The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

Endothelial cells (EC) form the inner lining of blood vessels and are positioned between circulating lymphocytes and tissues. Hypotheses have formed that EC may act as antigen presenting cells based on the intimate interactions with T cells, which are seen in diseases like multiple sclerosis, cerebral malaria (CM) and viral neuropathologies. Here, we investigated how human brain microvascular EC (HBEC) interact with and support the proliferation of T cells. We found HBEC to express MHC II, CD40 and ICOSL, key molecules for antigen presentation and co-stimulation and to take up fluorescently labeled antigens via macropinocytosis. In co-cultures, we showed that HBEC support and promote the proliferation of CD4+ and CD8+ T cells, which both are key in CM pathogenesis, particularly following T cell receptor activation and co-stimulation. Our findings provide novel evidence that HBEC can trigger T cell activation, thereby providing a novel mechanism for neuroimmunological complications of infectious diseases. © 2013 Wheway et al

On the Orthogonal Stability of the Pexiderized Quadratic Equation

The Hyers--Ulam stability of the conditional quadratic functional equation of Pexider type f(x+y)+f(x-y)=2g(x)+2h(y), x\perp y is established where \perp is a symmetric orthogonality in the sense of Ratz and f is odd.Comment: 10 pages, Latex; Changed conten

Formation of the simplest amide in molecular clouds: formamide (NH2_{2}CHO) and its derivatives in H2_2O-rich and CO-rich interstellar ice analogs upon VUV irradiation

The astronomical detection of formamide (NH$_2$CHO) toward various star-forming regions and in cometary material implies that the simplest amide might have an early origin in dark molecular clouds at low temperatures. Laboratory studies have proven the efficient NH$_2$CHO formation in interstellar CO:NH$_3$ ice analogs upon energetic processing. However, it is still under debate, whether the proposed radical-radical recombination reactions forming complex organic molecules remain valid in an abundant H$_2$O environment. The aim of this work was to investigate the formation of NH$_2$CHO in H$_2$O- and CO-rich ices under conditions prevailing in molecular clouds. Therefore, different ice mixtures composed of H$_2$O:CO:NH$_3$ (10:5:1), CO:NH$_3$ (4:1), and CO:NH$_3$ (0.6:1) were exposed to vacuum ultraviolet photons in an ultra-high vacuum chamber at 10 K. Fourier-transform infrared spectroscopy was utilized to monitor in situ the initial and newly formed species as a function of photon fluence. The infrared spectral identifications are complementarily secured by a temperature-programmed desorption experiment combined with a quadrupole mass spectrometer. The energetic processing of CO:NH$_3$ ice mixtures mainly leads to the NH$_2$CHO formation, along with its chemical derivatives such as isocyanic acid (HNCO) and cyanate ion (OCN$^-$). The formation kinetics of NH$_2$CHO shows an explicit dependency on ice ratios and compositions; the highest yield is found in H$_2$O-rich ice. The astronomical relevance of the resulting reaction network is discussed.Comment: 16 pages, 6 figures, 2 table

Cerebral malaria: Gamma-interferon redux

There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence consistent with both ideas has accumulated from studies of the human disease and experimental models. Thus, some combination of these concepts seems necessary to explain the very complex pattern of changes seen in cerebral malaria. The interactions between malaria parasites, erythrocytes, the cerebral microvascular endothelium, brain parenchymal cells, platelets and microparticles need to be considered. One factor that seems able to knit together much of this complexity is the cytokine interferon-gamma (IFN-?). In this review we consider findings from the clinical disease, in vitro models and the murine counterpart of human cerebral malaria in order to evaluate the roles played by IFN-? in the pathogenesis of this often fatal and debilitating condition. © 2014 Hunt, Ball, Hansen, Khaw, Guo, Bakmiwewa, Mitchell, Combes and Grau

Phi-values in protein folding kinetics have energetic and structural components

Phi-values are experimental measures of how the kinetics of protein folding is changed by single-site mutations. Phi-values measure energetic quantities, but are often interpreted in terms of the structures of the transition state ensemble. Here we describe a simple analytical model of the folding kinetics in terms of the formation of protein substructures. The model shows that Phi-values have both structural and energetic components. In addition, it provides a natural and general interpretation of "nonclassical" Phi-values (i.e., less than zero, or greater than one). The model reproduces the Phi-values for 20 single-residue mutations in the alpha-helix of the protein CI2, including several nonclassical Phi-values, in good agreement with experiments.Comment: 15 pages, 3 figures, 1 tabl

Patient-Reported Outcomes in ATLAS and FLAIR Participants on Long-Acting Regimens of Cabotegravir and Rilpivirine Over 48 Weeks

The phase 3 ATLAS and FLAIR studies demonstrated that maintenance with Long-Acting (LA) intramuscular cabotegravir and rilpivirine is non-inferior in efficacy to current antiretroviral (CAR) oral therapy. Both studies utilized Patient-Reported Outcome instruments to measure treatment satisfaction (HIVTSQ) and acceptance (ACCEPT general domain), health status (SF-12), injection tolerability/acceptance (PIN), and treatment preference. In pooled analyses, LA-treated patients (n = 591) demonstrated greater mean improvements from baseline than the CAR group (n = 591) in treatment satisfaction (Week 44, + 3.9 vs. +0.5 HIVTSQs-points; p /= 97% of LA group participants with recorded data preferred LA treatment compared with prior oral therapy. These results further support the potential of a monthly injectable option for people living with HIV seeking an alternative to daily oral treatment

Environmental variability in aquatic ecosystems: avenues for future multifactorial experiments

The relevance of considering environmental variability for understanding and predicting biological responses to environmental changes has resulted in a recent surge in variability-focused ecological research. However, integration of findings that emerge across studies and identification of remaining knowledge gaps in aquatic ecosystems remain critical. Here, we address these aspects by: (1) summarizing relevant terms of variability research including the components (characteristics) of variability and key interactions when considering multiple environmental factors; (2) identifying conceptual frameworks for understanding the consequences of environmental variability in single and multi-factorial scenarios; (3) highlighting challenges for bridging theoretical and experimental studies involving transitioning from simple to more complex scenarios; (4) proposing improved approaches to overcome current mismatches between theoretical predictions and experimental observations; and (5) providing a guide for designing integrated experiments across multiple scales, degrees of control, and complexity in light of their specific strengths and limitations