Publications by authors named "Ashutosh Kumar"

472 Publications

Coil assisted glue embolization to improve safety and accuracy in endovascular management of Vein of Galen patients.

Clin Neurol Neurosurg 2021 Apr 21;205:106652. Epub 2021 Apr 21.

Army Hospital (Referral & Research), Delhi Cantt, New Delhi 110010, India. Electronic address:

Background: Vein of Galen malformation (VOGM) patients present in neonatal age with cardiac failure or significant neurologic consequences. The most established method of treatment has been transarterial embolization with high concentration glue (N-Butyl Cyano Acrylate) which may be difficult to control due to very high flow rates and may migrate to the venous side with undesirable consequences. We describe our experience in four patients in whom initial coil placement in prominent feeding arteries helped inflow reduction thereby facilitating controlled glue injection with a good result and no incidence of non-target embolization.

Materials And Methods: Four neonates who had presented during the last three years with cardiac failure were included in the study. Prominent feeders identified on imaging or DSA were treated with transarterial helical coil placement in the terminal segment just before the VOGM sac followed by controlled glue injection. The outcome was assessed by detailed clinical and imaging follow-up.

Results: A total of 10 most prominent feeders were embolized in four patients. Complete embolization of the VOGM was achieved in two patients in a single session. One patient with residual small feeders showed subsequent thrombosis of these feeders, possibly secondary to flow reduction in the sac. One patient still shows thin residual feeders but good clinical improvement and is being planned for follow-up and a second session at one year of age. No complications were observed. All patients showed immediate improvement in cardiac failure and good neurological development on follow-up. On imaging, the VOGM sac regressed completely (3 patients) or significantly in size (1 patient).

Conclusion: Planned coil placement in the terminal part of prominent feeding arteries reduced the flow and provided lattice on which glue deposits in a controlled manner without any incidence of non-target embolization in our study. This relatively less described technique increases the safety and accuracy of the endovascular treatment in VOGM patients.
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http://dx.doi.org/10.1016/j.clineuro.2021.106652DOI Listing
April 2021

Fabrication of methotrexate-loaded gold nanoconjugates and its enhanced anticancer activity in breast cancer.

3 Biotech 2021 Apr 18;11(4):175. Epub 2021 Mar 18.

Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad, Gujarat 380009 India.

Methotrexate (MTX) is known antagonist of folic acid and widely used as an anti-cancer drug. The folate receptor (FR) and reduced folate carrier are mostly responsible for internalization of methotrexate in tumor cells. Mutation in reduced folate carrier (RFC) leads to resistance against MTX in various tumor cell lines including MDA-MB-231 breast cancer cells. To overcome the resistance of MTX, folate receptor targeted nanoparticles have been commonly used for targeting breast tumors. The aim of the study is to determine the ability of methotrexate gold nanoparticles (MTX-GNPs) in the induction of apoptosis and to explore the molecular changes at genomics and proteomics level. Different assays like cell viability assay, cell cycle analysis, apoptosis, real-time PCR and western blot were carried out to evaluate the anti-cancer effect of MTX-Gold NPs on MCF-7 and MDA-MB-231 cells. Our observations demonstrated the decrease in the percent viable cells after the treatment of MTX-GNPs, with an arrest in cell cycle at G0/G1 phase and a significant increase in apoptotic cell population and loss of mitochondrial membrane potential in MCF-7 and MDA-MB-231 cells. Folate receptor targeted MTX-GNPs showed significant cellular uptake in breast cancer cells along with significant down-regulation in expression of anti-apoptotic gene (Bcl-2) and up-regulation in expression of pro-apoptotic genes (Bax, Caspase-3, Caspase-9, APAF-1, p53). These results unveil the increased anti-cancer effect of MTX-GNPs in cancer cells.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-02718-7.
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http://dx.doi.org/10.1007/s13205-021-02718-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973353PMC
April 2021

A case of Philadelphia chromosome-positive acute myeloid leukaemia with missense mutation R132c (c.394 c>t) and single nucleotide polymorphism rs11554137(G105G) in isocitrate dehydrogenase 1 gene.

Natl Med J India 2020 May-Jun;33(3):146-148

Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, India.

Acute myeloid leukaemia (AML) is a heterogeneous disease due to its variable clinical, morphological and genetic features. New chromosomal and molecular abnormalities are being studied to evaluate novel treatment options and prognostic implications. We report a patient with AML who was Philadelphia chromosome-positive along with IDH1R132 mutation and SNP rs11554137(IDH1). Due to limited reports regarding these aberrations in patients with AML, there is no consensus regarding their prognostic implications. To the best of our knowledge, the presence of Philadelphia chromosome, IDH1R132 and SNP rs11554137 in a single AML patient with good prognosis is a novel finding.
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http://dx.doi.org/10.4103/0970-258X.314004DOI Listing
April 2021

Lean-Docking: Exploiting Ligands' Predicted Docking Scores to Accelerate Molecular Docking.

J Chem Inf Model 2021 Apr 16. Epub 2021 Apr 16.

Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka 820-8502, Japan.

In structure-based virtual screening (SBVS), a binding site on a protein structure is used to search for ligands with favorable nonbonded interactions. Because it is computationally difficult, docking is time-consuming and any docking user will eventually encounter a chemical library that is too big to dock. This problem might arise because there is not enough computing power or because preparing and storing so many three-dimensional (3D) ligands requires too much space. In this study, however, we show that quality regressors can be trained to predict docking scores from molecular fingerprints. Although typical docking has a screening rate of less than one ligand per second on one CPU core, our regressors can predict about 5800 docking scores per second. This approach allows us to focus docking on the portion of a database that is predicted to have docking scores below a user-chosen threshold. Herein, usage examples are shown, where only 25% of a ligand database is docked, without any significant virtual screening performance loss. We call this method "lean-docking". To validate lean-docking, a massive docking campaign using several state-of-the-art docking software packages was undertaken on an unbiased data set, with only wet-lab tested active and inactive molecules. Although regressors allow the screening of a larger chemical space, even at a constant docking power, it is also clear that significant progress in the virtual screening power of docking scores is desirable.
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http://dx.doi.org/10.1021/acs.jcim.0c01452DOI Listing
April 2021

Craniovertebral junction instability in Larsen syndrome: An institutional series and review of literature.

J Craniovertebr Junction Spine 2020 Oct-Dec;11(4):276-286. Epub 2020 Nov 26.

Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Objective: Larsen syndrome (LS) is characterized by osteo-chondrodysplasia, multiple joint dislocations, and craniofacial abnormalities. Symptomatic myelopathy is attributed to C1-C2 instability and sub-axial cervical kyphosis. In this article, we have analyzed the surgical outcome after posterior fixation in LS with craniovertebral junction instability.

Methods: Ten symptomatic pediatric patients, operated between 2011 and 2019, were included, and the clinical outcome was assessed by Nurick grade, neurological improvement, and complications. The requirement of anti-spasticity drugs, the degree of bony fusion, and restriction of neck movement were also noted. At last follow-up, patient satisfaction score (PSS) and back to school status were studied. We also reviewed the literature and categorized two types of presentation of reported LS patients and discussed the pattern of disease progression among both.

Results: Ten patients, age range 1.5-16 years, underwent 12 surgeries (6 C1-C2 fixation, 4 long-segment posterior cervical fixation, and 2 trans-oral decompressions as the second stage); the mean follow-up was 23 (range, 6-86 months). All the ten patients in our study had the characteristic "dish-" like face and nine patients had acral anomalies. The median Nurick grade improved from preoperative (median = 4) to follow-up (median = 3). The requirement of anti-spasticity drugs decreased in seven patients and the neck-pain improved in nine patients. The median satisfaction at follow-up was good (median PSS = 2); five patients were going back to school.

Conclusion: Craniovertebral junction instability in LS is rare and surgically challenging. Early posterior fixation showed a promising outcome with a halt in the disease progression.
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http://dx.doi.org/10.4103/jcvjs.JCVJS_164_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019120PMC
November 2020

Remembering William Hunter (1718-1783) the Pioneer in Obstetrics: A Prelude to Sestercentennial Anniversary of .

J Obstet Gynaecol India 2021 Feb 16;71(1):97-100. Epub 2019 Oct 16.

Department of Anatomy, 3rd Floor, Academic Building, All India Institute of Medical Sciences, Phulwarisharif, Patna, Bihar 801507 India.

William Hunter (1718-1783) was a Scottish anatomist and physician. He started his career as a man midwife and went on to become the leading obstetrician in London. He prepared anatomically dissected specimens depicting anatomy of gravid uterus and undelivered fetus with placenta in different stages of gestation. Hunter compiled illustrations prepared from these specimens with his clinical notes and published his treatise in 1774. This article is a tribute to William Hunter as we approach the 250th year of publication of his work which is a significant milestone in the history of obstetrics and its practice.
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http://dx.doi.org/10.1007/s13224-019-01283-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960833PMC
February 2021

Crystal Structure and Structure-Based Discovery of Inhibitors of the Nematode Chitinase Cht1.

J Agric Food Chem 2021 Mar 10;69(11):3519-3526. Epub 2021 Mar 10.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Nematode chitinases play crucial roles in various processes of the nematode lifecycle, including hatching, molting, and reproduction. Small-molecule inhibitors of nematode chitinases have shown promise for controlling nematode pests. However, the lack of structural information makes it a challenge to develop nematicides targeting nematode chitinases. Here, we report the first crystal structure of a representative nematode chitinase, that of Cht1 from the model nematode , to a 1.7 Å resolution. Cht1 is a highly conserved chitinase among nematodes, and structural comparison with other chitinases revealed that Cht1 has a classical TIM-barrel fold with some subtle structural differences in the substrate-binding cleft. Benefiting from the obtained crystal structure, we identified a series of novel inhibitors by hierarchical virtual screening. Analysis of the structure-activity relationships of these compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities. This work gives an insight into the structural features of nematode chitinases and provides a solid basis for the development of inhibitors.
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http://dx.doi.org/10.1021/acs.jafc.1c00162DOI Listing
March 2021

A Comprehensive Review of COVID-19 Associated Neurological Manifestations.

S D Med 2020 Dec;73(12):569-571

Department of Internal Medicine, Penn State Milton S. Hershey Medical Center.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 utilizes the angiotensin-converting enzyme 2 (ACE-2) receptor of cells in order to gain entry and continue infection. Recent literature has focused on acute respiratory distress syndrome (ARDS) and other associated pulmonary complications; however, only a scarce amount of literature exists on neurological complications. Such complications also pose a high morbidity in these patients. The exact pathogenesis of nervous system involvement by COVID-19 still remains poorly understood. The aim of this article is to review the neurological symptoms seen in COVID-19 infection and discuss the probable pathogenesis, management and outcome of associated neurological complications.
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December 2020

Multiomics Analysis and Systems Biology Integration Identifies the Roles of IL-9 in Keratinocyte Metabolic Reprogramming.

J Invest Dermatol 2021 Mar 3. Epub 2021 Mar 3.

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Mumbai, India. Electronic address:

IL-9‒producing T cells are present in healthy skin as well as in the cutaneous lesions of inflammatory diseases and cancers. However, the roles of IL-9 in human skin during homeostasis and in the pathogenesis of inflammatory disorders remain obscure. In this study, we examined the roles of IL-9 in metabolic reprogramming of human primary keratinocytes (KCs). High-throughput quantitative proteomics revealed that IL-9 signaling in human primary KCs disrupts the electron transport chain by downregulating multiple electron transport chain proteins. Nuclear magnetic resonance-based metabolomics showed that IL-9 also reduced the production of tricarboxylic acid cycle intermediates in human primary KCs. An integration of multiomics data with systems-level analysis using the constraint-based MitoCore model predicted marked IL-9-dependent effects on central carbohydrate metabolism, particularly in relation to the glycolytic switch. Stable isotope metabolomics and biochemical assays confirmed increased glucose consumption and redirection of metabolic flux toward lactate by IL-9. Functionally, IL-9 inhibited ROS production by IFN-γ and promoted human primary KC survival by inhibiting apoptosis. In conclusion, our data reveal IL-9 as a master regulator of KC metabolic reprogramming and survival.
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http://dx.doi.org/10.1016/j.jid.2021.02.013DOI Listing
March 2021

Infant Stroke Associated With Left Atrial Thrombus and Supraventricular Tachycardia.

Child Neurol Open 2021 Jan-Dec;8:2329048X21995296. Epub 2021 Feb 16.

Department of Pediatrics, Division of Child Neurology, Penn State Health College of Medicine, Hershey, PA, USA.

We report a rare case of cardioembolic stroke in the setting of supraventricular tachycardia (SVT) in an infant. After a week of irritability, a 10-week-old male presented to the emergency department with SVT requiring treatment with adenosine. He developed right-sided hemiparesis and focal motor seizures. Imaging of the brain showed ischemic infarct in the left middle cerebral artery (MCA) territory. Echocardiogram showed a newly formed large left atrial intracardiac thrombus. A coagulopathy workup was negative. He was treated with beta-blocker and anticoagulation therapy. He had mild residual right hemiparesis. During childhood, he developed medically refractory focal epilepsy from the left hemisphere, requiring epilepsy surgery at age 10. A child presenting with sustained SVT can be at increased risk for intracardiac thrombi and stroke.
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http://dx.doi.org/10.1177/2329048X21995296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894682PMC
February 2021

The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function.

Elife 2021 Feb 25;10. Epub 2021 Feb 25.

Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States.

The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure, and blood flow. The endothelial volume-regulated anion channel (VRAC) has been proposed to be mechanosensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the leucine-rich repeat-containing protein 8a, LRRC8A (SWELL1), is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-endothelial nitric oxide synthase (eNOS) signaling under basal, stretch, and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.
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http://dx.doi.org/10.7554/eLife.61313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997661PMC
February 2021

TRPM8 channel inhibitor-encapsulated hydrogel as a tunable surface for bone tissue engineering.

Sci Rep 2021 Feb 12;11(1):3730. Epub 2021 Feb 12.

School of Biological Sciences, National Institute of Science Education and Research (NISER)-Bhubaneswar, Jatni, Khurda, 752050, Odisha, India.

A major limitation in the bio-medical sector is the availability of materials suitable for bone tissue engineering using stem cells and methodology converting the stochastic biological events towards definitive as well as efficient bio-mineralization. We show that osteoblasts and Bone Marrow-derived Mesenchymal Stem Cell Pools (BM-MSCP) express TRPM8, a Ca-ion channel critical for bone-mineralization. TRPM8 inhibition triggers up-regulation of key osteogenesis factors; and increases mineralization by osteoblasts. We utilized CMT:HEMA, a carbohydrate polymer-based hydrogel that has nanofiber-like structure suitable for optimum delivery of TRPM8-specific activators or inhibitors. This hydrogel is ideal for proper adhesion, growth, and differentiation of osteoblast cell lines, primary osteoblasts, and BM-MSCP. CMT:HEMA coated with AMTB (TRPM8 inhibitor) induces differentiation of BM-MSCP into osteoblasts and subsequent mineralization in a dose-dependent manner. Prolonged and optimum inhibition of TRPM8 by AMTB released from the gels results in upregulation of osteogenic markers. We propose that AMTB-coated CMT:HEMA can be used as a tunable surface for bone tissue engineering. These findings may have broad implications in different bio-medical sectors.
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http://dx.doi.org/10.1038/s41598-021-81041-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881029PMC
February 2021

Modified tamarind kernel polysaccharide-based matrix alters neuro-keratinocyte cross-talk and serves as a suitable scaffold for skin tissue engineering.

Mater Sci Eng C Mater Biol Appl 2021 Feb 4;121:111779. Epub 2020 Dec 4.

School of Biotechnology, Kalinga Institute of Industrial Technology, Patia, Bhubaneswar 751024, India; School of Chemical Technology, Kalinga Institute of Industrial Technology, Patia, Bhubaneswar 751024, India. Electronic address:

Advanced technologies like skin tissue engineering are requisite of various disorders where artificially synthesized materials need to be used as a scaffold in vivo, which in turn can allow the formation of functional skin and epidermal layer with all biological sensory functions. In this work, we present a set of hydrogels which have been synthesized by the method utilizing radical polymerization of a natural polymer extracted from kernel of Tamarindus indica, commonly known as Tamarind Kernel Powder (TKP) modified by utilizing the monomer acrylic acid (AA) in different mole ratios. These materials are termed as TKP: AA hydrogels and characterized by Atomic Force Microscopy (AFM), surface charge, and particle size distribution using Dynamic Light Scattering measurements. These materials are biocompatible with mouse dermal fibroblasts (NIH- 3T3) and human skin keratinocytes (HaCaT), as confirmed by MTT and biocompatibility assays. These TKP: AA hydrogels do not induce unwanted ROS signaling as confirmed by mitochondrial functionality determined by DCFDA staining, Mitosox imaging, and measuring the ATP levels. We demonstrate that in the co-culture system, TKP: AA allows the establishment of proper neuro-keratinocyte contact formation, suggesting that this hydrogel can be suitable for developing skin with sensory functions. Skin corrosion analysis on SD rats confirms that TKP: AA is appropriate for in vivo applications as well. This is further confirmed by in vivo compatibility and toxicity studies, including hemocompatibility and histopathology of liver and kidney upon direct introduction of hydrogel into the body. We propose that TKP: AA (1: 5) offers a suitable surface for skin tissue engineering with sensory functions applicable in vitro, in vivo, and ex vivo. These findings may have broad biomedical and clinical importance.
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http://dx.doi.org/10.1016/j.msec.2020.111779DOI Listing
February 2021

Human islet amyloid polypeptide (hIAPP) - a curse in type II diabetes mellitus: insights from structure and toxicity studies.

Biol Chem 2021 01 4;402(2):133-153. Epub 2020 Sep 4.

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, Maharashtra, India.

The human islet amyloid polypeptide (hIAPP) or amylin, a neuroendocrine peptide hormone, is known to misfold and form amyloidogenic aggregates that have been observed in the pancreas of 90% subjects with Type 2 Diabetes Mellitus (T2DM). Under normal physiological conditions, hIAPP is co-stored and co-secreted with insulin; however, under chronic hyperglycemic conditions associated with T2DM, the overexpression of hIAPP occurs that has been associated with the formation of amyloid deposits; as well as the death and dysfunction of pancreatic β-islets in T2DM. Hitherto, various biophysical and structural studies have shown that during this process of aggregation, the peptide conformation changes from random structure to helix, then to β-sheet, subsequently to cross β-sheets, which finally form left-handed helical aggregates. The intermediates, formed during this process, have been shown to induce higher cytotoxicity in the β-cells by inducing cell membrane disruption, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, islet inflammation, and DNA damage. As a result, several research groups have attempted to target both hIAPP aggregation phenomenon and the destabilization of preformed fibrils as a therapeutic intervention for T2DM management. In this review, we have summarized structural aspects of various forms of hIAPP viz. monomer, oligomers, proto-filaments, and fibrils of hIAPP. Subsequently, cellular toxicity caused by toxic conformations of hIAPP has been elaborated upon. Finally, the need for performing structural and toxicity studies to fill in the gap between the structural and cellular aspects has been discussed.
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http://dx.doi.org/10.1515/hsz-2020-0174DOI Listing
January 2021

Myricetin protects pancreatic β-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function.

Biol Chem 2021 01 16;402(2):179-194. Epub 2020 Sep 16.

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, 400076Mumbai, Maharashtra, India.

The aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)-a hormone that is co-secreted with insulin from pancreatic β-cells-into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of β-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like ). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.
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http://dx.doi.org/10.1515/hsz-2020-0176DOI Listing
January 2021

Transients generate memory and break hyperbolicity in stochastic enzymatic networks.

J Chem Phys 2021 Jan;154(3):035101

Department of Chemistry, Indian Institute of Technology, Madras, Chennai 600036, India.

The hyperbolic dependence of catalytic rate on substrate concentration is a classical result in enzyme kinetics, quantified by the celebrated Michaelis-Menten equation. The ubiquity of this relation in diverse chemical and biological contexts has recently been rationalized by a graph-theoretic analysis of deterministic reaction networks. Experiments, however, have revealed that "molecular noise"-intrinsic stochasticity at the molecular scale-leads to significant deviations from classical results and to unexpected effects like "molecular memory," i.e., the breakdown of statistical independence between turnover events. Here, we show, through a new method of analysis, that memory and non-hyperbolicity have a common source in an initial, and observably long, transient peculiar to stochastic reaction networks of multiple enzymes. Networks of single enzymes do not admit such transients. The transient yields, asymptotically, to a steady-state in which memory vanishes and hyperbolicity is recovered. We propose new statistical measures, defined in terms of turnover times, to distinguish between the transient and steady-states and apply these to experimental data from a landmark experiment that first observed molecular memory in a single enzyme with multiple binding sites. Our study shows that catalysis at the molecular level with more than one enzyme always contains a non-classical regime and provides insight on how the classical limit is attained.
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http://dx.doi.org/10.1063/5.0031368DOI Listing
January 2021

Expression of SARS-CoV-2 Host Cell Entry Factors in Immune System Components of Healthy Individuals and Its Relevance for COVID-19 Immunopathology.

Viral Immunol 2021 Jan 21. Epub 2021 Jan 21.

Etiologically Elusive Disorders Research Network (EEDRN), New Delhi, India.

Intense immunological dysregulation including immune cell lesions has been characteristically observed in severe cases of coronavirus disease-2019 (COVID-19), for which molecular mechanisms are not properly understood. A study of physiological expressions of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) host cell entry-related factors in immune system components may help explain molecular mechanisms involved in COVID-19 immunopathology. We analyzed transcriptomic and proteomic expression metadata for SARS-CoV-2 host cell entry receptor and entry associated proteases (, , and ) across immune system components including the blood lineage cells. was not detected in any of the studied immune cell components; however, varying transcriptomic and proteomic expressions were observed for , , and . Nondetectable expressions of SARS-CoV-2 host cell entry receptor in immune system components or blood lineage cells indicate it does not mediate immune cell lesions in COVID-19. Alternative mechanisms need to be explored for COVID-19 immunopathogenesis.
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http://dx.doi.org/10.1089/vim.2020.0277DOI Listing
January 2021

Dual mutation (MTHFR A1298C with PAI (4G) mutation) manifesting with bilateral lower limb gangrene in a neonate.

BMJ Case Rep 2021 Jan 18;14(1). Epub 2021 Jan 18.

Department of Pediatrics, Army Hospital Research and Referral, New Delhi, India.

Neonates are at highest risk of thrombosis among paediatric patients. The relative prothrombotic state in a well neonate is compensated by other factors preventing spontaneous thrombosis; however, in a neonate with genetic predisposition, the balance is tilted predisposing them to a life-threatening thrombotic episode. We describe a rare case of methylenetetrahydrofolate reductase A1298C (homozygous) mutation along with plasminogen activator inhibitor (4G) mutation in a neonate who developed bilateral lower limb gangrene following thrombosis of the iliac vessels without any triggering factor. The neonate underwent thrombectomy as debulking measure along with thrombolytic therapy followed by unfractionated heparin and low-molecular-weight heparin which is still being continued along with oral aspirin. The neonate had to undergo amputation of both the involved lower limbs in view of dry gangrene. This case highlights that the dual mutations causing the prothrombotic state predispose the individual to the spontaneous life-threatening thrombotic episode as compared with the single mutation.
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http://dx.doi.org/10.1136/bcr-2020-237340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816929PMC
January 2021

Thermal conductivity of PbTe-CoSb bulk polycrystalline composite: role of microstructure and interface thermal resistance.

Dalton Trans 2021 Feb;50(4):1261-1273

AGH University of Science and Technology, Faculty of Materials Science and Ceramics, Al. A. Mickiewicza 30, 30-059 Krakow, Poland.

Systematic experimental and theoretical research on the role of microstructure and interface thermal resistance on the thermal conductivity of the PbTe-CoSb3 bulk polycrystalline composite is presented. In particular, the correlation between the particle size of the dispersed phase and interface thermal resistance (Rint) on the phonon thermal conductivity (κph) is discussed. With this aim, a series of PbTe-CoSb3 polycrystalline composite materials with different particle sizes of CoSb3 was prepared. The structural (XRD) and microstructural analysis (SEM/EDXS) confirmed the intended chemical and phase compositions. Acoustic impedance difference (ΔZ) was determined from measured sound velocities in PbTe and CoSb3 phases. It is shown that κph of the composite may be reduced when particle size of the dispersed phase (CoSb3) is smaller than the critical value of ∼230 nm. This relationship was concluded to be crucial for controlling the heat transport phenomena in composite thermoelectric materials. The selection of the components with different elastic properties (acoustic impedance) and particle size smaller than Kapitza radius leads to a new direction in the engineering of composite TE materials with designed thermal properties.
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http://dx.doi.org/10.1039/d0dt03752dDOI Listing
February 2021

Monitoring size and oligomeric-state distribution of therapeutic mAbs by NMR and DLS: Trastuzumab as a case study.

J Pharm Biomed Anal 2021 Feb 13;195:113841. Epub 2020 Dec 13.

Department of Chemical Engineering, Indian Institute of Technology, 110016, Hauz Khas, India. Electronic address:

Monoclonal antibodies (mAbs) are the modalities of choice for immunotherapy. This class of products are known to exhibit considerable heterogeneity with respect to size, aggregation states, and charge. This makes it challenging for biopharmaceutical manufacturers, in particular biosimilar producers, to maintain consistency in product quality. In order to fingerprint these biotherapeutic products, multiple, high-resolution analytical tools are used to characterize the numerous critical quality attributes. Recently, there has been growing interest in enhancing adaptability of 1D and 2D NMR platforms for characterization of higher order structure with emphasis on 1D H, 2D H-N and H-C NMR experiments at natural abundance. In this communication, we report the applicability of 2D-DOSY NMR for quantification of colloidal diffusivities, namely diffusion coefficient (and associated hydrodynamic radius) for monomeric IgG1 mAb formulations at physiological conditions. Similarity assessment has been performed for trastuzumab originator (multiple batches) and marketed biosimilars to showcase the applicability of this approach. While dynamic light scattering measurements are known to be sensitive to presence of larger particles with a concentration dependence for estimation of colloidal diffusivities, size estimated by NMR experiments was found to be more in agreement with the computational hydrodynamic size estimations derived from the published crystal structures of intact mAb at formulation concentration.
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http://dx.doi.org/10.1016/j.jpba.2020.113841DOI Listing
February 2021

A macroscopic salivary gland and a potential organ or simply tubarial sero-mucinous glands?

Radiother Oncol 2021 01 24;154:324-325. Epub 2020 Dec 24.

Department of Anatomy, All India Institute of Medical Sciences (AIIMS), Patna, India. Electronic address:

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http://dx.doi.org/10.1016/j.radonc.2020.12.016DOI Listing
January 2021

Critical review of photocatalytic disinfection of bacteria: from noble metals- and carbon nanomaterials-TiO composites to challenges of water characteristics and strategic solutions.

Sci Total Environ 2021 Mar 4;758:143953. Epub 2020 Dec 4.

Department of Civil and Environmental Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China. Electronic address:

This critical review covers ways to improve TiO-based photocatalysts, how water characteristics may affect photocatalytic disinfection, and strategies to tackle the challenges arising from water characteristics. Photocatalysis has shown much promise in the disinfection of water/wastewater, because photocatalysis does not produce toxic by-products, and is driven by green solar energy. There are however several drawbacks that are curbing the prevalence of photocatalytic disinfection applications: one, the efficiency of photocatalysts may limit popular utilization; two, the water characteristics may present some challenges to the process. TiO-based photocatalysts may be readily improved if composited with noble metals or carbon nanomaterials. Noble metals give TiO-based composites a higher affinity for dissolved oxygen, and induce plasmonic and Schottky effects in the TiO; carbon nanomaterials with a tunable structure, on the other hand, give the composites an improved charge carrier separation performance. Other than photocatalyst materials, the characteristics of water/wastewater is another crucial factor in the photocatalysis process. Also examined in this review are the crucial impacts that water characteristics have on photocatalysts and their interaction with bacteria. Accordingly, strategies to address the challenge of water characteristics on photocatalytic disinfection are explored: one, to modify the semiconductor conduction band to generate long-lifetime reactive species; two, to improve the interaction between bacteria and photocatalysts.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143953DOI Listing
March 2021

Many-Body Quantum Chemistry on Massively Parallel Computers.

Chem Rev 2021 Feb 11;121(3):1203-1231. Epub 2020 Dec 11.

Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.

The deployment of many-body quantum chemistry methods onto massively parallel high-performance computing (HPC) platforms is reviewed. The particular focus is on highly accurate methods that have become popular in predictive description of chemical phenomena, such as the coupled-cluster method. The account of relevant literature is preceded by a discussion of the modern and near-future HPC landscape and the relevant computational traits of the many-body methods, in their canonical and reduced-scaling formulations, that underlie the challenges in their HPC realization.
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http://dx.doi.org/10.1021/acs.chemrev.0c00006DOI Listing
February 2021

Identification of a Selective RelA Inhibitor Based on DSE-FRET Screening Methods.

Int J Mol Sci 2020 Nov 30;21(23). Epub 2020 Nov 30.

Department of Cellular and Molecular Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological functions, including tumorigenesis. Hence, NF-κB has attracted attention as a target factor for cancer treatment, leading to the development of several inhibitors. However, existing NF-κB inhibitors do not discriminate between its subunits, namely, RelA, RelB, cRel, p50, and p52. Conventional methods used to evaluate interactions between transcription factors and DNA, such as electrophoretic mobility shift assay and luciferase assays, are unsuitable for high-throughput screening (HTS) and cannot distinguish NF-κB subunits. We developed a HTS method named DNA strand exchange fluorescence resonance energy transfer (DSE-FRET). This assay is suitable for HTS and can discriminate a NF-κB subunit. Using DSE-FRET, we searched for RelA-specific inhibitors and verified RelA inhibition for 32,955 compounds. The compound A55 (2-(3-carbamoyl-6-hydroxy-4-methyl-2-oxopyridin-1(2H)-yl) acetic acid) selectively inhibited RelA-DNA binding. We propose that A55 is a seed compound for RelA-specific inhibition and could be used in clinical applications.
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http://dx.doi.org/10.3390/ijms21239150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734590PMC
November 2020

Relevance of SARS-CoV-2 related factors ACE2 and TMPRSS2 expressions in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients.

Med Hypotheses 2020 Nov 13;144:110271. Epub 2020 Sep 13.

Etiologically Elusive Disorders Research Network (EEDRN), New Delhi, India; Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, USA.

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Based on the human tissue specific distribution of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 and other supportive evidence from the literature, we hypothesize that SARS-CoV-2 host cell entry receptor-ACE2 based mechanism in GI tissue may be involved in COVID-19 (i) in the pathogenesis of digestive symptoms, (ii) in increased diabetic complications, (iii) in disease recurrence.
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http://dx.doi.org/10.1016/j.mehy.2020.110271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487155PMC
November 2020

Role of surface functional groups of hydrogels in metal adsorption: From performance to mechanism.

J Hazard Mater 2021 Apr 4;408:124463. Epub 2020 Nov 4.

Department of Civil and Environmental Engineering, The Hong Kong University of Science and Technology, Hong Kong, China; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China. Electronic address:

Hydrogels have been studied quite intensively in recent decades regarding whether their metal adsorption abilities may be modified or even enhanced via functionalization (i.e., functionalizing the surfaces of hydrogels with specific functional groups). Studies have found that functionalizing hydrogels can in fact give them higher adsorptive power. This enhanced adsorptive performance is articulated in this paper through critically reviewing more than 120 research articles in such terms as the various techniques of synthesizing functionalized hydrogels, the roles that specific functional groups play on adsorption performance, selectivity, reusability, as well as on adsorption mechanism. Moreover, this critical review offers insight into future designs of functionalized hydrogels with specific metal adsorption capabilities.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124463DOI Listing
April 2021

A Comprehensive Review of Neurologic Manifestations of COVID-19 and Management of Pre-existing Neurologic Disorders in Children.

J Child Neurol 2021 03 28;36(4):324-330. Epub 2020 Oct 28.

Department of Pediatrics and Neurology, 12311Penn State Health Milton Hershey Medical Center, Hershey, PA, USA.

Since the first reports of SARS-CoV-2 infection from China, multiple studies have been published regarding the epidemiologic aspects of COVID-19 including clinical manifestations and outcomes. The majority of these studies have focused on respiratory complications. However, recent findings have highlighted the systemic effects of the virus, including its potential impact on the nervous system. Similar to SARS-CoV-1, cellular entry of SARS-CoV-2 depends on the expression of ACE2, a receptor that is abundantly expressed in the nervous system. Neurologic manifestations in adults include cerebrovascular insults, encephalitis or encephalopathy, and neuromuscular disorders. However, the presence of these neurologic findings in the pediatric population is unclear. In this review, the potential neurotropism of SARS-CoV-2, known neurologic manifestations of COVID-19 in children, and management of preexisting pediatric neurologic conditions during the COVID-19 pandemic are discussed.
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http://dx.doi.org/10.1177/0883073820968995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859660PMC
March 2021

Pathogenesis guided therapeutic management of COVID-19: an immunological perspective.

Int Rev Immunol 2021 28;40(1-2):54-71. Epub 2020 Oct 28.

Etiologically Elusive Disorders Research Network (EEDRN), New Delhi, India.

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.
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http://dx.doi.org/10.1080/08830185.2020.1840566DOI Listing
April 2021

Quantum simulation of electronic structure with a transcorrelated Hamiltonian: improved accuracy with a smaller footprint on the quantum computer.

Phys Chem Chem Phys 2020 Nov 22;22(42):24270-24281. Epub 2020 Oct 22.

IBM Quantum, IBM Research - Almaden, 650 Harry Road, San Jose, CA 95120, USA.

Quantum simulations of electronic structure with a transformed Hamiltonian that includes some electron correlation effects are demonstrated. The transcorrelated Hamiltonian used in this work is efficiently constructed classically, at polynomial cost, by an approximate similarity transformation with an explicitly correlated two-body unitary operator. This Hamiltonian is Hermitian, includes no more than two-particle interactions, and is free of electron-electron singularities. We investigate the effect of such a transformed Hamiltonian on the accuracy and computational cost of quantum simulations by focusing on a widely used solver for the Schrödinger equation, namely the variational quantum eigensolver method, based on the unitary coupled cluster with singles and doubles (q-UCCSD) Ansatz. Nevertheless, the formalism presented here translates straightforwardly to other quantum algorithms for chemistry. Our results demonstrate that a transcorrelated Hamiltonian, paired with extremely compact bases, produces explicitly correlated energies comparable to those from much larger bases. For the chemical species studied here, explicitly correlated energies based on an underlying 6-31G basis had cc-pVTZ quality. The use of the very compact transcorrelated Hamiltonian reduces the number of CNOT gates required to achieve cc-pVTZ quality by up to two orders of magnitude, and the number of qubits by a factor of three.
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http://dx.doi.org/10.1039/d0cp04106hDOI Listing
November 2020

SARS-CoV-2-specific virulence factors in COVID-19.

J Med Virol 2021 03 1;93(3):1343-1350. Epub 2020 Nov 1.

Etiologically Elusive Disorders Research Network (EEDRN), New Delhi, India.

The paucity of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific virulence factors has greatly hampered the therapeutic management of patients with coronavirus disease 2019 (COVID-19). Recently, a cluster of studies appeared, which presented empirical evidence for SARS-CoV-2-specific virulence factors that can explain key elements of COVID-19 pathology. These studies unravel multiple structural and nonstructural specifics of SARS-CoV-2, such as a unique FURIN cleavage site, papain-like protease (SCoV2-PLpro), ORF3b and nonstructural proteins, and dynamic conformational changes in the structure of spike protein during host cell fusion, which give it an edge in infectivity and virulence over previous coronaviruses causing pandemics. Investigators provided robust evidence that SARS-CoV-2-specific virulence factors may have an impact on viral infectivity and transmissibility and disease severity as well as the development of immunity against the infection, including response to the vaccines. In this article, we are presenting a summarized account of the newly reported studies.
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http://dx.doi.org/10.1002/jmv.26615DOI Listing
March 2021