Interleukin 28B-related polymorphisms: A pathway for understanding hepatitis C virus infection?

AIM:To analyze the role of rs12979860 and rs8099917polymorphisms in hepatitis C virus(HCV)genotype 1infection of Brazilians.METHODS:A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C(CHC)who had completed a 48-wk regimen of pegylated-interferonα-2a or-2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and199 healthy blood donors(controls)from a single site between January 2010 and January 2012.Data on the patients’response to treatment was collected.Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin(IL)28B gene fragment encompassing the single nucleotide polymorphisms(SNPs)rs12979860(C/T)and rs8099917(T/G)was carried out for 79 of the CHC patients and 199 of the controls.Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients.RESULTS:SNP rs12979860 genotyping was successful in 99.5%of the controls and 97.2%of the CHC patients,whereas the SNP rs8099917 genotyping was successful in 95.5%of the controls and 100%of the CHC patients.The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups,with significantly higher genotype frequencies of CC and TT in the controls(P=0.037 and 0.046,respectively)and of TT and GG in the CHC patients(P=0.0009and 0.0001,respectively).Analysis of the CHC patients who achieved sustained virological response(SVR)to treatment(n=55)indicated that the rs12979860 C allele and CC genotype were predictors of SVR(P=0.02).No significant correlation was found between rs8099917 genotypes and treatment response,but carriers of the T allele showed significantly higher rates of SVR(P=0.02).Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917(P=0.07).CONCLUSION:The higher allele frequency of rs12979860 C and rs8099917 T observed in non-HCVinfected individuals may indicate a potential pro     

Functional evaluation of immunoregulatory molecules HLA-G,galectin-1, and IL-10 in people living with HIV

Objective(s):Investigate polymorphisms and expressions of human leukocyte antigen-G (HLA-G), galectin-1 (Gal-1), and interleukin-10 (IL-10) in people living with HIV (PLHIV) with and without comorbidities to help understanding the mechanisms involved in triggering these disorders in PLHIV and in their prognosis.Design:Here we evaluated the potential correlation between the genetic polymorphism and/or protein levels of HLA-G, Gal-1, and IL-10 with and without comorbidities of PLHIV.Methods:Two hundred HIV patients under antiretroviral treatment (83 with comorbidities and 117 without comorbidities) and 200 healthy individuals (controls) were genotyped, using PCR, for HLA-G 14-base pair polymorphism located at the 3’ untranslated region in exon 8 insertion/insertion (Ins/Ins: low HLA-G expression) or deletion/deletion (Del/Del: high HLA-G expression). Soluble levels of HLA-G (sHLA-G), Gal-1, and IL-10 were quantified by enzyme-linked immunosorbet assay.Results:HIV patients without comorbidities exhibited higher frequency of 14-base pair Del/Del genotype than HIV patients with comorbidities. As expected, HIV patients Ins/Ins with and without comorbidities produced less sHLA-G than controls. However, HIV patients Del/Del with comorbidities expressed sHLA-G more than controls and HIV patients Del/Del without comorbidities. Interestingly, patients that showed low levels sHLA-G, and presence of comorbidities, exhibited high Gal-1 serum levels. However, an increase in soluble levels of IL-10 in PLHIV was observed when compared to controls, especially in the PLHIV group without comorbidities suggesting, a protective role of IL-10 in the development of comorbidities.Conclusions:These data suggested that the high expression of sHLA-G and IL-10 or Gal-1 could be associated and could be associated with the development or not of comorbidities in PLHIV.     

Direct measurement of the viscoelectric effect in water

The viscoelectric effect concerns the increase in viscosity of a polar liquid in an electric field due to its interaction with the dipolar molecules and was first determined for polar organic liquids more than 80 y ago. For the case of water, however, the most common polar liquid, direct measurement of the viscoelectric effect is challenging and has not to date been carried out, despite its importance in a wide range of electrokinetic and flow effects. In consequence, estimates of its magnitude for water vary by more than three orders of magnitude. Here, we measure the viscoelectric effect in water directly using a surface force balance by measuring the dynamic approach of two molecularly smooth surfaces with a controlled, uniform electric field between them across highly purified water. As the water is squeezed out of the gap between the approaching surfaces, viscous damping dominates the approach dynamics; this is modulated by the viscoelectric effect under the uniform transverse electric field across the water, enabling its magnitude to be directly determined as a function of the field. We measured a value for this magnitude, which differs by one and by two orders of magnitude, respectively, from its highest and lowest previously estimated values.

The viscoelectric effect concerns the change in the viscosity of polar liquids in the presence of an electric field (1–3). It arises from the interaction of the field with the dipolar molecules, and while its molecular origins are still not well understood (4–6), it has considerable relevance in areas ranging from surface potential measurements (7–9) and boundary lubrication (10) to nanofluidics and its applications (11–13). Knowing the magnitude of the viscoelectric effect is thus of clear importance. It was first measured by Andrade and Dodd (1–3) for a range of polar organic liquids, by monitoring their flow in a narrow channel between metal electrodes across which a known electric field E was applied, and quantified via a viscoelectric coefficient f using an empirical relation based on their results:η(E)= η0(1 + f∣E∣2),[1]a simplified analysis leading to such a relation is given in Ref. (8). Here, η₀ is the unperturbed bulk liquid viscosity (i.e., in the absence of any field). For the case of water, however, the most ubiquitous and important polar liquid, measurement of its viscosity in the presence of a strong, uniform field presents a strong challenge (as discussed later in this section), and to our knowledge no such direct measurements have been reported. Over the past six decades, therefore, the magnitude of the viscoelectric effect in water has been only indirectly estimated by extrapolation from its values for organic liquids (8), from estimates of its effect on electrokinetic phenomena (11, 14–19), or by other approaches (7, 12, 20, 21). These estimated values, as expressed in the viscoelectric coefficient f, vary over more than three orders of magnitude, ranging from f ∼10⁻¹⁷–2.5 × 10⁻¹⁴ (V/m)² (SI Appendix, Section 7). For completeness, we note that results contradictory to the viscoelectric model have also been reported (22) (i.e., suggesting a decreased water viscosity in an electric field). The reasons for the large span of these estimated f values were attributed to various factors such as solid/liquid coupling, varying ionic sizes, and varying water permittivity (12, 19); however, while these factors may play some role, there is no evidence that they could lead to such large discrepancies.We believe, rather, that the origin of the large variance in the estimated magnitude of the viscoelectric effect arises because none of the experimental studies on water to date in which the f values were estimated was direct, in the sense of probing how the water viscosity varied with field in a uniform electric field. In all cases, viscosity changes were assumed to occur only in the nonuniform, rapidly decaying electrostatic potential near charged surfaces immersed in water. Changes in electrophoretic mobility, electro-osmosis, or hydrodynamic dissipation or water mobility between similarly charged solid surfaces were then attributed to some mean viscosity increase in these thin surface-adjacent layers (7, 11, 12, 14–21). In practice, however, the effect on these electrokinetic phenomena of viscosity or water mobility changes in the thin layers where such nonuniform, rapidly decaying fields are present is not easy to quantify reliably, especially in the presence of salt ions (12). At the same time, measuring the viscosity of water in a uniform electric field between two surfaces at different potentials, as was done for the polar organic solvents (2, 3) and which would provide a direct determination of its viscoelectric effect, presents a considerable difficulty. This is due to two main factors and arises because, in contrast to organic solvents, water may self-dissociate. Firstly, the potential difference that may be applied between the surfaces across water is limited, if electrolysis is to be avoided (23, 24), and secondly, electrostatic screening implies that the field decays strongly (within a Debye screening length) away from the surfaces (25–27). Even in purified water with no added salt (as in the present study), the potential decays rapidly away from a charged surface (see, e.g., Fig. 1C), so that to measure viscosity in a uniform field between two surfaces, one would require flow channels of width of order some tens of nanometers or less, presenting a major challenge.Open in a separate windowFig. 1.Numerical solution to the nonlinearized PB equation with σ_mica = −8.1 mC/m², ψ_gold = 0.07 V, and ion concentration c_b = 8 × 10⁻⁵ M, corresponding to the conditions of Fig. 4A. (A) Surface potential on the mica surface and surface charge on the gold surface as a function of separation D. (B) Average electric field approximated as (|ψ_gold − ψ_mica|/D). (C) Local potential ψ as a function of distance d from the mica surface for different separations D. Dashed line in larger-scale inset is an eye guide of a linear approximation.In the present study, we overcome this by directly probing the viscosity of purified water across which a uniform electric field acts while it is confined between two surfaces in a surface force balance (SFB). In our experiments, a molecularly smooth gold surface at a controlled (positive) surface potential approaches an atomically smooth mica surface at constant surface (negative) charge density, so that a known electric field acts across the water-filled gap of width D between them; moreover, this field is very close to uniform at the most relevant surface separations (D ≲ 30 nm, Fig. 1C). The dynamics of approach is strongly modulated by the viscous damping due to squeeze-out of the water as D decreases, and hence by its viscosity in the uniform electric field; by monitoring the approach rate of the surfaces at high temporal (millisecond) and spatial (approximately angstrom) resolutions, we are able therefore to directly evaluate the magnitude of the viscoelectric effect (the value of f).     

Prevalence of mandibular asymmetry in different skeletal sagittal patterns:: A systematic review

ObjectivesTo analyze the prevalence of mandibular asymmetry in skeletal sagittal malocclusions.Materials and MethodsPubMed/MEDLINE, EMBASE, LILACS, Web of Science, Scopus, LIVIVO and gray literature (OpenGrey, ProQuest, and Google Scholar) were electronically searched. Two independent investigators selected the eligible studies, and assessed risk of bias and certainty of evidence (GRADE). One reviewer independently extracted the data and the second reviewer checked this information. Any disagreement between the reviewers in each phase was resolved by discussion between them and/or involved a third reviewer for final decision.ResultsElectronic search identified 5,132 studies, and 5 observational studies were included. Risk of bias was low in two studies, moderate in one, and high in two. The studies showed high heterogeneity. Mandibular asymmetry ranged from 17.43% to 72.95% in overall samples. Horizontal chin deviation showed a prevalence of 17.66% to 55.6% asymmetry in Class I malocclusions, and 68.98% in vertical asymmetry index. In Class II patients, prevalence of mandibular asymmetry varied from 10% to 25.5% in horizontal chin deviation, and 71.7% in vertical asymmetry index. The Class III sample showed a prevalence of mandibular asymmetry ranging from 22.93% to 78% in horizontal chin deviation and 80.4% in vertical asymmetry index. Patients seeking orthodontic or orthognathic surgery treatment showed greater prevalence of mandibular asymmetry.ConclusionsSkeletal Class III malocclusion showed the greatest prevalence of mandibular asymmetry. Mandibular vertical asymmetry showed a marked prevalence in all malocclusions. However, conclusions should be interpreted with caution due to use of convenience samples and low-quality study outcomes.     

CD7– T cells in rheumatoid arthritis

Objective. Rheumatoid arthritis (RA) is characterized by decreased expression of CD7 in the peripheral blood and in the synovium. The present study was designed to identify the basis for and functional consequences of this decreased expression. Methods. Peripheral blood lymphocytes from normal controls and from patients with RA or systemic lupus erythematosus (SLE), and T cell lines derived from rheumatoid synovium, were evaluated using 3-color fluorescence-activated cell sorter analysis. Results. Normal subjects and most SLE patients expressed homogeneous, bright CD7 on CD4+, CD45RA+ cells, whereas RA patients demonstrated a significantly increased proportion of CD7– cells. T cell lines derived from rheumatoid synovium demonstrated a striking deficiency of CD7 on CD4+, CD45RA– cells. CD4+, CD45RA+ cells from RA patients changed phenotype after in vitro activation to CD45RA negativity, with up-regulation of CD7. CD7–, CD4+, CD45RA– cells were assessed for their ability to induce pokeweed mitogen-driven IgM and IgM-rheumatoid factor synthesis, and they were found to be potent helper/inducer cells. An increased population of CD7-, CD4+ cells in peripheral blood was found to predict a low response to recall antigens. Conclusion. The low expression of CD7 in RA may explain some of the immune abnormalities which may contribute to the pathogenesis of this disease.     

An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins

Background and objectivesIschemic events, such as ischemic heart disease and stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to ischemic events, other species, such as marine mammals, have evolved a unique tolerance to chronic ischemia/reperfusion during apneic diving. To identify possible molecular features of an increased tolerance for apnea, we examined changes in gene expression in breath-holding dolphins.MethodologyHere, we capitalized on the adaptations possesed by bottlenose dolphins (Tursiops truncatus) for diving as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath holding. Given that signals in the blood may influence physiological changes during diving, we used RNA-Seq and enzyme assays to examine time-dependent changes in gene expression in the blood of breath-holding dolphins.ResultsWe observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene and increased lipoxygenase activity during breath holding. ALOX5 has been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction.Conclusions and implicationsThe upregulation of ALOX5 mRNA occurred within the calculated aerobic dive limit of the species, suggesting that ALOX5 may play a role in the dolphin’s physiological response to diving, particularly in a pro-inflammatory response to ischemia and in promoting vasoconstriction. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, respond to the prolonged breath holds associated with diving.