Cortico-brainstem mechanisms of biased perceptual decision-making in the context of pain

Perceptual decision-making is commonly studied using stimuli with different physical properties but of comparable affective value. Here, we investigate neural processes underlying human perceptual decisions in the affectively rich domain of pain using a drift-diffusion model in combination with a probabilistic cueing paradigm. This allowed us to characterize a novel role for the dorsolateral prefrontal cortex (DLPFC), whose anticipatory responses reflecting a decision bias were dependent on the affective value of the stimulus. During intense noxious stimulation, these model-based anticipatory DLPFC responses were linked to an engagement of the periaqueductal gray (PAG), a midbrain region implicated in defensive responses including analgesia. Complementing these findings on biased decision-making, the model parameter reflecting sensory processing predicted subcortical responses (in amygdala and PAG) when expectations were violated. Our findings highlight the importance of taking a broader perspective on perceptual decisions and link decisions about pain with subcortical circuitry implicated in endogenous pain modulation

Sequence, expression and mutational analysis of BAF1, a transcriptional activator and ARS1-binding protein of the yeast Saccharomyces cerevisiae.

We report the cloning and sequence analysis of the yeast BAF1 gene which encodes an abundant protein previously shown to act as a transcription activator in the YPT1-TUB2 intergene region. As predicted from the DNA sequence, the highly hydrophilic BAf1 protein is 731 amino acids long and has a molecular mass of 81 748 daltons. The protein product of the cloned BAF1 gene produced in Escherichia coli is able to form specific complexes with DNA fragments containing the conserved element TCN7ACG. The protein binds also to the ABF1-binding site of the B-domain of ARS1, entertaining the possibility that BAF1 and ABF1 are identical proteins. Extensive deletion studies identified the N-terminal two thirds of the Baf1 protein to be required for specific DNA binding. Amino acid substitutions point to the N-terminal sequence CysX7HisX3HisX4CysX4Cys to form an atypical metal-binding 'finger' structure. Disruption of the BAF1 gene is lethal. The existence of five potential Baf1-protein binding sites in the 5' region of the gene suggests the involvement of the Baf1 protein in transcription regulation of its own gene

CD32+CD4+memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice

CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4(+) T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32(+) memory CD4(+) T cells were enriched in cell associated (CA) HIV-1 DNA but not in CA HIV-1 RNA as compared to the CD32(-) CD4(+) fraction. Using multidimensional reduction analysis, several memory CD4(+)CD32(+) T-cell clusters were identified expressing HLA-DR, TIGIT, or PD-1. Importantly, although tissue-resident CD32(+)CD4(+) memory cells were enriched with translation-competent reservoirs, most of it was detected in memory CD32-CD4(+) T cells. Our findings support that CD32 labels highly activated/exhausted memory CD4(+) T-cell subsets that contain only a small proportion of the translation-competent reservoir

Herpes Simplex Virus Type 1 Penetrates the Basement Membrane in Human Nasal Respiratory Mucosa

Background: Herpes simplex virus infections are highly prevalent in humans. However, the current therapeutics suffer important drawbacks such as limited results in neonates, increasing occurrence of resistance and impeded treatment of stromal infections. Remarkably, interactions of herpesviruses with human mucosa, the locus of infection, remain poorly understood and the underlying mechanisms in stromal infection remain controversial. Methodology/Principal Findings: A human model consisting of nasal respiratory mucosa explants was characterised. Viability and integrity were examined during 96 h of cultivation. HSV1-mucosa interactions were analysed. In particular, we investigated whether HSV1 is able to reach the stroma. Explant viability and integrity remained preserved. HSV1 induced rounding up and loosening of epithelial cells with very few apoptotic and necrotic cells observed. Following 16-24 h of infection, HSV1 penetrated the basement membrane and replicated in the underlying lamina propria. Conclusions/Significance: This human explant model can be used to study virus-mucosa interactions and viral mucosal invasion mechanisms. Using this model, our results provide a novel insight into the HSV1 stromal invasion mechanism and for the first time directly demonstrate that HSV1 can penetrate the basement membrane

In vitro protection of vascular function from oxidative stress and inflammation by pulsatility in resistance arteries

ObjectiveResistance arteries remain subject to pulsatility, a potent regulator of large elastic artery tone and structure, but the effect is incompletely understood. Extracorporeal circulation during cardiac surgery is often associated with absence of pulsatility, which may affect vascular tone. To define the role of the vascular wall in the inflammatory process that may occur with or without pulsatility, we studied resistance arteries functions ex vivo. We measured vascular reactivity, oxidative stress, and inflammation in the arterial wall. Methods Isolated rat mesenteric resistance arteries were mounted in an arteriograph and subjected to pulsatility or not in vitro. Arteries were perfused with a physiologic salt solution without circulating cells. Results After 180 minutes, flow-mediated dilation was higher and pressure-induced myogenic tone lower in arteries subjected to pulsatility. Without pulsatility, reactive oxygen species and markers of inflammation (monocyte chemotactic protein 1 and tumor necrosis factor α) were higher than baseline. In perfused mesenteric beds under similar conditions, tumor necrosis factor α was higher in perfusate after 180 minutes of nonpulsatility (5.7 ± 1.6 pg/mL vs 1.1 ± 0.4 pg/mL; P < .01). In arteries treated with the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol), flow-mediated dilation and myogenic tone were similar in nonpulsatile and pulsatile arteries; monocyte chemotactic protein 1 and nuclear factor κB expression levels were not increased in tempol-treated nonpulsatile arteries. Conclusions Absence of pulsatility in resistance arteries increased oxidative stress, which in turn induced inflammation and preferentially altered pressure and flow-dependent tone, which play a key role in control of local blood flow

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse