Association of killer cell immunoglobulin-like receptor polymorphisms with chronic hepatitis C and responses to therapy in Brazil

ABSTRACT: Soroprevalence for Hepatitis C virus is reported as 2.12% in Northern Brazil, with about 50% of the patients exhibiting a sustained virological response (SVR). Aiming to associate polymorphisms in Killer Cell Immunoglobulin-like Receptors (KIR) with chronic hepatitis C and therapy responses we investigated 125 chronic patients and 345 controls. Additionally, 48 ancestry markers were genotyped to control for population stratification. The frequency of the KIR2DL2 and KIR2DL2+HLA-C^Asp80 gene and ligand was higher in chronic infected patients than in controls (p < 0.0009, OR = 3.4; p = 0.001, OR = 3.45). In fact, KIR2DL3 is a weaker inhibitor of NK activity than KIR2DL2, which could explain the association of KIR2DL2 with chronic infection. Moreover, KIR2DS2 and KIR2DS2+HLA-C^Asp80 (p < 0.0001, OR = 2.51; p = 0.0084, OR = 2.62) and KIR2DS3 (p < 0.0001; OR = 2.57) were associated with chronic infection, independently from KIR2DL2. No differences in ancestry composition were observed between control and patients, even with respect to therapy response groups. The allelic profile KIR2DL2/KIR2DS2/KIR2DS3 was associated with the chronic hepatitis C (p < 0.0001; OR = 3). Furthermore, the patients also showed a higher mean number of activating genes and a lower frequency of the homozygous AA profile, which is likely secondary to the association with non-AA and/or activating genes. In addition, the KIR2DS5 allele was associated with SVR (p = 0.0261; OR = 0.184).The ancestry analysis of samples ruled out any effects of population substructuring and did not evidence interethnic differences in therapy response, as suggested in previous studies.

Controlador PID utilizando microcontrolador PIC

This monograph proposes the implementation of a low cost PID controller utilizing a PIC microcontroller, and its application in a positioning system previously controlled by a dedicated integrated circuit for a positioning system. Applying the closed-loop PID control, the system instability was reduced, and its response was smoother, eliminating vibrations and mechanical wear compared to its response with the dedicated integrated circuit, which has a very limited control action. The actuator of the system is a DC motor, whose speed is controlled by the Pulse Width Modulation (PWM) technique, using a Full-Bridge circuit, allowing the shift of direction of rotation. The utilized microcontroller was the PIC16F684, which has an enhanced PWM module, with its analog converters used as reference and position feedback. The positioning sensor is a multiturn potentiometer coupled to the motor axis by gears. The possibility of programming the PID coefficients in the microcontroller, as well as the adjustment of the sampling rate, allows the implemented system achieving high level of versatility

Assessment Of Dynamic Properties Of A Crowd Model For Human-Structure Interaction Modeling

As lightweight and slender structural elements are more frequently used in the design, large scale structures become more flexible and susceptible to excessive vibrations. To ensure the functionality of the structure, dynamic properties of the occupied structure need to be estimated during the design phase. Traditional analysis method models occupants simply as an additional mass; however, research has shown that human occupants could be better modeled as an additional degree-of- freedom. In the United Kingdom, active and passive crowd models are proposed by the Joint Working Group as a result of a series of analytical and experimental research. It is expected that the crowd models would yield a more accurate estimation to the dynamic response of the occupied structure. However, experimental testing recently conducted through a graduate student project at Bucknell University indicated that the proposed passive crowd model might be inaccurate in representing the impact on the structure from the occupants. The objective of this study is to provide an assessment of the validity of the crowd models proposed by JWG through comparing the dynamic properties obtained from experimental testing data and analytical modeling results. The experimental data used in this study was collected by Firman in 2010. The analytical results were obtained by performing a time-history analysis on a finite element model of the occupied structure. The crowd models were created based on the recommendations from the JWG combined with the physical properties of the occupants during the experimental study. During this study, SAP2000 was used to create the finite element models and to implement the analysis; Matlab and ME¿scope were used to obtain the dynamic properties of the structure through processing the time-history analysis results from SAP2000. The result of this study indicates that the active crowd model could quite accurately represent the impact on the structure from occupants standing with bent knees while the passive crowd model could not properly simulate the dynamic response of the structure when occupants were standing straight or sitting on the structure. Future work related to this study involves improving the passive crowd model and evaluating the crowd models with full-scale structure models and operating data.

Cellular immune response, stress resistance and competitiveness in nestling great tits in relation to maternally transmitted carotenoids

1. Egg yolks contain carotenoids that protect biological molecules against free-radical damage and promote maturation of the immune system. Availability of carotenoids to birds is often limited. Trade-offs can thus arise in the allocation of carotenoids to different physiological functions, and mothers may influence the immunocompetence of nestlings by modulating the transfer of carotenoid to the yolk.;2. In the great tit Parus major, we experimentally manipulated the dietary supply of carotenoid to mothers, and partially cross-fostered hatchlings to investigate the effect of an increased availability of carotenoids during egg laying on immunocompetence of nestlings.;3. In addition, we infested half of the nests with hen fleas Ceratophyllus gallinae to investigate the relationship between carotenoid availability, resistance to ectoparasites and immunocompetence.;4. We found that the procedure of cross-fostering can reduce the immune response of nestlings, but this effect can be compensated by the maternally transferred carotenoids. Cross-fostered nestlings of carotenoid-supplemented females show a similar immune response to non-cross-fostered nestlings, while cross-fostered nestlings of control females mounted a weaker cell-mediated immune response. This suggests that yolk carotenoids may help nestlings to cope with stress, for example the one generated by cross-fostering and/or they may enhance nestling competitiveness.;5. There was no statistically significant interaction between parasite and carotenoid treatments, as would be expected if carotenoids helped nestlings to fight parasites. Under parasite pressure, however, lighter nestlings raised a lower immune response, while the immune response was only weakly correlated with body mass in uninfested nests.

Water-use efficiency and transpiration across European forests during the Anthropocene

The Earth’s carbon and hydrologic cycles are intimately coupled by gas exchange through plant stomata1, 2, 3. However, uncertainties in the magnitude4, 5, 6 and consequences7, 8 of the physiological responses9, 10 of plants to elevated CO2 in natural environments hinders modelling of terrestrial water cycling and carbon storage11. Here we use annually resolved long-term δ13C tree-ring measurements across a European forest network to reconstruct the physiologically driven response of intercellular CO2 (Ci) caused by atmospheric CO2 (Ca) trends. When removing meteorological signals from the δ13C measurements, we find that trees across Europe regulated gas exchange so that for one ppmv atmospheric CO2 increase, Ci increased by ~0.76 ppmv, most consistent with moderate control towards a constant Ci/Ca ratio. This response corresponds to twentieth-century intrinsic water-use efficiency (iWUE) increases of 14 ± 10 and 22 ± 6% at broadleaf and coniferous sites, respectively. An ensemble of process-based global vegetation models shows similar CO2 effects on iWUE trends. Yet, when operating these models with climate drivers reintroduced, despite decreased stomatal opening, 5% increases in European forest transpiration are calculated over the twentieth century. This counterintuitive result arises from lengthened growing seasons, enhanced evaporative demand in a warming climate, and increased leaf area, which together oppose effects of CO2-induced stomatal closure. Our study questions changes to the hydrological cycle, such as reductions in transpiration and air humidity, hypothesized to result from plant responses to anthropogenic emissions.

Anger and fear: Separable effects of emotion and motivational direction on somatovisceral responses.

We studied whether emotion (anger vs. fear) and motivational direction (approach vs. withdrawal) have specific, separable, and independent somatovisceral response patterns. Imagination scripts about soccer game episodes with crossed Emotion x Motivational Direction content resulting in four experimental groups were presented to a total of N = 118 active soccer players. Self-reports reflected the emotion but not the motivational direction induction. Univariate and multivariate analyses of 24 somatovisceral variables and 2 a priori defined summary variables showed that anger and fear had specific response profiles with effect sizes correlating r = 0.53 with the respective effect sizes from a previous study. Approach and withdrawal profiles varied only in intensity. Emotion and motivational direction did not interact and had independent somatovisceral effects. Results suggest that anger and fear have separate underlying neurobiological organizations each capable of bi-directional motivational tuning of efferent pathways. Results support the Component Model of Somatovisceral Response Organization.

Cis-acting elements and developmental regulators govern toxin gene expression in Bacillus anthracis

Expression of the structural genes for the anthrax toxin proteins is coordinately controlled by host-related signals such as elevated CO2 , and the trans-acting positive regulator, AtxA. No specific binding of AtxA to the toxin gene promoters has been demonstrated and no sequence-based similarities are apparent in the promoter regions of toxin genes. We hypothesized that the toxin genes possess common structural features that are required for positive regulation. To test this hypothesis, I performed an extensive characterization of the toxin gene promoters. I determined the minimal sequences required for atxA-mediated toxin gene expression and compared these sequences for structural similarities. In silico modeling and in vitro experiments indicated significant curvature within these regions. Random mutagenesis revealed that point mutations associated with reduced transcriptional activity, mostly mapped to areas of high curvature. This work enabled the identification of two potential cis-acting elements implicated in AtxA-mediated regulation of the toxin genes. In addition to the growth condition requirements and AtxA, toxin gene expression is under growth phase regulation. The transition state regulator AbrB represses atxA expression to influence toxin synthesis. Here I report that toxin gene expression also requires sigH, a gene encoding the RNA polymerase sigma factor associated with development in B. subtilis. In the well-studied B. subtilis system, σH is part of a feedback control pathway that involves AbrB and the major response regulator of sporulation initiation, Spo0A. My data indicate that in B. anthracis, regulatory relationships exist between these developmental regulators and atxA . Interestingly, during growth in toxin-inducing conditions, sigH and abrB expression deviates from that described for B. subtilis, affecting expression of the atxA gene. These findings, combined with previous observations, suggest that the steady state level of atxA expression is critical for optimal toxin gene transcription. I propose a model whereby, under toxin-inducing conditions, control of toxin gene expression is fine-tuned by the independent effects of the developmental regulators on the expression of atxA . The growth condition-dependent changes in expression of these regulators may be crucial for the correct timing and uninterrupted expression of the toxin genes during infection. ^

Planktonic foraminifera and sea surface temperture reconstruction for Red Sea sediment cores

In order to assess how insolation-driven climate change superimposed on sea level rise and millennial events influenced the Red Sea during the Holocene, we present new paleoceanographic records from two sediment cores to develop a comprehensive reconstruction of Holocene circulation dynamics in the basin. We show that the recovery of the planktonic foraminiferal fauna after the Younger Dryas was completed earlier in the northern than in the central Red Sea, implying significant changes in the hydrological balance of the northern Red Sea region during the deglaciation. In the early part of the Holocene, the environment of the Red Sea closely followed the development of the Indian summer monsoon and was dominated by a circulation mode similar to the current summer circulation, with low productivity throughout the central and northern Red Sea. The climatic signal during the late Holocene is dominated by a faunal transient event centered around 2.4 ka BP. Its timing corresponds to that of North Atlantic Bond event 2 and to a widespread regionally recorded dry period. This faunal transient is characterized by a more productive foraminiferal fauna and can be explained by an intensification of the winter circulation mode and high evaporation. The modern distribution pattern of planktonic foraminifera, reflecting the prevailing circulation system, was established after 1.7 ka BP.

Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes.

Using transgenic mice that replicate the hepatitis B virus (HBV) genome, we recently demonstrated that class I-restricted, hepatitis B surface antigen-specific cytotoxic T lymphocytes (CTLs) can noncytolytically eliminate HBV pregenomic and envelope RNA transcripts from the hepatocyte. We now demonstrate that the steady-state content of these viral transcripts is profoundly reduced in the nucleus and cytoplasm of CTL-activated hepatocytes, but their transcription rates are only slightly reduced. Additionally, we demonstrate that transcripts covering the HBV X coding region are resistant to downregulation by the CTL. These results imply the existence of CTL-inducible hepatocellular factors that interact with a discrete element(s) between nucleotides 3157 and 1239 within the viral pregenomic and envelope transcripts and mediate their degradation, thus converting the hepatocyte from a passive victim to an active participant in the host response to HBV infection.

Platelet-derived growth factor BB induces functional vascular anastomoses in vivo.

Neovascularization that generates collateral blood flow can limit the extent of tissue damage after acute ischemia caused by occlusion of the primary blood supply. The neovascular response stimulated by the BB homodimeric form of recombinant platelet-derived growth factor (PDGF-BB) was evaluated for its capacity to protect tissue from necrosis in a rat skin flap model of acutely induced ischemia. Complete survival of the tissue ensued, when the original nutritive blood supply was occluded, as early as 5 days after local PDGF-BB application, and the presence of a patent vasculature was evident compared to control flaps. To further evaluate the vascular regenerative response, PDGF-BB was injected into the muscle/connective tissue bed between the separated ends of a divided femoral artery in rats. A patent new vessel that functionally reconnected the ends of the divided artery within the original 3- to 4-mm gap was regenerated 3 weeks later in all PDGF-BB-treated limbs. In contrast, none of the paired control limbs, which received vehicle with an inactive variant of PDGF-BB, had vessel regrowth (P < 0.001). The absence of a sustained inflammatory response and granulation tissue suggests locally delivered PDGF-BB may directly stimulate the angiogenic phenotype in endothelial cells. These findings indicate that PDGF-BB can generate functional new blood vessels and nonsurgically anastomose severed vessels in vivo. This study supports the possibility of a therapeutic modality for the salvage of ischemic tissue through exogenous cytokine-induced vascular reconnection.

Turbulence ahead: disputes within the Russian ruling elite are gathering force. OSW Commentary No. 91, 2012-09-27

The last month has seen a public confrontation between Igor Sechin, the president of Rosneft, and Arkady Dvorkovich, the deputy prime minister, concerning the consolidation of the energy sector. This is the latest in a series of disputes between the Kremlin & businessmen from Putin’s inner circle on one side, and the government & Prime Minister Medvedev on the other. These disputes have been wide-ranging in nature, concerning economic policy, the scope of competency of individual members of the elite, but also the ‘tough line’ adopted by the Kremlin since Vladimir Putin’s return to the presidency. The Kremlin, which is still the main decision-making centre in Russia, has been effectively forcing its opinions through in its short-term disputes with the government. However, a new element in the ongoing conflicts, which is unfavourable to President Putin, is their exceptional strength, their much more public nature, and their wide range (which has included criticism of the president himself) and ever-changing context, especially the worsening socio-economic situation. These conflicts have been overlapping with signs of dissent among Putin’s business supporters, and their declining political willingness to support the leader unconditionally. The Kremlin’s response to the unrest consists of intensifying efforts to discipline the elite and weakening those groups in which Vladimir Putin has limited confidence. The elite’s support is crucial to the stability of his government; to maintain this support, the Kremlin is ready to introduce restrictive and repressive actions against both parliamentarians and government officials. In the short term, such a policy will force the Kremlin’s supporters back into obedience, but fears of a further increase in repression are also starting to be expressed on the sidelines.