Molecular Mechanisms Regulating Macrophage Response to Hypoxia

Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ

Onset of a pandemic: characterizing the initial phase of the swine flu (H1N1) epidemic in Israel

<p>Abstract</p> <p>Background</p> <p>The swine influenza H1N1 first identified in Mexico, spread rapidly across the globe and is considered the fastest moving pandemic in history. The early phase of an outbreak, in which data is relatively scarce, presents scientific challenges on key issues such as: scale, severity and immunity which are fundamental for establishing sound and rapid policy schemes. Our analysis of an Israeli dataset aims at understanding the spatio-temporal dynamics of H1N1 in its initial phase.</p> <p>Methods</p> <p>We constructed and analyzed a unique dataset from Israel on all confirmed cases (between April 26 to July 7, 2009), representing most swine flu cases in this period. We estimated and characterized fundamental epidemiological features of the pandemic in Israel (e.g. effective reproductive number, age-class distribution, at-risk social groups, infections between sexes, and spatial dynamics). Contact data collected during this stage was used to estimate the generation time distribution of the pandemic.</p> <p>Results</p> <p>We found a low effective reproductive number (<it>R</it>_{<it>e </it>}= 1.06), an age-class distribution of infected individuals (skewed towards ages 18-25), at-risk social groups (soldiers and ultra Orthodox Jews), and significant differences in infections between sexes (skewed towards males). In terms of spatial dynamics, the pandemic spread from the central coastal plain of Israel to other regions, with higher infection rates in more densely populated sub-districts with higher income households.</p> <p>Conclusions</p> <p>Analysis of high quality data holds much promise in reducing uncertainty regarding fundamental aspects of the initial phase of an outbreak (e.g. the effective reproductive number R_e, age-class distribution, at-risk social groups). The formulation for determining the effective reproductive number <it>R</it>_{<it>e </it>}used here has many advantages for studying the initial phase of the outbreak since it neither assumes exponential growth of infectives and is independent of the reporting rate. The finding of a low <it>R</it>_{<it>e </it>}(close to unity threshold), combined with identification of social groups with high transmission rates would have enabled the containment of swine flu during the summer in Israel. Our unique use of contact data provided new insights into the differential dynamics of influenza in different ages and sexes, and should be promoted in future epidemiological studies. Thus our work highlights the importance of conducting a comprehensive study of the initial stage of a pandemic in real time.</p

A Semantic Web Services Architecture

The semantic Web services initiative architecture (SWSA) committee has created a set of architectural and protocol abstractions that serve as a foundation for semantic Web service technologies. This article summarizes the committee\u27s findings, emphasizing its review of requirements gathered from several different environments. We also identify the scope and potential requirements for a semantic Web services architecture

Post-transcriptional regulation of IGF1R by key microRNAs in long-lived mutant mice

Long-lived mutant mice, both Ames dwarf and growth hormone receptor genedisrupted or knockout strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here, we report, in both these long-lived mice, that three up-regulated lead microRNAs, miR-470, miR-669b, and miR-681, are involved in posttranscriptional regulation of genes pertinent to growth hormone/IGF1 signaling. All three are most prominently localized in the hippocampus and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase. The decline in these genes expression translates into decreased phosphorylation of downstream molecules AKT and FoxO3a. Cultures transfected with either miR-470, miR-669b, or miR-681 show repressed endogenous expression of all three genes of the IGF1 signaling axis, most significantly IGF1R, while other similarly up-regulated microRNAs, including let-7g and miR-509, do not induce the same levels of repression. Transduction study in IGF1-responsive cell cultures shows significantly reduced IGF1R expression, and AKT to some extent, most notably by miR-681. This is accompanied by decreased levels of downstream phosphorylated forms of AKT and FoxO3a upon IGF1 stimulation. Suppression of IGF1R by the three microRNAs is further validated by IGF1R 3\u27UTR reporter assays. Taken together, our results suggest that miR-470, miR-669b, and miR-681 are all functionally able to suppress IGF1R and AKT, two upstream genes controlling FoxO3a phosphorylation status. Their up-regulation in growth hormone signaling-deficient mutant mouse brain suggests reduced IGF1 signaling at the posttranscriptional level, for numerous gains of neuronal function in these long-lived mice

Touristification, smartization, and social sustainability in European regions

Touristification and smartization processes are commonly associated with economic growth strategies. Here we emphasize and demonstrate the need to consider the implication of these processes on social sustainability. Initial results imply that: (1) regions not specialized in tourism are associated with a lower share of population in poverty; and (2) regions’ ‘smartness’ level is negatively associated with the share of poverty. However, in regions highly specialized in tourism, smartization demonstrated an opposite association of increased intra-regional poverty. As residents’ quality of life is becoming a key policy consideration, understanding the effect of these socio-economic processes on socially sustainable growth has timely implications for regional planning, including for post-COVID-19 recovery strategies.This research has been funded by the H2020 programme, SMARTDEST project under grant agreement no. 870753

Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event