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Reactive arthritis (ReA) is an aseptic synovitis condition that often develops 2-4 weeks after a distant (extra-articular) infection with Chlamydia, Salmonella, Shigella, Campylobacter, and Yersinia species. The metabolic changes in the synovial fluid (SF) may serve as indicative markers to both improve the diagnostic accuracy and understand the underlying inflammatory pathology of ReA. With this aim, the metabolic profiles of SF collected from ReA (n = 58) and non-ReA, i.e., rheumatoid arthritis (RA, n = 21) and osteoarthritis (OA, n = 20) patients, respectively, were measured using NMR spectroscopy and compared using orthogonal partial least-squares discriminant analysis (OPLS-DA). The discriminatory metabolic features were further evaluated for their diagnostic potential using the receiver operating characteristic (ROC) curve analysis. Compared to RA, two (alanine and carnitine), and compared to OA, six (NAG, glutamate, glycerol, isoleucine, alanine, and glucose) metabolic features were identified as diagnostic biomarkers. We further demonstrated the impact of ReA synovitis condition on the serum metabolic profiles through performing a correlation analysis. The Pearson rank coefficient (r) was estimated for 38 metabolites (profiled in both SF and serum samples obtained in pair from ReA patients) and was found significantly positive for 71% of the metabolites (r ranging from 0.17 to 0.87).

Purpose This study aims to identify the operational and financial risks associated with the city gas distribution project in India and suggest appropriate strategies to mitigate them. Design/methodology/approach This study aims to identify the operational and financial risks associated with the city gas distribution project in India and suggest appropriate strategies to mitigate them. The survey data is evaluated using factor analysis to understand the latent structure of the critical risk factors. Second, the author uses Situation, Actor and Process–Learning, Action and Performance framework to suggest the mitigation strategies for the identified operational and financial risk factors. Findings The research identified five critical risk factors and suggested 39 mitigation strategies to address operational and risk factors impacting CGD projects. The findings of this research will enable the CGD companies to formulate long-term strategies for their business and adopt proactive measures to mitigate the operational and financial risks causing delay and increasing project costs. This study also highlights the importance of government support in developing a conducive environment for CGD industry to thrive. Originality/value The CGD projects are critical for natural gas growth in India’s energy mix. The project delay leads to a rise in the total cost involved and increases the payback period for the CGD companies. To the best of authors’ knowledge, this research is first of its kind that identifies the critical operational and financial risks affecting CGD projects in India and suggests the mitigating strategies for them.

Purpose This study aims to identify and rank the operational and financial risks causing a delay in the commencement of the city gas distribution project in India. Design/methodology/approach This study reviews the literature to identify operational and financial risks variables associated with infrastructure projects. Followed by a survey to isolate and assess the critical risk factors for city gas distribution network project in India. The survey data is evaluated using factor analysis to understand the latent structure of the critical risk factors. Second, the author ranks the identified variables as per significance by using the mean score method. Findings Five critical risk factors with 20 variables were extracted and assessed to build more understanding of their significance and impact on city gas distribution network project. Originality/value This study is the first attempt to follow the management approach to identify and rank operational and financial risks impacting city gas distribution project.

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that elicits several pro-tumoral responses. It has been linked to proliferation and invasiveness in glioblastomas. In the present study, prevalence of the receptor (PAR-1) and its associated downstream signaling was studied in two human glioblastoma cell lines D-54 MG and U-87 MG. The expression of PAR1 was found to be significantly higher in D-54 MG cell-line when compared to U-87 MG cell-line. The activation of PAR-1 in the presence of TFLLR (a synthetic peptide activator of PAR-1) led to an increase in ERK ½ activity along with a significant increase in the migration and invasion of these cell-lines. Subsequent treatment with SCH-79797 (PAR-1 inhibitor) significantly decreased the migration and invasion in these glioma cell lines, respectively. The relative increase and decrease in the migration and invasion of these cell lines in presence of activator and inhibitor respectively was found to be linked with the expression of PAR-1. To conclude the study links the PAR-1 signaling with progression of Glioblastoma. PAR-1 and associated downstream signaling may be a potential therapeutic target to preclude the pathogenesis of gliomas.

The COVID-19 pandemic has posed unprecedented challenges to the global economy. India faces a multitude of challenges due to COVID-19 impacts. The pandemic-induced economic lockdown has posed barriers to various clean energy and low carbon infrastructure development projects. The renewable energy sector, which has been heavily dependent on global supply chains for meeting the equipment and material demand is expected to fall short of the proposed target of installed capacity. Simultaneously, India’s plans towards developing low carbon infrastructure and the smart cities also have been seriously delayed owing to the pandemic induced crisis. The paper examines the impact of the pandemic on low carbon infrastructure development in the country which mainly includes renewable energy development plans and smart cities. The paper argues that it is critical for the country to develop an adequate emergency response system and sustainable recovery measures to minimize the impacts of economic volatilities in the future.

Impaired re-epithelialization characterized by hyperkeratotic nonmigratory wound epithelium is a hallmark of nonhealing diabetic wounds. In chronic wounds, the copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte (KC) activator. This work sought to understand the signal transduction pathway responsible for wound re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57BL/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering KC proliferation and migration. OSM activated the Jak-signal transducer and activator of transcription pathway as manifested by signal transducer and activator of transcription 3 phosphorylation. Such signal transduction in the human KC induced TP63, the master regulator of KC function. Elevated TP63 induced ITGB1, a known effector of KC migration. In diabetic wounds, OSM was more abundant than the level in nondiabetic wounds. However, in diabetic wounds, OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued the compromised KC migration caused by glycated OSM. Finally, topical application of recombinant OSM improved KC migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound site, OSM is inactivated by glycation, and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure.

Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.

Background Diabetes is among the most prevalent diseases worldwide, of all the affected individuals a significant proportion of the population remains undiagnosed due to lack of specific symptoms early in this disorder and inadequate diagnostics. Diabetes and its associated sequela, i.e., comorbidity are associated with microvascular and macrovascular complications. As diabetes is characterized by an altered metabolism of key metabolites and regulatory pathways. Metabolic phenotyping can provide us with a better understanding of the unique set of regulatory perturbations that predispose to diabetes and its associated complication/comorbidities. Methodology The present study utilizes the analytical platform NMR spectroscopy coupled with Random Forest statistical analysis to identify the discriminatory metabolites in diabetes (DB = 38) vs. diabetes-related complication (DC = 35) along with the healthy control (HC = 50) subjects. A combined and pairwise analysis was performed to identify the discriminatory metabolites responsible for class separation. The perturbed metabolites were further rigorously validated using t-test, AUROC analysis to examine the statistical significance of the identified metabolites. Results The DB and DC patients were well discriminated from HC. However, 15 metabolites were found to be significantly perturbed in DC patients compared to DB, the identified panel of metabolites are TCA cycle (succinate, citrate), methylamine metabolism (trimethylamine, methylamine, betaine), -intermediates; energy metabolites (glucose, lactate, pyruvate); and amino acids (valine, arginine, glutamate, methionine, proline, and threonine). Conclusion The 1H NMR metabolomics may prove a promising technique to differentiate and predict diabetes and its complication on their onset or progression by determining the altered levels of the metabolites in serum.

The pathogenesis of the diabetic foot ulcer (DFU) is very complex. Among other known factors, such as poor innervation and vascularization, chronic infection and inflammation are critical factors that result in chronicity of these wounds. Novel and emerging concepts in chronic infection and inflammatory response are discussed in this chapter. Lack of adequate solutions for treatment of chronic wound infections such as antibiotic resistant and biofilm infections may result in serious consequences, including poor quality of life and amputations in patients with diabetes. Novel solutions that can counter these threats are urgently needed. A thorough understanding of the principles of immune dysfunction and insufficient resolution of inflammation will lead to innovative interventions that can drive a diabetic wound towards resolution of inflammation, which is conducive to healing.

Natural gas has been gaining popularity as a fuel for the next century across the globe. The Indian government has been pushing to boost the natural gas share in the energy mix to 15% by 2030. City Gas Distribution (CGD) plays a crucial role in meeting the set target as the Indian government has given it a tag of priority sector. The Indian Government has been aggressively expanding the CGD footprints across India by conducting the bidding rounds for new Geographic Areas (GAs). This paper provides a comprehensive review of city gas distribution and delivers insights on developing a sustainable natural gas business in India.

Collagen containing wound-care dressings are extensively used. However, the mechanism of action of these dressings remain unclear. Earlier studies utilizing a modified collagen gel (MCG) dressing demonstrated improved vascularization of ischemic wounds and better healing outcomes. Wound macrophages are pivotal in facilitating wound angiogenesis and timely healing. The current study was designed to investigate the effect of MCG on wound macrophage phenotype and function. MCG augmented recruitment of macrophage at the wound-site, attenuated pro-inflammatory and promoted anti-inflammatory macrophage polarization. Additionally, MCG increased anti-inflammatory IL-10, IL-4 and pro-angiogenic VEGF production, indicating a direct role of MCG in resolving wound inflammation and improving angiogenesis. At the wound-site, impairment in clearance of apoptotic cell bioburden enables chronic inflammation. Engulfment of apoptotic cells by macrophages (efferocytosis) resolves inflammation via a miR-21-PDCD4-IL-10 pathway. MCG-treated wound macrophages exhibited a significantly bolstered efferocytosis index. Such favorable outcome significantly induced miR-21 expression. MCG-mediated IL-10 production was dampened under conditions of miR-21 knockdown pointing towards miR-21 as a causative factor. Pharmacological inhibition of JNK attenuated IL-10 production by MCG, implicating miR-21-JNK pathway in MCG-mediated IL-10 production by macrophages. This work provides direct evidence demonstrating that a collagen-based wound-care dressing may influence wound macrophage function and therefore modify wound inflammation outcomes.

Ethnopharmacological relevance Ficus racemosa (FR) has been used for thousands of years in Ayurvedic system of medicine in India and is closely associated with prevention, treatment and cure of various human ailments like obesity and diabetes. It is popularly known as gular. A vast and wide range of chemical compounds like polyphenols, friedelane-type triterpenes, norfriedelane type triterpene, eudesmane-type sesquiterpene including various glycosides had been isolated from this plant. However, no detail studies related to isolation of flavonoids has been reported previously with their antidiabetic, hypolipidemic and toxicological consequences. Aim of the study The present study was undertaken to evaluate antidiabetic, hypolipidemic and toxicological assessments of flavonoids isolated from Ficus racemosa (FR) stem bark. Materials and methods We isolated four flavonoids from stem bark of FR and structures were confirmed by Infrared spectroscopy (IR), Nuclear Magnetic Resonance (NMR) (both 1D and 2D), mass spectroscopy (MS). Later, these flavonoids were administered to streptozotocin (STZ) rats once in a day for a period of seven days at 100 mg/kg dose. We measured blood glucose level and body weight changes at different days (1st, 3rd, 5th and 7th days). Serum lipid profiles were also estimated to investigate the hypolipidemic potential of flavonoids in the similar experiment. Various oxidative stress parameters in pancreas and liver and hepatic biomarker enzymes in plasma were also determined to investigate the toxicity potential of isolated flavonoids. Finally, we performed docking studies to find out the mechanism of action. Results Our results collectively suggested that four flavonoids reduced blood glucose level and restored body weight, signifying antidiabetic action. There were reduction of other lipid profile parameters and increase of high density lipoprotein (HDL) during administration of flavonoids, also signifying hypolipidemic action. Various oxidative stress biomarkers and hepatic enzymes levels were also normalized with respect to diabetic control at the same time. Docking studies revealed that isolated flavonoids showed their antidiabetic potential via binding to PPARγ and GLUT1 receptors. Conclusion The isolated four flavonoids demonstrated good antidiabetic, hypolipidemic and antioxidant properties in STZ diabetic rats which supported the use of FR stem bark as useful supplementary drug for future antidiabetic therapy.

Background: Diabetes is among the most prevalent diseases worldwide, of all the affected individuals a significant proportion of the population remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. Diabetes and its associated sequela, i.e., comorbidity are associated with microvascular and macrovascular complications. As diabetes is characterized by an altered metabolism of key metabolites and regulatory pathways. Metabolic phenotyping can provide us with a better understanding of the unique set of regulatory perturbations that predispose to diabetes and its associated comorbidities. Methodology: The present study utilizes the analytical platform NMR spectroscopy coupled with Random Forest statistical analysis to identify the discriminatory metabolites of diabetes (DB) and diabetes-related comorbidity (DC) along with the healthy control (HC) subjects. A combined and pairwise analysis was performed, between the serum samples of HC (n=50), and DB (n=38), and DC (n=35) individuals to identify the discriminatory metabolites responsible for class separation. The perturbed metabolites were further rigorously validated using t-test, AUROC analysis to examine the statistical significance of the identified metabolites. Results: The DB and DC patients were well discriminated from HC. However, 15 metabolites were found to be significantly perturbed in DC patients compared to DB, the identified panel of metabolites are TCA cycle (succinate, citrate), methylamine metabolism (trimethylamine, methylamine, betaine), -intermediates; energy metabolites (glucose, lactate, pyruvate); and amino acids (valine, arginine, glutamate, methionine, proline and threonine). The metabolites were further used to identify the perturbed metabolic pathway and correlation of metabolites in DC patients. Conclusion: The 1H NMR metabolomics may prove a promising technique to differentiate and predict diabetes and its comorbidities on their onset or progression by determining the altered levels of the metabolites in serum.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patient's response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

Background There is an unmet need for biomarkers in Systemic Sclerosis (SSc). Despite its shortcomings, the modified Rodnan skin score (mRSS) has remained the standard disease assessment tool for SSc. Expression of certain genes, cartilage oligomeric matrix protein ( COMP ), thrombospondin-1 ( THS1 ), interferon-induced 44 ( IFI44 ) and sialoadhesin ( SIG1 ), and, more recently, Tenascin-C ( TNSC ), have been shown to correlate with skin fibrosis. However, assessment of the expression of these genes requires a skin biopsy. Hence, we used an open-ended approach to identify a serum-based biomarker of SSc. Objectives To identify small molecules in serum that correlate with mRSS and profibrotic genes that are upregulated in skin of SSc patients Methods We obtained serum and skin biopsies from 25 consenting adult patients with SSc and serum from 25 age- and sex-similar controls. mRNA levels of five genes: COMP , THS1 , IFI44 , SIG1 , and TNSC were estimated as fold-change relative to Glyceraldehyde 3-phosphate dehydrogenase ( GAPDH) , a housekeeping gene. H 1 NMR (Nuclear Magnetic Resonance) based metabolomics studies were performed on the sera using standard protocols. Principal component analysis (PCoA) and Partial Least Squares Discriminant Analysis (PLSDA) were used to delineate metabolites that were different between patients and healthy controls. Then spearman correlations (ρ) of these metabolites with mRSS and the fold-expression of the five pro-fibrotic genes were estimated. Results H 1 NMR based metabolomics identified 126 peaks that were different between patients and controls. Out of these, the levels of glycine had the best correlation with pro-fibrotic gene expression (ρ=0.5, p IFI44 ; ρ=0.44, p TNSC ). Choline inversely correlated with SIG1 (ρ=-0.41; p=0.05) while Glycerophosphocholine correlated with mRSS (ρ=0.50, p Conclusions H 1 NMR based metabolomics identified glycine, choline and their metabolites as potential biomarkers for skin fibrosis in SSc. These findings require validation in a larger cohort. References Farina G, Lafyatis D, Lemaire R, Lafyatis R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2010 Feb;62(2):580–8. Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Lafyatis R, Lee J, Hinchcliff M, Feghali-Bostwick C, Lakota K, Budinger GR, Raparia K, Tamaki Z, Varga J.Tenascin-C drives persistence of organ fibrosis. Nat Commun. 2016 Jun 3;7:11703. Disclosure of Interest None declared

Background Takayasu arteritis (TA) is a chronic large vessel vasculitis of unknown etiopathogenesis. The serological and radiological parameters currently used to assess the disease activity are not highly specific and there is a pertinent need for a biomarker discovery. In our previous study [1], NMR based serum metabolomics had revealed distinctive metabolic signatures in patients with TA compared to age/sex matched healthy controls. In this study we sought to investigate whether these distinctive metabolites correlate with disease activity. Objectives To identify the discriminatory serum metabolic profiles and their correlation with disease activity. Methods Patients with TA fulfilling ACR criteria were assessed for disease activity by ITAS 2010, with a score of 4 or more, considered as active. The serum metabolic profiles of active and inactive TA patients were obtained at 800 MHZ NMR spectrometer and were compared using multivariate orthogonal partial least-squares discriminant analysis (OPLS-DA) to identify metabolites that changed in response to disease activity [based on PLS-DA VIP (variable importance on projection) score >2.0 and permutation test, p-value Results 88 patients were categorized into active (34) and inactive (54) groups. Median age in active and inactive groups was 25 years and 27 years respectively. Female to male ratio was 3.4:1 in the active group and 5:1 in the inactive group. Majority had class V disease. Mean duration of illness was 4.0±3.5 years in active TA and 6.5±5.5 years in inactive TA group. An exquisite separation in OPLS-DA score plot showed metabolic differences between active and inactive TA patients (Fig. 1A). The key metabolite entities identified with highest discriminatory potential (VIP score >2) were glucose, glutamine, glycine, N-acetyl glycoprotein (NAG), choline, and low/very-low density lipoproteins (LDL/VLDL). Of them glucose, glycine, and NAGs were elevated in the sera of active TA patients, whereas glutamine, choline and LDL levels were decreased in these patients. Receiver operating characteristic (ROC) curve analysis revealed NAG has the highest potential to discriminate active from inactive TA patients (area under the ROC curve was 0.75 (p-value Conclusions The study revealed discriminatory metabolites between active and inactive TA patients and evaluated the possibility of NAG as a clinical biomarker for activity judgment in this disease. However, more work needs to be done to validate the results in a large cohort of patients in a longitudinal manner. References Guleria A, Misra DP, Rawat A, Dubey D, Khetrapal CL, Bacon PA, Misra R, and Kumar D, NMR based serum metabolomics discriminates Takayasu Arteritis from Healthy Individuals: A proof of principle study” Journal of Proteome Research (2015), 14 (8), 3372–3381. Disclosure of Interest None declared

Management of patient with Lupus Nephritis (LN) continues to remain a challenge for the treating physicians because of considerable morbidity and even mortality. The search of biomarkers in serum and urine is a focus of researchers to unravel new targets for therapy. In the present study, the utility of NMR-based serum metabolomics has been evaluated for the first time in discriminating LN patients from non-nephritis lupus patients (SLE) and further to get new insights into the underlying disease processes for better clinical management. Metabolic profiling of sera obtained from 22 SLE patients, 40 LN patients and 30 healthy controls (HC) were performed using high resolution 1D 1H-CPMG and diffusion edited NMR spectra to identify the potential molecular biomarkers. Using multivariate analysis, we could distinguish SLE and LN patients from HC and LN from SLE patients. Compared to SLE patients, the LN patients had increased serum levels of lipid metabolites (including LDL/VLDL lipoproteins), creatinine and decreased levels of acetate. Our results revealed that metabolic markers especially lipids and acetate derived from NMR spectroscopy has high sensitivity and specificity to distinguish LN among SLE patients and has the potential to be a useful adjunctive tool in diagnosis and clinical management of LN.