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Amidst global environmental reforms, the role of energy systems is under scrutiny to promote ecological welfare through low-carbon alternatives. Amongst the solutions, the role of renewable energy as a clean source has become popular to mitigate climate change. However, the impact of debt on renewable energy consumption remains limited in the economic literature. The debt initiatives provide funding for environmental initiatives primarily, while it is also credited as a barrier to limiting the growth of clean energy programs. Within such discussion, the current study extended the dialogue by examining how external debt impacts energy transition in Brazil, Russia, India, China, and South Africa (BRICS) economies in the presence of institutional quality, education expenditures, and banking development. Using the novel CS-ARDL, AMG, and CCEMG tests, the study results showed that external debt decreases renewable energy consumption, while institutional quality, educational expenditures, banking developments, and economic growth are essential elements of green energy developments. Based on these conclusions, this study provides novel policy guidelines to align BRICS energy and economic agendas., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study contributes to the environment-growth nexus literature by examining corruption's effect on environmental quality in 17 Middle East and North Africa (MENA) countries between 1984 and 2018. We use four different indicators of environmental degradation (ecological footprint, carbon dioxide emissions, greenhouse gas emissions, and carbon emission intensity) to gain a comprehensive view of the relationship. This study's methodological value added is the application of the method of moments quantile regression, which enables us to account for different relationships between the independent variables and environmental quality at different levels of environmental degradation. The results indicate that corruption worsens environmental quality based on three of the four indicators of environmental degradation, while the impact appears to become less severe at higher levels of environmental deterioration. The results also indicate that traditional mean-based panel data estimation methods provide an incomplete picture of the factors behind environmental problems: The explanatory variables' impacts tend to vary at different levels of environmental quality, and the impact's sign can even change when moving from the lowest to the highest environmental degradation quantiles. Overall, the results highlight the importance of curbing corruption to enable enforcement of more stringent environmental regulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Given the alarming rate of climate change and environmental degradation, major countries are seeking ways to curtail environmental damage and attain sustainability in the future. In the quest for a green economy, countries are motivated to adopt renewable energy that can assist in resource conservation and efficiency. Accordingly, this study examines the diverse effects of the underground economy, environmental policy strictness, geopolitical risk, gross domestic product, carbon emissions, population, and oil prices on renewable energy for 30 high- and middle-income countries from 1990 to 2018. The empirical outcomes based on quantile regression document significant variations across two country groups. For instance, for high-income countries, the shadow economy has a detrimental effect across all quantiles but it is statistically significant at the top quantiles. Nonetheless, the effect of the shadow economy on renewable energy is detrimental and significant statistically across all quantiles for middle-income countries. In the context of environmental policy stringency, the effect is positive across both country groups, though there is heterogeneity in outcomes. Geopolitical risk has a positive influence on the deployment of renewable energy for high-income countries but negatively impacts renewables for middle-income countries. As far as policy suggestions are concerned, the policymakers of both high- and middle-income countries need to take steps to constrain the growth of the shadow economy by adopting effective policy strategies. Policies need to be implemented for middle income-countries to reduce the unfavorable effect of geopolitical uncertainty. The findings of this study contribute to a better and more precise understanding of factors shaping the role of renewables whereby the energy crisis would be mitigated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The United Nations Climate Change Conference (COP26) recommended that the member nations enhance their technological progression and structural transformation to mitigate the problems of climate change. The BRICS-T countries consisting of Brazil, Russia, India, China, South Africa, and Turkey agreed to implement COP26's policy suggestions. These countries accounted for 40% of global greenhouse gas emissions in 2017, thus posing severe threats to the global environment. The current study explores the role of renewable energy, forest depletion, eco-innovations, and export diversification in impacting the ecological footprint for those BRICS-T countries. We further examine the moderating effect of eco-innovations on agriculture on the BRICS-T nations. The study contributes to the existing literature by providing newer empirical insights on how eco-innovations and export diversification, along with renewable energy, forest cover, and agriculture, affecting the ecological footprint in the BRICS-T nations. It utilizes novel empirical methods like parametric and non-parametric techniques to derive the short-run and long-run empirical results. The empirical findings based on the augmented mean group and the kernel regularized least square methods document that economic growth, agriculture value added, and forest depletion increase the ecological footprint. In contrast, renewable energy and eco-innovations decrease the level of ecological footprint. In the long run, a 1% rise in GDP leads to a rise in the ecological footprint by 0.64% using the augmented mean group (AMG) estimation. The mean marginal effects are - 0.27%, 0.29%, and 0.17% for renewable energy; agriculture and forest cover, respectively, using the kernel-based regularized least square methods. The study suggests that policies designed for controlling the ecological footprints focus on the use of energy efficient technologies, particularly in the agricultural sector., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The cascade of amyloid formation relates to multiple complex events at the molecular level. Previous research has established amyloid plaque deposition as the leading cause of Alzheimer's disease (AD) pathogenesis, detected mainly in aged population. The primary components of the plaques are two alloforms of amyloid-beta (Aβ), Aβ 1 - 42 and Aβ 1 - 40 peptides. Recent studies have provided considerable evidence contrary to the previous claim indicating that amyloid-beta oligomers (AβOs) as the main culprit responsible for AD-associated neurotoxicity and pathogenesis. In this review, we have discussed the primary features of AβOs, such as assembly formation, the kinetics of oligomer formation, interactions with various membranes/membrane receptors, the origin of toxicity, and oligomer-specific detection methods. Recently, the discovery of rationally designed antibodies has opened a gateway for using synthesized peptides as a grafting component in the complementarity determining region (CDR) of antibodies. Thus, the Aβ sequence motif or the complementary peptide sequence in the opposite strand of the β-sheet (extracted from the Protein Data Bank: PDB) helps design oligomer-specific inhibitors. The microscopic event responsible for oligomer formation can be targeted, and thus prevention of the overall macroscopic behaviour of the aggregation or the associated toxicity can be achieved. We have carefully reviewed the oligomer formation kinetics and associated parameters. Besides, we have depicted a thorough understanding of how the synthesized peptide inhibitors can impede the early aggregates (oligomers), mature fibrils, monomers, or a mixture of the species. The oligomer-specific inhibitors (peptides or peptide fragments) lack in-depth chemical kinetics and optimization control-based screening. In the present review, we have proposed a hypothesis for effectively screening oligomer-specific inhibitors using the chemical kinetics (determining the kinetic parameters) and optimization control strategy (cost-dependent analysis). Further, it may be possible to implement the structure-kinetic-activity-relationship (SKAR) strategy instead of structure-activity-relationship (SAR) to improve the inhibitor's activity. The controlled optimization of the kinetic parameters and dose usage will be beneficial for narrowing the search window for the inhibitors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Asides from renewable energy consumption, technological innovation and remittances are mostly ignored as critical tools and resources that can be adopted to ameliorate environmental worries, even when remittances have more considerable resource inflow than official development aids. Based on this information, the current research investigates the implications of technological innovation, remittances, globalization, financial development, and renewable energy on CO 2 emissions in top remittances-receiving countries from 1990 to 2021. To obtain reliable estimates, we use a battery of advanced econometric techniques and method of moments quantile regression (MMQR) method. The AMG results suggest that innovation, remittances, renewable energy, and financial development alleviate CO 2 emanations, whereas globalization and economic growth worsen environmental sustainability by increasing CO 2 emissions. Besides, the MMQR results confirm that renewable energy, innovation, and remittances decrease CO 2 emissions across all quantiles. A bidirectional causality exists amid financial development and CO 2 emanations, and across remittances and CO 2 emissions. However, one-way causality flows from economic growth, renewable energy and innovation to CO 2 . This study suggests some essential measures for ecological sustainability in light of the findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aims to evaluate the role of preoperative vitamin D supplementation before coronary artery bypass grafting (CABG) surgery in preventing postoperative atrial fibrillation (POAF) in vitamin D deficient or insufficient patients. Three randomized controlled trials (RCTs) comprising 448 subjects were selected after a detailed search was conducted on PubMed, Cochrane CENTRAL, Scopus, and Embase in December 2022. Analysis was run using RevMan (version 5.4.1; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The analysis collected risk ratio (RR) and 95% confidence interval (CI) data from the relevant studies, which were then pooled using a random effects model. A significance level of less than 0.05 (p<0.05) was considered significant. Our analysis showed that compared with the standard of care, preoperative vitamin D supplementation in vitamin D deficient and insufficient patients effectively reduced POAF after CABG surgery (RR=0.6, 95% CI=0.4-0.9, P=0.01). There was no significant difference in the duration of hospitalization between the vitamin D supplementation group compared with the control following CABG (mean difference -0.85, 95% CI -2.13 to 0.43, P = 0.19). This meta-analysis shows that preoperative vitamin D supplementation in vitamin D deficient and insufficient patients undergoing CABG can reduce the rate of POAF. As POAF is associated with many complications, providing vitamin D supplementation to individuals with a vitamin D deficiency undergoing CABG can improve long-term cardiovascular outcomes following surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ansari et al.)

There is a plethora of studies on the energy-consumption-environmental-quality nexus. Nevertheless, empirical research on the impact of global uncertainties on environmental quality is lacking. This study contributes to the literature by examining the impact of economic policy uncertainty (EPU), geopolitical risk (GPR), and economic complexity on the ecological footprint and carbon emissions of E7 economies for the period 1995-2018. Our empirical results indicate a long-term relationship between economic complexity, EPU, GPR, energy consumption, and two environmental quality indicators, carbon dioxide emissions and ecological footprint. In the long run, a divergence from disequilibrium takes 3 years to return to the equilibrating position. The environmental effects of key determinants are different in terms of direction, magnitude, and time span. Specifically, an inverted U-shape describes the relationship between economic complexity and environmental degradation in the long-term only, which confirms the environmental Kuznets curve (EKC) hypothesis. The environmental effects of EPU and GPR are harmful in the short run but prove to be beneficial in the long run. Higher energy consumption significantly degrades environment quality as expected. Based on these findings, the paper provides several useful suggestions for policymakers in the context of E7 countries., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Self-assembly of disordered amyloid-beta (Aβ) peptides results in highly ordered amyloid fibrils. The structural information of the early-stage events and also in the presence of inhibitors is of great significance. It is challenging to acquire due to the nature of the amyloids and experimental constraints. Here, we demonstrate the cascade of aggregation (early to late) of the Aβ 25-35 peptide in the absence and presence of carvedilol, a nonselective β-adrenergic receptor blocker. The aggregation process of Aβ 25-35 peptide is monitored using Thioflavin T (ThT) fluorescence, dynamic light scattering (DLS), circular dichroism (CD), Raman spectroscopic techniques, and imaging experiments. We find that the Aβ 25-35 peptide undergoes an early-stage (3-6 h) helical intermediate formation across the fibrillation pathway using CD and Raman measurements. Carvedilol obstructs the helical intermediate formation of Aβ 25-35 peptide resulting in inhibition. CD spectra and deconvolution of the Raman bands suggest the β-sheet formation (24-100 h) in the absence of carvedilol. Spectroscopic results indicate a disordered structure for the peptide in the presence of carvedilol (24-100 h). Electron microscopy (EM) shows the formation of polymorphic fibrils for the peptide alone and non-amyloidal aggregates in the presence of carvedilol. Molecular docking study suggests that the plausible mode of interaction with carvedilol involves the C-terminal residues of the peptide., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Diverse pathogens can potentially persist and proliferate in reclaimed water distribution systems (RWDSs). The goal of this study was to evaluate interactive effects of reclaimed water treatments and water age on persistence and proliferation of multiple fecal (e.g., Klebsiella , Enterobacter ) and non-fecal (e.g., Legionella , mycobacteria) gene markers in RWDSs. Six laboratory-scale RWDSs were operated in parallel receiving the influent with or without biologically active carbon (BAC) filtration + chlorination, chloramination, or no disinfectant residual. After 3 years of operation, the RWDSs were subject to sacrificial sampling and shotgun metagenomic sequencing. We developed an in-house metagenome-derived pathogen quantification pipeline, validated by quantitative polymerase chain reaction and mock community analysis, to estimate changes in abundance of ∼30 genera containing waterborne pathogens. Microbial community composition in the RWDS bulk water, biofilm, and sediments was clearly shaped by BAC filtration, disinfectant conditions, and water age. Key commonalities were noted in the ecological niches occupied by fecal pathogen markers in the RWDSs, while non-fecal pathogen markers were more varied in their distribution. BAC-filtration + chlorine was found to most effectively control the widest range of target genera. However, filtration alone or chlorine secondary disinfection alone resulted in proliferation of some of these genera containing waterborne pathogens.

Appropriate management approaches are needed to minimize the proliferation of antibiotic resistance genes (ARGs) in reclaimed water distribution systems (RWDSs). Six laboratory-scale RWDSs were operated over 3 years receiving influent with or without biologically active carbon (BAC) filtration + chlorination, chloramination, or no disinfectant residual. Shotgun metagenomic sequencing was applied toward comprehensive characterization of resistomes, focusing on total ARGs, ARG mobility, and specific ARGs of clinical concern. ARGs such as aadA, bacA , bla OXA , mphE , msrE , sul1 , and sul2 were found to be particularly sensitive to varying RWDS conditions. BAC filtration with chlorination most effectively achieved and maintained the lowest levels of nearly all metagenomically derived antibiotic resistance indicators. However, BAC filtration or addition of residual disinfectants alone tended to increase these indicators. Biofilm and sediment compartments harbored ARGs in disinfected systems, presenting a concern for their release to bulk water. Relative and absolute abundances of most ARGs tended to decrease with water age (up to 5 days), with notable exceptions in BAC-filtered chloraminated and no residual systems. Superchlorination of unfiltered water especially raised concerns in terms of elevation of clinically relevant and mobile ARGs. This study revealed that BAC filtration and disinfection must be carefully coordinated in order to effectively mitigate ARG dissemination via RWDSs.

In this study, the asymmetric Granger causality relationship between tourist arrivals and world pandemic uncertainty index is examined by controlling inflation, consumer confidence index, and industrial production for the period 2000M1 and 2020M1 in Italy. To the best of our knowledge, the current study is one of the few studies to investigate the relationship between tourist arrivals and world pandemic uncertainty in an asymmetric framework. The empirical results show that using the Granger causality test in a linear framework causes bias results due to misspecification. Therefore, the study relies on asymmetric Granger causality test results which reveal that the positive shock of world pandemic uncertainty Granger causes a negative shock of tourist arrivals. It is suggested that international tourist arrivals are sensitive to external shocks such as pandemics and in such instances the government of the concerned country can insulate the tourism-service and hospitality industry against the shocks by developing strategies to promote full information between all stakeholders., Competing Interests: Conflict of interestThe author declare that they have no conflict of interest., (© Springer Nature B.V. 2020.)

Competing Interests: There are no conflicts of interest.

Patients with COVID-19 present with a myriad of comorbidities. An immunocompromised state like HIV in patients with COVID-19 can be life-threatening. We searched PubMed/Medline, Scopus, and Web of Science for case reports and case series about COVID-19 in HIV patients. We finally reviewed 20 case reports including cases of 43 patients with HIV and COVID-19. The mean age of 43 adult patients was 51.56 ± 27.56 years (range 24-76 years). Of these, 30 were male (69.77%), 11 were female (25.58%), and 2 were transgender (4.65%). A total of 25 patients (58.14%) were above 50 years of age. The most common cardiovascular comorbidities were hypertension and hyperlipidemia (48.8%), diabetes (20.93%), and morbid obesity (11.63%). Out of 43 HIV patients with COVID-19, 6 resulted in death (13.95%). All the patients who died were elderly above 50 years and required mechanical ventilation. HIV patients infected with COVID-19 had a high mortality rate. A high burden of pre-existing comorbidities and an advanced age in these patients make them prone to disease progression and worse outcomes., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Small heat shock proteins (sHSPs) belong to the superfamily of molecular chaperones. They prevent aggregation of partially unfolded or misfolded client proteins, providing protection to organisms under stress conditions. Here, we report the biophysical and structural characterization of a small heat shock protein (HspA) from a thermophilic cyanobacterium Thermosynechococcus vulcanus in the presence of 2 M urea. HspA has been shown to be important for the protection of Photosystem II and the Phycobilisome antenna complex at elevated temperatures. Heterologously expressed HspA requires the presence of 1-2 M urea to maintain its solubility at concentrations required for most characterization methods. Spectroscopic studies reveal the presence of the β-sheet structure and intactness of the tertiary fold in HspA. In vitro assays show that the HspA maintains chaperone-like activity in protecting soluble proteins from thermal aggregation. Chromatography and electron microscopy show that the HspA exists as a mixture of oligomeric forms in the presence of 2 M urea. HspA was successfully crystallized only in the presence of 2 M urea. The crystal structure of HspA shows urea-induced loss of about 30% of the secondary structure without major alteration in the tertiary structure of the protein. The electron density maps reveal changes in the hydrogen bonding network which we attribute to the presence of urea. The crystal structure of HspA demonstrates a mixture of both direct interactions between urea and protein functionalities and interactions between urea and the surrounding solvent that indirectly affect the protein, which are in accordance with previously published studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The risk of cardiovascular disease has been reported to have a linear relationship with LDL levels. Additionally, the currently recommended LDL target goal of 70 mg/dl does not diminish the CV risk entirely leaving behind some residual risk. Previous attempts to maximally lower the LDL levels with statin monotherapy have met dejection due to the increased side effects associated with the treatment. Nevertheless, with the new advancements in clinical medicine, it has now become possible to bring down the LDL levels to as low as 15 mg/dl using PCSK9 monoclonal antibodies alone or in combination with statins. The development of inclisiran, siRNA silencer targeting PCSK9 gene, is a one step forward in these endeavors. Moreover, various studies aiming to lower the CV risk and mortality by lowering LDL levels have demonstrated encouraging results. The current challenge is to explore this arena to redefine the target LDL levels, if required, to avoid any suboptimal treatment. After thorough literature search in the PubMed, Embase, Scopus, and Google Scholar, we present this article to provide a brief overview of the safety and efficacy of lowering LDL below the current goal.

Iliopsoas abscess (IPA) is an uncommon diagnosis in medical wards. Herein, we present two unusual cases of IPA. First patient was an elderly diabetic patient who had gas-forming bilateral IPA caused by Escherichia coli. This infection proved fatal and patient succumbed on third day of hospital admission. Second patient was a young boy who had right sided sacroilitis with IPA. Staphylococcus aureus was isolated from the pus culture and patient was successfully treated without any sequelae.

Tropical pulmonary eosinophilia (TPE) is a rare allergic manifestation to the filarial nematode. A 38-year old male and a 15-year old female presented with cough and breathlessness. Their complete blood count showed eosinophilia. This finding was overshadowed by the radiological findings suggestive of tuberculosis. The diagnosis of TPE was confirmed by filarial antigen detection test and both the patients were successfully treated with diethylcarbamazine. TPE presents with cough and breathlessness and can be often confused with tuberculosis, especially in endemic settings. An important clue in differentiating the two entities is the presence of eosinophilia in the former.

Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB) 1 and CB 2 receptors; however, only CB 2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Several DNA binding proteins exist in dimeric form when bound with DNA to be able to exhibit various biological processes such as DNA repair, DNA replication and gene expression. Various dimeric forms of Ribonuclease A (RNase A) and other members of the ribonuclease A superfamily are endowed with a multitude of biological activities such as antitumor and antiviral activity. In the present study, we have compared the DNA binding properties between the RNase A monomer and the dityrosine (DT) cross-linked RNase A dimer, and checked the inhibitory effect of DNA on the ribonucleolytic activity of the dimeric protein. An agarose gel based assay shows that like the monomer, the dimer also binds with DNA. The number of nucleotides bound per monomer unit of the dimer is higher than the number of nucleotides that bind with the each monomer. From fluorescence measurements, the association constant (Ka) values for complexation of the monomer and the dimer with ct-DNA are (4.95±0.45)×10(4)M(-1) and (1.29±0.05)×10(6)M(-1) respectively. Binding constant (Kb) values for the binding of the monomer and the dimer with ct-DNA were determined using UV-vis spectroscopy and were found to be (4.96±1.67)×10(4)M(-1) and (4.32±0.31)×10(5)M(-1) respectively. Circular dichroism studies shows that the dimer possesses significant effect on DNA conformation. The melting profile for the ct-DNA-dimer indicated that the melting temperature (Tm) for the ct-DNA-dimer complex is lower compared to the ct-DNA-monomer complex. The ribonucleolytic activity of the dimer, like the monomer, diminishes upon binding with DNA., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

Pseudomonas aeruginosa is a ubiquitous environmental bacterium and an opportunistic pathogen with the ability to rapidly develop multidrug resistance under selective pressure. Previous work demonstrated that upon exposure to the environmental contaminant pentachlorophenol (PCP), P. aeruginosa PAO1 increases expression of multiple multidrug efflux pumps, including the MexAB-OprM pump. The current study describes increases in the antibiotic resistance of PAO1 upon exposure to PCP and other chlorinated organics, including triclosan. Only exposure to chlorinated phenols induced the mexAB-oprM-mediated antibiotic-resistant phenotype. Thus, chlorinated phenols have the potential to contribute to transient phenotypic increases of antibiotic resistance that are relevant when both compounds are present in the environment., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states with minimal cannabimimetic effects., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

TetX is a flavin-dependent monooxygenase. It has been reported to inactivate all tested tetracyclines. In this study, Escherichia coli overexpressing TetX was added to soil bacterial enrichment cultures along with varying levels of tetracycline and was found to affect community-wide tetracycline resistance levels. Soil microbial communities developed lower levels of tetracycline resistance upon exposure to 25 μg/mL of tetracycline when an E. coli expressing TetX was present (6% of cultivable bacteria were resistant to 40 μg/mL tetracycline). In contrast, in the absence of TetX activity, a similar tetracycline exposure selected for greater levels of resistant bacteria in the soil microbial community (90% of cultivable bacteria were resistant to 40 μg/mL tetracycline). We also describe new metabolites formed after tetracycline transformation by TetX and report the transient generation of redox-active metabolite(s). The results presented here are particularly pertinent in the light of the recent emergence of tet(X) in different bacterial species, including clinical isolates., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In vitro fibrillation of hen egg white lysozyme (HEWL) causes complete reduction of Cu(II) to Cu(I) at pH 7. Here in the present article, we have shown the presence of both Cu(II) and Cu(I) at pH 11 during fibrillation of HEWL using electron paramagnetic resonance and Raman spectroscopy. Our results suggest the existence of a partially reducing environment during fibrillation of hen egg white lysozyme at pH 11. The fibrillation process is governed by the pH of the solution and maximum fibrillation is found to occur at pH 11. Fibrils formed in the absence of Cu(II) were also found to cause significant hemolysis of RBC., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Hen egg white lysozyme (HEWL) adopts a molten globule-like state at high pH (~12.75) and is found to form amyloid fibrils at alkaline pH. Here, we report that Cu(II) inhibits self-association of HEWL at pH 12.75 both at 37 and 65 °C. A significant reduction in Thioflavin T fluorescence intensity, attenuation in β-sheet content and reduction in hydrophobic exposure were observed with increasing Cu(II) stoichiometry. Electron paramagnetic resonance spectroscopy suggests a 4N type of coordination pattern around Cu(II) during fibrillation. Cu(II) is also capable of altering the cytotoxicity of the proteinaceous aggregates. Fibrillar species of diverse morphology were found in the absence of Cu(II) with the generation of amorphous aggregates in the presence of Cu(II), which are more toxic compared to the fibrils alone.

Lactoferrin (LF) has several biological effects ranging from ribonuclease activity to antiangiogenic activity. It thus serves as a potential target protein for studies related to ribonucleolytic activity in association with its antiangiogenic activity. We have isolated buffalo LF and checked the ribonucleolytic activity via an agarose gel-based assay and precipitation assay. The ribonucleolytic activity of LF is lower compared to RNase A and the pH profile is a bell-shaped curve, with a pK1 value of 5.43 and pK2 of 7.65. The ribonuclease inhibitor that inhibits many ribonuclease-type proteins by forming a tight complex is unable to inhibit the ribonucleolytic property of LF. Fe(III) behaves as a noncompetitive inhibitor for the ribonucleolytic activity of protein. The superoxide-scavenging activity of the protein has also been measured. Histidine modification by diethylpyrocarbonate was monitored by UV-Vis spectroscopy at pH 7 and pH 8 and the effect towards the ribonucleolytic activity was determined. The antiangiogenic property of LF was investigated by the chorioallantoic membrane assay. Finally, the possible active site was analyzed via docking studies and correlated with the experimental study.

During the past several years, studies on the protein aggregation process in the presence of cosolvents/ co-solutes have been looked into which provides significant insight in the stability of proteins in a crowded cellular milieu. Here, in the present report we have investigated the fibrillation of human serum albumin (HSA) under the mixed aqueous-ethanol solvent conditions at two different temperatures (37 °C and 65 °C). Self-association of protein was monitored using various spectroscopic and microscopic techniques. Results obtained from detailed investigation have shown that fibrillation of human serum albumin is favored at higher temperature (65 °C) at lower ethanol concentration. However, at 37 °C comparatively higher ethanol concentration is the prerequisite condition for fibrillation process to take place.

The genome of Sphingobacterium sp. strain PM2-P1-29 was sequenced. The bacterium contains a physiologically active tet(X) gene, encoding a tetracycline-degrading monooxygenase. To our knowledge, this is the only bacterium naturally harboring tet(X) for which tetracycline degradation has been demonstrated., (Copyright © 2014 Ghosh et al.)

Molten globule state plays a crucial role in the amyloidogenesis of several proteins. Hen egg white lysozyme (HEWL) acquires a molten globule state at alkaline pH (12.75). Our study reveals a significant inhibitory effect of high molecular weight polyethylene glycols (PEG) (PEG 20000 and PEG 35000) against alkali-salt mediated fibrillation of HEWL. Native state of HEWL is stabilized in the presence of PEGs accompanied by a decrease in the β-sheet content. Enzymatic activity of HEWL is mostly retained in the presence of polyethylene glycols. The comparable hydrodynamic radius (Rh) of PEG 20000 and native HEWL is central reason to the greater inhibitory potency of PEG 20000 against HEWL fibrillation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Unlabelled: Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent preclinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinociceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FAAH inhibitor PF-3845 in models of neuropathic pain (i.e., chronic constrictive injury of the sciatic nerve (CCI)) and inflammatory pain induced by an intraplantar injection of carrageenan. Here, we report that combined administration of subthreshold doses of these drugs produced enhanced antinociceptive effects in CCI and carrageenan pain models, the latter of which was demonstrated to require both CB1 and CB2 receptors. The combined administration of subthreshold doses of these drugs also increased AEA levels and decreased prostaglandin levels in whole brain. Together, these data add to the growing research that dual blockade of FAAH and COX represents a potential therapeutic strategy for the treatment of neuropathic and inflammatory pain states., Perspective: Tandem inhibition of FAAH and COX attenuates inflammatory and neuropathic pain states, which may avoid potentially harmful side effects of other therapeutic options, such as NSAIDs or opioids., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The biocide triclosan is used in many personal care products, including toothpastes, soaps, clothing, and medical equipment. Consequently, it is present as a contaminant in the environment and has been detected in some human fluids, including serum, urine, and milk. Staphylococcus aureus is an opportunistic pathogen that colonizes the noses and throats of approximately 30% of the population. Colonization with S. aureus is known to be a risk factor for several types of infection. Here we demonstrate that triclosan is commonly found in the nasal secretions of healthy adults and the presence of triclosan trends positively with nasal colonization by S. aureus. We demonstrate that triclosan can promote the binding of S. aureus to host proteins such as collagen, fibronectin, and keratin, as well as inanimate surfaces such as plastic and glass. Lastly, triclosan-exposed rats are more susceptible to nasal colonization with S. aureus. These data reveal a novel factor that influences the ability of S. aureus to bind surfaces and alters S. aureus nasal colonization. IMPORTANCE Triclosan has been used as a biocide for over 40 years, but the broader effects that it has on the human microbiome have not been investigated. We demonstrate that triclosan is present in nasal secretions of a large portion of a test population and its presence correlates with Staphylococcus aureus nasal colonization. Triclosan also promotes the binding of S. aureus to human proteins and increases the susceptibility of rats to nasal colonization by S. aureus. These findings are significant because S. aureus colonization is a known risk factor for the development of several types of infections. Our data demonstrate the unintended consequences of unregulated triclosan use and contribute to the growing body of research demonstrating inadvertent effects of triclosan on the environment and human health.

Protein aggregation is related to a series of pathological disorders the main cause of which are the fibrillar species generated during the process. Human serum albumin (HSA) undergoes rapid fibrillation in the presence of Cu(II) at pH 7.4 in 60% ethanol after 6-h incubation (∼65 °C) followed by room temperature incubation. Here, we have investigated the effect of a stoichiometric variation of Cu(II) on the self-assembly of HSA using Congo red and thioflavin T dye-binding studies, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, electron paramagnetic resonance spectroscopy, fluorescence microscopy and transmission electron microscopy. The simulation of EPR spectra suggests that with the increment in Cu(II) ion concentration, there is a change in ligand field coordination. Kinetic parameters indicate reduced cooperativity that may be related to the nonspecific coordination on increment of Cu(II) concentration. Cu(II) is also able to direct the accumulation of a large number of fibers along with a formation of dense fibrillar network which is evident from microscopic images.

Knowing the distribution of Ramachandran angles helps in understanding peptide and protein backbone conformation. Empirical relations are proposed to correlate the spectral profile of the amide III3 band, obtained from ultraviolet resonance Raman measurements (UVRR), with the Ramachandran dihedral psi angle distribution in small peptide and protein molecules, in different environmental conditions (Mikhonin et al. J. Phys. Chem. B 2006, 110, 1928-1943). It has also been used for more complicated structures, like large globular proteins and protein fibrils. In our work here, we use visible Raman spectra and available empirical relations to obtain similar correlations for human serum albumin, hen egg white lysozyme, and human gamma crystallin. We also report the dihedral angle distribution in fibrils and a denatured protein in an ethanol environment using the same spectroscopic technique.

Non proteinaceous substances are found to be associated with toxic protein aggregates commonly known as fibrils. Hen egg white lysozyme (HEWL) is able to form fibrillar species under various conditions. Here for the first time we report concentration dependent binding affinities of preformed HEWL fibrils towards DNA and RNA at physiological pH (pH 7.4). We have found that HEWL fibrils bind with DNA and RNA that is distinctly different when compared to native HEWL. The association constant (Ka) of native HEWL and ct-DNA at pH 7.4 is 6.8×10(5)M(-1). We have also investigated the conformational alterations of DNA that occur on binding with HEWL fibrils. Our study has demonstrated dominant electrostatic interactions between oppositely charged polyelectrolytes which accounts for the binding of nucleic acids with fibrils. The affinity between the moieties could lead to disruption in the functions of cellular components that might be attributed to the toxicity of the aggregates formed in vivo., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The difference in molecular structure of native HEWL and its fibrils, grown at a pH value near physiological pH 7.4 and at a pH value just above the pI, 10.7 in presence and absence of Cu(II) ions, is discussed. We focus on differences between the molecular structure of the native protein and fibrils using principal component analysis of their Raman spectra. The overlap areas of the scores of each species are used to quantify the difference in the structure of the native HEWL and fibrils in different environments. The overall molecular structures are significantly different for fibrils grown at two pH values. However, in presence of Cu(II) ions, the fibrils have similarities in their molecular structures at these pH environments. Spectral variation within each species, as obtained from the standard deviations of the scores in PCA plots, reveals the variability in the structure within a particular species., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The endogenous deposition of protein aggregates with fibrillar morphology is known to govern the genesis of several neurodisorders. The investigation of naturally occurring small molecules which can restrict the fibrillation process can help in the design of rational therapeutics for neurodegenerative diseases. We report the inhibition of HSA fibrillation in the presence of naturally occurring sugars such as glucose, fructose, ribose and sucrose with fructose being the most potent. We have characterized the inhibitory potency of the sugars, using different spectroscopic and microscopic techniques., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Glycation causes severe damage to protein structure that could lead to amyloid formation in special cases. Here in this report, we have shown for the first time that hen egg white lysozyme (HEWL) does not undergo amyloid formation even after prolonged glycation in the presence of D-glucose, D-fructose and D-ribose. Cross-linked oligomers were formed in all the cases and ribose was found to be the most potent among the three sugars. Ribose mediated oligomers, however, exhibit Thioflavin T binding properties although microscopic images clearly show amorphous and globular morphology of the aggregates. Our study demonstrates that the structural damage of hen egg white lysozyme due to glycation generates unstructured aggregates.

The central reason behind pathogenesis of various neurological disorders is usually attributed to the accumulation of aggregated proteins particularly in fibrillar morphology in vivo. One of the plausible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating formed fibrils. The effect of cationic surfactants cetyl trimethylammonium bromide (CTAB), dodecyl trimethylammonium bromide (DTAB) and the anionic surfactant sodium dodecyl sulfate (SDS) in vitro toward mature HSA fibrils has been investigated. The process has been monitored using ThT fluorescence, FTIR, circular dichroism, fluorescence microscopy and HRTEM. It was observed that the micelles of cationic surfactants were able to effectively disrupt the HSA fibrils, among which CTAB was found to be the most potent., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: The present study tested whether the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 would reduce allodynia and paw edema in the carrageenan test., Main Methods: The anti-edematous and anti-allodynic effects of JZL184 were compared to those of PF-3845, an inhibitor of fatty acid amide hydrolase (FAAH), and diclofenac, a non-selective cyclooxygenase inhibitor. Cannabinoid receptor involvement in the anti-edematous and anti-allodynic effects of JZL184 was evaluated by administration of the respective CB1 and CB2 receptor antagonists rimonabant and SR144528 as well as with CB1(-/-) and CB2(-/-) mice. JZL184 (1.6, 4, 16, or 40mg/kg) was administered for six days to assess tolerance., Key Findings: JZL184 administered before or after carrageenan significantly attenuated carrageenan-induced paw edema and mechanical allodynia. Complementary genetic and pharmacological approaches revealed that the anti-allodynic effects of JZL184 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, both the anti-edematous and anti-allodynic effects underwent tolerance following repeated injections of high dose JZL184 (16 or 40mg/kg), but repeated administration of low dose JZL184 (4mg/kg) retained efficacy., Significance: These results suggest that the MAGL inhibitor JZL184 reduces inflammatory nociception through the activation of both CB1 and CB2 receptors, with no evidence of tolerance following repeated administration of low doses., (Copyright © 2012. Published by Elsevier Inc.)

Green tea polyphenols (GTPs) are found to be potent inhibitors of amyloid fibril formation. We report the effective inhibitory property of (-)-epicatechin gallate (ECG) during the alkali-salt induced fibrillogenesis of hen egg white lysozyme (HEWL) at 37 °C. Spectroscopic techniques such as fluorescence, circular dichroism and microscopic images show that (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG) show moderate inhibition of fibrillation with ECG as the most potent polyphenol. Aromatic interactions, hydrophobic interactions, the radical scavenging activity and autoxidation of polyphenols are likely to be the major reasons for ECG being the most effective inhibitor., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Agonists and positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer's disease. Though α7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of α7 nAChRs PAMs on chronic pain and inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate α7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice. We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models. We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan. Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan. In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive. Systemic administration of the α7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral α7 nAChRs. Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model. Our results indicate that the type II α7 nAChRs PAM PNU-120596, but not the type I α7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Copper is known to exert diverse effects on the self-association of proteins and has been found in amyloid deposits that are involved in neurodegenerative disease processes. The effects of the metal ion on the protein during fibrillation were investigated by fluorescence, circular dichroism spectroscopy and fluorescence microscopy. We report for the first time, the complete reduction of Cu(II)→Cu(I) in vitro during fibrillation of hen egg white lysozyme at pH 7. This was confirmed by the lack of any signal for Cu(II) in electron paramagnetic resonance spectroscopy and quantification of Cu(I) was achieved by a bathocuproine disulfonate based assay., (Copyright © 2012 Elsevier B.V. All rights reserved.)