Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction.

RATIONALE: The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. OBJECTIVES: This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. METHODS: TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. RESULTS: Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. CONCLUSIONS: This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.CHK received funding from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI11C1183). CJH, LMS and TJB were funded by Medical Research Council/Wellcome Trust grant 089703/Z/09/Z. CR, LMS and TJB were funded by Alzheimer’s Research UK [ART/ESG2010/1]. ACM, MHE, CAO, LMS and TJB also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement no 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013).This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00213-015-4017-

Genomic Consequences of Fragmentation in the Endangered Fennoscandian Arctic Fox (Vulpes lagopus)

Accelerating climate change is causing severe habitat fragmentation in the Arctic, threatening the persistence of many cold-adapted species. The Scandinavian arctic fox (V. lagopus) is highly fragmented, with a once continuous, circumpolar distribution, it struggled to recover from a demographic bottleneck in the late 19th century. The future persistence of the entire Scandinavian population is highly dependent on the northernmost Fennoscandian subpopulations (Scandinavia and the Kola Peninsula), to provide a link to the viable Siberian population. By analyzing 43 arctic fox genomes, we quantified genomic variation and inbreeding in these populations. Signatures of genome erosion increased from Siberia to northern Sweden indicating a stepping-stone model of connectivity. In northern Fennoscandia, runs of homozygosity (ROH) were on average ~1.47-fold longer than ROH found in Siberia, stretching almost entire scaffolds. Moreover, consistent with recent inbreeding, northern Fennoscandia harbored more homozygous deleterious mutations, whereas Siberia had more in heterozygous state. This study underlines the value of documenting genome erosion following population fragmentation to identify areas requiring conservation priority. With the increasing fragmentation and isolation of Arctic habitats due to global warming, understanding the genomic and demographic consequences is vital for maintaining evolutionary potential and preventing local extinctions. inbreeding; runs of homozygosity; bottleneck; fragmentation; mutational load; conservatio

EPRDF's Revolutionary Democracy and Religious Plurality: Islam and Christianity in post-Derg Ethiopia

In 1991 the Ethiopian Peoples’ Revolutionary Democratic Front (EPRDF) introduced policies aimed at recognizing the country’s long-standing religious diversity, providing a public arena for religious groups, and maintaining a sharp division between religion and the state. This further roded the traditionally dominant position of the Ethiopian Orthodox Church, strengthened Protestant Christian and Muslim communities, and created a more flux and competitive configuration among the religious communities. Seeking to maintain its political power, the EPRDF has at the same time made efforts to monitor and control the different religious communities. Therefore, the last 20 years have been marked by uneven developments, in which the government’s accommodating attitudes have been interlaced with efforts to curtail the influence of the religious communities. This article surveys the intersection and reciprocal influences between EPRDF policies and religious communities over the last 20 years, and discusses how Muslims and Christians (Orthodox and Protestant) have negotiated their roles in relation to politics and public life. These developments have, the article argues, led to the emergence of divergent and competing narratives, reconfiguring self-understanding, political aspirations and views of the religious other. The EPRDF ideology of ‘‘revolutionary democracy’’ has, in this sense, enabled religion to surface as a force for social mobilization and as a point of reference for attempting to define nationhood in Ethiopia

Irs2 Silencing Increases Apoptosis And Potentiates The Effects Of Ruxolitinib In Jak2v617f-positive Myeloproliferative Neoplasms.

The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2V617F HEL cells, but not in the JAK2WT U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2V617F-positive but not JAK2WT specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34+ cells from essential thrombocythemia patients compared to healthy donors, and in JAK2V617F MPN patients when compared to JAK2WT. Our data indicate that IRS2 is a binding partner of JAK2V617F in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.

Uncertainty in humanities network visualization

Network visualization is one of the most widely used tools in digital humanities research. The idea of uncertain or “fuzzy” data is also a core notion in digital humanities research. Yet network visualizations in digital humanities do not always prominently represent uncertainty. In this article, we present a mathematical and logical model of uncertainty as a range of values which can be used in network visualizations. We review some of the principles for visualizing uncertainty of different kinds, visual variables that can be used for representing uncertainty, and how these variables have been used to represent different data types in visualizations drawn from a range of non-humanities fields like climate science and bioinformatics. We then provide examples of two diagrams: one in which the variables displaying degrees of uncertainty are integrated/pinto the graph and one in which glyphs are added to represent data certainty and uncertainty. Finally, we discuss how probabilistic data and what-if scenarios could be used to expand the representation of uncertainty in humanities network visualizations

Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.Peer reviewe

How to realize the benefits of point-of-care testing at the general practice: a comparison of four high-income countries

BACKGROUND: In some countries, such as the Netherlands and Norway, point-of-care testing (POCT) is more widely implemented in general practice compared to countries such as England and Australia. To comprehend what is necessary to realize the benefits of POCT, regarding its integration in primary care, it would be beneficial to have an overview of the structure of healthcare operations and the transactions between stakeholders (also referred to as value networks). The aim of this paper is to identify the current value networks in place applying to POCT implementation at general practices in England, Australia, Norway and the Netherlands and to compare these networks in terms of seven previously published factors that support the successful implementation, sustainability and scale-up of innovations. METHODS: The value networks were described based on formal guidelines and standards published by the respective governments, organizational bodies and affiliates. The value network of each country was validated by at least two relevant stakeholders from the respective country. RESULTS: The analysis revealed that the biggest challenge for countries with low POCT uptake was the lack of effective communication between the several organizations involved with POCT as well as the high workload for general practitioners (GPs) aiming to implement POCT. It is observed that countries with a single national authority responsible for POCT have a better uptake as they can govern the task of POCT roll-out and management and reduce the workload for GPs by assisting with set-up, quality control, training and support. CONCLUSION: Setting up a single national authority may be an effective step towards realizing the full benefits of POCT. Although it is possible for day-to-day operations to fall under the responsibility of the GP, this is only feasible if support and guidance are readily available to ensure that the workload associated with POCT is limited and as low as possible

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08)