Intracerebral Hemorrhage and Ischemic Stroke of Different Etiologies Have Distinct Alternatively Spliced mRNA Profiles in the Blood: a Pilot RNA-seq Study.

Whole transcriptome studies have used 3'-biased expression microarrays to study genes regulated in the blood of stroke patients. However, alternatively spliced messenger RNA isoforms have not been investigated for ischemic stroke or intracerebral hemorrhage (ICH) in animals or humans. Alternative splicing is the mechanism whereby different combinations of exons of a single gene produce distinct mRNA and protein isoforms. Here, we used RNA sequencing (RNA-seq) to determine if alternative splicing differs for ICH and cardioembolic, large vessel and lacunar causes of ischemic stroke compared to controls. RNA libraries from 20 whole blood samples were sequenced to 200 M 2 × 100 bp reads using Illumina sequencing-by-synthesis technology. Differential alternative splicing was assessed using one-way analysis of variance (ANOVA), and differential exon usage was calculated. Four hundred twelve genes displayed differential alternative splicing among the groups (false discovery rate, FDR; p < 0.05). They were involved in cellular immune response, cell death, and cell survival pathways. Distinct expression signatures based on usage of 308 exons (292 genes) differentiated the groups (p < 0.0005; fold change >|1.2|). This pilot study demonstrates that alternatively spliced genes from whole blood differ in ICH compared to ischemic stroke and differ between different ischemic stroke etiologies. These results require validation in a separate cohort

Working with the homeless: The case of a non-profit organisation in Shanghai

This article addresses a two-pronged objective, namely to bring to the fore a much neglected social issue of homelessness, and to explore the dynamics of state-society relations in contemporary China, through a case study of a non-profit organisation (NPO) working with the homeless in Shanghai. It shows that the largely invisible homelessness in Chinese cities was substantially due to exclusionary institutions, such as the combined household registration and 'detention and deportation' systems. Official policy has become much more supportive since 2003 when the latter was replaced with government-run shelters, but we argue that the NPO case demonstrates the potential for enhanced longer-term support and enabling active citizenship for homeless people. By analysing the ways in which the NPO offers services through collaboration and partnership with the public (and private) actors, we also argue that the transformations in postreform China and the changes within the state and civil society have significantly blurred their boundaries, rendering state-society relations much more complex, dynamic, fluid and mutually embedded

A millimeter-wave kinetic inductance detector camera for long-range imaging through optical obscurants

Millimeter-wave imaging provides a promising option for long-range target detection through optical obscurants such as fog, which often occur in marine environments. Given this motivation, we are currently developing a 150 GHz polarization-sensitive imager using a relatively new type of superconducting pair-breaking detector, the kinetic inductance detector (KID). This imager will be paired with a 1.5 m telescope to obtain an angular resolution of 0.09° over a 3.5° field of view using 3,840 KIDs. We have fully characterized a prototype KID array, which shows excellent performance with noise strongly limited by the irreducible fluctuations from the ambient temperature background. Full-scale KID arrays are now being fabricated and characterized for a planned demonstration in a maritime environment later this year

Designer Reagents for Mass Spectrometry-Based Proteomics: Clickable Cross-Linkers for Elucidation of Protein Structures and Interactions

We present novel homobifunctional amine-reactive clickable cross-linkers (CXLs) for investigation of three-dimensional protein structures and protein–protein interactions (PPIs). CXLs afford consolidated advantages not previously available in a simple cross-linker, including (1) their small size and cationic nature at physiological pH, resulting in good water solubility and cell-permeability, (2) an alkyne group for bio-orthogonal conjugation to affinity tags via the click reaction for enrichment of cross-linked peptides, (3) a nucleophilic displacement reaction involving the 1,2,3-triazole ring formed in the click reaction, yielding a lock-mass reporter ion for only clicked peptides, and (4) higher charge states of cross-linked peptides in the gas-phase for augmented electron transfer dissociation (ETD) yields. Ubiquitin, a lysine-abundant protein, is used as a model system to demonstrate structural studies using CXLs. To validate the sensitivity of our approach, biotin-azide labeling and subsequent enrichment of cross-linked peptides are performed for cross-linked ubiquitin digests mixed with yeast cell lysates. Cross-linked peptides are detected and identified by collision induced dissociation (CID) and ETD with linear quadrupole ion trap (LTQ)-Fourier transform ion cyclotron resonance (FTICR) and LTQ-Orbitrap mass spectrometers. The application of CXLs to more complex systems (e.g., in vivo cross-linking) is illustrated by Western blot detection of Cul1 complexes including known binders, Cand1 and Skp2, in HEK 293 cells, confirming good water solubility and cell-permeability

Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies

Connectionist natural language parsing

The key developments of two decades of connectionist parsing are reviewed. Connectionist parsers are assessed according to their ability to learn to represent syntactic structures from examples automatically, without being presented with symbolic grammar rules. This review also considers the extent to which connectionist parsers offer computational models of human sentence processing and provide plausible accounts of psycholinguistic data. In considering these issues, special attention is paid to the level of realism, the nature of the modularity, and the type of processing that is to be found in a wide range of parsers

Cholestasis of pregnancy

This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of cholestasis of pregnancy