Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a BmimBr accelerated multicomponent reaction ...strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile,
viz.
3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs
via
two CC, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 μM) and BChE (18.14 ± 0.06 μM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with
in vitro
experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (−93.5 ± 11.9 kcal mol
−1
) compared to the standard drug galantamine (−66.2 ± 12.3 kcal mol
−1
) for AChE but exhibited similar values (−98.1 ± 11.2 and −97.9 ± 11.5 kcal mol
−1
) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.
Spiropyrrolidines were synthesized in good yields by cycloaddition protocol, these compounds showed potent cholinesterase inhibitory activities. Experimental
in vitr
o findings are consistent with docking and molecular dynamics simulations.
In eukaryotes, transcripts that carry premature termination codons (PTC) leading to truncated proteins are degraded by the Nonsense Mediated Decay (NMD) machinery. Missense and nonsense Single ...Nucleotide Polymorphisms (SNPs) in proteins belonging to Exon junction complex (EJC) and up-frameshift protein (UPF) will compromise NMD leading to the accumulation of truncated proteins in various diseases. The EJC and UPF which are involved in NMD is a good model system to study the effect of SNPs at a system level. Despite the availability of crystal structures, computational tools, and data on mutational and deletion studies, with functional implications, an integrated effort to understand the impact of SNPs at the systems level is lacking. To study the functional consequences of missense SNPs, sequence-based techniques like SIFT and PolyPhen which classify SNPs as deleterious or non-deleterious and structure-based methods like FoldX which calculate the Delta Delta G, (ddGs, ∆∆G) are used. Using FoldX, the ddG for mutations with experimentally validated functional effects is calculated and compared with those calculated for SNPs in the same protein-protein interaction interface. Further, a model is conceived to explain the functional implications of SNPs based on the effects observed for known mutants. The results are visualized in a network format. The effects of nonsense mutations are discerned by comparing with deletion mutation studies and loss of interaction in the crystal structure. The present work not only integrates genomics, proteomics, and classical genetics with 'Structural Biology' but also helps to integrate it into a 'systems-level functional network'.
Communicated by Ramaswamy H. Sarma
The global prevalence of myopia, or nearsightedness, has increased at an alarming rate over the last few decades. An eye is myopic if incoming light focuses prior to reaching the retinal ...photoreceptors, which indicates a mismatch in its shape and optical power. This mismatch commonly results from excessive axial elongation. Important drivers of the myopia epidemic include environmental factors, genetic factors, and their interactions, e.g., genetic factors influencing the effects of environmental factors. One factor often hypothesized to be a driver of the myopia epidemic is environmental light, which has changed drastically and rapidly on a global scale.
In support of this, it is well established that eye size is regulated by a homeostatic process that incorporates visual cues (emmetropization). This process allows the eye to detect and minimize refractive errors quite accurately and locally over time by modulating the rate of elongation of the eye via remodeling its outermost coat, the sclera. Critically, emmetropization is not dependent on post-retinal processing. Thus, visual cues appear to influence axial elongation through a retina-to-sclera, or retinoscleral, signaling cascade, capable of transmitting information from the innermost layer of the eye to the outermost layer.
Despite significant global research interest, the specifics of retinoscleral signaling pathways remain elusive. While a few pharmacological treatments have proven to be effective in slowing axial elongation (most notably topical atropine), the mechanisms behind these treatments are still not fully understood. Additionally, several retinal neuromodulators, neurotransmitters, and other small molecules have been found to influence axial length and/or refractive error or be influenced by myopigenic cues, yet little progress has been made explaining how the signal that originates in the retina crosses the highly vascular choroid to affect the sclera.
Here, we compile and synthesize the evidence surrounding three of the major candidate pathways receiving significant research attention — dopamine, retinoic acid, and adenosine. All three candidates have both correlational and causal evidence backing their involvement in axial elongation and have been implicated by multiple independent research groups across diverse species. Two hypothesized mechanisms are presented for how a retina-originating signal crosses the choroid — via 1) all-trans retinoic acid or 2) choroidal blood flow influencing scleral oxygenation. Evidence of crosstalk between the pathways is discussed in the context of these two mechanisms.
•Environmental visual cues appear to be driving a rise in global myopia prevalence.•Eye size is influenced by visual cues via a retina-to-sclera signaling cascade.•Dopamine, adenosine, and retinoic acid have been causally linked to eye size.•Retinoic acid or oxygen from the choroid may contribute to regulation of eye size.
Protein engineering by directed evolution is time-consuming. Hence, in silico techniques like FoldX-Yasara for ∆∆G calculation, and SNPeffect for predicting propensity for aggregation, amyloid ...formation, and chaperone binding are employed to design proteins. Here, we used in silico techniques to engineer BDNF-NTF3 interaction and validated it using mutations with known functional implications for NGF dimer. The structures of three mutants representing a positive, negative, or neutral ∆∆G involving two interface residues in BDNF and two mutations representing a neutral and positive ∆∆G in NGF, which is aligned with BDNF, were selected for molecular dynamics (MD) simulation. Our MD results conclude that the secondary structure of individual protomers of the positive and negative mutants displayed a similar or different conformation from the NTF3 monomer, respectively. The positive mutants showed fewer hydrophobic interactions and higher hydrogen bonds compared to the wild-type, negative, and neutral mutants with similar SASA, suggesting solvent-mediated disruption of hydrogen-bonded interactions. Similar results were obtained for mutations with known functional implications for NGF and BDNF. The results suggest that mutations with known effects in homologous proteins could help in validation, and in silico directed evolution experiments could be a viable alternative to the experimental technique used for protein engineering.
Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease leading to inflammation, cartilage cell death, synoviocyte proliferation, and increased and impaired differentiation of osteoclasts ...and osteoblasts leading to joint erosions and deformities. Transcriptomics, proteomics, and metabolomics datasets were analyzed to identify the critical pathways that drive the RA pathophysiology. Single nucleotide polymorphisms (SNPs) associated with RA were analyzed for the functional implications, clinical outcomes, and blood parameters later validated by literature. SNPs associated with RA were grouped into pathways that drive the immune response and cytokine production. Further gene set enrichment analysis (GSEA) was performed on gene expression omnibus (GEO) data sets of peripheral blood mononuclear cells (PBMCs), synovial macrophages, and synovial biopsies from RA patients showed enrichment of Th1, Th2, Th17 differentiation, viral and bacterial infections, metabolic signalling and immunological pathways with potential implications for RA. The proteomics data analysis presented pathways with genes involved in immunological signaling and metabolic pathways, including vitamin B12 and folate metabolism. Metabolomics datasets analysis showed significant pathways like amino-acyl tRNA biosynthesis, metabolism of amino acids (arginine, alanine aspartate, glutamate, glutamine, phenylalanine, and tryptophan), and nucleotide metabolism. Furthermore, our commonality analysis of multi-omics datasets identified common pathways with potential implications for joint remodeling in RA. Disease-modifying anti-rheumatic drugs (DMARDs) and biologics treatments were found to modulate many of the pathways that were deregulated in RA. Overall, our analysis identified molecular signatures associated with the observed symptoms, joint erosions, potential biomarkers, and therapeutic targets in RA.
Communicated by Ramaswamy H. Sarma
A photovoltaic (PV) system's output power fluctuates according to the weather conditions. Fluctuating PV power causes frequency deviations in the power utilities when the penetration is large. ...Usually, an energy storage system (ESS) is used to smooth the PV output power fluctuations and then the smoothed power is supplied to the utility. In this paper, a simple fuzzy-based frequency-control method is proposed for the PV generator in a PV-diesel hybrid system without the smoothing of PV output power fluctuations. By means of the proposed method, output power control of a PV generator considering the conditions of power utilities and the maximizing of energy capture are achieved. Here, fuzzy control is used to generate the PV output power command. This fuzzy control has average insolation, change of insolation, and frequency deviation as inputs. The proposed method is compared with a maximum power point tracking control-based method and with an ESS-based conventional control method. The numerical simulation results show that the proposed method is effective in providing frequency control and also delivers power near the maximum PV power level.
Aims/hypothesis
This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose ...tolerance) in India.
Methods
A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose.
Results
Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status.
Conclusions/interpretations
We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.
The present study aimed at evaluating the extracellular synthesis of silver nanoparticles by soil fungus Aspergillus melleus SSS-10 for antibacterial and cytotoxic activity. In this study, the ...formation of silver nanoparticles (AgNPs) was estimated by the colour change in cell free extract from pale yellow to golden yellow after 24 h of the reaction. UV‐Vis study showed the absorbance maxima at 410 nm. Tauc plot analysis revealed the band gap energy as 2.34 eV. Dynamic Light Scattering (DLS) data revealed polydisperse anisotropic silver nanoparticles with average hydrodynamic diameter of 92.006 nm. Zeta potential of − 19.6 mV provided evidence of stable silver nanoparticles. X-ray diffraction (XRD) analysis revealed four prominent Bragg peaks corresponding to (111), (200), (220) and (311) planes characteristic of silver (Ag) in FCC structural configuration. Average crystallite size was found to be 87.3 nm from Scherrer equation. Scanning Electron Microscope (SEM) analysis revealed irregular morphology of silver nanoparticles. EDS analysis displayed characteristic energy peaks of silver from 2.72 keV to 3.52 keV confirming the presence of silver nanoparticles. Biosynthesized AgNPs exhibited strong cytotoxic potential on MG-63 cells. AgNPs also showed antibacterial activity against both Staphylococcus aureus and Escherichia coli. In conclusion, this study provides a platform to explore the utility of fungal mediated silver nanoparticles synthesized for various pharmaceutical and cosmeceutical applications.
•The present study aimed at evaluating the extracellular synthesis of silver nanoparticles (AgNPs) for the first time by using soil fungus Aspergillus melleus SSS-10 for antibacterial and cytotoxic activity.•Tauc plot analysis revealed the band gap energy as 2.34 eV.•Dynamic Light Scattering (DLS) data revealed polydisperse anisotropic silver nanoparticles with average hydrodynamic diameter of 92.006 nm.•Zeta potential of – 19.6 mV provided evidence of stable silver nanoparticles.•X-ray diffraction (XRD) analysis revealed four prominent Bragg peaks corresponding to (111), (200), (220) and (311) planes characteristic of silver (Ag) in FCC structural configuration. Average crystallite size was found to be 87.3 nm from Scherrer equation.•Scanning Electron Microscope (SEM) analysis revealed irregular morphology of silver nanoparticles. EDS analysis displayed characteristic energy peaks of silver from 2.72 keV to 3.52 keV confirming the presence of silver nanoparticles.•Biosynthesized AgNPs exhibited strong cytotoxic potential on MG-63 cells and antibacterial activity.
This experiment was conducted to study the effects of supplementation of seaweed-based formulation (SWBF) on performance of lactating Murrah buffaloes. Eighteen lactating Murrah buffaloes were ...divided into 3 groups (T
0
, T
1
and T
2
) based on their body weight, parity, days in milk and milk yield following randomized block design. Two SWBF were tested; SWBF-I was combination of two tropical red seaweed species namely
Kappaphycus alvarezii
) and
Gracilaria salicornia
, whereas SWBF-II was combination of the two red seaweeds and one brown seaweed species
Turbinaria conoides
. All the animals were fed to meet their requirements (ICAR
2013
). Animals in control (T
0
) group were fed concentrate mixture, Hybrid Napier fodder and wheat straw without any supplemental seaweed. However, SWBF-I and SWBF-II were supplemented at 2.5% of the concentrate feed of groups T
1
and T
2
, respectively. Intake and apparent digestibility of nutrients, plasma concentrations of selected metabolites, enzymes and hormones were similar among the groups. A tendency of decreased (
P
=0.060) plasma concentration of cortisol was observed in treatment groups. Total antioxidant capacity was improved (
P
=0.001) due to SWBF supplementation; the best response was observed in group T
2
, followed by T
1
. Concentration of lipid peroxides decreased (
P
<0.004) in treatment groups as compared to control. Supplementation of SWBF-augmented cell-mediated (
P
=0.002) and humoral (
P
<0.001) immune response in treatment groups as compared to the control group. Milk yield and the 6% fat corrected milk yield (kg day
−1
) were higher (
P
=0.002) in T
2
, followed by T
1
and minimum in T
0
. Thus, supplementation of both the SWBF improved antioxidant status, cellular and humoral immunity, and milk yield; the best response was obtained in T
2
. It is concluded that supplementation of SWBF-II (
K. alvarezii
,
G. salicornia
and
T. conoides
) at 2.5% in the concentrate mixture of lactating Murrah buffaloes improves antioxidant status, immunity and milk yield.
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