How analysts think: sense-making strategies in the analysis of temporal evolution and criminal network structures and activities

Analysis of criminal activity based on offenders’ social networks is an established procedure in intelligence analysis. The complexity of the data poses an obstacle for analysts to gauge network developments, e.g. detect emerging problems. Visualization is a powerful tool to achieve this, but it is essential to know how the analysts’ sense-making strategies can be supported most efficiently. Based on a think aloud study we identified ten cognitive strategies on a general level to be useful for designers. We also provide some examples how these strategies can be supported through appropriate visualizations

Multiple Kinase Involvement in the Regulation of Vascular Growth

The initial discovery of protein phosphorylation as a regulatory mechanism for the control of glycogen metabolism has led to intense interest of protein phosphorylation in regulating protein function (Cohen et al., 2001). Kinases play a variety of roles in many physiological processes within cells and represent one of the largest families in the human genome with over 500 members comprising protein serine/threonine, tyrosine, and dual-specificity kinases (Manning et al., 2002). Phosphorylation of proteins is one of the most significant signal transduction mechanisms which regulate intracellular processes such as transport, growth, metabolism, apoptosis, cystoskeletal arrangement and hormone responses (Bononi et al., 2011; Heidenreich et al., 1991; Manning et al., 2002; Pawson et al., 2000). As such, abnormal phosphorylation of proteins can be either a cause or a consequence of disease. Kinases are regulated by activator and inhibitor proteins, ligand binding, and phosphorylation by other proteins or via autophosphorylation (Hanks et al., 1991; Hug et al., 1993; Scott, 1991; Taylor et al., 1990; Taylor et al., 1992). Since kinases play key functions in many cellular processes, they represent an attractive target for therapeutic interventions in many disease states such as cancer, inflammation, diabetes and arthritis (Cohen et al., 2010; Fry et al., 1994; Karin, 2005; Mayers et al., 2005). In particular, the serine/threonine family of kinases comprises approximately 125 of the 500 family of kinases and includes the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), and protein kinase C (PKC). These kinases are implicated in the regulation of cell growth and are the focus of this current study.We would like to acknowledge Jonathan C. Fox and Patti Shaver for assistance with isolation and culture of rat primary vascular smooth muscle cells. This project was supported by Award Number R01HL081720 from the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI), by ARRA Award Number R01HL081720-03S2, and by Post-doctoral Research Supplement Award Number R01HL081720-05S1 from the NHLBI

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders

Consensus on Upper Gastrointestinal Endoscopy Key Performance Indicators to Reduce Post Endoscopy Upper Gastrointestinal Cancer

\ua9 2025 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.Background: Upper gastrointestinal (UGI) endoscopy lacks established key performance indicators. Up to three-fold variation in post endoscopy upper gastrointestinal cancer rates has been observed among endoscopy providers in England, highlighting the need for standardisation of UGI endoscopy practices. Objective: We aimed to achieve consensus on evidence-based key performance indicators to reduce post endoscopy upper gastrointestinal cancer. Methods: Modified nominal group technique was employed in two consensus workshops, with representation from clinicians, patients and relatives, moderated by James Lind Alliance facilitators. Potential indicators were identified from the umbrella systematic review, English provider post endoscopy upper gastrointestinal cancer rates, and differences in endoscopy practices from the National Endoscopy Database between providers with the highest (worst) and lowest (best) post endoscopy upper gastrointestinal cancer rates. KPIs were categorised as provider or endoscopist/procedure related and ranked as of major or minor importance. Minimum standards were proposed where possible. Results: Participants included 14 clinicians (gastroenterologists and UGI surgeons), 3 nurse endoscopists, 2 UGI cancer nurse specialists, 14 patients, their relatives and representatives from patient support groups and four observers. Endoscopy provider related major key performance indicators and proposed standards included monitoring post endoscopy upper gastrointestinal cancer rates (minimum standard ≤ 7%); less intense endoscopy lists (maximum 10 ‘points’ per list [one point is equivalent to 15 min]); endoscopy provider accreditation (all providers); and premalignant condition surveillance on dedicated lists by endoscopists with adequate training (> 90% surveillance endoscopies). Endoscopist/procedure related major key performance indicators included: examination time ≥ 7 min; training in early UGI neoplasia recognition (all endoscopists); mucosal view quality recorded and cleansing agents used if not excellent (> 90% endoscopies); intravenous sedation offered to all appropriate patients; recommended number of biopsies from cancer associated or premalignant lesions (> 90% endoscopy where such lesions identified); and endoscopists\u27 annual UGI endoscopy volume > 100 (all endoscopists). Conclusion: This study offers a consensus on the key performance indicators and minimum standards that should be used to improve UGI endoscopy quality and reduce post endoscopy upper gastrointestinal cancer

‘Smart Cities’ - Issues and Challenges for ‘Old World’ Economies: A Case from the United Kingdom.

The rapid and dynamic rate of urbanization, particularly in emerging world economies, has resulted in a need to find\ud sustainable ways of dealing with the excessive strains and pressures that come to bear on existing infrastructures and\ud relationships. Increasingly during the twenty-first century policy makers have turned to technological solutions to deal\ud with this challenge and the dynamics inherent within it. This move towards the utilization of technology to underpin\ud infrastructure has led to the emergence of the term ‘Smart City’. Smart cities incorporate technology based solutions\ud in their planning development and operation. This paper explores the organizational issues and challenges facing a\ud post-industrial agglomeration in the North West of England as it attempted to become a ‘Smart City’. In particular the\ud paper identifies and discusses the factors that posed significant challenges for the dynamic relationships residents,policymakers and public and private sector organizations and as a result aims to use these micro-level issues to inform the macro-debate and context of wider Smart City discussions. In order to achieve this, the paper develops a range of recommendations that are designed to inform Smart City design, planning and implementation strategies

Patient expectations of pressure ulcer prevention in the NHS, healthcare demands and national policy : a critical commentary

Preventive care was recently identified as a Government priority, which is likely to affect pressure ulcer (PU) preventive care in the NHS. Contemporary economic analyses of PU prevention interventions are undermined by factors including methodological challenges and poor inter-rater reliability of PU risk assessment tools. Healthcare demands on the NHS created by PU prevention remain unclear, although the burden is high, with litigation costs rising continuously. The poorly understood economics of PU prevention may create variation in practice. Patient expectations of PU prevention may be influenced by mainstream media, national awareness campaigns and the varied information and advice offered by professionals. Patient expectations and low levels of functional health literacy may create confusion and unrealistic expectations. This article critically examines the impact of recent changes in Government priorities related to PU prevention, considering the effects of healthcare demand, economics and patient expectations

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies

Apoptosis Governs the Elimination of Schistosoma japonicum from the Non-Permissive Host Microtus fortis

The reed vole, Microtus fortis, is the only known mammalian host in which schistosomes of Schistosoma japonicum are unable to mature and cause significant pathogenesis. However, little is known about how Schistosoma japonicum maturation (and, therefore, the development of schistosomiasis) is prevented in M. fortis. In the present study, the ultrastructure of 10 days post infection schistosomula from BALB/c mice and M. fortis were first compared using scanning electron microscopy and transmission electron microscopy. Electron microscopic investigations showed growth retardation and ultrastructural differences in the tegument and sub-tegumental tissues as well as in the parenchymal cells of schistosomula from M. fortis compared with those in BALB/c mice. Then, microarray analysis revealed significant differential expression between the schistosomula from the two rodents, with 3,293 down-regulated (by ≥2-fold) and 71 up-regulated (≥2 fold) genes in schistosomula from the former. The up-regulated genes included a proliferation-related gene encoding granulin (Grn) and tropomyosin. Genes that were down-regulated in schistosomula from M. fortis included apoptosis-inhibited genes encoding a baculoviral IAP repeat-containing protein (SjIAP) and cytokine-induced apoptosis inhibitor (SjCIAP), genes encoding molecules involved in insulin metabolism, long-chain fatty acid metabolism, signal transduction, the transforming growth factor (TGF) pathway, the Wnt pathway and in development. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and PI/Annexin V-FITC assays, caspase 3/7 activity analysis, and flow cytometry revealed that the percentages of early apoptotic and late apoptotic and/or necrotic cells, as well as the level of caspase activity, in schistosomula from M. fortis were all significantly higher than in those from BALB/c mice

Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

BACKGROUND: Prostaglandin I(2) (PGI(2)), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI(2) signaling suppressed Th1 and Th2 immune responses, the role of PGI(2) in Th17 differentiation is not known. METHODOLOGY/PRINCIPAL FINDINGS: In mouse CD4(+)CD62L(+) naïve T cell culture, the PGI(2) analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI(2) receptor IP signaling. In mouse bone marrow-derived CD11c(+) dendritic cells (BMDCs), PGI(2) analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI(2) promotes in vivo Th17 responses. CONCLUSION: The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI(2) and its analogs are commonly used to treat human pulmonary hypertension