Speed, dissipation, and error in kinetic proofreading

Proofreading mechanisms increase specificity in biochemical reactions by allowing for the dissociation of intermediate complexes. These mechanisms disrupt and reset the reaction to undo errors at the cost of increased time of reaction and free energy expenditure. Here, we draw an analogy between proofreading and microtubule growth which share some of the features described above. Our analogy relates the statistics of growth and shrinkage of microtubules in physical space to the cycling of intermediate complexes in the space of chemical states in proofreading mechanisms. Using this analogy, we find a new kinetic regime of proofreading in which an exponential speed-up of the process can be achieved at the cost of a somewhat larger error rate. This regime is analogous to the transition region between two known growth regimes of microtubules (bounded and unbounded) and is sharply defined in the limit of large proofreading networks. We find that this advantageous regime of speed-error tradeoff might be present in proofreading schemes studied earlier in the charging of tRNA by tRNA synthetases, in RecA filament assembly on ssDNA, and in protein synthesis by ribosomes.     

Comparable efficacy of standardized Ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the treatment of rheumatoid arthritis (RA): a randomized investigator-blind controlled study

Hydroxychloroquine sulfate (HCQS) is a popular disease-modifying antirheumatic drug (DMARD) despite modest efficacy and toxicity. Ayurveda (ancient India medicinal system) physicians treat rheumatoid arthritis (RA) with allegedly safer herbal formulations. We report a head-to-head comparison in an exploratory drug trial. The objective is to compare standardized Ayurvedic formulations and HCQS in the treatment of RA. One hundred twenty-one patients with active moderately severe RA (ACR 1988 classified) were randomized into a 24-week investigator-blind, parallel efficacy, three-arm (two Ayurvedic and HCQS) multicenter drug trial study; polyherb (Tinospora cordifolia and Zingiber officinale based) and monoherb (Semecarpus anacardium). Study measures included joint counts (pain/tenderness and swelling), pain visual analogue scale, global disease assessments, and health assessment questionnaire. Oral meloxicam (fixed-dosage schedule) was prescribed to all patients during the initial 16 weeks. Patients on prednisolone could continue a fixed stable dose (<7.5 mg daily). Rescue oral use of paracetamol was permitted and monitored. All groups matched well at baseline. An intent-to-treat analysis (ANOVA, significance P < 0.05) did not show significant differences by treatment groups. In the polyherb, monoherb, and HCQS arms, 44%, 36%, and 51%, respectively, showed ACR 20 index improvement. Several efficacy measures improved significantly in the HCQS and polyherb groups with no difference between the groups (corrected P). However, the latter was individually superior to monoherb. Only mild adverse events (gut and skin, and none withdrew) were reported with no differences between the groups. Forty-two patients dropped out. This preliminary drug trial controlled for HCQS demonstrated a standardized Ayurvedic polyherb drug to be effective and safe in controlling active RA. A better-designed study with a longer evaluation period is recommended.     

Current concepts in clavicle fractures

Clavicle fractures are common injuries which any orthopaedic surgeon encounters in the clinical practice. There are ongoing debates about the optimal treatment for displaced fractures and a consensus is yet to be agreed. This article aims to present an overview on current concepts and suggest some recommendations for the management of these injuries.     

Lipid‐Altering Efficacy of Ezetimibe/Simvastatin 10/20 mg Compared to Rosuvastatin 10 mg in High‐Risk Patients with and without Type 2 Diabetes Mellitus Inadequately Controlled Despite Prior Statin Monotherapy

Aims: This post hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) or rosuvastatin 10 mg (ROSUVA) in uncontrolled high‐risk hypercholesterolemic patients with/without type 2 diabetes mellitus (T2DM) despite statin monotherapy. Methods: Patients (n = 618) at high risk for coronary vascular disease with elevated LDL‐C ≥100 and ≤190 mg/dL despite use of statins were randomized 1:1 to double‐blind EZE/SIMVA 10/20 mg or ROSUVA 10 mg for 6 weeks. Patients were classified as having T2DM based on ≥1 of the following: diagnosis of T2DM, antidiabetic medication, or FPG ≥126 mg/dL. This analysis evaluated percent changes from baseline in lipids among patients with (n = 182) and without T2DM (n = 434). Results: EZE/SIMVA was more effective than ROSUVA at lowering LDL‐C, TC, non‐HDL‐C, and apo B in the overall study population and within both subgroups. Numerically, greater between‐treatment reductions in LDL‐C, TC, non‐HDL‐C, and apo B were seen in patients with T2DM versus those without T2DM. A significant interaction (P= 0.015) was seen for LDL‐C indicating that patients with T2DM achieved larger between‐group reductions versus those without T2DM. Conclusions: Switching to EZE/SIMVA 10/20 mg versus ROSUVA 10 mg provided superior lipid reductions in patients with/without T2DM.     

Protective effect of ferulic acid on 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in Swiss albino mice

Our aim was to evaluate and compare the chemopreventive potential of topically applied and orally administered ferulic acid in 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis. Estimating the status of phase I and phase II detoxication agents, lipid peroxidation byproducts and antioxidants during DMBA-induced skin carcinogenesis assessed the mechanistic pathway for its chemopreventive efficacy. Skin squamous cell carcinoma was induced in the shaved back of mice, by painting with DMBA (25 μg in 0.1 mL^?1 acetone) twice weekly for 8 weeks. We have observed 100% tumor formation in the 15th week of experimental period in mice treated with DMBA alone. Marked alterations in the status of phase I and phase II detoxication agents, lipid peroxidaton byproducts and antioxidants were observed in tumor bearing mice. Oral administration of ferulic acid completely prevented the formation of skin tumors, whereas topically applied ferulic acid did not show significant chemopreventive activity during DMBA-induced mouse skin carcinogenesis. Also, oral administration of ferulic acid reverted the status of phase I and phase II detoxication agents, lipid peroxidaton byproducts and antioxidants to near-normal range in DMBA-treated mice. Our results thus demonstrate that orally administered ferulic acid has potent suppressing effect on cell proliferation during DMBA-induced skin carcinogenesis. This is probably due to its modulating effect on the status of lipid peroxidation, antioxidants and detoxication agents during DMBA-induced skin carcinogenesis.     

Prevalence of open-angle glaucoma in a rural south Indian population

PURPOSE: To determine the prevalence of primary open-angle glaucoma (POAG) and the associated risk factors in a rural population in southern India. METHODS: Subjects aged 40 years or more (n = 3934) underwent a complete ophthalmic examination. Glaucoma was diagnosed according to the International Society of Geographical and Epidemiologic Ophthalmology classification. RESULTS: Complete data were available for 3924 subjects (response rate, 81.75%). In eyes with normal suprathreshold visual fields, the mean intraocular pressure was 14.29 +/- 3.32 mm Hg (97.5th and 99.5th percentiles, 21 and 25 mm Hg, respectively). The mean vertical cup-to-disc ratio was 0.39 +/- 0.17 (97.5th and 99.5th percentiles, 0.7 and 0.8, respectively). Sixty-four subjects had definite POAG (1.62%, 9.5% CI 1.42-1.82); 30 were men and 34 were women. Subjects with POAG (59.85 +/- 10.43 years) were older (P < 0.001) than the study population (53.78 +/- 10.71 years). In only one (1.5%) person was POAG diagnosed before the study. Two (3.12%) subjects were blind due to POAG; 21 (32.81%) subjects had a presenting IOP >21 mm Hg, and 43 (67.19%) had an IOP <21 mm Hg. The mean central corneal thickness in subjects with POAG (502.82 +/- 35.29 microm) was not different from that of the normal study population (505.93 +/- 31.11 microm). No association was found with diabetes mellitus, systemic hypertension, gender, and myopia. Increasing IOP (per mm Hg) was associated with the disease (OR 1.12; 95% CI, 1.08-1.16). The odds for POAG increased with advancing age after adjustment for gender. CONCLUSIONS: The prevalence of POAG in this population was 1.62%. The prevalence increased with age, and 98.5% were not aware of the disease.     

Mechanistic Insights into PEPT1-Mediated Transport of a Novel Antiepileptic, NP-647

The present study, in general, is aimed to uncover the properties of the transport mechanism or mechanisms responsible for the uptake of NP-647 into Caco-2 cells and, in particular, to understand whether it is a substrate for the intestinal oligopeptide transporter, PEPT1 (SLC15A1). NP-647 showed a carrier-mediated, saturable transport with Michaelis-Menten parameters K(m) = 1.2 mM and V(max) = 2.2 μM/min. The effect of pH, sodium ion (Na(+)), glycylsarcosine and amoxicillin (substrates of PEPT1), and sodium azide (Na(+)/K(+)-ATPase inhibitor) on the flux rate of NP-647 was determined. Molecular docking and molecular dynamics simulation studies were carried out to investigate molecular interactions of NP-647 with transporter using homology model of human PEPT1. The permeability coefficient (P(appCaco-2)) of NP-647 (32.5 × 10(-6) cm/s) was found to be four times higher than that of TRH. Results indicate that NP-647 is transported into Caco-2 cells by means of a carrier-mediated, proton-dependent mechanism that is inhibited by Gly-Sar and amoxicillin. In turn, NP-647 also inhibits the uptake of Gly-Sar into Caco-2 cells and, together, this evidence suggests that PEPT1 is involved in the process. Docking and molecular dynamics simulation studies indicate high affinity of NP-647 toward PEPT1 binding site as compared to TRH. High permeability of NP-647 over TRH is attributed to its increased hydrophobicity which increases its affinity toward PEPT1 by interacting with the hydrophobic pocket of the transporter through hydrophobic forces.     

Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides

Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p < 0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37 ± 2.15 vs. 6.24 ± 1.37 tail% DNA, p < 0.001). Further, the workers with CYP2D6*3 PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p < 0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions.     

Protective effect of Sharbat-e-Deenar against acetaminophen-induced hepatotoxicity in experimental animals

Objective

To investigate the effect of Sharbat-e-Deenar (SD) on acetaminophen (APAP)-induced hepatotoxicity in rat model.