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Motivation: A fundamental problem for disease treatment is that while antibiotics are a powerful counter to bacteria, they are ineffective against viruses. Often, bacterial and viral infections are confused due to their similar symptoms and lack of rapid diagnostics. With many clinicians relying primarily on symptoms for diagnosis, overuse and misuse of modern antibiotics are rife, contributing to the growing pool of antibiotic resistance. To ensure an individual receives optimal treatment given their disease state and to reduce over-prescription of antibiotics, the host response can in theory be measured quickly to distinguish between the two states. To establish a predictive biomarker panel of disease state (viral/bacterial/no-infection), we conducted a meta-analysis of human blood infection studies using machine learning. Results: We focused on publicly available gene expression data from two widely used platforms, Affymetrix and Illumina microarrays as they represented a significant proportion of the available data. We were able to develop multi-class models with high accuracies with our best model predicting 93% of bacterial and 89% viral samples correctly. To compare the selected features in each of the different technologies, we reverse-engineered the underlying molecular regulatory network and explored the neighbourhood of the selected features. The networks highlighted that although on the gene-level the models differed, they contained genes from the same areas of the network. Specifically, this convergence was to pathways including the Type I interferon Signalling Pathway, Chemotaxis, Apoptotic Processes and Inflammatory/Innate Response.

The paper provides evidence for localism to be represented through ‘local public service television’. The author suggests that communication responsibilities (including broadcasting and wireless broadband) should be based on the principles of devolution and subsidiarity (or double-devolution): with progressively greater localization of regulation from state to nation to the local scale. A tiered regulatory structure of state, nation and local would conform to European cross border terrestrial and satellite regulation while transforming the scope as well as scale of public service broadcasting, introducing a greater equity for civic as well as the devolved nation democratic representation alongside the present state-wide and state-dominated channels. Satellite TV would continue to operate across frontiers although these may become influenced by the greater critical mass afforded nation and local content that the tiered regulatory model proposes., El texto proporciona evidencias del contenido local que se representa a través del ‘servicio público de televisión local’. El autor sugiere que las responsabilidades de comunicación (incluídas la emisión televisiva y la banda ancha inalámbrica) deberían basarse en los principios de descentralización y subsidiariedad (o doble descentralización: con un desplazamiento cada vez mayor de la regulación del Estado hacia la escala de la nación y de lo local. Una estructura reguladora a niveles del Estado, de la nación y lo local, conformaría una normativa europea de redes terrestres y de satélite transfronteriza, al tiempo que se transforma el alcance así como la escala del servicio público de radiotelevisión, con la introducción de una mayor equidad cívica y una representación democrática de la nación descentralizada, frente a los actuales canales de ámbito estatal dominados por el Estado. La TV por satélite continuaría operando a través de las fronteras, aunque podría llegar a ser influenciada por la gran masa crítica que ofrece contenido local y nacional en un modelo normativo escalonado.

Notch signalling is an evolutionarily conserved pathway involved in cell-fate specification. The initiating event in this pathway is the binding of a Notch receptor to a DSL (Delta/Serrate/Lag-2) ligand on neighbouring cells triggering the proteolytic cleavage of Notch within its extracellular juxtamembrane region; a process known as proteolytic 'shedding' and catalysed by members of the ADAM (a disintegrin and metalloproteinase) family of enzymes. Jagged1 is a Notch-binding DSL ligand which is also shed by an ADAM-like activity raising the possibility of bi-directional cell-cell Notch signalling. In the present study we have unequivocally identified the sheddase responsible for shedding Jagged1 as ADAM17, the activity of which has previously been shown to be localized within specialized microdomains of the cell membrane known as 'lipid rafts'. However, we have shown that replacing the transmembrane and cytosolic regions of Jagged1 with a GPI (glycosylphosphatidylinositol) anchor, thereby targeting the protein to lipid rafts, did not enhance its shedding. Furthermore, the Jagged1 holoprotein, its ADAM-cleaved C-terminal fragment and ADAM17 were not enriched in raft preparations devoid of contaminating non-raft proteins. We have also demonstrated that wild-type Jagged1 and a truncated polypeptide-anchored variant lacking the cytosolic domain were subject to similar constitutive and phorbol ester-regulated shedding. Collectively these data demonstrate that Jagged1 is shed by ADAM17 in a lipid-raft-independent manner, and that the cytosolic domain of the former protein is not a pre-requisite for either constitutive or regulated shedding.