 298 located in NEIL1's disordered C-terminal domain. NEIL1 mutant having the substitution of Lys 296-298 with neutral Ala loses nuclear localization, whereas Lys > Arg substitution (in 3KR mutant) at the same sites does not affect NEIL1's nuclear localization or chromatin binding, presumably due to retention of the positive charge. Although non-acetylated NEIL1 can bind to chromatin, acetylated NEIL1 is exclusively chromatin-bound. NEIL1 acetylation while dispensable for its glycosylase activity enhances it due to increased product release. The acetylation-defective 3KR mutant forms less stable complexes with various chromatin proteins, including histone chaperones and BER/single-strand break repair partners, than the wild-type (WT) NEIL1. We also showed that the repair complex with WT NEIL1 has significantly higher BER activity than the 3KR mutant complex. This is consistent with reduced resistance of non-acetylable mutant NEIL1 expressing cells to oxidative stress relative to cells expressing the acetylable WT enzyme. We thus conclude that the major role of acetylable Lys residues in NEIL1 is to stabilize the formation of chromatin-bound repair complexes which protect cells from oxidative stress.
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http://dx.doi.org/10.1016/j.dnarep.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992913PMC
October 2018

Radiotherapy dose-distribution to the perirectal fat space (PRS) is related to gastrointestinal control-related complications.

Clin Transl Radiat Oncol 2017 Dec 6;7:62-70. Epub 2017 Nov 6.

School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.

Traditionally rectal symptoms following pelvic/prostate radiotherapy are correlated to the dosimetry of the anorectum or a substructure of this. It has been suggested that the perirectal fat space (PRS) surrounding the rectum may also be relevant. This study considers the delineation and dosimetry of the PRS related to both rectal bleeding and control-related toxicity. Initially, a case-control cohort of 100 patients from the RADAR study were chosen based on presence/absence of rectal control-related toxicity. Automated contouring was developed to delineate the PRS. 79 of the 100 auto-segmentations were considered successful. Balanced case-control cohorts were defined from these cases. Atlas of Complication Incidence (ACI) were generated to relate the DVH of the PRS with specific rectal symptoms; rectal bleeding and control-related symptoms (LENT/SOM). ACI demonstrated that control-related symptoms were related to the dose distribution to the PRS which was confirmed with Wilcoxon rank sum test ( < 0.05). To the authors knowledge this is the first study implicating the dose distribution to the PRS to the incidence of control-related symptoms of rectal toxicity.
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http://dx.doi.org/10.1016/j.ctro.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862665PMC
December 2017

D-Meson Azimuthal Anisotropy in Midcentral Pb-Pb Collisions at sqrt[s]_{NN}=5.02  TeV.

Phys Rev Lett 2018 Mar;120(10):102301

Physikalisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.

The azimuthal anisotropy coefficient v_{2} of prompt D^{0}, D^{+}, D^{*+}, and D_{s}^{+} mesons was measured in midcentral (30%-50% centrality class) Pb-Pb collisions at a center-of-mass energy per nucleon pair sqrt[s_{NN}]=5.02  TeV, with the ALICE detector at the LHC. The D mesons were reconstructed via their hadronic decays at midrapidity, |y|<0.8, in the transverse momentum interval 1
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http://dx.doi.org/10.1103/PhysRevLett.120.102301DOI Listing
March 2018

Production of [Formula: see text] and [Formula: see text] in p-Pb collisions at [Formula: see text] TeV.

Eur Phys J C Part Fields 2017 13;77(6):389. Epub 2017 Jun 13.

101Rudjer Bošković Institute, Zagreb, Croatia.

The transverse momentum distributions of the strange and double-strange hyperon resonances ([Formula: see text], [Formula: see text]) produced in p-Pb collisions at [Formula: see text] TeV were measured in the rapidity range [Formula: see text] for event classes corresponding to different charged-particle multiplicity densities, [Formula: see text]d[Formula: see text]/d[Formula: see text]. The mean transverse momentum values are presented as a function of [Formula: see text]d[Formula: see text]/d[Formula: see text], as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of [Formula: see text]d[Formula: see text]/d[Formula: see text]. The equivalent ratios to pions exhibit an increase with [Formula: see text]d[Formula: see text]/d[Formula: see text], depending on their strangeness content.
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http://dx.doi.org/10.1140/epjc/s10052-017-4943-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797483PMC
June 2017

Resistive switching in individual ZnO nanorods: delineating the ionic current by photo-stimulation.

Nanotechnology 2018 Mar;29(10):105701

Resistive switching in nanostructured metal oxide semiconductors has been broadly understood to originate from the dynamics of its native point defects. Experimental results of switching observed in individual n-ZnO nanorods grown on a p-type polymer is presented along with an empirical model describing the underlying defect dynamics necessary to observe bi-polar switching. Selective photo excitation of electrons into the defect states delineates the incidence and role of an ionic current in the switching behavior. The understanding further extends to the observance of a negative differential resistance regime that is often coincident in such systems. The analysis not only unifies the underlying physics of the two phenomena but also offers further confidence in the proposed mechanism. We conclude by demonstrating that the effective memresistance of such devices is a strong function of the operating bias and identify parameters that optimize switching performance.
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http://dx.doi.org/10.1088/1361-6528/aaa63fDOI Listing
March 2018
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