Publications by authors named "Vandana Gupta"

97 Publications

hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies.

Muscle Nerve 2021 Mar 2. Epub 2021 Mar 2.

Department of Medicine, Molecular Cardiology Research Institute, Boston, MA.

Introduction/aims: RNA binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (Muscleblind-like) is sequestered by toxic CUG repeats, leading to mis-splicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Here we sought to evaluate the functional role of hnRNP L in normal and DM1 muscle cells. We sought to test if modulation of hnRNP L expression affected DM1 splicing targets and myogenic outcomes.

Methods: Co-immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and expression profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrnpl and hnrnpl2 were injected into one-cell zebrafish for developmental and muscle analysis. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated.

Results: Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, further suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued mis-splicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells.

Discussion: Together, these studies reveal that hnRNP L modulated DM1 pathologies, and is a potential therapeutic target. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mus.27216DOI Listing
March 2021

Recent advances in the diagnosis of COVID-19: a bird's eye view.

Expert Rev Mol Diagn 2021 Mar 1:1-17. Epub 2021 Mar 1.

Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi, 110021, India.

Introduction: The COVID-19 pandemic is still escalating and has shaped an extraordinary and pressing need for rapid diagnostics with high sensitivity and specificity. Prompt diagnosis is the key to mitigate this situation. As several diagnostic tools for COVID-19 are already available and others are still under development, mandating a comprehensive review of the efficacy of existing tools and evaluate the potential of others.

Areas Covered: Currently explored platforms for SARS-CoV-2 diagnostics and surveillance centered on qRT-PCR, RT-PCR, CRISPR, microarray, LAMP, lateral flow immunoassays, proteomics-based approaches, and radiological scans are overviewed and summarized in this review along with their advantages and downsides. A narrative literature review was carried out by accessing the freely available online databases to encapsulate the developments in medical diagnostics.

Expert Opinion: An ideal detection method should be sensitive, specific, rapid, cost-effective, and should allow early diagnosis of the infection as near as possible to the point of care that could alter the current situation for the better. Medical diagnostics is a highly dynamic field as no diagnostic method available for SARS-CoV-2 detection offers a perfect solution and requires more attention and continuous R&D to challenge the present-day pandemic situation.
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http://dx.doi.org/10.1080/14737159.2021.1874354DOI Listing
March 2021

SARS-CoV-2 therapeutics: how far do we stand from a remedy?

Pharmacol Rep 2021 Jan 3. Epub 2021 Jan 3.

Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi, 110021, India.

The SARS-CoV-2 has affected millions worldwide and has posed an immediate need for effective pharmacological interventions. Ever since the outbreak was declared, the medical fraternity across the world is facing a unique situation of offering assistance and simultaneously generating reliable data with high-quality evidence to extend the scope of finding a treatment. With no proven vaccine or other interventions available hitherto, there is a frenzied urgency of sharing preliminary data from laboratories and trials to shape a global response against the virus. Several clinical trials with investigational and approved repurposed therapeutics have shown promising results. This review aims to compile the information of the reported molecules approved for emergency use and those under clinical trials and still others with good results in the studies conducted so far. Being an RNA virus, SARS-CoV-2 is prone to mutation; thus, the possibility of gaining resistance to available drugs is high. Consequently, a cocktail therapy based on drug interaction with different stages of its replicative cycle is desirable to reduce the chances of evolving drug resistance. Since this virus encodes several proteins, including 16 nonstructural and 4 structural proteins, this review also offers an insight into potential drug targets within SARS-CoV-2.
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http://dx.doi.org/10.1007/s43440-020-00204-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778692PMC
January 2021

COVID-19 Vaccine: A comprehensive status report.

Virus Res 2020 10 13;288:198114. Epub 2020 Aug 13.

Department of Microbiology, Ram Lal Anand College, University of Delhi, Benito Juarez Road, New Delhi 110021, India. Electronic address:

The current COVID-19 pandemic has urged the scientific community internationally to find answers in terms of therapeutics and vaccines to control SARS-CoV-2. Published investigations mostly on SARS-CoV and to some extent on MERS has taught lessons on vaccination strategies to this novel coronavirus. This is attributed to the fact that SARS-CoV-2 uses the same receptor as SARS-CoV on the host cell i.e. human Angiotensin Converting Enzyme 2 (hACE2) and is approximately 79% similar genetically to SARS-CoV. Though the efforts on COVID-19 vaccines started very early, initially in China, as soon as the outbreak of novel coronavirus erupted and then world-over as the disease was declared a pandemic by WHO. But we will not be having an effective COVID-19 vaccine before September, 2020 as per very optimistic estimates. This is because a successful COVID-19 vaccine will require a cautious validation of efficacy and adverse reactivity as the target vaccinee population include high-risk individuals over the age of 60, particularly those with chronic co-morbid conditions, frontline healthcare workers and those involved in essentials industries. Various platforms for vaccine development are available namely: virus vectored vaccines, protein subunit vaccines, genetic vaccines, and monoclonal antibodies for passive immunization which are under evaluations for SARS-CoV-2, with each having discrete benefits and hindrances. The COVID-19 pandemic which probably is the most devastating one in the last 100 years after Spanish flu mandates the speedy evaluation of the multiple approaches for competence to elicit protective immunity and safety to curtail unwanted immune-potentiation which plays an important role in the pathogenesis of this virus. This review is aimed at providing an overview of the efforts dedicated to an effective vaccine for this novel coronavirus which has crippled the world in terms of economy, human health and life.
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http://dx.doi.org/10.1016/j.virusres.2020.198114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423510PMC
October 2020

Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β.

ACS Med Chem Lett 2020 Jun 7;11(6):1130-1136. Epub 2020 May 7.

Department of Pathology, University of Alabama at Birmingham, VH G001A, 1720 Second Avenue South, Birmingham, Alabama 35294, United States.

TGF-β has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-β include antagonists of the active ligand or TGF-β receptor kinase activity. These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-β are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-β complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 (), is effective but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 () with a single chiral center, which blocks TGF-β activation (pIC = 8.12 nM) and has a plasma half life of 1.8 h (iv).
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http://dx.doi.org/10.1021/acsmedchemlett.9b00540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294719PMC
June 2020

Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.

Ann Neurol 2020 04 8;87(4):568-583. Epub 2020 Feb 8.

Department of Child Neurology, Centre Hospitalier de l'Université Laval et Centre Mère-Enfant Soleil, Université Laval, Quebec City, Quebec, Canada.

Objective: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy.

Methods: Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype.

Results: Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so.

Interpretation: This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.
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http://dx.doi.org/10.1002/ana.25685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078025PMC
April 2020

In silico study of chikungunya polymerase, a potential target for inhibitors.

Virusdisease 2019 Sep 26;30(3):394-402. Epub 2019 Oct 26.

3Department of Microbiology, Ram Lal Anand College, University of Delhi South Campus (UDSC), Benito Juarez Marg, New Delhi, 110021 India.

Non-structural protein 4 (nsP4) polymerase of chikungunya virus (CHIKV) has a crucial role in genome replication and hence could act as a promising target for novel therapeutics. Though, nsP4 is important in viral life cycle, but it is less explored as therapeutic target. The catalytic core of nsP4 Polymerase includes conserved GDD motif which is present not only across different CHIKV strains but also across other . This emphasizes the uniqueness and importance of this motif in the functioning of nsP4 polymerase and hence, we focused on GDD motif for docking of drug molecules. Herein, a model of nsP4 polymerase was developed using Swiss Model, validated by Ramachandran plot and molecular dynamic simulation. Molecular docking was performed using LeadIT FlexX flexible docking module with FDA approved drug molecule library. On the basis of flexX score, top 5 leads with flexX scores - 33.7588, - 30.2555, - 29.6043, - 28.916 and - 28.5042 were selected. The bonding pattern of these leads were analysed in discovery studio and were further screened on the basis of molecular dynamic simulation studies. Simulation analysis revealed that only the top lead, Mitoxantrone Hydrochloride which is an anticancer drug and is currently indicated in leukemias and lymphomas interacted favourably and stably with nsP4. Our findings suggest that Mitoxantrone Hydrochloride can be a potential novel inhibitor of CHIKV polymerase and should be further validated by in vitro assays.
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http://dx.doi.org/10.1007/s13337-019-00547-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864021PMC
September 2019

A Somatostatin Receptor Subtype-3 (SST) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

Clin Cancer Res 2020 02 17;26(4):957-969. Epub 2019 Oct 17.

Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.

Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST and SST. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST-agonists and characterize their effects on experimental NFPT models.

Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST-agonist.

Results: We successfully identified the first SST-agonist peptides. SST-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST-agonist treatments. Concurrently, silencing increased cell viability in a subset of NFPTs.

Conclusions: This study demonstrates that SST-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2154DOI Listing
February 2020

Virtual screening of inhibitors against Envelope glycoprotein of Chikungunya Virus: a drug repositioning approach.

Bioinformation 2019 15;15(6):439-447. Epub 2019 Jun 15.

Department of Microbiology, Ram Lal Anand College, University of Delhi South Campus (UDSC), Benito Juarez Marg, New Delhi 110021, India.

Chikungunya virus (CHIKV) a re-emerging mosquito-borne alpha virus causes significant distress which is further accentuated in the lack of specific therapeutics or a preventive vaccine, mandating accelerated research for anti-CHIKV therapeutics. In recent years, drug repositioning has gained recognition for the curative interventions for its cost and time efficacy. CHIKV envelope proteins are considered to be the promising targets for drug discovery because of their essential role in viral attachment and entry in the host cells. In the current study, we propose structure-based virtual screening of drug molecule on the crystal structure of mature Chikungunya envelope protein (PDB 3N41) using a library of FDA approved drug molecules. Several cephalosporin drugs docked successfully within two binding sites prepared at E1-E2 interface of CHIKV envelop protein complex with significantly low binding energies. Cefmenoxime, ceforanide, cefotetan, cefonicid sodium and cefpiramide were identified as top leads with a cumulative score of -67.67, -64.90, -63.78, -61.99, and - 61.77, forming electrostatic, hydrogen and hydrophobic bonds within both the binding sites. These shortlisted leads could be potential inhibitors of E1-E2 hetero dimer in CHIKV, hence might disrupt the integrity of envelope glycoprotein leading to loss of its ability to form mature viral particles and gain entry into the host.
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http://dx.doi.org/10.6026/97320630015439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614119PMC
June 2019

Expression, purification and functional characterization of recombinant hypervariable region (HVR) of Chikungunya virus nsP3 protein.

3 Biotech 2019 Jun 27;9(6):235. Epub 2019 May 27.

1Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh 201 307 India.

One of the most important rapidly emerging mosquito-borne alphavirus is Chikungunya virus (CHIKV). There is a necessity to develop anti-CHIKV therapeutics, as neither antiviral drug nor vaccines have been licensed yet. Several CHIKV proteins are being studied worldwide, but non-structural protein 3 (nsP3) has been less explored. This protein consists of three domains: macrodomain, alphavirus unique domain (AUD) and hypervariable region (HVR). The proline-rich regions of HVR contain SRC homology 3 (SH3)-binding domain which is essential for its functionality. Interaction of these motifs with host amphiphysin protein is crucial for viral RNA replication. Restricting the interactions of HVR could lead to inhibition of viral life cycle. Therefore, the present study focuses on purification of HVR protein and its structural and functional assay for therapeutic intervention in future use. In order to obtain purified protein, HVR region was amplified from TOPO clones of nsP3 of IND-06-Guj strain and cloned into expression vector. Expression and solubilization of the protein were optimized at various conditions of salt, detergent and imidazole before purification. The soluble recombinant HVR (His-HVR) protein was purified using affinity chromatography. Purified protein was analyzed for structural studies and functional assays. Circular dichroism of His-HVR protein was performed for structural study, and it was observed that it consists of mostly random coils. For functional assay, co-pull down of His-HVR protein was performed with endogenous amphiphysin-I protein of N2a cells and was analyzed using Western blotting. This purified protein obtained could be used as a potential target reagent for novel therapeutic interventions in the future.
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http://dx.doi.org/10.1007/s13205-019-1759-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536559PMC
June 2019

Homozygous mutation causes congenital distal spinal muscular atrophy and arthrogryposis.

Neurol Genet 2019 Apr 7;5(2):e312. Epub 2019 Mar 7.

Department of Molecular and Cellular Biology (J.V., R.G.), Harvard University, Cambridge; Division of Genetics (M.M.M., A.T.-P., C.G., A.H.B., N.C., B.T.D., N.Y.F., J.K., V.A.G.), Brigham Genomic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Division of Genetics (E.E.), Boston Children's Hospital; and Division of Neurology (B.T.D.), Boston Children's Hospital, Harvard Medical School, MA.

Objective: To identify the genetic cause of disease in a form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).

Methods: A 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement. Whole-exome sequencing (WES) was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.

Results: WES revealed a homozygous mutation in the gene (c.281C>T; p.S94L). The identification of a recessive mutation in extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by Western blot and immunohistochemical analysis show that p.S94L increased TRPV4 activity-based cytotoxicity and resultant decreased TRPV4 expression levels, therefore involves a gain-of-function mechanism.

Conclusions: This study identifies a novel homozygous mutation in as a cause of the recessive form of CSMAA.
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http://dx.doi.org/10.1212/NXG.0000000000000312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454305PMC
April 2019

Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy.

Hum Mol Genet 2019 Aug;28(15):2549-2560

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
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http://dx.doi.org/10.1093/hmg/ddz078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644164PMC
August 2019

ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).

Acta Neuropathol 2019 03 30;137(3):501-519. Epub 2019 Jan 30.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.
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http://dx.doi.org/10.1007/s00401-019-01963-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545377PMC
March 2019

Development of Biocompatible Iron-Carboxylate Metal Organic Frameworks for pH-Responsive Drug Delivery Application.

J Nanosci Nanotechnol 2019 Feb;19(2):646-654

DAV University, Jalandhar 144012, Punjab, India.

Metal organic frameworks (MOFs), MIL-101-Fe (Materials of Institute Lavoisier), have been synthesized by solvothermal method. The as-synthesized MIL-101-Fe particles are observed to have hexagonal shaped morphology with average particle size ranging from 480 to 500 nm. The functionalization of the surface of as-synthesized MIL-101-Fe particles was done with the integration of amine group into the framework to facilitate the conjugation of the drug and other entities. Further, the drug conjugated MOF particles were coated with polyethyleneglycol (PEG) layer so as to extend the drug release time by controlling the faster pH mediated MOF degradation in biological buffers. pH dependent drug release study of the MOF particles was carried out at 3 different pH values, i.e., 5, 6 and 7.4. The drug release profiles showed that the drug released from NH₂-MIL-101-Fe takes less time which was further increased after coating the NH₂-MIL-101-Fe with polyethyleneglycol (PEG@Drug@NH₂-MIL-101-Fe). This confirmed that PEG coated particles have great stability for drug delivery application.
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http://dx.doi.org/10.1166/jnn.2019.15402DOI Listing
February 2019

Transgenic zebrafish model of DUX4 misexpression reveals a developmental role in FSHD pathogenesis.

Hum Mol Genet 2019 01;28(2):320-331

Division of Genetics and Genomics,Boston Children's Hospital, Boston, MA, USA.

Facioscapulohumeral dystrophy type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of ∼1 in 8000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germ line, primate-specific transcription factor DUX4-fl (double homeobox 4, full-length isoform) linked to the chromosome 4q35. In vitro and in vivo studies have demonstrated that very low levels of DUX4-fl expression are sufficient to induce an apoptotic and/or lethal phenotype, and therefore modeling of the disease has proved challenging. In this study, we expand upon our previously established injection model of DUX4 misexpression in zebrafish and describe a DUX4-inducible transgenic zebrafish model that better recapitulates the expression pattern and late onset phenotype characteristic of FSHD patients. We show that an induced burst of DUX4 expression during early development results in the onset of FSHD-like phenotypes in adulthood, even when DUX4 is no longer detectable. We also utilize our injection model to study long-term consequences of DUX4 expression in those that fail to show a developmental phenotype. Herein, we introduce a hypothesis that DUX4 expression during developmental stages is sufficient to induce FSHD-like phenotypes in later adulthood. Our findings point to a developmental role of DUX4 misexpression in the pathogenesis of FSHD and should be factored into the design of future therapies.
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http://dx.doi.org/10.1093/hmg/ddy348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489409PMC
January 2019

Interlaboratory validation of cerebrospinal fluid α-synuclein quantification in the diagnosis of sporadic Creutzfeldt-Jakob disease.

Alzheimers Dement (Amst) 2018 7;10:461-470. Epub 2018 Jul 7.

Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

Introduction: Cerebrospinal fluid α-synuclein level is increased in sporadic Creutzfeldt-Jakob disease cases. However, the clinical value of this biomarker remains to be established. In this study, we have addressed the clinical validation parameters and the interlaboratory reproducibility by using an electrochemiluminescent assay.

Methods: Cerebrospinal fluid α-synuclein was quantified in a total of 188 sporadic Creutzfeldt-Jakob disease and non-Creutzfeldt-Jakob-disease cases to determine sensitivity and specificity values and lot-to-lot variability. Two round robin tests with 70 additional cases were performed in six independent laboratories.

Results: A sensitivity of 93% and a specificity of 96% were achieved in discriminating sporadic Creutzfeldt-Jakob disease. No differences were detected between lots. The mean interlaboratory coefficient of variation was 23%, and the intralaboratory coefficient of variations ranged 2.70%-11.39%. Overall, 97% of samples were correctly diagnosed.

Discussion: The herein validated α-synuclein assay is robust, accurate, and reproducible in identifying Creutzfeldt-Jakob disease cases. Thus, it is ready for implementation in the clinical practice to support the diagnosis of Creutzfeldt-Jakob disease.
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http://dx.doi.org/10.1016/j.dadm.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171371PMC
July 2018

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

NPJ Genom Med 2018 13;3:21. Epub 2018 Aug 13.

1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.
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http://dx.doi.org/10.1038/s41525-018-0060-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089983PMC
August 2018

Association of acylation stimulating protein and adiponectin with metabolic risk marker in North Indian obese women.

Diabetes Metab Syndr 2019 Sep - Oct;13(5):2987-2990. Epub 2018 Jul 30.

Department of Biochemistry, King George Medical University, Lucknow, India.

Background: Plasma concentrations of Acylation stimulating protein (ASP) and adiponectin are associated with body weight and energy homeostasis. The purpose of this study is to describe the potential role of acylation stimulating protein and adiponectin with metabolic risk marker in North Indian obese women.

Methods: This is a case control study. Total 520 women were recruited for the study n = 260 women with obesity (BMI>30) study group and n = 260 women without obesity (BMI<25) control group. Serum ASP and adiponectin level were determined by enzyme linked immunosorbent assay.

Results: Result indicated that WC, BP, lipid profile, FPG, FPI, IR (HOMA-IR), ASP were significantly higher but adiponectin and HDL were significantly lower in women with obesity than in women without obesity. Furthermore ASP was significantly positive correlated with WC, FPG, TG, VLDL, FPI and IR, whereas the correlation of adiponectin was significantly negative correlated with WC, FPG, TG, IR, ASP and significantly positive correlated with HDL in women with obesity.

Conclusion: The study shows that high level of ASP and low level of Adiponectin could be a potential marker of women with obesity among metabolic syndrome.
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http://dx.doi.org/10.1016/j.dsx.2018.07.017DOI Listing
February 2020

An open source microcontroller based flume for evaluating swimming performance of larval, juvenile, and adult zebrafish.

PLoS One 2018 26;13(6):e0199712. Epub 2018 Jun 26.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.

Zebrafish are a preferred vertebrate model for delineating genotype-phenotype relationships. One of the most studied features of zebrafish is their exceptional swimming ability. By 7 days postfertilization (dpf), zebrafish spend over two-thirds of their time engaged in spontaneous swimming activity and several months later they are capable of attaining some of the fastest swimming velocities relative to body length ever recorded in the laboratory. However, laboratory-assembled flumes capable of achieving the slow flow velocities characteristics of larvae as well as the relatively fast maximal velocities of adults have not been described in sufficient detail to allow easy replication. Here we describe an easily assembled, open-source zebrafish-scaled flume for assessing swimming performance. The flume uses two independent spherical-impeller pumps modulated by a microcontroller to achieve flow velocities ranging from 1 to 70 cm s-1. The microcontroller also monitors water temperature and flow velocity and sends these data to a personal computer for real-time display and storage. Incremental protocols for assessing maximal swimming speed (Umax) were developed, stored in custom software, and then uploaded to the microcontroller in order to assess performance of larval (14, 21, 28 dpf), juvenile (35, 42 dpf), and adult (8, 22 month) zebrafish. The flume had sufficient range and sensitivity to detect developmental changes in Umax of larvae and juveniles, an 18-24% faster Umax of adult males vs. females, and a 14-20% age-related reduction in Umax for the oldest zebrafish. Detailed information is provided to assemble and operate this low-cost, versatile, and reliable tool for assessing zebrafish swimming performance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019105PMC
December 2018

RNA helicase, DDX27 regulates skeletal muscle growth and regeneration by modulation of translational processes.

PLoS Genet 2018 03 8;14(3):e1007226. Epub 2018 Mar 8.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Gene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in skeletal muscle remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for skeletal muscle growth and regeneration. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts during myogenesis. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression in skeletal muscles.
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http://dx.doi.org/10.1371/journal.pgen.1007226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843160PMC
March 2018

Association of Leptin: Adiponectin ratio and metabolic risk markers in postmenopausal women.

Immunol Lett 2018 04 2;196:63-67. Epub 2018 Feb 2.

Department of Physiology, King George's Medical University, Lucknow, India. Electronic address:

Leptin and adiponectin play an important role in the regulation of body weight and energy homeostasis. The purpose of the present study was to ascertain the relationship between leptin to adiponectin ratio (L:A) and metabolic risk factors in postmenopausal women.This is a cross sectional case-control study. A total of 523 postmenopausal women were recruited for the study 270 postmenopausal women with metabolic syndrome and 253 apparently healthy control postmenopausal women without metabolic syndrome. Biochemical and Anthropometrical parameters were measured. Leptin and adiponectin levels were determined by sandwich enzyme-linked immunosorbent assay, insulin resistance was determined by homeostasis model assessment for insulin resistance (HOMA-IR). Results of this study indicate that leptin (15.92 ± 10.50 vs.9.43 ± 4.39 pg/ml, p < 0.001), L:A ratio (1.08 ± 1.06 vs.0.42 ± 0.38 pg/ml, p < 0.001), HOMA-IR, the lipid profile, and other metabolic risk factors (waist circumference (WC), waist-to-hip ratio(WHR), body mass index((BMI)), fasting plasma glucose (FPG) level and fasting plasma insulin(FPI)) were significantly higher but HDL, HDL/LDL and adiponectin level (20.55 ± 10.76 vs.30.08 ± 13.08 pg/ml, p < 0.001)were significantly lower in postmenopausal women with metabolic syndrome than in women without the syndrome (p < 0.001). Further, in postmenopausal women with metabolic syndrome, L: A ratio was significantly positive (p < 0.05 or p < 0.001) correlated with WC, BMI, WHR, TG, FPG, TC/HDL, LDL/HDL, FPI and HOMA-IR (p < 0.01), and negatively correlated with HDL and HDL/LDL (p < 0.001). Conclusively L: A ratio was found to be significantly associated with central obesity and other metabolic risk factors so that high L:A ratio may act as a diagnostic marker for metabolic syndrome in postmenopausal women.
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http://dx.doi.org/10.1016/j.imlet.2018.01.008DOI Listing
April 2018

Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Clinical Practice Guideline.

J Glob Oncol 2017 Oct 12;3(5):635-657. Epub 2016 Oct 12.

, PATH, Seattle, WA; , Global Coalition Against Cervical Cancer, Albert Einstein College of Medicine, Arlington; , American Society of Clinical Oncology, Alexandria, VA; , University of Cape Town, Cape Town, South Africa; , V Care; , Tata Memorial Center, Mumbai, India; , Harvard T.H. Chan School of Public Health, Boston, MA; , PanAmerican Health Organization, Washington, DC; , Uganda Women's Health Initiative, Kampala, Uganda; , International Network for Cancer Treatment and Research, Dar Es Salaam, Tanzania; , Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; , University of Melbourne, Melbourne, Victoria, Australia; , International Agency for Research on Cancer, Lyon, France; , Queen Mary, University of London, London, United Kingdom; and , The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: To provide resource-stratified, evidence-based recommendations on the secondary prevention of cervical cancer globally.

Methods: ASCO convened a multidisciplinary, multinational panel of oncology, primary care, epidemiology, health economic, cancer control, public health, and patient advocacy experts to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, a formal consensus-based process, and a modified ADAPTE process to adapt existing guidelines were conducted. Other experts participated in formal consensus.

Results: Seven existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Four systematic reviews plus cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement.

Recommendations: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies by setting are as follows: maximal: ages 25 to 65, every 5 years; enhanced: ages 30 to 65, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: ages 30 to 49, every 10 years; and basic: ages 30 to 49, one to three times per lifetime. For basic settings, visual assessment is recommended as triage; in other settings, genotyping and/or cytology are recommended. For basic settings, treatment is recommended if abnormal triage results are present; in other settings, colposcopy is recommended for abnormal triage results. For basic settings, treatment options are cryotherapy or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure (or ablation) is recommended. Twelve-month post-treatment follow-up is recommended in all settings. Women who are HIV positive should be screened with HPV testing after diagnosis and screened twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information can be found at www.asco.org/rs-cervical-cancer-secondary-prev-guideline and www.asco.org/guidelineswiki.It is the view of of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement, but not replace, local guidelines.
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http://dx.doi.org/10.1200/JGO.2016.006577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646891PMC
October 2017

An increase level of acylation stimulating protein is correlated with metabolic risk markers in North Indian obese women.

Diabetes Metab Syndr 2017 Dec 10;11 Suppl 2:S797-S801. Epub 2017 Jun 10.

Department of Obstetrics and Gynecology, King George Medical University, Lucknow, India.

Background And Aims: The present study was to investigate the association between serum acylation stimulating protein (ASP) level with metabolic risk factors in North Indian obese women.

Methods: This is a case control study, total n=322 women aged between 20 and 45 years (n=162 with metabolic syndrome & n=160 without metabolic syndrome) were recruited for the study according to National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Serum ASP level were determined by enzyme linked immunosorbent assay.

Results: Results indicated that circulating ASP and other metabolic risk factors (waist circumference, triglycerides, fasting plasma glucose etc) were significantly higher in women with metabolic syndrome (WmetS) than in women without syndrome (WometS) (p<0.001). Furthermore circulating ASP was significantly higher possitively correlated with waist circumference (r=0.51, p<0.001), triglyceride (r=0.56, p<0.001), glucose (r=0.70, p<0.001), and negatively correlated with high density lipoprotein(r=-0.56, p<0.001) in women with metabolic syndrome.

Conclusions: Conclusively circulating ASP was found to be significantly associated with hyperlipidemia, obesity and obesity related disorders in North Indian obese women.
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http://dx.doi.org/10.1016/j.dsx.2017.06.001DOI Listing
December 2017

Clinical characteristics of COPD patients with tidal expiratory flow limitation.

Int J Chron Obstruct Pulmon Dis 2017 22;12:1503-1506. Epub 2017 May 22.

Medicines Evaluation Unit, Manchester.

We have used impulse oscillometry to identify COPD patients with tidal expiratory flow limitation (EFL), which is a measurement related to small airway disease. We report that 37.4% of COPD patients had EFL; these patients had multiple clinical characteristics of more severe disease including lower forced expiratory volume in 1 second values, greater hyperinflation, reduced exercise performance, and increased small airway impairment. We highlight that EFL can be used to identify a subgroup of COPD patients with distinct characteristics associated with small airway disease.
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http://dx.doi.org/10.2147/COPD.S137865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446959PMC
March 2018

L:A ratio, Insulin resistance and metabolic risk in women with polycystic ovarian syndrome.

Diabetes Metab Syndr 2017 Dec 10;11 Suppl 2:S697-S701. Epub 2017 May 10.

Department of Physiology, King George Medical University, Lucknow, India. Electronic address:

Background And Aims: The plasma leptin-adiponectin ratio (L:A) has been suggested as a one of the potentially independent predictor of metabolic risk and Insulin resistance in women with polycystic ovarian syndrome (PCOS).

Methods: This is a case-control study, total 439 female subjects, comprises in to two group 223 cases (PCOS) and 216 control (non-PCOS women) according to their clinical characteristics. Further both case and control group were sub-grouped in PCOS and non-PCOS with metabolic syndrome (wMetS) and without metabolic syndrome (woMetS) as per National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Anthropometrical measurements and biochemical analysis were done. Leptin and adiponectin level were estimated by enzyme-linked immunosorbent assay.

Results: Results indicated that SAD, WHR, BMI, BP, lipid profile, FPG, fasting plasma insulin, IR (HOMA-IR), leptin and L:A ratio were significantly higher (p=<0.001) in PCOS women compare to non PCOS. Furthermore anthropometrical values and level of FPG, TC, TG, Insulin, IR (HOMA-IR) and L:A ratio were significantly high (p=<0.001) in PCOS wMetS compare woMetS, however HDL (p=<0.001) and adiponectin level (p=<0.001) were significantly low. The same trend was also found in comparison between with and without MetS among non-PCOS women. The correlation between L:A Ratio with different metabolic risk markers, L:A ratio was positively significant with SAD (r=0.97, p <0.001), FPG (r=0.96, p<0.001), TC (r=0.44, p<0.001), insulin (r=0.98, p<0.001), IR (r=0.97, p<0.001), Adiponectin (r=0.21, p<0.01) and negatively significant with HDL(r=-0.42, p<0.001) in PCOS wMetS whereas L:A ratio was also positively correlated with SAD, BMI, TG in PCOS woMetS.

Conclusions: Study concluded L:A ratio may be one of the potential biomarker for metabolic syndrome and insulin resistance which is independent for presence of PCOS disease.
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http://dx.doi.org/10.1016/j.dsx.2017.05.001DOI Listing
December 2017

Blood and sputum eosinophils in COPD; relationship with bacterial load.

Respir Res 2017 05 8;18(1):88. Epub 2017 May 8.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, M23 9QZ, UK.

Background: Sputum and blood eosinophil counts predict corticosteroid effects in COPD patients. Bacterial infection causes increased airway neutrophilic inflammation. The relationship of eosinophil counts with airway bacterial load in COPD patients is uncertain. We tested the hypothesis that bacterial load and eosinophil counts are inversely related.

Methods: COPD patients were seen at stable state and exacerbation onset. Sputum was processed for quantitative polymerase chain reaction detection of the potentially pathogenic microorganisms (PPM) H. influenzae, M. catarrhalis and S. pneumoniae. PPM positive was defined as total load ≥1 × 10copies/ml. Sputum and whole blood were analysed for differential cell counts.

Results: At baseline, bacterial counts were not related to blood eosinophils, but sputum eosinophil % was significantly lower in patients with PPM positive compared to PPM negative samples (medians: 0.5% vs. 1.25% respectively, p = 0.01). Patients with PPM positive samples during an exacerbation had significantly lower blood eosinophil counts at exacerbation compared to baseline (medians: 0.17 × 10/L vs. 0.23 × 10/L respectively, p = 0.008), while no blood eosinophil change was observed with PPM negative samples.

Conclusions: These findings indicate an inverse relationship between bacterial infection and eosinophil counts. Bacterial infection may influence corticosteroid responsiveness by altering the profile of neutrophilic and eosinophilic inflammation.
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http://dx.doi.org/10.1186/s12931-017-0570-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422866PMC
May 2017

A novel early onset phenotype in a zebrafish model of merosin deficient congenital muscular dystrophy.

PLoS One 2017 27;12(2):e0172648. Epub 2017 Feb 27.

Departments of Pediatrics and Molecular Genetics, University of Toronto, Toronto, Canada.

Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening. Our goal in this study was to elucidate novel, early onset abnormalities in the candyfloss (caf) zebrafish, a model of MDC1A. We uncovered and characterize abnormalities in spontaneous coiling, the earliest motor movement in the zebrafish, as a fully penetrant change specific to caf mutants that is ideal for future drug testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172648PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328290PMC
September 2017

Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients.

BMC Pulm Med 2017 02 20;17(1):42. Epub 2017 Feb 20.

Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, University of Manchester, Manchester, UK.

Background: The characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression.

Methods: Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used.

Results: One hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B.

Conclusions: Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.
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http://dx.doi.org/10.1186/s12890-017-0384-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319137PMC
February 2017

Involvement of general public in biomedical research.

Perspect Clin Res 2016 Oct-Dec;7(4):152-155

TMC Research Administrative Council (TRAC), Tata Memorial Centre, Mumbai, India.

Biomedical research is crucial for any country's progress and the health of its ethnic population. This effort needs to be sustained and well supported for it to bear optimum results. The major stakeholders in medical research are the general public, patients, researchers, physicians (and medical institutions), the pharmaceutical industry, regulatory authorities, and the government. Much of the pressure to perform cutting edge research in developed countries is driven by the general public; however, this has been conspicuous by its absence in India. This is largely due to misconceptions that medical research in developing countries is an experimental exercise using human beings as guinea pigs, primarily benefiting only the pharmaceutical industry and a general lack of awareness about the importance of original research within the country. This editorial addresses various issues related to public involvement in biomedical research and suggests the need for solutions and imperative remedial measures.
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http://dx.doi.org/10.4103/2229-3485.192029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079086PMC
November 2016