Publications by authors named "Ruchi Jain"

93 Publications

Impact of a pharmacist driven anticoagulation reversal program at a large academic medical center.

J Thromb Thrombolysis 2021 Jun 7. Epub 2021 Jun 7.

Department of Pharmacy, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ, 07601, USA.

In major/life-threatening bleeding, administration of timely and appropriate reversal agents is imperative to reduce morbidity and mortality. Due to complexities associated with the use of reversal agents, a clinical pharmacist-driven anticoagulation reversal program (ARP) was developed. The goal of this program was to ensure appropriateness of reversal agents based on the clinical scenario, optimize selection and avoid unintended consequences. This study describes the impact of a pharmacist-driven anticoagulation program on patient outcomes and cost. A single center retrospective chart review of adult patients whom the ARP was consulted from October 2018 to January 2020 was performed. Patients were included in the efficacy analysis if they were > 18 years of age and presented with acute bleeding. Patients were excluded from the efficacy analysis if the recommended reversal agent was not administered, if a repeat head CT was not available for patients who presented with intracranial hemorrhage (ICH), or if the patient was not bleeding. All patients were included in the economic evaluation. The primary outcome was the percentage of patients who achieved effective hemostasis within 24 h of anticoagulation reversal. Secondary outcomes include incidence of thromboembolic events, in-hospital mortality, and cost avoidance. One hundred twenty-one patients were evaluated by the ARP with 92 patients included in the efficacy analysis. The primary sites of bleeding were ICH in 46% and gastrointestinal (GI) in 29%. Hemostasis was achieved in 84% of patients. Thrombotic events occurred in 7.4% of patients and in-hospital mortality was 26.4%. Total cost avoidance was $1,005,871.78. To our knowledge, this is the first study to evaluate the impact of a pharmacist-driven ARP on clinical and economic outcomes. Implementation of a pharmacist-driven ARP was associated with favorable outcomes and cost savings.
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http://dx.doi.org/10.1007/s11239-021-02491-7DOI Listing
June 2021

SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.

Science 2021 05;372(6543)

Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell-specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2's mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.
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http://dx.doi.org/10.1126/science.aba4220DOI Listing
May 2021

Mass spectrometric identification and sequencing of novel conotoxins from vermivorous cone snail (), and preliminary screening of its venom for biological activities and .

Saudi J Biol Sci 2021 Mar 24;28(3):1582-1595. Epub 2020 Dec 24.

Molecular & Nanomedicine Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama Institute of Science and Technology, Chennai 600119, India.

Venom of , a vermivorous cone snail found abundantly in the southern coastal waters was studied to yield conotoxins through proteomic analysis. A total of 37 conotoxins (4 with single disulfide bonds, 20 with two disulfide bonds and 11 three disulfide-bonded peptides) were identified using mass spectrometric analysis. Among them, amino acid sequences of 11 novel conopeptides with one, two and three disulfides belonging to different classes were derived through manual sequencing. Based on the established primary sequence, they were pharmacologically classified into α conotoxins, µ conotoxins and contryphans. Except In1696 all other conopeptides have undergone C-terminal amidation. The natural venom exhibited 50% lethality at 304.82 µg/mL against zebrafish embryo and 130.31 µg/mL against brine shrimp nauplii. The anticonvulsant study of natural venom effectively reduced the locomotor activity against pentylenetetrazole (PTZ) treated zebrafish. This concludes that the venom peptides from exhibit potential anticonvulsant function, which leads to the discovery of lead molecules against seizures.
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http://dx.doi.org/10.1016/j.sjbs.2020.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938137PMC
March 2021

Genome-wide DNA methylation changes in oral submucous fibrosis.

Oral Dis 2021 Feb 21. Epub 2021 Feb 21.

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.

Objective: Oral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease, we hypothesized that there would be extensive epigenetic changes in OSF tissues.

Materials And Methods: Using the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses was conducted to find commonly regulated genes.

Results: A total of 3,294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated-hypermethylated genes and 55 hypomethylated-upregulated genes. Using methylation-specific and qRT-PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3, and ACSL4 genes were confirmed. Pathways involved in insulin signaling, ubiquitin-mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter.

Conclusions: This study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF.
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http://dx.doi.org/10.1111/odi.13811DOI Listing
February 2021

Rapid Implementation of a Multidisciplinary COVID-19 Cytokine Storm Syndrome Task Force.

ACR Open Rheumatol 2021 Mar 6;3(3):133-137. Epub 2021 Feb 6.

Montefiore Medical Center - Albert Einstein College of Medicine, Bronx, New York.

Objective: Patients with coronavirus disease 2019 (COVID-19) can progress to a state of unregulated inflammation called cytokine storm syndrome (CSS). We describe formation and operation of a COVID-19 multidisciplinary consultation service that was allowed to individualize treatment for critically ill patients with COVID-19 during the pandemic.

Methods: Institutional experts from different subspecialties formed a COVID-19 CSS task force at Montefiore Medical Center, Bronx, NY. They agreed on a set of four clinical and six laboratory parameters that can help early identify COVID-19 CSS. We describe the formation and implementation of the COVID-19 task force. The case series description of the COVID-19 CSS consultation cohort highlights consultation volume, baseline characteristics, clinical and laboratory parameters, and how biologic treatments were allocated to these patients.

Results: Between April 4,2020, and May 7,2020, the COVID-19 CSS task force was formed, consisting of adult and pediatric rheumatologists and allergy and immunology physicians. The task force evaluated a total of 288 patients, of whom 197 (68%) were male, the median (interquartile range [IQR]) age was 62 (51-70) years, 122 (42%) were Hispanic, and 88 (31%) were Black or African American. The common presenting symptoms in all referred patients were dyspnea (85%) and diarrhea (80%). Thirty-one patients who received biologic therapy were younger, with a median (IQR) age of 53 (32-63) years, as opposed to 62.5 (52-70) years in the nonbiologic group (P = 0.008). A higher proportion receiving biologics was in the critical care setting (26 [84%] vs 151 [59%]; P = 0.006).

Conclusion: To the best of our knowledge, this is the first multidisciplinary collaborative effort to provide individualized patient recommendations for evaluation and treatment of patients with COVID-19 who may have CSS. This working model helped to devise an approach that may have identified patients who were most likely to benefit from biologic therapy in the absence of evidence-based guidelines.
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http://dx.doi.org/10.1002/acr2.11220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966876PMC
March 2021

Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes.

Comput Struct Biotechnol J 2021 17;19:153-160. Epub 2020 Dec 17.

Al Jalila Genomics Center, Al Jalila Children's Hospital, Dubai, United Arab Emirates.

Characterizing key molecular and cellular pathways involved in COVID-19 is essential for disease prognosis and management. We perform shotgun transcriptome sequencing of human RNA obtained from nasopharyngeal swabs of patients with COVID-19, and identify a molecular signature associated with disease severity. Specifically, we identify globally dysregulated immune related pathways, such as cytokine-cytokine receptor signaling, complement and coagulation cascades, JAK-STAT, and TGF- β signaling pathways in all, though to a higher extent in patients with severe symptoms. The excessive release of cytokines and chemokines such as , , and and certain interferons and interleukins related genes like , , and were significantly higher in patients with severe clinical presentation compared to mild and moderate presentations. Differential gene expression analysis identified a small set of regulatory genes that might act as strong predictors of patient outcome. Our data suggest that rapid transcriptome analysis of nasopharyngeal swabs can be a powerful approach to quantify host molecular response and may provide valuable insights into COVID-19 pathophysiology.
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http://dx.doi.org/10.1016/j.csbj.2020.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773686PMC
December 2020

Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With and Gene Polymorphisms.

Front Endocrinol (Lausanne) 2020 30;11:575469. Epub 2020 Oct 30.

Center for Diabetes Research, Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the and gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that and gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.
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http://dx.doi.org/10.3389/fendo.2020.575469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664831PMC
June 2021

Utility and Predictive Value of CHIIDA Score in Pediatric Traumatic Brain Injury: A Prospective Observational Study.

J Neurosurg Anesthesiol 2020 Nov 10. Epub 2020 Nov 10.

Department of Anesthesia, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, Maharshtra, India.

Background: The Children's Intracranial Injury Decision Aid (CHIIDA) is a tool designed to stratify children with mild traumatic brain injury (mTBI). The aim of this study was to assess the utility and predictive value of CHIIDA in the assessment of the need for intensive care unit (ICU) admission in pediatric patients with mTBI.

Methods: This prospective observational study included 425 children below 18 years of age admitted to the ICU of a tertiary care hospital with mTBI (Glasgow Coma Scale 13 to 15). The primary outcome was the composite of neurosurgical intervention, intubation for more than 24 hours for TBI, or death from TBI. Sensitivity, specificity, predictive values and likelihood ratios were calculated at CHIIDA scores 0 and 2.

Results: Among 425 children with mTBI, 210 (49%) had a CHIIDA score 0, 16 (4%) scored 2 points, and 199 (47%) scored more than 2 points. Thirty-six (8.47%) patients experienced the primary outcome, and there were 3 deaths. A cutoff CHIIDA >0 to admit to ICU had a sensitivity of 97.22% (95% confidence interval [CI], 97.05%-97.39%) and a negative predictive value of 99.54% (95% CI, 99.50%-99.56%). A cutoff of score >2 had a sensitivity of 97.22% (95% CI, 97.05%-97.39%), and negative predictive value of 99.56% (95% CI, 99.54%-99.59%). The post-test probability at cutoff score of 0 and 2 was 16.65% and 16.27%, respectively.

Conclusions: CHIIDA score does not serve as reliable triage tool for identifying children with TBI who do not require ICU admission.
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http://dx.doi.org/10.1097/ANA.0000000000000743DOI Listing
November 2020

A histology-free description of a new species of the genus Tetrastemma (Nemertea: Hoplonemertea: Monostilifera) from Hawaii and India.

Zootaxa 2020 Jul 2;4808(2):zootaxa.4808.2.10. Epub 2020 Jul 2.

A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Street 17, Vladivostok 690041, Russia Far Eastern Federal University, Vladivostok 690091, Russia.

A new species of the genus Tetrastemma Ehrenberg, 1831, T. freyae sp. nov., is described and illustrated from Hawaii and India. The description is based on light microscopy examination of the external and internal morphology, as well as on two gene markers (cytochrome c oxidase subunit I and histone H3 DNA).
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http://dx.doi.org/10.11646/zootaxa.4808.2.10DOI Listing
July 2020

Telemedicine During COVID-19 and Beyond: A Practical Guide and Best Practices Multidisciplinary Approach for the Orthopedic and Neurologic Pain Physical Examination.

Pain Physician 2020 08;23(4S):S205-S238

LSU Health Science Center, New Orleans.

Background: The COVID pandemic has impacted almost every aspect of human interaction, causing global changes in financial, health care, and social environments for the foreseeable future. More than 1.3 million of the 4 million cases of COVID-19 confirmed globally as of May 2020 have been identified in the United States, testing the capacity and resilience of our hospitals and health care workers. The impacts of the ongoing pandemic, caused by a novel strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have far-reaching implications for the future of our health care system and how we deliver routine care to patients. The adoption of social distancing during this pandemic has demonstrated efficacy in controlling the spread of this virus and has been the only proven means of infection control thus far. Social distancing has prompted hospital closures and the reduction of all non-COVID clinical visits, causing widespread financial despair to many outpatient centers. However, the need to treat patients for non-COVID problems remains important despite this pandemic, as care must continue to be delivered to patients despite their ability or desire to report to outpatient centers for their general care. Our national health care system has realized this need and has incentivized providers to adopt distance-based care in the form of telemedicine and video medicine visits. Many institutions have since incorporated these into their practices without financial penalty because of Medicare's 1135 waiver, which currently reimburses telemedicine at the same rate as evaluation and management codes (E/M Codes). Although the financial burden has been alleviated by this policy, the practitioner remains accountable for providing proper assessment with this new modality of health care delivery. This is a challenge for most physicians, so our team of national experts has created a reference guide for musculoskeletal and neurologic examination selection to retrofit into the telemedicine experience.

Objectives: To describe and illustrate musculoskeletal and neurologic examination techniques that can be used effectively in telemedicine.

Study Design: Consensus-based multispecialty guidelines.

Setting: Tertiary care center.

Methods: Literature review of the neck, shoulder, elbow, wrist, hand, lumbar, hip, and knee physical examinations were performed. A multidisciplinary team comprised of physical medicine and rehabilitation, orthopedics, rheumatology, neurology, and anesthesia experts evaluated each examination and provided consensus opinion to select the examinations most appropriate for telemedicine evaluation. The team also provided consensus opinion on how to modify some examinations to incorporate into a nonhealth care office setting.

Results: Sixty-nine examinations were selected by the consensus team. Household objects were identified that modified standard and validated examinations, which could facilitate the examinations.The consensus review team did not believe that the modified tests altered the validity of the standardized tests.

Limitations: Examinations selected are not validated for telemedicine. Qualitative and quantitative analyses were not performed.

Conclusions: The physical examination is an essential component for sound clinical judgment and patient care planning. The physical examinations described in this manuscript provide a comprehensive framework for the musculoskeletal and neurologic examination, which has been vetted by a committee of national experts for incorporation into the telemedicine evaluation.
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August 2020

Sonographically Guided Percutaneous Sectioning of the Coracohumeral Ligament for the Treatment of Refractory Adhesive Capsulitis: Proof of Concept.

Pain Med 2020 12;21(12):3314-3319

Memorial Sloan Kettering Cancer Center, New York City, New York, USA.

Introduction: Treatment options are limited for nonsurgical chronic refractory cases of adhesive capsulitis. We describe a novel percutaneous tenotomy technique for coracohumeral ligament interruption with cadaveric validation.

Objective: The objective of this study was to describe and validate a novel technique for percutaneous interruption of the coracohumeral ligament.

Design: Cadaveric study.

Setting: Academic tertiary care center.

Methods: Eight cadavers underwent ultrasound (US)-guided percutaneous incision of the coracohumeral (CHL) ligament. Performance of the procedure requires that the practitioner make oscillatory motions with a needle that uses ultrasound energy to cut through tissue. Each pass removes a pinhead-sized amount of tissue. The number of passes and the cutting time are recorded during the procedure. As a standard for this procedure does not exist, the authors created their own based on the preclinical information presented here. Postprocedure dissection was performed to assess the extent of CHL interruption and injury to surrounding tissue.

Results: The average resection time was seven minutes, requiring 500 passes. The technique described in this paper completely interrupted the CHL in all subjects. Cadaveric analysis demonstrated interruption of the CHL with respect to control shoulders requiring an average of seven minutes of cutting time and ∼500 micro-perforations.

Conclusion: US-guided percutaneous CHL ligament sectioning is possible with a commercially available ultrasonic probe.
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http://dx.doi.org/10.1093/pm/pnaa262DOI Listing
December 2020

Electric field stimulates production of highly conductive microbial OmcZ nanowires.

Nat Chem Biol 2020 10 17;16(10):1136-1142. Epub 2020 Aug 17.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.

Multifunctional living materials are attractive due to their powerful ability to self-repair and replicate. However, most natural materials lack electronic functionality. Here we show that an electric field, applied to electricity-producing Geobacter sulfurreducens biofilms, stimulates production of cytochrome OmcZ nanowires with 1,000-fold higher conductivity (30 S cm) and threefold higher stiffness (1.5 GPa) than the cytochrome OmcS nanowires that are important in natural environments. Using chemical imaging-based multimodal nanospectroscopy, we correlate protein structure with function and observe pH-induced conformational switching to β-sheets in individual nanowires, which increases their stiffness and conductivity by 100-fold due to enhanced π-stacking of heme groups; this was further confirmed by computational modeling and bulk spectroscopic studies. These nanowires can transduce mechanical and chemical stimuli into electrical signals to perform sensing, synthesis and energy production. These findings of biologically produced, highly conductive protein nanowires may help to guide the development of seamless, bidirectional interfaces between biological and electronic systems.
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http://dx.doi.org/10.1038/s41589-020-0623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502555PMC
October 2020

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

J Clin Invest 2020 11;130(11):6093-6108

Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
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http://dx.doi.org/10.1172/JCI136363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598066PMC
November 2020

Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes.

Sci Rep 2020 07 14;10(1):11561. Epub 2020 Jul 14.

Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden.

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
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http://dx.doi.org/10.1038/s41598-020-68130-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360755PMC
July 2020

Global chemical effects of the microbiome include new bile-acid conjugations.

Nature 2020 03 26;579(7797):123-129. Epub 2020 Feb 26.

Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA.

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.
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http://dx.doi.org/10.1038/s41586-020-2047-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252668PMC
March 2020

Modulation of flagellar rotation in surface-attached bacteria: A pathway for rapid surface-sensing after flagellar attachment.

PLoS Pathog 2019 11 4;15(11):e1008149. Epub 2019 Nov 4.

Department of Medicine (Infectious Diseases), Yale University, New Haven, Connecticut, United States of America.

Attachment is a necessary first step in bacterial commitment to surface-associated behaviors that include colonization, biofilm formation, and host-directed virulence. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa can initially attach to surfaces via its single polar flagellum. Although many bacteria quickly detach, some become irreversibly attached and express surface-associated structures, such as Type IV pili, and behaviors, including twitching motility and biofilm initiation. P. aeruginosa that lack the GTPase FlhF assemble a randomly placed flagellum that is motile; however, we observed that these mutant bacteria show defects in biofilm formation comparable to those seen for non-motile, aflagellate bacteria. This phenotype was associated with altered behavior of ΔflhF bacteria immediately following surface-attachment. Forward and reverse genetic screens led to the discovery that FlhF interacts with FimV to control flagellar rotation at a surface, and implicated cAMP signaling in this pathway. Although cAMP controls many transcriptional programs in P. aeruginosa, known targets of this second messenger were not required to modulate flagellar rotation in surface-attached bacteria. Instead, alterations in switching behavior of the motor appeared to result from direct or indirect effects of cAMP on switch complex proteins and/or the stators associated with them.
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http://dx.doi.org/10.1371/journal.ppat.1008149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855561PMC
November 2019

Comparison of intramuscular methylergometrine, rectal misoprostol, and low-dose intravenous oxytocin in active management of the third stage of labor.

Ci Ji Yi Xue Za Zhi 2019 Jul-Sep;31(3):158-162

Department of Urology, S. P. Medical College, Bikaner, Rajasthan, India.

Objective: Active management of the third stage of labor (AMTSL) is a critical intervention for the prevention of postpartum hemorrhage (PPH), which is still the most common cause of maternal morbidity and mortality worldwide. The objective of the study is to compare the effect of intramuscular methylergometrine, rectal misoprostol, and low-dose intravenous oxytocin in the AMTSL in terms of amount of blood loss and duration of the third stage of labor, cost-effectiveness, and side effect profile.

Materials And Methods: Seventy-five pregnant patients admitted in the maternity ward for vaginal delivery from February 2017 to February 2018 received either intramuscular methylergometrine (0.2 mg) or rectal misoprostol (400 mcg) or low-dose intravenous oxytocin (5 units oxytocin in 100 mL normal saline) for AMTSL. Data were recorded in three groups: Group A (methylergometrine), Group B (misoprostol), and Group C (oxytocin) consisting of 25 cases each.

Results: Mean blood loss was found to be least in methylergometrine group (246.87 ± 65.44 mL) as compared to misoprostol (346.13 ± 58.35 mL) and oxytocin (334.5 ± 69.20 mL) ( = 0.000) Mean duration of the third stage of labor was also least in methylergometrine group (6.21 ± 1.58 min) ( = 0.0008).

Conclusion: Although methylergometrine was found to have higher incidence of side effects such as nausea, vomiting, headache, and raised blood pressure, it was found to be the most effective drug for minimizing blood loss in the third stage of labor. In remote places where healthcare facilities are limited and drugs cannot be administered by parenteral route, rectal misoprostol remains an alternative.
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http://dx.doi.org/10.4103/tcmj.tcmj_89_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559031PMC
July 2019

Proteome based de novo sequencing of novel conotoxins from marine molluscivorous cone snail Conus amadis and neurological activities of its natural venom in zebrafish model.

Protein Pept Lett 2019 Jun 14. Epub 2019 Jun 14.

Molecular & Nanomedicine Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama Institute of Science and Technology, Chennai 600119. India.

Conus amadis is a carnivorous snail found abundantly in coastal waters of India. They are equipped with potent chemical arsenal made of neurotoxic peptide concoction used for predation and competition. In this study, we have identified 19 novel conotoxins containing 1, 2 & 3 disulfides, belonging to different classes, from a molluscivorous cone snail Conus amadis using proteome based MALDI-TOF and LC-MS-MS analysis. Among them, 2 novel contryphans, 3 T-superfamily conotoxin, 2 A-superfamily conotoxins and 2 Mini M-Superfamily conotoxins were sequenced to its amino acid level from the fragmented spectrum of singly and doubly charged parent ions using de novo sequencing strategies. ama1054, a contryphan peptide toxin, possesses post translationally modified bromo tryptophan at its seventh position. Except ama1251, all the sequenced peptide toxins possess modified C-terminal amidation. Moreover, we have screened the crude venom for the presence of biological function in zebrafish model. Crude venom exhibited anticonvulsant properties in pentylenetetrazole-induced seizure in zebrafish larvae which suggested anti-epileptic properties of the venom cocktail. Acetyl cholinesterase activity was also identified in the venom complex.
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http://dx.doi.org/10.2174/0929866526666190614144006DOI Listing
June 2019

Structures of Polar and Lateral Flagella Revealed by Cryo-Electron Tomography.

J Bacteriol 2019 07 10;201(13). Epub 2019 Jun 10.

Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA

The bacterial flagellum is a sophisticated self-assembling nanomachine responsible for motility in many bacterial pathogens, including , spp., and The bacterial flagellum has been studied extensively in the model systems and serovar Typhimurium, yet the range of variation in flagellar structure and assembly remains incompletely understood. Here, we used cryo-electron tomography and subtomogram averaging to determine structures of polar flagella in and peritrichous flagella in Typhimurium, revealing notable differences between these two flagellar systems. Furthermore, we observed flagellar outer membrane complexes as well as many incomplete flagellar subassemblies, which provide additional insight into mechanisms underlying flagellar assembly and loss in both and Typhimurium. The bacterial flagellum has evolved as one of the most sophisticated self-assembled molecular machines, which confers locomotion and is often associated with virulence of bacterial pathogens. Variation in species-specific features of the flagellum, as well as in flagellar number and placement, results in structurally distinct flagella that appear to be adapted to the specific environments that bacteria encounter. Here, we used cutting-edge imaging techniques to determine high-resolution structures of polar flagella in and peritrichous flagella in serovar Typhimurium, demonstrating substantial variation between flagella in these organisms. Importantly, we observed novel flagellar subassemblies and provided additional insight into the structural basis of flagellar assembly and loss in both and Typhimurium.
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http://dx.doi.org/10.1128/JB.00117-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560136PMC
July 2019

Morphology-dependent, green, and selective catalytic styrene oxidation on CoO.

Dalton Trans 2019 Apr;48(14):4574-4581

Catalysis Division, CSIR-National Chemical Laboratory, Dr Homi Bhabha Road, Pune 411 008, India.

Despite the great successes in the controlled fabrication of nanomaterials with specific composition and morphology, it is still challenging to have the desired control on the defect sites of catalyst materials. For unfolding the mystery of this aspect, catalytic styrene epoxidation was attempted on spinel Co3O4 with two different morphologies, namely, SNR (nanorods prepared by the solvothermal method with the (110) facet), HNR (nanorods prepared by the hydrothermal methodwith the (111) facet) and NC (nanocubes with the (110) facet) were synthesized and subjected to olefin oxidation with O2. Even without any catalyst pretreatment, all three Co3O4 catalyst systems were found to be active for selective epoxidation of styrene with O2 at ambient pressure in the liquid phase. The correlation between catalytic activity and selectivity trend suggests that the reaction is highly structure-sensitive and facile on the (110) facet. Temperature-dependent near ambient pressure X-ray photoelectron spectroscopy (NAPXPS) was carried out at 0.1 mbar O2 pressure to understand the mechanistic aspects. The distinct catalytic activity of NC (110) and SNR (110) can be attributed to the population of defect sites on the catalyst surface. NC morphology with comparatively fewer defect sites shows high activity and selectivity, suggesting that styrene oxidation on Co3O4 is structure-sensitive; however, unlike metal surfaces, fewer defects are more favourable for catalytic styrene epoxidation due to facile adsorption and activation of the substrate and O2 on Co3+ sites. The present investigations suggest that surface defects need not necessarily increase catalytic activity.
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http://dx.doi.org/10.1039/c8dt05154bDOI Listing
April 2019

Should I Stay or Should I Go? Pseudomonas Just Can't Decide.

Cell Host Microbe 2019 01;25(1):5-7

Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA. Electronic address:

Surface sensing is a fundamental yet poorly understood behavior of swimming bacteria. In this issue of Cell Host & Microbe, Laventie et al. (2019) describe a cyclic-di-GMP-dependent pathway used by the opportunistic pathogen Pseudomonas aeruginosa to respond to surface binding on a several second timescale.
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http://dx.doi.org/10.1016/j.chom.2018.12.011DOI Listing
January 2019

Transcriptome profiling reveals PDZ binding kinase as a novel biomarker in peritumoral brain zone of glioblastoma.

J Neurooncol 2019 Jan 20;141(2):315-325. Epub 2018 Nov 20.

Department of Neuropathology, National Institute of Mental Health and Neuroscience, Bangalore, India.

Purpose: Peritumoural brain zone (PT) of glioblastoma (GBM) is the area where tumour recurrence is often observed. We aimed to identify differentially regulated genes between tumour core (TC) and PT to understand the underlying molecular characteristics of infiltrating tumour cells in PT.

Methods: 17 each histologically characterised TC and PT tissues of GBM along with eight control tissues were subjected to cDNA Microarray. PT tissues contained 25-30% infiltrating tumour cells. Data was analysed using R Bioconductor software. Shortlisted genes were validated using qRT-PCR. Expression of one selected candidate gene, PDZ Binding Kinase (PBK) was correlated with patient survival, tumour recurrence and functionally characterized in vitro using gene knock-down approach.

Results: Unsupervised hierarchical clustering showed that TC and PT have distinct gene expression profiles compared to controls. Further, comparing TC with PT, we observed a significant overlap in gene expression profile in both, despite PT having fewer infiltrating tumour cells. qRT-PCR for 13 selected genes validated the microarray data. Expression of PBK was higher in PT as compared to TC and recurrent when compared to newly diagnosed GBM tumours. PBK knock-down showed a significant reduction in cell proliferation, migration and invasion with increase in sensitivity to radiation and Temozolomide treatment.

Conclusions: We show that several genes of TC are expressed even in PT contributing to the vulnerability of PT for tumour recurrence. PBK is identified as a novel gene up-regulated in PT of GBM with a strong role in conferring aggressiveness, including radio-chemoresistance, thus contributing to recurrence in GBM tumours.
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http://dx.doi.org/10.1007/s11060-018-03051-5DOI Listing
January 2019

Anaesthetic management of tracheal restenosis in operated cases of tracheal resection and anastomosis: A retrospective review.

Indian J Anaesth 2018 Oct;62(10):815-818

Department of ENT Surgery, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Mumbai, Maharashtra, India.

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http://dx.doi.org/10.4103/ija.IJA_213_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190414PMC
October 2018

Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function.

Proc Natl Acad Sci U S A 2018 12 15;115(49):E11523-E11531. Epub 2018 Nov 15.

Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505;

The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of or in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in macrophages. mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand-receptor contact causes inflammatory disease in SMCR8-deficient mice.
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http://dx.doi.org/10.1073/pnas.1814753115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298088PMC
December 2018

New Strategy toward a Dual Functional Nanocatalyst at Ambient Conditions: Influence of the Pd-Co Interface in the Catalytic Activity of [email protected] Core-Shell Nanoparticles.

ACS Appl Mater Interfaces 2018 Dec 21;10(48):41268-41278. Epub 2018 Nov 21.

Catalysis Division , National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411 008 , India.

Bimetallic nanostructures with a combination of noble and nonnoble metals hold promise for improving catalyst activity and selectivity. Here, we report the synthesis of [email protected] (PC) core-shell morphology nanoparticles with three different ratios of palladium (Pd) and cobalt (Co), and a possibility to fine tune the ratio of core and shell thickness. PC exhibits superior and selective hydrogenation as well as oxidation catalytic activity at ambient or near-ambient conditions. Various characterization techniques have been employed to confirm the core-shell morphology. Without any pre-treatment or activation, fresh catalysts with different Pd to Co ratios, that is, 2:1, 1:1, and 1:2, were subjected to olefin (phenylacetylene) hydrogenation and oxidation (styrene to styrene oxide) reaction. The catalytic activity results demonstrate that the 1:1 ratio of Pd/Co is the most active composition for controlled and stepwise reduction of phenyl acetylene to styrene and then to ethyl benzene; 1:1 Pd/Co shows 100% styrene conversion in 30 min. with an order of magnitude higher turnover frequency than other catalysts. The 1:1 PC ratio is also the most active composition for selective oxidation of styrene to styrene oxide. NAPXPS (near-ambient pressure XPS) results show that the active sites for catalytic C═C hydrogenation and oxidation reaction are Co and Co, respectively. However, the superior catalytic performance can be attributed to Co (for reduction) or Co (for oxidation), and the Pd-Co interface plays a critical role in stabilizing the required functional character. NAPXPS results confirm that the superior catalytic performance can be attributed not only to Co or Co, but also to the Pd-Co interface. The electronic effect and synergism between Co and Pd helps Co to stabilize in different oxidation states depending on the reaction conditions, and making it a dual functional catalyst.
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http://dx.doi.org/10.1021/acsami.8b12940DOI Listing
December 2018

Mumps outbreak investigation in Jaisalmer, Rajasthan, India, June-September 2016.

J Med Virol 2019 03 31;91(3):347-350. Epub 2018 Oct 31.

Department of Epidemiology, National Centre of Disease Control, Delhi, India.

Mumps, a vaccine-preventable disease, cause inflammation of salivary glands and may cause severe complications, such as encephalitis, meningitis, deafness, and orchitis/oophoritis. In India, mumps vaccine is not included in the universal immunization program and during 2009 to 2014, 72 outbreaks with greater than 1500 cases were reported. In August 2016, a suspected mumps outbreak was reported in Jaisalmer block, Rajasthan. We investigated to confirm the etiology, describe the epidemiology, and recommend prevention and control measures. We defined a case as swelling in the parotid region in a Jaisalmer block resident between 23 June 2016 and 10 September 2016. We searched for cases in health facilities and house-to-house in affected villages and hamlets. We tested blood samples of cases for mumps immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA). We found 162 cases (60% males) with a median age of 9.4 years (range: 7 month-38 years) and 65 (40%) were females. Symptoms included fever (70%) and bilateral swelling in neck (65%). None of them were vaccinated against mumps. Most (84%) cases were school-going children (3-16 years old). The overall attack rate was 2%. Village A, with two hamlets, had the highest attack rate (hamlet 1 = 13% and hamlet 2 = 12%). School A of village A, hamlet 1, which accommodated 200 children in two classrooms, had an attack rate of 55%. Of 18 blood samples from cases, 11 tested positive for mumps IgM ELISA. This was a confirmed mumps outbreak in Jaisalmer block that disproportionately affected school-going children. We recommended continued surveillance, 5-day absence from school, and vaccination.
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http://dx.doi.org/10.1002/jmv.25324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409212PMC
March 2019

MicroRNAs Enable mRNA Therapeutics to Selectively Program Cancer Cells to Self-Destruct.

Nucleic Acid Ther 2018 10 8;28(5):285-296. Epub 2018 Aug 8.

1 Department of Molecular Biology, Moderna Therapeutics , Cambridge, Massachusetts.

The advent of therapeutic mRNAs significantly increases the possibilities of protein-based biologics beyond those that can be synthesized by recombinant technologies (eg, monoclonal antibodies, extracellular enzymes, and cytokines). In addition to their application in the areas of vaccine development, immune-oncology, and protein replacement therapies, one exciting possibility is to use therapeutic mRNAs to program undesired, diseased cells to synthesize a toxic intracellular protein, causing cells to self-destruct. For this approach to work, however, methods are needed to limit toxic protein expression to the intended cell type. Here, we show that inclusion of microRNA target sites in therapeutic mRNAs encoding apoptotic proteins, Caspase or PUMA, can prevent their expression in healthy hepatocytes while triggering apoptosis in hepatocellular carcinoma cells.
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http://dx.doi.org/10.1089/nat.2018.0734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157376PMC
October 2018

Current practice patterns of supraglottic airway device usage in paediatric patients amongst anaesthesiologists: A nationwide survey.

Indian J Anaesth 2018 Apr;62(4):269-279

Department of Anaesthesiology, Lokmanya Tilak Municipal General Hospital, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.

Background And Aims: Supraglottic airway devices (SGADs) are increasingly being used for airway management in paediatric patients undergoing general anaesthesia. This survey was designed to assess the nationwide practice patterns of SGAD usage in paediatric patients.

Methods: A questionnaire of 28 questions was circulated amongst 16,532 members of the Indian Society of Anaesthesiologists through online survey engine Google Forms and served manually to 500 delegates attending the Asian Society of Paediatric Anaesthesiologists conference 2017. Percentage, mean and standard deviation were calculated using Microsoft Excel 2016 (Redmond, WA, USA).

Results: Four hundred and five (2.3%) valid responses were obtained. The most commonly used device was i-gel (60.74%). Three hundred and four (75.06%) respondents had access to second-generation SGADs. Second-generation devices (60.74%) were more commonly used than first-generation devices (39.26%). Anaesthesiologists utilised SGADs in various challenging scenarios such as in the difficult airway (53.33%), remote locations (55.47%), ophthalmologic (38.77%) and long-duration surgeries (17.53%). Sixty per cent respondents did not use SGADs in laparoscopic surgery. Disposable SGADs were reused by 77.28% respondents. Oropharyngeal seal and intracuff pressures were not measured by 86.91% and 56.92% respondents, respectively. Difficulty in size selection (84.19%), securing position (82.22%) and maintaining unobstructed ventilation (78.76%) were common problems encountered while using SGADs.

Conclusion: Although there is a widespread use of second-generation SGADs in Indian paediatric anaesthesia, safe practices such as using capnography, measurement of oropharyngeal seal pressure, cuff pressure and appropriate disinfection are lacking.
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http://dx.doi.org/10.4103/ija.IJA_65_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907432PMC
April 2018

ERK Activation Pathways Downstream of GPCRs.

Int Rev Cell Mol Biol 2018 5;338:79-109. Epub 2018 Apr 5.

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India; Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India. Electronic address:

GPCRs, the 7-TM receptors, represent a class of cell surface receptors which modulate a variety of physiological responses. The serpentine structure in addition to contributing the diversity of stimuli these receptors can sense also provides flexibility to the extracellular and intracellular regions where other proteins can interact with and can form functionally active multimeric entities. The range in signaling and physiological responses generated by these receptors can be attributed to a large repertoire of the receptor subtypes as well as their differential coupling to various classes of G-protein subunits and other proteins which facilitate multistate activation. A multistate GPCR can engage diverse signaling molecules, thereby modulating not only the canonical cellular responses but also noncanonical responses typically associated with activation of other cascades such as RTK and MAPK/ERK signaling. Given the crucial involvement of MAP kinase/ERK signaling in cell fate determination specially with respect to regulating cell proliferation, cellular apoptosis, and survival, GPCR-mediated cross-activation of MAPK has been explored in various systems and shown to involve functional integration of multiple pathways. This review describes the present knowledge of the different mechanisms of ERK activation downstream of GPCRs and our present understanding of receptor-dependent and -independent MAPK activation cascades.
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http://dx.doi.org/10.1016/bs.ircmb.2018.02.003DOI Listing
January 2019

Spatiotemporal Modulation of ERK Activation by GPCRs.

Int Rev Cell Mol Biol 2018 7;338:111-140. Epub 2018 Apr 7.

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India; Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India. Electronic address:

ERK1/2 (extracellular signal-regulated protein kinases) are the nodal proteins that regulate diverse cellular functions primarily in response to activation from receptor tyrosine kinases (RTKs). Not only is ERK activated through a variety of RTKs, but noncanonical signaling through GPCRs also activates them. Such multimodal activation allows appropriate integration of many inputs to critical cell fate decisions such as proliferation and differentiation that MAP kinases typically regulate. MAP kinases also regulate many polar responses such as apoptosis and proliferation, dedifferentiation-differentiation, and the diversity in the outcomes though the same terminal molecule can be explained based on differences in the activation dynamics and rates. However, two processes have now been established as drivers for most of the diversity recorded in the outcomes of MAP kinase signaling. These parameters are cellular compartmentalization, i.e., spatial confinement of the molecules participating in a pathway and changes in the kinetics of the activation-deactivation, i.e., temporal regulation. While phosphorylation is the key to activating responses, specifically for ERK, the terminal MAP kinase, it is the spatiotemporal dynamics that governs the outcome generated by it. This chapter reviews our present understanding of the spatial and temporal regulation of MAP kinase cascade and the ERK activity, specifically through GPCRs.
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http://dx.doi.org/10.1016/bs.ircmb.2018.02.004DOI Listing
January 2019