Circulating soluble CD4 directly prevents host resistance and delayed-type hypersensitivity response to Cryptococcus neoformans in mice

In the present study, we examined the effect of soluble CD4 (sCD4) on host resistance and delayed-type hypersensitivity (DTH) response to Cryptococcus neoformans using a novel mutant mouse that exhibits a defect in the expression of membrane-bound CD4 but secretes high levels of sCD4 in the serum. In these mice, host resistance to this pathogen was impaired as indicated by an increased number of live pathogens in the lung. To elucidate the mechanism of immunodeficiency, three different sets of experiments were conducted. First, administration of anti-CD4 mAb restored the attenuated host defense. Second, in CD4 gene-disrupted (CD4KO) mice, host resistance was not attenuated compared to control mice. Third, implantation of sCD4 gene-transfected myeloma cells rendered the CD4KO mice susceptible to this infection, while similar treatment with mock-transfected cells did not show such an effect. These results indicated that immunodeficiency in the mutant mice was attributed to the circulating sCD4 rather than to the lack of CD4+ T cells. In addition, DTH response to C. neoformans evaluated by footpad swelling was reduced in the mutant mice compared to that in the control, and the reduced response was restored by the administration of anti-CD4 mAb. Finally, serum levels of IFN-gamma, IL-12 and IL-18 in the mutant mice were significantly reduced, while there was no difference in Th2 cytokines, such as IL-4 and IL-10. Considered collectively, our results demonstrated that sCD4 could directly prevent host resistance and DTH response to C. neoformans through interference with the production of Th1-type cytokines.     

Human lens high-molecular-weight alpha-crystallin aggregates

Alpha-crystallin high-molecular-weight (HMW) aggregates can be formed in vitro by many mechanisms, but the mechanism of in vivo aggregation has not been clearly established. HMW and LMW (low-molecular-weight) alpha-crystallins were isolated from human lenses 50-60 years of age and some spectroscopic measurements were performed. Conformational differences were suggested based on data of increased bis-ANS (4,4'-dianilino-1,1'-binaphthalene-5, 5'-disulfonic acid) and ThT (thioflavin T) fluorescence as well as increased far-UV and decreased near-UV circular dichroism (CD). These results indicated that HMW alpha-crystallin was more hydrophobic than LMW alpha-crystallin, possibly resulting from partial unfolding of alpha-crystallin. On the other hand, the increased ThT fluorescence and far-UV CD intensities indicate that an increased amount of beta-sheet conformation was involved in aggregation. These data, along with little difference in chaperone-like activity between the LMW and HMW alpha-crystallins, strongly suggest that HMW alpha-crystallin aggregates resulted from partial unfolding and disassembling-reassembling of LMW alpha-crystallin caused by posttranslational modification rather than chaperone complex formation.     

Effect of ninhydrin on the biochemical and histopathological changes induced by ethanol in gastric mucosa of rats

Studies on the effect of ninhydrin in the normal gastric mucosa and against the ethanol induced gastric injury were undertaken in rats in view of the presence of a carbonyl function as well as hydroxyl groups in its chemical structure. In spite of its potentials to generate hydroxyl radicals, it is deemed to possess antioxidant property by virtue of its electrophilic nature. Recent studies have shown gastro-protection to mediate through a reaction between the electrophilic compounds and sulfhydryl groups of the mucosa. Hence it was found worthwhile to evaluate the interaction between the oxidant and antioxidant functions in the structure of the same compound. The effects of ninhydrin pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl and 0.2M NaOH were investigated in rats. The gastric tissue in ethanol-treated rats was analyzed for different histopathological lesions. In addition, the effects on ethanol-induced changes in the gastric levels of proteins, nucleic acids, non-protein sulfhydryl (NP-SH) and malondialdehyde (MDA) were also evaluated. Ninhydrin, as such, failed to induce any significant changes in normal gastric mucosa, while its pretreatment at oral doses of 5, 10 and 20 mg/kg was found to provide a dose-dependent protection against the ulcers induced by ethanol, NaOH and NaCl. The results of histopathological evaluation revealed a protective effect of ninhydrin on congestion, hemorrhage, edema, erosions and necrosis caused by ethanol. Furthermore, the pretreatment afforded a dose-dependent inhibition of the ethanol-induced depletion of proteins, nucleic acids, NP-SH and increase of MDA in the gastric tissue. The results obtained clearly demonstrate the anti-ulcerogenic activity of ninhydrin. The exact mechanism of action is not known. However, the carbonyl function in ninhydrin appears to achieve antioxidant balance and protect the gastric mucosa from the ethanol-induced gastric injury. Further studies are warranted to investigate the toxicity and detailed mechanism of action of this potent compound before any clinical trials, especially at the effective lower doses.     

“I Have No Clue What I Drunk Last Night” Using Smartphone Technology to Compare In-Vivo and Retrospective Self-Reports of Alcohol Consumption

AimThis research compared real-time measurements of alcohol consumption with retrospective accounts of alcohol consumption to examine possible discrepancies between, and contextual influences on, the different accounts.MethodBuilding on previous investigations, a specifically designed Smartphone technology was utilized to measure alcohol consumption and contextual influences in de facto real-time. Real-time data (a total of 10,560 data points relating to type and number of drinks and current social / environmental context) were compared with daily and weekly retrospective accounts of alcohol consumption.ResultsParticipants reported consuming more alcoholic drinks during real-time assessment than retrospectively. For daily accounts a higher number of drinks consumed in real-time was related to a higher discrepancy between real-time and retrospective accounts. This effect was found across all drink types but was not shaped by social and environmental contexts. Higher in-vivo alcohol consumption appeared to be related to a higher discrepancy in retrospectively reported weekly consumption for alcohol beverage types other than wine. When including contextual factors into the statistical models, being with two or more friends (as opposed to being alone) decreased the discrepancy between real-time and retrospective reports, whilst being in the pub (relative to being at home) was associated with greater discrepancies.ConclusionsOverall, retrospective accounts may underestimate the amount of actual, real-time alcohol consumed. Increased consumption may also exacerbate differences between real-time and retrospective accounts. Nonetheless, this is not a global effect as environmental and social contexts interact with the type of alcohol consumed and the time frame given for reporting (weekly vs. daily retrospective). A degree of caution therefore appears warranted with regards to the use of retrospective self-report methods of recording alcohol consumption. Whilst real-time sampling is unlikely to be completely error free, it may be better able to account for social and environmental influences on self-reported consumption.     

Comparison of Univariate and Multivariate Models of 13C SSNMR and XRPD Techniques for Quantification of Nimodipine Polymorphs

The focus of the present investigation was to explore the use of solid-state nuclear magnetic resonance (¹³C ssNMR) and X-ray powder diffraction (XRPD) for quantification of nimodipine polymorphs (form I and form II) crystallized in a cosolvent formulation. The cosolvent formulation composed of polyethylene glycol 400, glycerin, water, and 2.5% drug, and was stored at 5°C for the drug crystallization. The ¹³C ssNMR and XRPD data of the sample matrices containing varying percentages of nimodipine form I and form II were collected. Univariate and multivariate models were developed using the data. Least square method was used for the univariate model generation. Partial least square and principle component regressions were used for the multivariate models development. The univariate models of the ¹³C ssNMR were better than the XRPD as indicated by statistical parameters such as correlation coefficient, R², root mean square error, and standard error. On the other hand, the XRPD multivariate models were better than the ¹³C ssNMR as indicated by precision and accuracy parameters. Similar values were predicted by the univariate and multivariate models for independent samples. In conclusion, the univariate and multivariate models of ¹³C ssNMR and XRPD can be used to quantitate nimodipine polymorphs.KEY WORDS: nimodipine polymorphs, X-ray powder diffraction, solid-state nuclear magnetic resonance, univariate, multivariate     

A cytogenetic study of R. constantinopolitanus and R. sericeus (Ranunculaceae) in Iran

With 600 species Ranunculus is the largest genus in Ranunculaceae, and has a broad global distribution. We studied the karyotypes of R. constantinopolitanus and R. sericeus species of Ranunculaceae and identified their symmetry level. New chromosome numbers of 2n = 21 (Nodeh woods population) and 2n ca. 63 (Javaherdeh population) are reported for R. constantinopolitanus. Two different populations of R. sericeus had two different chromosome results. We investigated morphological and karyological studies along with pollens micromorphology. Different populations of R. constantinopolitanus and R. sericeus, with different chromosome numbers showed morphological and micromorphological differences. Therefore, we considered the two populations of R. sericeus as cytotypes. There was a correlation between the studied morphological characters and pollen size with ploidy levels in the two R. constantinopolitanus populations.     

SHER: A Colored Petri Net Based Random Mobility Model for Wireless Communications

In wireless network research, simulation is the most imperative technique to investigate the network’s behavior and validation. Wireless networks typically consist of mobile hosts; therefore, the degree of validation is influenced by the underlying mobility model, and synthetic models are implemented in simulators because real life traces are not widely available. In wireless communications, mobility is an integral part while the key role of a mobility model is to mimic the real life traveling patterns to study. The performance of routing protocols and mobility management strategies e.g. paging, registration and handoff is highly dependent to the selected mobility model. In this paper, we devise and evaluate the Show Home and Exclusive Regions (SHER), a novel two-dimensional (2-D) Colored Petri net (CPN) based formal random mobility model, which exhibits sociological behavior of a user. The model captures hotspots where a user frequently visits and spends time. Our solution eliminates six key issues of the random mobility models, i.e., sudden stops, memoryless movements, border effect, temporal dependency of velocity, pause time dependency, and speed decay in a single model. The proposed model is able to predict the future location of a mobile user and ultimately improves the performance of wireless communication networks. The model follows a uniform nodal distribution and is a mini simulator, which exhibits interesting mobility patterns. The model is also helpful to those who are not familiar with the formal modeling, and users can extract meaningful information with a single mouse-click. It is noteworthy that capturing dynamic mobility patterns through CPN is the most challenging and virulent activity of the presented research. Statistical and reachability analysis techniques are presented to elucidate and validate the performance of our proposed mobility model. The state space methods allow us to algorithmically derive the system behavior and rectify the errors of our proposed model.     

Metabolomics and Incidence of Atrial Fibrillation in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

Background

Atrial fibrillation (AF) is a common arrhythmia. Application of metabolomic approaches, which may identify novel pathways and biomarkers of disease risk, to a longitudinal epidemiologic study of AF has been limited.

Methods

We determined the prospective association of 118 serum metabolites identified through untargeted metabolomics profiling with the incidence of newly-diagnosed AF in 1919 African-American men and women from the Atherosclerosis Risk in Communities study without AF at baseline (1987–1989). Incident AF cases through 2011 were ascertained from study electrocardiograms, hospital discharge codes, and death certificates.

Results

During a median follow-up of 22 years, we identified 183 incident AF cases. In Cox proportional hazards models adjusted for age, sex, smoking, body mass index, systolic blood pressure, use of antihypertensive medication, diabetes, prevalent heart failure, prevalent coronary heart disease, and kidney function, two conjugated bile acids (glycolithocholate sulfate and glycocholenate sulfate) were significantly associated with AF risk after correcting for multiple comparisons (p<0.0004). Multivariable-adjusted hazard ratios (95% confidence intervals) of AF were 1.22 (1.12–1.32) for glycolithocholate sulfate and 1.22 (1.10–1.35) for glycocholenate sulfate per 1-standard deviation higher levels. Associations were not appreciably different after additional adjustment for alcohol consumption or concentrations of circulating albumin and liver enzymes.

Conclusion

We found an association of higher levels of two bile acids with an increased risk of AF, pointing to a potential novel pathway in AF pathogenesis. Replication of results in independent studies is warranted.