Background:Systemic lupus erythematosus (SLE) affects people in childhood (childhood onset) or in adulthood (adult onset). Observational studies that have previously compared childhood-onset versus adult-onset SLE were often restricted to 1 ethnic group, or to a particular area, with a small sample size of patients. We aimed to systematically compare childhood-onset versus adult-onset SLE through a meta-analysis.Methods:Electronic databases were searched for relevant publications comparing childhood-onset with adult-onset SLE. Adverse clinical features were considered as the endpoints. The Newcastle Ottawa Scale (NOS) was used to assess the methodological quality of the studies and RevMan software (version 5.3) was used to carry out this analysis whereby risk ratios (RRs) and 95% confidence intervals (95% CIs) were used as the statistical parameters.Results:A total number of 10,261 participants (1560 participants with childhood-onset SLE and 8701 participants with adult-onset SLE) were enrolled. Results of this analysis showed that compared with childhood-onset SLE, pulmonary involvement was significantly higher with adult-onset SLE (RR: 1.51, 95% CI: 1.18–1.93; P = .001), whereas renal involvement was significantly higher with childhood-onset SLE (RR: 0.65, 95% CI: 0.55–0.77; P = .00001). Raynaud phenomenon and photosensitivity were significantly higher in adult-onset SLE (RR: 1.29, 95% CI: 1.04–1.60; P = .02) and (RR: 1.08, 95% CI: 1.01–1.17; P = .03), respectively. Malar rash significantly favored adult-onset SLE (RR: 0.84, 95% CI: 0.75–0.94; P = .002). Childhood-onset SLE was associated with significantly higher hemolytic anemia, thrombocytopenia, leukocytopenia, and lymphopenia. Seizure and ocular manifestations were significantly higher with childhood-onset SLE (RR: 0.57, 95% CI: 0.47–0.70; P = .00001) and (RR: 0.34, 95% CI: 0.21–0.55; P = .00001), respectively, whereas pleuritis was significantly higher with adult-onset SLE (RR: 1.45, 95% CI: 1.17–1.79; P = .0008). Vasculitis and fever were significantly higher with childhood-onset SLE (RR: 0.51, 95% CI: 0.36–0.74; P = .0004) and (RR: 0.78, 95% CI: 0.68–0.89; P = .0002) respectively.Conclusion:Significant differences were observed between childhood-onset versus adult-onset SLE, showing the former to be more aggressive.

Bicarbonate (HCO 3 2 ) has a central place in human physiology as the waste product of mitochondrial energy production and for its role in pH buffering throughout the body. Because bicarbonate is impermeable to membranes, bicarbonate transport proteins are necessary to enable control of bicarbonate levels across membranes. In humans, 14 bicarbonate transport proteins, members of the SLC4 and SLC26 families, function by differing transport mechanisms. In addition, some anion channels and ZIP metal transporters contribute to bicarbonate movement across membranes. Defective bicarbonate transport leads to diseases, including systemic acidosis, brain dysfunction, kidney stones, and hypertension. Altered expression levels of bicarbonate transporters in patients with breast, colon, and lung cancer suggest an important role of these transporters in cancer. V C 2014 IUBMB Life, 66(9): [596][597][598][599][600][601][602][603][604][605][606][607][608][609][610][611][612][613][614][615] 2014

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Manganese is a micronutrient required for activities of several important enzymes under conditions of oxidative stress and iron starvation. In Escherichia coli, the manganese homeostasis network primarily constitutes a manganese importer (MntH) and an exporter (MntP), which are regulated by the MntR dual regulator. In this study, we find that deletion of E. coli hflX, which encodes a ribosome-associated GTPase with unknown function, renders extreme manganese sensitivity characterized by arrested cell growth, filamentation, lower rate of replication, and DNA damage. We demonstrate that perturbation by manganese induces unprecedented influx of manganese in ⌬hflX cells compared to that in the wild-type E. coli strain. Interestingly, our study indicates that the imbalance in manganese homeostasis in the ⌬hflX strain is independent of the MntR regulon. Moreover, the influx of manganese leads to a simultaneous influx of zinc and inhibition of iron import in ⌬hflX cells. In order to review a possible link of HflX with the phage life cycle, we performed a lysis-lysogeny assay to show that the Mn-perturbed ⌬hflX strain reduces the frequency of lysogenization of the phage. This observation raises the possibility that the induced zinc influx in the manganese-perturbed ⌬hflX strain stimulates the activity of the zinc-metalloprotease HflB, the key determinant of the lysis-lysogeny switch. Finally, we propose that manganese-mediated autophosphorylation of HflX plays a central role in manganese, zinc, and iron homeostasis in E. coli cells.

Citation: Chiu AM, Mandziuk JJ, Loganathan SK, Alka K, Casey JR. High throughput assay identifies glafenine as a corrector for the folding defect in corneal dystrophy-causing mutants of SLC4A11. Invest Ophthalmol Vis Sci. 2015;56:7739-7753. DOI:10.1167/ iovs.15-17802 PURPOSE. Protein misfolding, causing retention of nascent protein in the endoplasmic reticulum (ER), is the most common molecular phenotype for disease alleles of membrane proteins. Strategies are needed to identify therapeutics able to correct such folding/trafficking defects. Mutations of SLC4A11, a plasma membrane transport protein of the human corneal endothelial cell layer, cause cases of congenital hereditary endothelial dystrophy, Harboyan syndrome, and Fuchs' endothelial corneal dystrophy. Most SLC4A11 mutations induce SLC4A11 misfolding and retention in the ER.METHODS. An assay amenable to high-throughput screening was developed to quantify SLC4A11 at the plasma membrane, enabling a search for potential traffic-correcting small molecules. The assay was validated by comparing cell surface abundance of SLC4A11 mutants measured in the assay to observations from confocal immunofluorescence and values from cell surface biotinylation. Functionality of mutant proteins was assessed, using a confocal microscopic green fluorescent protein (GFP) water flux assay where relative rates of cell swelling are compared. RESULTS.A small-scale screen revealed that the nonsteroidal anti-inflammatory drugs (NSAIDs), glafenine, ibuprofen, and acetylsalicylic acid dissolved in 0.2% dimethyl sulfoxide (DMSO), partially rescued the trafficking defect in some SLC4A11 mutants, expressed in HEK293 cells. These SLC4A11 mutants retained functional activity when rescued to the plasma membrane by glafenine treatment. Glafenine was effective with an EC 50 of 1.5 6 0.7 lM.CONCLUSIONS. These data suggest that glafenine, and perhaps other NSAIDs, hold potential as therapeutics for misfolded membrane proteins, like SLC4A11. The high throughput approach described here can be modified to identify correctors of other misfolded plasma membrane proteins that cause eye disease.

SLC4A11 mutations cause cases of congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (HS), and Fuchs endothelial corneal dystrophy (FECD). Defective water reabsorption from corneal stroma by corneal endothelial cells (CECs) leads to these corneal dystrophies. SLC4A11, in the CEC basolateral membrane, facilitates transmembrane movement of H 2 O, NH 3 , and H + -equivalents. Some SLC4A11 disease mutants have impaired folding, leading to a failure to move to the cell surface, which in some cases can be corrected by the drug, glafenine. To identify SLC4A11 mutants that are targets for folding-correction therapy, we examined 54 SLC4A11 missense mutants. Cell-surface trafficking was assessed on immunoblots, by the level of mature, high molecular weight, cell surface-associated form, and using a bioluminescence resonance energy transfer assay. Low level of cell surface trafficking was found in four out of 18 (20%) of FECD mutants, 19/ out of 31 (61%) of CHED mutants, and three out of five (60%) of HS mutants.Amongst ER-retained mutants, 16 showed increased plasma membrane trafficking when grown at 30 • C, suggesting that their defect has potential for rescue. CHED-causing point mutations mostly resulted in folding defects, whereas the majority of FECD missense mutations did not affect trafficking, implying functional impairment. We identified mutations that make patients candidates for folding correction of their corneal dystrophy.

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The solubility of benzoic acid in (acetic acid + water) and (acetic acid + toluene) binary mixtures has been investigated by the gravimetric method. The study was carried out at different mass fractions of acetic acid ranging from 0.1 to 0.8 at 299.15 K. The results indicated that the solubility of benzoic acid in both binary mixtures exhibited an increasing trend with an increase in the mass fraction of acetic acid. The solubility of benzoic acid with respect to acetic acid in the (acetic acid + water) mixture was less than that in the (acetic acid + toluene) mixture. Furthermore, the refractive indices, n D , and densities, ρ, have been measured for (acetic acid + water) and (acetic acid + toluene) binary mixtures as well as mixtures saturated with benzoic acid salt at different temperatures over the entire composition range, and the same have been reported. The molar refractivity, R m , was estimated using refractive index, n D , and molar volume, V m , employing the Lorentz−Lorenz equation. The excess properties, namely deviations in molar refractivity, ΔR, and excess molar volumes, V m E , were calculated for both binary mixtures. The deviations in molar refractivity resulted in negative values for both binary mixtures, whereas the excess molar volumes V m E gave negative values for the (acetic acid + water) mixture and positive values for the (acetic acid + toluene) mixtures. The results obtained in the present study are discussed in terms of structural packing and interactions present among the mixing components and are fitted to the Redlich−Kister third order polynomial equation. Different mixing rules were also employed to predict the refractive index and compared with experimental values.