Comparative genomic analysis of novel Acinetobacter symbionts : A combined systems biology and genomics approach

Acknowledgements This work was supported by University of Delhi, Department of Science and Technology- Promotion of University Research and Scientific Excellence (DST-PURSE). V.G., S.H. and U.S. gratefully acknowledge the Council for Scientific and Industrial Research (CSIR), University Grant Commission (UGC) and Department of Biotechnology (DBT) for providing research fellowship.Peer reviewedPublisher PD

Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators

Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS).Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS.Results: We found KIF5AS291F variant showed the most structure destabilizing behavior and the phytocompound “epigallocatechin gallate” showed the highest binding affinity (−9.0 Kcal/mol) as compared to wild KIF5A (−8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A).Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases

Incidence and etiology of omphalitis in Pakistan: a community-based cohort study

Introduction: Although omphalitis (umbilical infections) among newborns is common and a major cause of neonatal deaths in developing countries, information on its burden and etiology from community settings is lacking. This study aimed to determine the incidence and etiology of omphalitis in newborns in high neonatal mortality settings in Karachi, Pakistan. Methodology: Trained community health workers surveyed all new births in three low-income areas from September 2004 to August 2007. Pus samples from the umbilical stumps were obtained from babies with pre-defined signs of illness and subjected to culture and antimicrobial susceptibility testing. Results: Among 6904 births, 1501 (21.7%) newborns were diagnosed with omphalitis. Of these, 325 (21.6%) were classified as mild, 1042 (69.4%) as moderate, and 134 (8.9%) as severe, 141 (9.3%) were associated with clinical signs of sepsis. The incidence of omphalitis was 217.4/1000 live births, moderate-severe omphalitis 170.3 per 1000 live births, and associated with sepsis 20.4 per 1000 live births. Of 853 infants with purulent umbilical discharge, 64% yielded 583 isolates. The most common pathogens were Staphylococcus aureus, of which 291 (95.7%) were methicillin-susceptible Staphylococcus aureus (MSSA) and 13 (4.2%) methicillin-resistant S. aureus (MRSA), Streptococcus pyogenes 105 (18%), Group B beta-hemolytic streptococci 59 (10 %), Pseudomonas spp., 52 (8.9 %), Aeromonas spp. 19 (3.2%), and Klebsiella spp. 12 (2%). Conclusions: A high burden of omphalitis can be associated with sepsis among newborns in low-income communities in Pakistan. S. aureus is the most common pathogen isolated from umbilical pus. Appropriate low-cost prevention strategies need to be implemented

Ficus benghalensis as Potential Inhibitor of 5α-Reductase for Hair Growth Promotion: In Vitro, In Silico, and In Vivo Evaluation

The screening of hair follicles, dermal papilla cells, and keratinocytes through in vitro, in vivo, and histology has previously been reported to combat alopecia. Ficus benghalensis has been used conventionally to cure skin and hair disorders, although its effect on 5α-reductase II is still unknown. Currently, we aim to analyze the phytotherapeutic impact of F. benghalensis leaf extracts (FBLEs) for promoting hair growth in rabbits along with in vitro inhibition of the steroid isozyme 5α-reductase II. The inhibition of 5α-reductase II by FBLEs was assessed by RP-HPLC, using the NADPH cofactor as the reaction initiator and Minoxin (5%) as a positive control. In silico studies were performed using AutoDock Vina to visualize the interaction between 5α-reductase II and the reported phytoconstituents present in FBLEs. Hair growth in female albino rabbits was investigated by applying an oral dose of the FBLE formulation and control drug to the skin once a day. The skin tissues were examined by histology to see hair follicles. Further, FAAS, FTIR, and antioxidants were performed to check the trace elements and secondary metabolites in the FBLEs. The results of RP-HPLC and the binding energies showed that FBLEs reduced the catalytic activity of 5α-reductase II and improved cell proliferation in rabbits. The statistical analysis (p 70%) suggested that hydroalcoholic FBLE has more potential in increasing hair growth by elongating hair follicle’s anagen phase. FAAS, FTIR, and antioxidant experiments revealed sufficient concentrations of Zn, Cu, K, and Fe, together with the presence of polyphenols and scavenging activity in FBLE. Overall, we found that FBLEs are potent in stimulating hair follicle maturation by reducing the 5α-reductase II action, so they may serve as a principal choice in de novo drug designing to treat hair loss

Comparative genomic analysis reveals habitat-specific genes and regulatory hubs within the genus Novosphingobium

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in mSystems 2 (2017): e00020-17, doi:10.1128/mSystems.00020-17.Species belonging to the genus Novosphingobium are found in many different habitats and have been identified as metabolically versatile. Through comparative genomic analysis, we identified habitat-specific genes and regulatory hubs that could determine habitat selection for Novosphingobium spp. Genomes from 27 Novosphingobium strains isolated from diverse habitats such as rhizosphere soil, plant surfaces, heavily contaminated soils, and marine and freshwater environments were analyzed. Genome size and coding potential were widely variable, differing significantly between habitats. Phylogenetic relationships between strains were less likely to describe functional genotype similarity than the habitat from which they were isolated. In this study, strains (19 out of 27) with a recorded habitat of isolation, and at least 3 representative strains per habitat, comprised four ecological groups—rhizosphere, contaminated soil, marine, and freshwater. Sulfur acquisition and metabolism were the only core genomic traits to differ significantly in proportion between these ecological groups; for example, alkane sulfonate (ssuABCD) assimilation was found exclusively in all of the rhizospheric isolates. When we examined osmolytic regulation in Novosphingobium spp. through ectoine biosynthesis, which was assumed to be marine habitat specific, we found that it was also present in isolates from contaminated soil, suggesting its relevance beyond the marine system. Novosphingobium strains were also found to harbor a wide variety of mono- and dioxygenases, responsible for the metabolism of several aromatic compounds, suggesting their potential to act as degraders of a variety of xenobiotic compounds. Protein-protein interaction analysis revealed β-barrel outer membrane proteins as habitat-specific hubs in each of the four habitats—freshwater (Saro_1868), marine water (PP1Y_AT17644), rhizosphere (PMI02_00367), and soil (V474_17210). These outer membrane proteins could play a key role in habitat demarcation and extend our understanding of the metabolic versatility of the Novosphingobium species.This work was supported by grants from the Department of Biotechnology (DBT), R.K., S.H., K.P., A.B., and U.S. gratefully acknowledge the National Bureau of Agriculturally Important Microorganisms (NBAIM), Science and Engineering Research Board (SERB), N-PDF (PDF/2015/000062), (PDF/2015, 000319), University Grant Commission (UGC) for the Dr. D. S. Kothari Postdoctoral Fellowship and UGC for providing fellowships, respectively

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families

Hamiltonian energy as an efficient approach to identify the significant key regulators in biological networks.

The topological characteristics of biological networks enable us to identify the key nodes in terms of modularity. However, due to a large size of the biological networks with many hubs and functional modules across intertwined layers within the network, it often becomes difficult to accomplish the task of identifying potential key regulators. We use for the first time a generalized formalism of Hamiltonian Energy (HE) with a recursive approach. The concept, when applied to the Apoptosis Regulatory Gene Network (ARGN), helped us identify 11 Motif hubs (MHs), which influenced the network up to motif levels. The approach adopted allowed to classify MHs into 5 significant motif hubs (S-MHs) and 6 non-significant motif hubs (NS-MHs). The significant motif hubs had a higher HE value and were considered as high-active key regulators; while the non-significant motif hubs had a relatively lower HE value and were considered as low-active key regulators, in network control mechanism. Further, we compared the results of the HE analyses with the topological characterization, after subjecting to the three conditions independently: (i) removing all MHs, (ii) removing only S-MHs, and (iii) removing only NS-MHs from the ARGN. This procedure allowed us to cross-validate the role of 5 S-MHs, NFk-B1, BRCA1, CEBPB, AR, and POU2F1 as the potential key regulators. The changes in HE calculations further showed that the removal of 5 S-MHs could cause perturbation at all levels of the network, a feature not discernible by topological analysis alone

Ovarian Yolk Sac Tumor with Granulomatous Reaction Resembling Tuberculosis: A Unique Presentation

ABSTRACTYolk sac tumors (endodermal sinus tumors) are an important subgroup of germ cell tumors of the ovary. They are seen in young females andare highly aggressive, but respond well to treatment. Although different morphological patterns can be seen on light microscopy, granulomatousreaction and giant cells are a very rare occurrence. We report the case of a young female with ovarian yolk-sac tumor in which a widespreadgranulomatous reaction was seen, causing a diagnostic dilemma