Publications by authors named "Priya Gupta"

89 Publications

SMMPPI: a machine learning-based approach for prediction of modulators of protein-protein interactions and its application for identification of novel inhibitors for RBD:hACE2 interactions in SARS-CoV-2.

Brief Bioinform 2021 Apr 12. Epub 2021 Apr 12.

Bioinformatics & Computational Biology research group at NII, New Delhi 110067, India.

Small molecule modulators of protein-protein interactions (PPIs) are being pursued as novel anticancer, antiviral and antimicrobial drug candidates. We have utilized a large data set of experimentally validated PPI modulators and developed machine learning classifiers for prediction of new small molecule modulators of PPI. Our analysis reveals that using random forest (RF) classifier, general PPI Modulators independent of PPI family can be predicted with ROC-AUC higher than 0.9, when training and test sets are generated by random split. The performance of the classifier on data sets very different from those used in training has also been estimated by using different state of the art protocols for removing various types of bias in division of data into training and test sets. The family-specific PPIM predictors developed in this work for 11 clinically important PPI families also have prediction accuracies of above 90% in majority of the cases. All these ML-based predictors have been implemented in a freely available software named SMMPPI for prediction of small molecule modulators for clinically relevant PPIs like RBD:hACE2, Bromodomain_Histone, BCL2-Like_BAX/BAK, LEDGF_IN, LFA_ICAM, MDM2-Like_P53, RAS_SOS1, XIAP_Smac, WDR5_MLL1, KEAP1_NRF2 and CD4_gp120. We have identified novel chemical scaffolds as inhibitors for RBD_hACE PPI involved in host cell entry of SARS-CoV-2. Docking studies for some of the compounds reveal that they can inhibit RBD_hACE2 interaction by high affinity binding to interaction hotspots on RBD. Some of these new scaffolds have also been found in SARS-CoV-2 viral growth inhibitors reported recently; however, it is not known if these molecules inhibit the entry phase.
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http://dx.doi.org/10.1093/bib/bbab111DOI Listing
April 2021

Magnetic Resonance Imaging Provides Useful Diagnostic Information Following Equivocal Ultrasound in Children With Suspected Appendicitis.

Can Assoc Radiol J 2021 Mar 1:846537121993797. Epub 2021 Mar 1.

Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.

Purpose: In Canada, ultrasonography is the primary imaging modality for children with suspected appendicitis, yet equivocal studies are common. Magnetic resonance imaging provides promise as an adjunct imaging strategy. The primary objective of this study was to determine the proportion of children with suspected appendicitis and equivocal ultrasound where magnetic resonance imaging determined a diagnosis.

Methods: A prospective consecutive cohort of children aged 5-17 years presenting to a tertiary pediatric Emergency Department with suspected appendicitis were enrolled. Participants underwent diagnostic and management strategies according to our local suspected appendicitis pathway, followed by magnetic resonance (Siemens Avanto 1.5 Tesla) imaging. Sub-specialty pediatric radiologists reported all images.

Results: Magnetic resonance imaging was performed in 101 children with suspected appendicitis. The mean age was 11.9 (SD 3.4) years and median Pediatric Appendicitis Score was 6 [IQR 4,8]. Ultrasonography was completed in 98/101 (97.0%). Of 53/98 (54.1%) with equivocal ultrasound, magnetic resonance imaging provided further diagnostic information in 41 (77.4%; 10 positive, 31 negative; 12 remained equivocal). Secondary findings of appendicitis on magnetic resonance imaging in children with equivocal ultrasound included abdominal free fluid (24, 45.3%), peri-appendiceal fluid (12, 22.6%), intraluminal appendiceal fluid (9, 17.0%), fat stranding (8, 15.1%), appendicolith (2, 3.8%), and peri-appendiceal abscess (1, 1.9%). The observed agreement between magnetic resonance imaging results and final diagnosis was 94.9% (kappa = 0.89).
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http://dx.doi.org/10.1177/0846537121993797DOI Listing
March 2021

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype.

Eur J Paediatr Neurol 2021 Mar 16;31:54-60. Epub 2021 Feb 16.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India. Electronic address:

Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.005DOI Listing
March 2021

Perceived risk, attitudes, and behavior of cigarette smokers and nicotine vapers receiving buprenorphine treatment for opioid use disorder during the COVID-19 pandemic.

Drug Alcohol Depend 2021 01 25;218:108438. Epub 2020 Nov 25.

Tobacco Research and Treatment Center, Division of General Internal Medicine Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: Cigarette smoking may increase the risk of COVID-19 complications, reinforcing the urgency of smoking cessation in populations with high smoking prevalence such as individuals with opioid use disorder (OUD). Whether the COVID-19 pandemic has altered perceptions, motivation to quit, or tobacco use among cigarette smokers and nicotine e-cigarette vapers with OUD is unknown.

Methods: A telephone survey was conducted in March-July 2020 of current cigarette smokers or nicotine vapers with OUD who were stable on buprenorphine treatment at five Boston (MA) area community health centers. The survey assessed respondents' perceived risk of COVID-19 due to smoking or vaping, interest in quitting, quit attempts and change in tobacco consumption during the pandemic.

Results: 222/520 patients (43 %) completed the survey, and 145 were asked questions related to COVID-19. Of these, 61 % smoked cigarettes only, 13 % vaped nicotine only, and 26 % were dual users. Nearly 80 % of participants believed that smoking and vaping increased their risk of COVID-19 infection or complications. Smokers with this belief reported an increased interest in quitting (AOR 4.6, 95 % CI:1.7-12.4). Overall, 49 % of smokers and 42 % of vapers reported increased interest in quitting due to the pandemic; 24 % and 20 %, respectively, reported attempting to quit since the pandemic. However, 35 % of smokers and 27 % of vapers reported increasing smoking and vaping, respectively, during the pandemic.

Conclusions: Most patients with OUD believed that smoking and vaping increased their vulnerability to COVID-19, half reported increased interest in quitting, but others reported increasing smoking and vaping during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687365PMC
January 2021

A qualitative analysis of social scientists' opinions on socioeconomic and demographic implications of the lockdown during COVID-19 in India.

J Public Aff 2020 Oct 22:e2531. Epub 2020 Oct 22.

Department of Management Amrita Vishwa Vidyapeetham Bengaluru India.

The unpredictable dynamics of COVID-19 and policies surrounding its management has triggered severe debates and discussions among every section of society. There have been similarities as well as differences in opinions regarding spread of the disease, the lockdown, its implementations and impacts. This qualitative study attempts to identify and understand the emerging pattern within the opinions of 16 social scientists from eminent institutes with rich socioeconomic and demographic research experience. Several key themes emerged from this study. While it is opined that the lockdown initially slowed down the spread of virus among Indian population, it continues to surge exponentially. Economy faced extreme hardship because of this extensive and abrupt national lockdown. State-wise variation in the COVID-19 scenario is noticed and the reason is attributed to the strictness of implementation of the lockdown by the respective state governments. However, a lockdown in phases is suggested that could have averted the economic crisis. Small businesses were the hardest hit. Migrant workers were not given deserved attention and support in terms of their travel to their natives, health or financial sustenance during the lockdown. The bailout has not been timely and enough thereby creating a group of new poor. From the opinions it emerges that the policy measures intended to revive back the micro, small and medium scale enterprises may not bring short-term solution pertaining to the labor crisis. Relaxation of lockdown also calls for stringent awareness generation among general population about health and hygiene maintenance to avoid further spread of COVID-19.
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http://dx.doi.org/10.1002/pa.2531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645948PMC
October 2020

Impact of Microbiota: A Paradigm for Evolving Herd Immunity against Viral Diseases.

Viruses 2020 10 10;12(10). Epub 2020 Oct 10.

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.

Herd immunity is the most critical and essential prophylactic intervention that delivers protection against infectious diseases at both the individual and community level. This process of natural vaccination is immensely pertinent to the current context of a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection around the globe. The conventional idea of herd immunity is based on efficient transmission of pathogens and developing natural immunity within a population. This is entirely encouraging while fighting against any disease in pandemic circumstances. A spatial community is occupied by people having variable resistance capacity against a pathogen. Protection efficacy against once very common diseases like smallpox, poliovirus or measles has been possible only because of either natural vaccination through contagious infections or expanded immunization programs among communities. This has led to achieving herd immunity in some cohorts. The microbiome plays an essential role in developing the body's immune cells for the emerging competent vaccination process, ensuring herd immunity. Frequency of interaction among microbiota, metabolic nutrients and individual immunity preserve the degree of vaccine effectiveness against several pathogens. Microbiome symbiosis regulates pathogen transmissibility and the success of vaccination among different age groups. Imbalance of nutrients perturbs microbiota and abrogates immunity. Thus, a particular population can become vulnerable to the infection. Intestinal dysbiosis leads to environmental enteropathy (EE). As a consequence, the generation of herd immunity can either be delayed or not start in a particular cohort. Moreover, disparities of the protective response of many vaccines in developing countries outside of developed countries are due to inconsistencies of healthy microbiota among the individuals. We suggested that pan-India poliovirus vaccination program, capable of inducing herd immunity among communities for the last 30 years, may also influence the inception of natural course of heterologous immunity against SARS-CoV-2 infection. Nonetheless, this anamnestic recall is somewhat counterintuitive, as antibody generation against original antigens of SARS-CoV-2 will be subdued due to original antigenic sin.
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http://dx.doi.org/10.3390/v12101150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599628PMC
October 2020

Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells.

Oncotarget 2020 Aug 18;11(33):3129-3143. Epub 2020 Aug 18.

Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.

Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin. Recently, we have shown that carnosic acid (CA), a component of the food preservative Rosemary Extract, can markedly enhance the cytotoxic actions of Sf in several cell lines derived from HCC, but not in the cell line Hu1545 derived from normal hepatocytes. CA has been shown to enhance Sf-induced cell death in the neoplastic cell lines, principally due to the composite of increased apoptosis and cytotoxic autophagy. In the present study we focused on the mechanisms that underlie the reduced proliferation and survival of HCC cells when CA is added to Sf and how this relates to the increase in Sf-induced DNA damage as well as to the elevation of cytoplasmic levels of reactive oxygen species (ROS). Importantly, the elevation of ROS levels induced by Sf was increased by adding CA. We found that CA enhanced Sf-induced prolongation of cell cycle, and the overall decrease in cell growth was associated with reduced activation of both STAT3 transcription factor (TF) and extracellular signal-regulated protein kinase (Erk)1/2. Our data suggest that a regimen incorporating CA, an inexpensive and non-toxic food additive, in the treatment of advanced HCC merits clinical evaluation.
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http://dx.doi.org/10.18632/oncotarget.27687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443370PMC
August 2020

Improving assessment of child growth in a pediatric hospital setting.

BMC Pediatr 2020 09 3;20(1):419. Epub 2020 Sep 3.

Nutrition and Health Sciences Program, Laney Graduate School, Emory University, Atlanta, GA, USA.

Background: Accurate anthropometric measurements are essential for assessing nutritional status, monitoring child growth, and informing clinical care. We aimed to improve height measurements of hospitalized pediatrics patients through implementation of gold standard measurement techniques.

Methods: A quality improvement project implemented computerized training modules on anthropometry and standardized wooden boards for height measurements in a tertiary children's hospital. Heights were collected pre- and post-intervention on general pediatric inpatients under 5 years of age. Accuracy of height measurements was determined by analyzing the variance and by comparing to World Health Organization's defined biologically plausible height-for-age z-scores. Qualitative interviews assessed staff attitudes.

Results: Ninety-six hospital staff completed the anthropometry training. Data were available on 632 children pre- and 933 post-intervention. Training did not increase the proportion of patients measured for height (78.6% pre-intervention vs. 75.8% post-intervention, p = 0.19). Post-intervention, wooden height boards were used to measure height of 34.8% patients, while tape measures and wingspan accounted for 42.0% and 3.5% of measurements, respectively. There was no improvement in the quality of height measurements based on plausibility (approximately 3% height-for-age z-scores measurements flagged out of range pre- and post-intervention), digit preference (13.4% of digits pre- and 12.3% post-intervention requiring reclassification), or dispersion of measurements (height-for-age z-scores standard deviation 1.9 pre- and post-intervention). Staff reported that using the wooden board was too labor consuming and cumbersome.

Conclusions: Our findings suggest that efforts to improve anthropometric measurements of hospitalized children have multiple obstacles, and further investigation of less cumbersome methods of measurements may be warranted.
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http://dx.doi.org/10.1186/s12887-020-02289-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469098PMC
September 2020

Iron Content of Commercially Available Infant and Toddler Foods in the United States, 2015.

Nutrients 2020 Aug 13;12(8). Epub 2020 Aug 13.

Division of Nutrition, Physical Activity, and Obesity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341-3717, USA.

Objectives: To describe the iron content of commercially available infant and toddler foods.

Methods: Nutrition Facts label data were used from a 2015 database of 1037 commercial infant and toddler food and drink products. Products were grouped into food categories on the basis of name, ingredients, target age, and reference amounts customarily consumed (RACC). Mean and median iron content per 100 g and per RACC were calculated. The proportion of products considered good and excellent sources of iron were determined on the basis of percent daily value (% DV) thresholds.

Results: Among products marketed for infants (aged 4-12 months), infant cereals had the highest mean (6.19 mg iron per RACC; 41.25 iron mg per 100 g) iron content. Among products marketed for toddlers (aged 12-36 months), vegetable-based mixtures or meals contained the highest mean iron in mg per RACC (mean: 2.97 mg) and dry, grain-based desserts had the highest mean iron in mg per 100 g (mean: 6.45 mg). Juice and drink products had the lowest mean iron contents in both infant and toddler products.

Conclusions: Most commercially available infant cereals are considered to be an excellent source of iron, likely from fortification, but wide variability was observed in iron content by food category. Products that are considered good or excellent sources of iron (≥10% DV) can help consumers identify products with higher iron content, such as infant cereals or toddler vegetable-based mixtures/meals.
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http://dx.doi.org/10.3390/nu12082439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469030PMC
August 2020

Classifying Device-Related Complications Associated With Intrathecal Baclofen Pumps: A MAUDE Study.

World Neurosurg 2020 07 24;139:e652-e657. Epub 2020 Apr 24.

Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA.

Background: Intrathecal baclofen (ITB) is an effective treatment for spasticity, and therapeutic levels may be optimized using surgically implanted pumps. Though these devices are effective, complications can pose significant challenges to patients, decreasing the therapeutic effect and potentially requiring reoperation. As such, it is critical that complications associated with ITB be effectively characterized.

Methods: We queried the Manufacturer and User Facility Device Experience (MAUDE) database for cases reported during the past 3 years documenting adverse events specifically related to ITB pumps. We identified 1935 adverse events that were individually analyzed and categorized by type of complication.

Results: Out of the 1935 unique adverse events identified from the MAUDE database, 25.7% were device-related complications (n = 497). Of those, 50.3% were catheter-specific (n = 250), 21.3% (n = 106) were pump-specific, and 28.3% (n = 141) were included, more generally, in catheter or device erosion.

Conclusions: The MAUDE database may be a useful resource for evaluating ITB pump complications across a larger data set. By characterizing the complications and providing values for their total occurrences, patients and physicians may have more realistic expectations for the outcomes and morbidity of this device.
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http://dx.doi.org/10.1016/j.wneu.2020.04.070DOI Listing
July 2020

Baseline thrombocytopenia in women with coronary heart disease increases incident acute coronary syndrome: insights from national inpatient database.

J Thromb Thrombolysis 2020 Aug;50(2):462-467

Division of Cardiology, Garden City Hospital, Garden City, USA.

There are paucity of data on gender-based differences in the effect of thrombocytopenia and coronary heart disease (CHD) towards development of acute coronary syndrome (ACS). We used National Inpatient Sample (NIS) database of the United States to assess the gender-based differences in the association of thrombocytopenia with CHD and the impact of thrombocytopenia on mortality, length of stay and hospitalization costs on ACS subgroup of CHD. Our analysis found that thrombocytopenia was associated with increased odds of CHD on univariate (odds ratio [OR] 1.31 (95% CI 1.30-1.32) p < 0.001) and multivariate (OR 1.36 (95% CI 1.34-1.38) p < 0.001) analyses. Thrombocytopenic CHD patients had increased odds of developing ACS only in women (OR 1.15, 95% CI 1.12-1.17, p < 0.001). Thrombocytopenia was found to be associated with poor short-term outcome in ACS subgroup of CHD with higher in-hospital mortality (OR 1.64, CI 1.58 to 1.71, p < 0.001), length of stay (3.4 days, CI 3.30-3.52, p < 0.001), and cost of hospitalization ($55,652, CI 53,717-57,587, p < 0.001). Thrombocytopenic women with ACS have greater odds of mortality compared to men. Our study suggests that thrombocytopenia among women with CHD is associated with increased odds of developing ACS. Women with ACS have greater mortality compared to men. Thrombocytopenic ACS patients have worse in-hospital outcome compared to patients with normal platelet count. We demonstrated association only and is not possible to establish causality with our study.
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http://dx.doi.org/10.1007/s11239-020-02096-6DOI Listing
August 2020

The effect of salt and temperature on the conformational changes of P1LEA-22, a repeat unit of plant Late Embryogenesis Abundant proteins.

J Pept Sci 2020 Apr 11;26(4-5):e3247. Epub 2020 Mar 11.

Department of Chemistry, The College of New Jersey, Ewing, NJ, USA.

The effect of choline chloride on the conformational dynamics of the 11-mer repeat unit P1LEA-22 of group 3 Late Embryogenesis Abundant (G3LEA) proteins was studied. Circular dichroism data of aqueous solutions of P1LEA-22 revealed that the peptide favors a polyproline II (PPII) helix structure at low temperature, with increasing temperature promoting a gain of unstructured conformations. Furthermore, increases in sample FeCl or choline chloride concentrations causes a gain in PPII helical structure at low temperature. The potential role of PPII structure in intrinsically disordered and G3LEA proteins is discussed, including its ability to easily access other secondary structural conformations such as α-helix and β-sheet, which have been observed for dehydrated G3LEA proteins. The observed effect of FeCl and choline chloride salts on P1LEA-22 suggests favorable cation interactions with the PPII helix, supporting ion sequestration as a G3LEA protein function. As choline chloride is suggested to improve salt tolerance and protect cell membrane in plants at low temperature, our results support adoption of the PPII structure as a possible damage-preventing measure of Late Embryogenesis Abundant proteins.
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http://dx.doi.org/10.1002/psc.3247DOI Listing
April 2020

MEDEA-interacting protein LONG-CHAIN BASE KINASE 1 promotes pattern-triggered immunity in Arabidopsis thaliana.

Plant Mol Biol 2020 May 25;103(1-2):173-184. Epub 2020 Feb 25.

School of Life Sciences, Jawaharlal Nehru University, 415, New Delhi, 110067, India.

Key Message: Arabidopsis LONG-CHAIN BASE KINASE 1 (LCBK1) interacts with MEDEA, a component of PCR2 complex that negatively regulates immunity. LCBK1 phosphorylates phytosphingosine and thereby promotes stomatal immunity against bacterial pathogens. Arabidopsis polycomb-group repressor complex2 (PRC2) protein MEDEA (MEA) suppresses both pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). MEA represses the expression of RPS2 and thereby attenuates AvrRpt2 effector-mediated ETI. However, the mechanism of MEA-mediated PTI diminution was not known. By screening the Arabidopsis cDNA library using yeast-2-hybrid interaction, we identified LONG-CHAIN BASE KINASE1 (LCBK1) as an MEA-interacting protein. We found that lcbk1 mutants are susceptible to virulent bacterial pathogens, such as Pseudomonas syringae pv maculicola (Psm) and P. syringae pv tomato (Pst) but not the avirulent strain of Pst that carries AvrRpt2 effector. Pathogen inoculation induces LCBK1 expression, especially in guard cells. We found that LCBK1 has a positive regulatory role in stomatal closure after pathogen inoculation. WT plants close stomata within an hour of Pst inoculation or flg22 (a 22 amino acid peptide from bacterial flagellin protein that activates PTI) treatment, but not lcbk1 mutants. LCBK1 phosphorylates phytosphingosine (PHS). Exogenous application of phosphorylated PHS (PHS-P) induces stomatal closure and rescues loss-of-PTI phenotype of lcbk1 mutant plants. MEA overexpressing (MEA-Oex) plants are defective, whereas loss-of-function mea-6 mutants are hyperactive in PTI-induced stomatal closure. Exogenous application of PHS-P rescues loss-of-PTI in MEA-Oex plants. Results altogether demonstrate that LCBK1 is an interactor of MEA that positively regulates PTI-induced stomatal closure in Arabidopsis.
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http://dx.doi.org/10.1007/s11103-020-00982-4DOI Listing
May 2020

Standardized Xylocarpus moluccensis fruit fraction mitigates collagen-induced arthritis in mice by regulating immune response.

J Pharm Pharmacol 2020 Apr 9;72(4):619-632. Epub 2020 Feb 9.

Division of Pharmacology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, India.

Objective: This study was undertaken to evaluate the effect of Xylocarpus moluccensis fruit fraction (F018) on the pathogenesis of collagen-induced arthritis in mice.

Methods: Arthritis was induced by intradermal injection of collagen (2 mg/ml) with complete Freund's adjuvant in DBA/1J mice. F018 was administered orally at 1, 3 and 10 mg/kg for 20 days. Disease progression and mechanism were assessed by micro-CT analysis, RT-PCR, flow cytometry assay, myeloperoxidase (MPO) and MTT assay.

Results: F018 at 3 and 10 mg/kg significantly reduced paw thickness, clinical score, mononuclear cell infiltration and collagen layer depletion in the knee section of collagen-induced arthritis (CIA) mice when compared with collagen-induced arthritis mice alone. Furthermore, F018 treatment in collagen-induced arthritis mice significantly recovered bone volume and trabecular number and decreased the trabecular space by modulating RANKL and OPG mRNA expression in the synovial tissue. F018 treatment in collagen-induced arthritis mice significantly attenuated spleen index, lymphocyte proliferation and paw myeloperoxidase (MPO) activity, pro-inflammatory cytokine TNFα, IL1β, and IL6 mRNA expression and enhanced IL10 mRNA expression in paw tissue. Furthermore, F018 treatment in collagen-induced arthritis mice significantly reduced splenic dendritic cell maturation and Th17 cells. In culture, F018 significantly decreased collagen-induced arthritis-FLS proliferation and promoted apoptosis.

Conclusion: F018 may serve as a potential curative agent for arthritis.
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http://dx.doi.org/10.1111/jphp.13231DOI Listing
April 2020

Recurrent Stroke Like Episodes Secondary to Ornithine Transcarbamylase Deficiency.

Indian J Pediatr 2020 Oct 1;87(10):852-853. Epub 2020 Feb 1.

Department of Pediatrics, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India.

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http://dx.doi.org/10.1007/s12098-020-03193-3DOI Listing
October 2020

Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation.

J Lipid Res 2020 03 27;61(3):351-364. Epub 2020 Jan 27.

Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India

Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1-6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.
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http://dx.doi.org/10.1194/jlr.RA119000382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053835PMC
March 2020

Cellular cytokine receptor signaling and ATM pathway intersections affect hepatic DNA repair.

Cytokine 2020 03 11;127:154946. Epub 2019 Dec 11.

Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Diabetes Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Irwin S. and Sylvia Chanin Institute for Cancer Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx 10461, NY, USA. Electronic address:

Pathways involving ataxia telangiectasia mutated (ATM) gene and its downstream partners and effectors are critical for the DNA damage response. Cell survival, proliferation and tissue homeostasis are dependent upon preservation of DNA integrity but additional intracellular mechanisms contribute in these processes. As receptor-mediated signaling with beneficial intersections in ATM pathways could have therapeutic significance, we interrogated such intersections with assays using HuH-7 cells (hepatocytes). These cells were subjected to acetaminophen toxicity, which is a leading cause of hepatic injury and acute liver failure in people. The ATM pathway was examined in HuH-7-ATM-Prom-tdT cells containing fluorescent td-Tomato transgene reporter for ATM promoter activity. Titrated doses of specific growth factors were used as ligands for receptor-mediated signaling. The contribution of JAK/STAT3 signaling was defined by the loss-of-function approach with the JAK antagonist, ruxolitinib. In these assays, impairment in ATM-related DNA damage response following acetaminophen toxicity was ameliorated by selected growth factors, including fibroblast growth factors, granulocyte colony stimulating factor and vascular endothelial growth factor. The JAK/STAT3 signaling was exclusive to granulocyte colony stimulating factor but concerned additional pathways in cases of other growth factors. Antagonism of JAK/STAT3 by ruxolitinib abrogated benefits in ATM pathway-mediated DNA repair; and identification of the ruxolitinib-sensitive component of cytoprotection allowed separations of these pathway intersections. Therefore, this subtractive approach for ATM and other regulators in pathways will be informative for DNA damage response. These mechanisms will benefit therapeutic development for ATM-related tissue and organ injuries.
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http://dx.doi.org/10.1016/j.cyto.2019.154946DOI Listing
March 2020

Innovative use of mesh bolster for adult Morgagni hernia repair.

J Surg Case Rep 2019 Jul 3;2019(7):rjz205. Epub 2019 Jul 3.

Department of Medical Education, College of Osteopathic Medicine of the Pacific NW, Western University of Health Sciences, 200 Mullins Drive. Lebanon, OR, USA.

Morgagni hernia is a rare type of congenital diaphragmatic hernia caused by lack of fusion of the pleuroperitoneal membrane anteriorly leading to a defect in the foramen of Morgagni. These are rare hernias and typically present early in life. Those that do not get repaired during infancy or adolescence often present later in life with variable symptoms including obstruction, incarceration, strangulation, pulmonary symptoms, chest pain, etc. Herein we present an adult case that was found incidentally after a screening computerized tomography (CT) chest scan was done for history of smoking. There are two unique aspects to this case: first, given the large size of her hernia, her only complaint was mild shortness of breath and second, the innovative use of mesh as a suture bolster.
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http://dx.doi.org/10.1093/jscr/rjz205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607960PMC
July 2019

Interpregnancy interval and risk of stillbirth: a population-based case control study.

Ann Epidemiol 2019 07 11;35:35-41. Epub 2019 May 11.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.

Purpose: We examined the association between interpregnancy intervals (IPIs) and stillbirth (defined as fetal death ≥20 weeks), as both short and long IPIs have been associated with adverse perinatal outcomes. Prior pregnancy loss is also a known risk factor for stillbirth, and women who suffer a prior loss often have shorter IPIs. For these reasons, we also sought to quantify the proportion of the association between prior pregnancy loss and subsequent stillbirth risk that may be attributed to a short IPI.

Methods: We used data from the Stillbirth Collaborative Research Network, a multisite case-control study conducted in 2006-2008, restricted to singleton pregnancies among multiparous or multigravid women (985 controls and 291 cases). We accounted for complex sample design and nonparticipation with weighted multivariable logistic regression.

Results: In the adjusted models, IPIs <6 months, as compared with a reference of 18-23 months, were associated with increased odds of stillbirth (aOR 1.6, 95% CI: 0.8, 3.4). Long IPIs (60-100 months) were also associated with an increased odds of stillbirth (aOR 2.4, 95% CI: 1.2, 4.5). After control for covariates, about one-fifth (21.2%) of the association of prior pregnancy loss (stillbirth, ectopic pregnancy, molar pregnancy, or spontaneous abortion) and stillbirth may be attributable to a short IPI.

Conclusions: Our results suggest that women who experience a prior pregnancy loss may benefit from additional counseling on adequate birth spacing to reduce subsequent stillbirth risk.
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http://dx.doi.org/10.1016/j.annepidem.2019.05.001DOI Listing
July 2019

Fluorescein Angiography Does Not Alter the Initial Clinical Management of Choroidal Neovascularization in Age-Related Macular Degeneration.

Ophthalmol Retina 2018 07 9;2(7):659-666. Epub 2018 Mar 9.

Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa; Iowa City VA Health Care System, Iowa City, Iowa; Institute for Vision Research, University of Iowa, Iowa City, Iowa; Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa; Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa. Electronic address:

Purpose: Fundus fluorescein angiography (FFA) is the standard modality to diagnose and manage choroidal neovascularization (CNV). However, FFA is costly and has considerable morbidity from allergic reactions and a mortality of 1 per 220 000. Since the advent of anti-vascular endothelial growth factor (VEGF) therapy for CNV, OCT has been used extensively to manage CNV, but FFA is still widely used. One recent study found the sensitivity and specificity of OCT compared with FFA in diagnosis of CNV were 100% and 80.8%, respectively. We hypothesize that FFA does not affect the management of patients initially suspected of having CNV to a clinically significant degree.

Design: Evaluation of diagnostic test using vignettes.

Participants: A total of 99 patients (99 eyes) who had an initial presentation of later confirmed CNV.

Methods: We retrospectively extracted in de-identified form the FFA, OCT, and clinical histories of the subjects. Vignettes were created with a standard narrative clinical history, posterior-pole color fundus image, central B-scan OCT of the initial visit, and early, mid, and late FFA of the affected eye. Four masked retinal specialists reviewed, in randomized order, these vignettes without FFA images (FFA- arm) and answered a forced choice management question: observation, 3 consecutive anti-VEGF injections, or other. After re-randomization, experts again reviewed the vignettes with the addition of the FFA images (FFA+ arm).

Main Outcome Measures: Intraobserver and interobserver concordance and reliability statistics within and between specialists.

Results: Among our retina specialists, intraobserver concordances were 89.7%, 88.7%, 88.7%, and 95.9% (average 90.7%, 95% confidence interval [CI], 83.7-97.6). The average interobserver concordance for the FFA- arm was 84.0% (95% CI, 72.6-95.4), and for the FFA+ arm, 81.8% (95% CI, 68.5-95.2); paired t testing demonstrated no significant difference between the FFA- and FFA+ arms: t = 0.6, P = 0.55.

Conclusions: Our data suggest a high degree of agreement in clinical decision making whether FFA was used or not. There was a similar level of agreement among specialists in the FFA- and FFA+ groups, albeit at higher, not statistically significant, variability. We believe these findings further support deferring the use of FFA in the initial management of CNV in AMD, except in treatment failures and nonstandard cases.
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http://dx.doi.org/10.1016/j.oret.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055156PMC
July 2018

Hypomelanosis of Ito: streaks and whorls.

BMJ Case Rep 2019 Apr 23;12(4). Epub 2019 Apr 23.

Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.

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http://dx.doi.org/10.1136/bcr-2018-227693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510154PMC
April 2019

Effectuation to Cognize malignancy risk and accuracy of fine needle aspiration cytology in salivary gland using "Milan System for Reporting Salivary Gland Cytopathology": A 2 years retrospective study in academic institution.

Indian J Pathol Microbiol 2019 Jan-Mar;62(1):11-16

Department of Pathology, LLRM Medical College, Meerut, Uttar Pradesh, India.

Background: To accost things in a particular disciple, egress related to Fine Needle Aspiration Cytology (FNAC) and to standardize reporting pattern, a framework "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC) has been sponsored.

Aim: Aim of this study was to evaluate the potency of salivary gland FNAC reported under Milan guidelines, to calculate malignancy risk, and to compare the preoperative cytological diagnoses with the postoperative histopathological diagnoses.

Settings And Design: This was a retrospective study over a period of 2 years (May 2016 to April 2018), which was classified according to Milan system and correlation with histopathology. Furthermore, the risk of malignancy was calculated for all the diagnostic categories.

Materials And Methods: FNAC were analyzed on 105 patients with palpable salivary gland. Results were distributed into six categories. About 76 cases were surgically treated and resected tissues were submitted for histopathological examination.

Statistical Analysis: The various diagnostic values of the procedure were calculated using the standard formula.

Results: We reviewed 105 salivary gland FNA samples and recorded interpretations according to the proposed standardized six categories. Among them, category IV (neoplastic) had more cases (57.14%). The rates of malignancy in histology were as follows: (1) nondiagnostic, 0.0%; (2) nonneoplastic, 0.0%; (3) atypia of undermined significance, 50.00%; (4a) benign, 02.44%; (4b) uncertain malignant potential, 33.33%; (5) suspicious for malignancy, 100%; and (6) malignancy, 93.33%. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of Milan system came out to be 85.00%, 98.14%, 94.44%, 94.64%, and 94.59%, respectively.

Conclusion: The six-tier diagnostic categories of the Milan system helps in triaging patients with salivary gland swelling and thus facilitate individualized management.
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http://dx.doi.org/10.4103/IJPM.IJPM_380_18DOI Listing
May 2019

Free radical stress induces DNA damage response in RAW264.7 macrophages during Mycobacterium smegmatis infection.

Arch Microbiol 2019 May 1;201(4):487-498. Epub 2018 Nov 1.

Department of Molecular Biology and Bioinformatics, Tripura University, Suryamaninagar, Tripura, 799022, India.

Genomic instability resulting from oxidative stress responses may be traced to chromosomal aberration. Oxidative stress suggests an imbalance between the systemic manifestation of reactive free radicals and biological system's ability to repair resulting DNA damage and chromosomal aberration. Bacterial infection associated insult is considered as one of the major factors leading to such stress conditions. To study free radical responses by host cells, RAW 264.7 macrophages were infected with non-pathogenic M. smegmatis mc155 at different time points. The infection process was followed up with an assessment of free radical stress, cytokine, toll-like receptors (TLRs) and the resulting DNA damage profiles. Results of CFU count showed that maximum infection in macrophages was achieved after 9 h of infection. Host responses to the infection across different time periods were validated from nitric oxide quantification and expression of iNOS and were plotted at regular intervals. IL-10 and TNF-α expression profile at protein and mRNA level showed a heightened pro-inflammatory response by host macrophages to combat M. smegmatis infection. The expression of TLR4, a receptor for recognition of mycobacteria, in infected macrophages reached the highest level at 9 h of infection. Furthermore, comet tail length, micronuclei and γ-H2AX foci recorded the highest level at 9 h of infection, pointing to the fact that breakage in DNA double strands in macrophage reaches its peak at 9 h of infection. In contrast, treatment with ROS inhibitor N-acetyl-L-cysteine (NAC) prevented host cell death through reduction in oxidative stress and DNA damage response during M. smegmatis infection. Therefore, it can be concluded that enhanced oxidative stress response in M. smegmatis infected macrophages might be correlated with DNA damage response.
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http://dx.doi.org/10.1007/s00203-018-1587-yDOI Listing
May 2019

Iodine Status of Pregnant Women and Women of Reproductive Age in the United States.

Thyroid 2019 01 15;29(1):153-154. Epub 2018 Dec 15.

4 Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia.

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http://dx.doi.org/10.1089/thy.2018.0345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984425PMC
January 2019

Improving LARC Access for Urban Adolescents and Young Adults in the Pediatric Primary Care Setting.

Clin Pediatr (Phila) 2019 01 13;58(1):24-33. Epub 2018 Oct 13.

2 Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The objective of this quality improvement study was to assess the feasibility, acceptability, and impact of integrating long-acting reversible contraceptive (LARC) delivery services into an academic pediatric primary care practice. Adolescent medicine providers in Baltimore, Maryland, were trained in LARC placement with gynecology providers integrated to offer onsite LARC placement and procedural support. Referrals, appointments, and contraceptive method choice/receipt were tabulated. Of 212 individuals referred for LARC consultations, 104 attended appointments. LARC placement at the initial referral increased from year 1 (N = 1) to year 2 (N = 42; P < .01). Adolescent medicine providers placed more LARCs in year 2 (N = 34) than year 1 (N = 0; P < .01). Patients aged 18 to 24 years were less likely to have a LARC placed than those aged 13 to 17 years (unadjusted odds ratio = 0.47 [0.26-0.86]). In conclusion, provider training and service integration of LARC services within a pediatric practice is feasible, acceptable, and increases LARC access and placement.
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http://dx.doi.org/10.1177/0009922818805234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261697PMC
January 2019

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

Hum Gene Ther 2019 03 18;30(3):365-377. Epub 2018 Dec 18.

1 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.

Reconstitution of healthy endothelial cells in vascular beds offers opportunities for mechanisms in tissue homeostasis, organ regeneration, and correction of deficient functions. Liver sinusoidal endothelial cells express unique functions, and their transplantation is relevant for disease models and for cell therapy. As molecular targets for improving transplanted cell engraftment and proliferation will be highly significant, this study determined whether ET receptor antagonism by the drug bosentan could overcome cell losses due to cell transplantation-induced cytotoxicity. Cell engraftment and proliferation assays were performed with healthy wild-type liver sinusoidal endothelial cells transplanted into the liver of dipeptidylpeptidase IV knockout mice. Transplanted cells were identified in tissues by enzyme histochemistry. Cells with prospective ET antagonism engrafted significantly better in hepatic sinusoids. Moreover, these cells underwent multiple rounds of division under liver repopulation conditions. The gains of ET antagonism resulted from benefits in cell viability and membrane integrity. Also, in bosentan-treated cells, mitochondrial homeostasis was better maintained with less oxidative stress and DNA damage after injuries. Intracellular effects of ET antagonism were transduced by conservation of ataxia telangiectasia mutated protein, which directs DNA damage response. Therefore, ET antagonism in donor cells will advance vascular reconstitution. Extensive experience with ET antagonists will facilitate translation in people.
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http://dx.doi.org/10.1089/hum.2018.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437629PMC
March 2019

The Polycomb-Group Repressor MEDEA Attenuates Pathogen Defense.

Plant Physiol 2018 08 28;177(4):1728-1742. Epub 2018 Jun 28.

415, School of life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.

Plants recruit positive and negative regulators for fine tuning the balance between growth and development. Negative regulators of pathogen defense generally modulate defense hormone biosynthesis and signaling. Here, we report a mechanism for attenuation of the defense response in Arabidopsis (), which is mediated by the polycomb-group repressor MEDEA (MEA). Our results showed that pathogen inoculation or exogenous application of salicylic acid, methyl jasmonate, or the bacterial 22-amino acid domain of flagellin peptide induces the expression of expression was higher when plants were inoculated with the avirulent strain of pv. () carrying the effector () compared to the virulent strain. remains suppressed during the vegetative phase via DNA and histone (H3K27) methylation, and only the maternal copy is expressed in the female gametophyte and endosperm via histone and DNA demethylation. In contrast, induces high levels of expression via hyper-accumulation of H3K4me3 at the locus. -overexpressing transgenic plants are susceptible to the fungal pathogen and bacterial pathogens and , whereas mutant plants are more resistant to bacterial pathogens. -mediated immunity requires the function of RESISTANCE TO P. SYRINGAE2 (RPS2) in Arabidopsis. Using transcriptional analysis and chromatin immunoprecipitation, we established that MEA directly targets and suppresses its transcription. We screened an Arabidopsis cDNA library using MEA as the bait in a yeast two-hybrid assay and identified DROUGHT-INDUCED19, a transcription factor that interacts with MEA and recruits it at the promoter. The results identified a previously unknown mechanism of defense response attenuation in plants.
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http://dx.doi.org/10.1104/pp.17.01579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084662PMC
August 2018

IL-1 β genesis: the art of regulating the regulator.

Cell Mol Immunol 2018 11 19;15(11):998-1000. Epub 2018 Jun 19.

Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, UP, India.

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http://dx.doi.org/10.1038/s41423-018-0054-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207738PMC
November 2018

PAs reduce rounding interruptions in the pediatric intensive care unit.

JAAPA 2018 Jun;31(6):41-45

Rebecca L. Hascall is a student in the PA program at Stony Brook (N.Y.) University. R. Serene Perkins is director of surgical and clinical research at Legacy Health System in Portland, Ore. Lauren Kmiecik is a clinical research coordinator III at Legacy Health System. Priya R. Gupta is a medical student at Western University of Health Sciences College of Osteopathic Medicine in Lebanon, Ore. Carolyn F. Shelak is medical director of the pediatric intensive care unit, a pediatric intensivist, and chair of the pediatric medicine department at Randall Children's Hospital at Legacy Emanuel in Portland, Ore. Shaban Demirel is a senior clinical outcomes research scientist at Legacy Health System, an associate scientist at Legacy Health's Devers Eye Institute, an adjunct professor at Washington State University, and director of Legacy Health's Devers Visual Field Reading Center. Mark T. Buchholz is chair of the section of pediatric critical care at Randall Children's Hospital in Portland, Ore. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Objective: We investigated the proportion of encounters that were interrupted during family-centered rounds in the pediatric intensive care unit (PICU) to determine whether the use of a physician assistant (PA) significantly affected the proportion of interrupted encounters.

Methods: We evaluated 2,657 rounding encounters in our 24-bed regional referral unit. The duration of each rounding encounter and total rounding duration were recorded. The presence or absence of a PA during each rounding encounter, the occurrence of an interruption, and other potential predictors of interruptions were recorded.

Results: The presence of a PA during PICU rounds was significantly associated (P < .001) with a 35.4% lower likelihood of an interruption.

Conclusions: Family-centered rounds in the PICU are less likely to be interrupted when a PA is present. PAs help physicians and improve rounding efficiency by safely and effectively handling certain interruptions.
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http://dx.doi.org/10.1097/01.JAA.0000533661.80449.daDOI Listing
June 2018