MolDy: molecular dynamics simulation made easy.

MOTIVATION: Molecular dynamics (MD) is a computational experiment that is crucial for understanding the structure of biological macro and micro molecules, their folding, and the inter-molecular interactions. Accurate knowledge of these structural features is the cornerstone in drug development and elucidating macromolecules functions. The open-source GROMACS biomolecular MD simulation program is recognized as a reliable and frequently used simulation program for its precision. However, the user requires expertise, and scripting skills to carrying out MD simulations. RESULTS: We have developed an end-to-end interactive MD simulation application, MolDy for Gromacs. This front-end application provides a customizable user interface integrated with the Python and Perl-based logical backend connecting the Linux shell and Gromacs software. The tool performs analysis and provides the user with simulation trajectories and graphical representations of relevant biophysical parameters. The advantages of MolDy are (i) user-friendly, does not requiring the researcher to have prior knowledge of Linux; (ii) easy installation by a single command; (iii) freely available for academic research; (iv) can run with minimum configuration of operating systems; (v) has valid default prefilled parameters for beginners, and at the same time provides scope for modifications for expert users. AVAILABILITY AND IMPLEMENTATION: MolDy is available freely as compressed source code files with user manual for installation and operation on GitHub: https://github.com/AIBResearchMolDy/Moldyv01.git and on https://aibresearch.com/innovations.

CRISPR Interference (CRISPRi) Mediated Suppression of OmpR Gene in E. coli: An Alternative Approach to Inhibit Biofilm.

Biofilm plays an important role in the community and hospital-acquired infections. Especially E. coli biofilm that contributes towards the significant part of medical devices associated with microbial infections. OmpR/EnvZ, a two-component system, is one of the regulatory mechanisms involved in transcription regulation in response to environmental osmolarity changes. The main objective of this study was to elucidate the role of the OmpR/EnvZ two-component system in regulating the biofilm through curli and fimbriae (FimH gene), a contrary approach towards biofilm inhibition. In this study, the CRISPRi technique was used to suppress the expression of the OmpR gene. The RT-PCR assay was performed to quantify mRNA gene expression of curli and biofilm producing genes, and the data were further confirmed by different microscopic, spectroscopic and biofilm quantification assay (Crystal Violet). It is the first time we have shown downregulation of the OmpR gene in biofilm causing clinical isolates of E. coli, which further suppressed the FimH gene, leading to biofilm reduction. The crystal violet assay and microscopic studies also confirmed the biofilm reduction. We conclude that the OmpR gene of the OmpR/EnvZ two-component system could be one of the targets for biofilm mediated infection intervention. Our findings open new vistas to explore the pathways and targets to control biofilm mediated infections.

Understanding the mode of binding mechanism of doripenem to human serum albumin: Spectroscopic and molecular docking approaches.

The infections caused by multidrug resistant bacteria are widely treated with carabapenem antibiotics as a drug of choice, and human serum albumin (HSA) plays a vital role in binding with drugs and affecting its rate of delivery and efficacy. So, we have initiated this study to characterize the mechanism of doripenem binding and to locate its site of binding on HSA by using spectroscopic and docking approaches. The binding of doripenem leads to alteration of the environment surrounding Trp-214 residue of HSA as observed by UV spectroscopic study. Fluorescence spectroscopic study revealed considerable interaction and complex formation of doripenem and HSA as indicated by Ksv and Kq values of the order of 104  M-1 and 1012  M-1  s-1 , respectively. Furthermore, doripenem quenches the fluorescence of HSA spontaneously on a single binding site with binding constant of the order of 103  M-1 , through an exothermic process. Van der Waals forces and hydrogen bonding are the major forces operating to stabilize HSA-doripenem complex. Circular dichroism spectroscopic study showed changes in the structure of HSA upon doripenem binding. Drug displacement and molecular docking studies revealed that the binding site of doripenem on HSA is located on subdomain IB and III A. This study concludes that, due to significant interaction of doripenem on either subdomain IB or IIIA of HSA, the availability of doripenem on the target site may be compromised. Hence, there is a possibility of unavailability of threshold amount of drug to be reached to the target; consequently, resistance may develop in the bacterial population.

Graphene/transition metal dichalcogenides hybrid supercapacitor electrode: status, challenges, and perspectives.

Supercapacitors, based on fast ion transportation, are among the most promising energy storage solutions that can deliver fast charging-discharging within seconds and exhibit excellent cycling stability. The development of a good electrode material is one of the key factors in enhancing supercapacitor performance. Graphene (G), an allotrope of carbon that consists of a single layer of carbon atoms arranged in a hexagonal lattice, elicits research attention among scientists in the field of energy storage due to its remarkable properties, such as outstanding electrical conductivity, good chemical stability, and excellent mechanical behavior. Furthermore, numerous studies focus on 2D materials that are analogous to graphene as electrode supercapacitors, including transition metal dichalcogenides (TMDs). Recently, scientists and researchers are exploring TMDs because of the distinct features that make 2D TMDs highly attractive for capacitive energy storage. This study provides an overview of the structure, properties, synthesis methods, and electrochemical performance of G/TMD supercapacitors. Furthermore, the combination of G and TMDs to develop a hybrid structure may increase their energy density by introducing an asymmetric supercapacitor system. We will also discuss the future prospect of this system in the energy field.

Structural and Electronic Properties of Transition-Metal Oxides Attached to a Single-Walled CNT as a Lithium-Ion Battery Electrode: A First-Principles Study.

Single-walled carbon nanotubes (SWCNTs) and metal oxides (MOs), such as manganese(IV) oxide (MnO2), cobalt(II, III) oxide (Co3O4), and nickel(II) oxide (NiO) hybrid structures, have received great attention because of their promising application in lithium-ion batteries (LIBs). As electrode materials for LIBs, the structure of SWCNT/MOs provides high power density, good electrical conductivity, and excellent cyclic stability. In this work, first-principles calculations were used to investigate the structural and electronic properties of MOs attached to (5, 5) SWCNT and Li-ion adsorption to SWCNT/metal oxide composites as electrode materials in LIBs. Emphasis was placed on the synergistic effects of the composite on the electrochemical performance of LIBs in terms of adsorption capabilities and charge transfer of Li-ions attached to (5, 5) SWCNT and metal oxides. Also, Li adsorption energy on SWCNTs and three different metal oxides (NiO, MnO2, and Co3O4) and the accompanying changes in the electronic properties, such as band structure, density of states and charge distribution as a function of Li adsorption were calculated. On the basis of the calculation results, the top C atom was found to be the most stable position for the NiO and MnO2 attachment to SWCNT, while the Co3O4 molecule, the Co2+, was found to be the most stable attachment on SWCNT. The obtained results show that the addition of MOs to the SWCNT electrode enables an increase in specific surface area and improves the electronic conductivity and charge transfer of an LIB.

Trends of drug-resistance-associated mutations in the reverse transcriptase gene of HIV type 1 isolates from North India.

A major cause of failure of antiretroviral therapy (ART) is the presence of drug-resistance-associated mutations in the polymerase gene of HIV-1. The paucity of data regarding potential drug resistance to reverse transcriptase inhibitors (RTIs) prompted us to carry out this study. This information will shed light on the extent of drug resistance already present in HIV strains and will give future directions in patient treatment and in drug design. Drug resistance genotyping of a partial reverse transcriptase gene was done in 103 HIV-1-infected patients, including the ART-naive and ART-experienced population. The drug resistance pattern was analyzed using the Stanford HIV-DR database, the IAS-USA mutation list and the REGA algorithm-v8.0. Subtyping was done using the REGA HIV-1 subtyping tool-v2.01. The majority of our sequences (96 %) were found to be subtype C, and four (3.8 %) were subtype A1. Significant prevalence of DR mutations (28 %) was observed in the RT gene. Major amino acid substitutions were seen at positions 41, 90, 98, 103, 106, 108, 138, 181, 184, 190, 215, and 219, which confer high/intermediate levels of resistance to most RTIs, independently or together. Our results show that there is an urgent need to tailor ART drug regimens to the individual to achieve optimum therapeutic outcome in North India.

Intensifying spatially compound heatwaves: Global implications to crop production and human population.

Recent research has provided crucial insights on regional heatwaves, including their causal mechanisms and changes under global warming. However, detailed research on global-scale spatially compound heatwaves (SCHs) (concurrent heatwaves over multiple regions) is lacking. Here, we find statistically significant teleconnections in heatwaves and show that the frequency of global-scale SCHs and their areal extent have increased significantly, which has led to 50 % increase in the population exposed to extreme heat stresses in the two most recent decades. Crop yields were reduced in most of the years of anomalous heatwaves, which often happen during El-Niños. The internal climate variability appears to significantly influence the inter-annual variability of regional and global heatwave extents. Insights gained here are critical in better quantifying heat stress risks inflicted on socioecological systems.

Influence of Yb3+/Ho3+codoping on optical and thermal properties of TeO2-ZnO glass.

This paper reports the effect of incorporation of Yb3+ions on the frequency downconversion luminescence and thermal properties of triply ionised Ho3+doped zinc tellurite (TZ) glasses. The photoluminescence spectra of both the Ho3+/Yb3+doped and codoped glasses have been recorded and observed a green emission band corresponding to the5F4,5S2→5I8(∼550 nm) transition upon various excitations. In the downconversion (DC) emission process, the back energy transfer (BET) mechanism from Ho3+ions to Yb3+ions has also been explored. The colour emitted in the downconversion process is found to be non-tunable at different excitations. Thus, the Ho3+:TZ glass can be utilised for non-colour tunable optical devices under various UV excitations. Also the glass transition (Tg) and crystallisation (Tc) temperatures have been measured for both the doped and codoped glasses and found to be increased in the codoped glass. The singly Ho3+ions doped TZ glass shows better optical downconversion and glass forming ability.

Distinct inflammatory markers in primary and secondary dengue infection: can cytokines CXCL5, CXCL9, and CCL17 act as surrogate markers?

Dengue fever poses a significant global health threat, with symptoms including dengue hemorrhagic fever and dengue shock syndrome. Each year, India experiences fatal dengue outbreaks with severe manifestations. The primary cause of severe inflammatory responses in dengue is a cytokine storm. Individuals with a secondary dengue infection of a different serotype face an increased risk of complications due to antibody-dependent enhancement. Therefore, it is crucial to identify potential risk factors and biomarkers for effective disease management. In the current study, we assessed the prevalence of dengue infection in and around Aligarh, India, and explored the role of cytokines, including CXCL5, CXCL9, and CCL17, in primary and secondary dengue infections, correlating them with various clinical indices. Among 1,500 suspected cases, 367 tested positive for dengue using Real-Time PCR and ELISA. In secondary dengue infections, the serum levels of CXCL5, CXCL9, and CCL17 were significantly higher than in primary infections (P < 0.05). Dengue virus (DENV)-2 showed the highest concentrations of CXCL5 and CCL17, whereas DENV-1 showed the highest concentrations of CXCL9. Early detection of these cytokines could serve as potential biomarkers for diagnosing severe dengue, and downregulation of these cytokines may prove beneficial for the treatment of severe dengue infections.

Emergence of drug resistance-associated mutations in HIV-1 subtype C protease gene in north India.

A major cause of anti-retroviral therapy (ART) failure is the drug resistance-associated mutations in polymerase gene of HIV-1. Paucity of data regarding potential drug resistance to protease inhibitors (PIs) prompted us to carry out this study. Drug resistance (DR) genotyping of the entire protease gene was performed in 104 HIV-1 ART-naive and first-line ART-experienced patients. The DR pattern was analyzed using the Stanford HIV-DR database, International AIDS Society-USA mutation list and REGA algorithm version 8.0. Subtyping was done using Mega 4 and REGA HIV-1 subtyping tool-v2.01. Majority of our sequences 98 (96%) were subtype C and remaining four (3.92%) were subtype A1. In three (2.9%) DE patients, major DR-associated mutation at D30 N and M46I positions were detected. Approximately 70% polymorphisms as minor mutations were observed in protease gene, of which 14 distinct amino acids changes were linked to partial DR such as G16E, K20R, M36I, D60E, I62V, L63P, I64M, H69K, T74A/S, V77I, V82I, I85V, L89M, and I93L. The two major and several minor mutations detected in this study confer low/intermediate levels of resistance to most PIs independently or together. Our results conclude that resistance testing in HIV-1-infected patients should be performed before the initiation of PI therapy for better therapeutic outcome in this region. This information not only will shed light on the extent of current DR in HIV strains but also will aid in patient treatment and drug designing.

Prevalence and assessment of role of SEN virus in acute and chronic hepatitis in India.

BACKGROUND AND AIM: SEN virus (SENV), is a recently discovered single-stranded DNA virus of Annelloviridae family and is believed may play a role in non A-E hepatitis. We conducted this study to identify the prevalence and clinical association of SENV with acute and chronic hepatitis. METHODS: 135 liver disease patients were studied. Extent of liver damage was assessed using the Model for End Stage Liver Disease (MELD) score. A-E viruses and HIV were detected by enzyme immunoassay. Nested PCR was performed for detection of SENV and its genotypes D and H. RESULTS: 34 cases (25.18%) were positive for SEN virus DNA, a statistically significant finding (p < 0.01) of which 22 (64%) had acute viral hepatitis, 4 (11.76%) had chronic viral hepatitis, 3 (8.82%) fulminant hepatic failure and 5 (14.70%) cirrhosis. Mean AST was 47.85 IU/L, ALT 51.2 IU/L and INR 1.73, mean MELD score was 18.38 (11 to 24). 17.64% had severely deranged MELD score. SENV-D genotype was detected in 13 (38%) and SENV-H in 19 (58%) cases. SENV-H occurred in both acute (53%) and chronic hepatitis (47%). SENV-D was strongly associated with acute hepatitis (85%). Cirrhotic and FHF cases were SENV-H positive. 12 (44.11%) were co-infected with HBV, 5 (14.7%) with TTV, 4(11.76%) with HEV, 2 (5.88%) with HCV and 5 (14.4%) with HIV. CONCLUSION: Significant prevalence of SENV in hepatitis patients was observed. On the basis of clinical findings and abnormal liver function tests, we conclude that SENV appears to be not only hepatotropic but also capable of liver damage. Higher prevalence of SENV-H in cirrhotics may point to its possible role in the development of cirrhosis.

Updates on the Virulence Factors Produced by Multidrug-Resistant Enterobacterales and Strategies to Control Their Infections.

The Enterobacterales order is a massive group of Gram-negative bacteria comprised of pathogenic and nonpathogenic members, including beneficial commensal gut microbiota. The pathogenic members produce several pathogenic or virulence factors that enhance their pathogenic properties and increase the severity of the infection. The members of Enterobacterales can also develop resistance against the common antimicrobial agents, a phenomenon called antimicrobial resistance (AMR). Many pathogenic Enterobacterales members are known to possess antimicrobial resistance. This review discusses the virulence factors, pathogenicity, and infections caused by multidrug-resistant Enterobacterales, especially E. coli and some other bacterial species sharing similarities with the Enterobacterales members. We also discuss both conventional and modern approaches used to combat the infections caused by them. Understanding the virulence factors produced by the pathogenic bacteria will help develop novel strategies and methods to treat infections caused by them.

Insight into the seroepidemiology and dynamics of circulating serotypes of dengue virus over a 4 year period in western Uttar Pradesh, India.

An important public health problem in India is dengue infection, with every year seeing an increase in cases of dengue fever. Dengue affects all individuals irrespective of their gender and age, although the infection rate is higher among males and younger people. Despite low severity in general, dengue virus can cause severe health conditions in some individuals. Genetic characterization of circulating endemic dengue virus (DENV) serotypes plays a significant role in providing epidemiological knowledge and subsequent vaccine development. In the present study, over a 4 year period, we assessed DENV transmission dynamics in major regions of western Uttar Pradesh in North India. ELISA tests were used to diagnose dengue, and PCRs were used to determine the circulating serotype. We found that dengue infection peaks after the rainy season and affects all sexes and ages. A total of 1277 individuals were found positive for dengue; among them, 61.7 % were male and 38.3 % were female. DEN-1 was found in 23.12 %, DEN-2 in 45 %, DEN-3 in 29.06 % and DEN-4 in 1.5 % of the dengue-infected individuals. All four DENV serotypes were circulating in the study area, and DENV serotype-2 (DEN-2) was the most prevalent serotype.

CRISPRi-mediated suppression of E. coli Nissle 1917 virulence factors: A strategy for creating an engineered probiotic using csgD gene suppression.

Background: Biofilm formation is a complex phenomenon, and it is the causative agent of several human infections. Bacterial amyloids are involved in biofilm formation leading to infection persistence. Due to antibiotic resistance, their treatment is a great challenge for physicians. Probiotics, especially E. coli Nissle 1917 (EcN), are used to treat human intestinal disorders and ulcerative colitis. It also expresses virulence factors associated with biofilm and amyloid formation. EcN produces biofilm equivalent to the pathogenic UPEC strains. Methods: CRISPRi was used to create the knockdown mutants of the csgD gene (csgD-KD). The qRT-PCR was performed to assess the expression of the csgD gene in csgD-KD cells. The csgD-KD cells were also evaluated for the expression of csgA, csgB, fimA, fimH, ompR, luxS, and bolA genes. The gene expression data obtained was further confirmed by spectroscopic, microscopic, and other assays to validate our study. Results: CRISPRi-mediated knockdown of csgD gene shows reduction in curli amyloid formation, biofilm formation, and suppression of genes (csgA, csgB, fimA, fimH, ompR, bolA, and luxS) involved in virulence factors production. Conclusion: Curli amyloid fibers and fimbriae fibers play a critical role in biofilm formation leading to pathogenicity. CsgD protein is the master regulator of curli synthesis in E. coli. Hence, curli amyloid inhibition through the csgD gene may be used to improve the EcN and different probiotic strains by suppressing virulence factors.

A Combined Approach of Pharmacophore Modeling, QSAR Study, Molecular Docking and In silico ADME/Tox Prediction of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one Analogs to Identify Potential Reverse Transcriptase Inhibitor: Anti-HIV Agents.

BACKGROUND: Reverse transcriptase is an important therapeutic target to treat AIDS caused by the Human Immunodeficiency Virus (HIV). Despite many effective anti-HIV drugs, reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In the present work, we have expedited the use of different computational modules and presented an easy, costeffective, and high throughput screening method to identify potential reverse transcriptase inhibitors. METHODS: A congeneric series of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one analogs having anti-HIV activity were subjected to structure-based 2D, 3D QSAR, Pharmacophore Modeling, and Molecular Docking to elucidate the structural properties required for the design of potent HIV-RT inhibitors. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. RESULTS: The 2D and 3D- QSAR models were developed by correlating two and three-dimensional descriptors with activity (pIC50) by sphere exclusion method and k-nearest neighbor molecular field analysis approach, respectively. The significant 2D- QSAR model developed by Partial Least Square is associated with the Sphere Exclusion method (PLS-SE), having r2 and q2 values 0.9509 and 0.8038, respectively. The 3D-QSAR model by Step Wise variable selection method (SW-kNN MFA) is more significant, which has a cross-validated squared correlation coefficient q2= 0.8509 and a non-crossvalidated correlation coefficient pred_r2= 0.8102. The pharmacophore hypothesis was developed, which comprised 5 features includes 3 aliphatic regions (Ala), 1 H-bond donor (HDr) and 1 H-bond acceptor (HAc). Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond and π - π interaction with LYS-101, LYS-103, TYR- 181, TYR-188 and TRP-229 residues present at the active site. All the candidates with good bioavailability and ADMET drug likeliness properties. CONCLUSION: The results of the present work provide more useful information and important structural insights for the discovery, design of novel and potent reverse transcriptase inhibitors with high therapeutic windows in the future.

Recent Progress of Electrode Architecture for MXene/MoS2 Supercapacitor: Preparation Methods and Characterizations.

Since their discovery, MXenes have conferred various intriguing features because of their distinctive structures. Focus has been placed on using MXenes in electrochemical energy storage including a supercapacitor showing significant and promising development. However, like other 2D materials, MXene layers unavoidably experience stacking agglomeration because of its great van der Waals forces, which causes a significant loss of electrochemically active sites. With the help of MoS2, a better MXene-based electrodecan is planned to fabricate supercapacitors with the remarkable electrochemical performance. The synthesis of MXene/MoS2 and the ground effects of supercapacitors are currently being analysed by many researchers internationally. The performance of commercial supercapacitors might be improved via electrode architecture. This analysis will support the design of MXene and MoS2 hybrid electrodes for highly effective supercapacitors. Improved electrode capacitance, voltage window and energy density are discussed in this literature study. With a focus on the most recent electrochemical performance of both MXene and MoS2-based electrodes and devices, this review summarises recent developments in materials synthesis and its characterisation. It also helps to identify the difficulties and fresh possibilities MXenes MoS2 and its hybrid heterostructure in this developing field of energy storage. Future choices for constructing supercapacitors will benefit from this review. This review examines the newest developments in MXene/MoS2 supercapacitors, primarily focusing on compiling literature from 2017 through 2022. This review also presents an overview of the design (structures), recent developments, and challenges of the emerging electrode materials, with thoughts on how well such materials function electrochemically in supercapacitors.

Evaluation of the Cytotoxic Activity and Anti-Migratory Effect of Berberine-Phytantriol Liquid Crystalline Nanoparticle Formulation on Non-Small-Cell Lung Cancer In Vitro.

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, which is a leading cause of cancer-related deaths worldwide. Berberine is an isoquinoline alkaloid that is commercially available for use as a supplement for the treatment of diabetes and cardiovascular diseases. However, the therapeutic benefits of berberine are limited by its extremely low bioavailability and toxicity at higher doses. Increasing evidence suggests that the incorporation of drug compounds in liquid crystal nanoparticles provides a new platform for the safe, effective, stable, and controlled delivery of the drug molecules. This study aimed to formulate an optimized formulation of berberine-phytantriol-loaded liquid crystalline nanoparticles (BP-LCNs) and to investigate the in vitro anti-cancer activity in a human lung adenocarcinoma A549 cell line. The BP-LCN formulation possessing optimal characteristics that was used in this study had a favorable particle size and entrapment efficiency rate (75.31%) and a superior drug release profile. The potential mechanism of action of the formulation was determined by measuring the mRNA levels of the tumor-associated genes PTEN, P53, and KRT18 and the protein expression levels with a human oncology protein array. BP-LCNs decreased the proliferation, migration, and colony-forming activity of A549 cells in a dose-dependent manner by upregulating the mRNA expression of PTEN and P53 and downregulating the mRNA expression of KRT18. Similarly, BP-LCNs also decreased the expression of proteins related to cancer cell proliferation and migration. This study highlights the utility of phytantriol-based LCNs in incorporating drug molecules with low GI absorption and bioavailability to increase their pharmacological effectiveness and potency in NSCLC.

Phytantriol-Based Berberine-Loaded Liquid Crystalline Nanoparticles Attenuate Inflammation and Oxidative Stress in Lipopolysaccharide-Induced RAW264.7 Macrophages.

Inflammation and oxidative stress are interrelated processes that represent the underlying causes of several chronic inflammatory diseases that include asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies, diabetes, and cardiovascular diseases. Macrophages are key initiators of inflammatory processes in the body. When triggered by a stimulus such as bacterial lipopolysaccharides (LPS), these cells secrete inflammatory cytokines namely TNF-α that orchestrate the cellular inflammatory process. Simultaneously, pro-inflammatory stimuli induce the upregulation of inducible nitric oxide synthase (iNOS) which catalyzes the generation of high levels of nitric oxide (NO). This, together with high concentrations of reactive oxygen species (ROS) produced by macrophages, mediate oxidative stress which, in turn, exacerbates inflammation in a feedback loop, resulting in the pathogenesis of several chronic inflammatory diseases. Berberine is a phytochemical embedded with potent in vitro anti-inflammatory and antioxidant properties, whose therapeutic application is hindered by poor solubility and bioavailability. For this reason, large doses of berberine need to be administered to achieve the desired pharmacological effect, which may result in toxicity. Encapsulation of such a drug in liquid crystalline nanoparticles (LCNs) represents a viable strategy to overcome these limitations. We encapsulated berberine in phytantriol-based LCNs (BP-LCNs) and tested the antioxidant and anti-inflammatory activities of BP-LCNs in vitro on LPS-induced mouse RAW264.7 macrophages. BP-LCNs showed potent anti-inflammatory and antioxidant activities, with significant reduction in the gene expressions of TNF-α and iNOS, followed by concomitant reduction of ROS and NO production at a concentration of 2.5 µM, which is lower than the concentration of free berberine concentration required to achieve similar effects as reported elsewhere. Furthermore, we provide evidence for the suitability for BP-LCNs both as an antioxidant and as an anti-inflammatory agent with potential application in the therapy of chronic inflammatory diseases.

Coadministration of liposomal methylglyoxal increases the activity of amphotericin B against Candida albicans in leukopoenic mice.

In this study, we investigated the therapeutic efficacy of a combination of liposomal amphotericin B (Lip-Amp B) and Methylglyoxal (Lip-MG) against Candida albicans in the leukopoenic mice. The antifungal efficacy of Lip-Amp B or Lip-MG or a combination of Lip-Amp B and Lip-MG was evaluated by the analysis of the survival rate and the fungal load in the treated mice. The immune-stimulatory effect of Lip-MG on macrophages was evaluated by analysing the secretion of proinflammatory cytokines. C. albicans infected mice treated at the doses of 1 and 2 mg/kg of Lip-Amp B showed 20% and 50% survival rates, respectively. Whereas the mice treated with free Amp B at the same doses died within 40 days of treatment. Interestingly, C. albicans infected mice treated with a combination of Lip-Amp B and Lip-MG had 70% survival rate on day 40 postinfection. Moreover, treatment of macrophages with Lip-MG increased their fungicidal activity and the secretion of proinflammatory cytokines, including TNF-α and IL-1ß. These findings suggested that co-treatment with Lip-Amp B and Lip-MG had a synergistic effect and could be effective against C. albicans in immunocompromised subjects.

Glaciohydrology of the Himalaya-Karakoram.

Understanding the response of Himalayan-Karakoram (HK) rivers to climate change is crucial for ~1 billion people who partly depend on these water resources. Policy-makers tasked with sustainable water resources management require an assessment of the rivers' current status and potential future changes. We show that glacier and snow melt are important components of HK rivers, with greater hydrological importance for the Indus basin than for the Ganges and Brahmaputra basins. Total river runoff, glacier melt, and seasonality of flow are projected to increase until the 2050s, with some exceptions and large uncertainties. Critical knowledge gaps severely affect modeled contributions of different runoff components, future runoff volumes, and seasonality. Therefore, comprehensive field observation-based and remote sensing-based methods and models are needed.