Building up to an Awful Let-down

In modem construction, theoretically the duties, liabilities and warranties of those involved in a construction project ordinarily are broken down thus: The owner agrees to furnish the funds; the architect-engineer contracts to furnish experience, know-how, design, engineering plans, specifications, and supervision to assure the owner that he will receive what he requires and pays for; while the contractor agrees to furnish skilled labor,and proper material for the job. However, in actual practice, especially where the owner engages one firm to furnish the architectural drawings, specifications and supervision; another to do the necessary engineering design of the structural elements of the building; and still another to construct it, the theory breaks down

Building up to an Awful Let-down

In modem construction, theoretically the duties, liabilities and warranties of those involved in a construction project ordinarily are broken down thus: The owner agrees to furnish the funds; the architect-engineer contracts to furnish experience, know-how, design, engineering plans, specifications, and supervision to assure the owner that he will receive what he requires and pays for; while the contractor agrees to furnish skilled labor,and proper material for the job. However, in actual practice, especially where the owner engages one firm to furnish the architectural drawings, specifications and supervision; another to do the necessary engineering design of the structural elements of the building; and still another to construct it, the theory breaks down

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics

Anatomy of a Dansgaard-Oeschger warming transition: High-resolution analysis of the North Greenland Ice Core Project ice core

Large and abrupt temperature oscillations during the last glacial period, known as Dansgaard‐Oeschger (DO) events, are clearly observed in the Greenland ice core record. Here we present a new high‐resolution chemical (2 mm) and stable isotope (20 mm) record from the North Greenland Ice Core Project (NGRIP) ice core at the onset of one of the most prominent DO events of the last glacial, DO‐8, observed ∼38,000 years ago. The unique, subannual‐resolution NGRIP record provides a true sequence of change during a DO warming with detailed annual layer counting of very high depth resolution geochemical measurements used to determine the exact duration of the transition. The continental ions, indicative of long‐range atmospheric loading and dustiness from East Asia, are the first to change, followed by the snow accumulation, the moisture source conditions, and finally the atmospheric temperature in Greenland. The sequence of events shows that atmospheric and oceanic source and circulation changes preceded the DO warming by several years

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments

What Do Computer Scientists Tweet? Analyzing the Link-Sharing Practice on Twitter

Twitter communication has permeated every sphere of society. To highlight and share small pieces of information with possibly vast audiences or small circles of the interested has some value in almost any aspect of social life. But what is the value exactly for a scientific field? We perform a comprehensive study of computer scientists using Twitter and their tweeting behavior concerning the sharing of web links. Discerning the domains, hosts and individual web pages being tweeted and the differences between computer scientists and a Twitter sample enables us to look in depth at the Twitter-based information sharing practices of a scientific community. Additionally, we aim at providing a deeper understanding of the role and impact of altmetrics in computer science and give a glance at the publications mentioned on Twitter that are most relevant for the computer science community. Our results show a link sharing culture that concentrates more heavily on public and professional quality information than the Twitter sample does. The results also show a broad variety in linked sources and especially in linked publications with some publications clearly related to community-specific interests of computer scientists, while others with a strong relation to attention mechanisms in social media. This refers to the observation that Twitter is a hybrid form of social media between an information service and a social network service. Overall the computer scientists’ style of usage seems to be more on the information-oriented side and to some degree also on professional usage. Therefore, altmetrics are of considerable use in analyzing computer science

Process theory and research: Exploring the dialectic tension

We contest that although the notion of process is increasingly being applied to the study of organizations, these attempts are hampered by significant methodological shortcomings. We claim that the value of process theory is under-utilized because most attempts to apply process theory end up reverting to conventional non-process methods. We suggest that the cause of this reversion is primarily the challenge of making sense, of fixing the world, propelling us from process into the world of substance. To break free of these limitations we propose an approach that takes the researchers? audience alongside the subject processes rather than attempting to clinically intersect them. We illuminate this paper with our own story vignettes concerning the fortunes of an idea that passes by the name of value based management (VBM). 1 These vignettes are meant to both exemplify and disrupt the theoretical narrative

Hidden in the Middle : Culture, Value and Reward in Bioinformatics

Bioinformatics - the so-called shotgun marriage between biology and computer science - is an interdiscipline. Despite interdisciplinarity being seen as a virtue, for having the capacity to solve complex problems and foster innovation, it has the potential to place projects and people in anomalous categories. For example, valorised 'outputs' in academia are often defined and rewarded by discipline. Bioinformatics, as an interdisciplinary bricolage, incorporates experts from various disciplinary cultures with their own distinct ways of working. Perceived problems of interdisciplinarity include difficulties of making explicit knowledge that is practical, theoretical, or cognitive. But successful interdisciplinary research also depends on an understanding of disciplinary cultures and value systems, often only tacitly understood by members of the communities in question. In bioinformatics, the 'parent' disciplines have different value systems; for example, what is considered worthwhile research by computer scientists can be thought of as trivial by biologists, and vice versa. This paper concentrates on the problems of reward and recognition described by scientists working in academic bioinformatics in the United Kingdom. We highlight problems that are a consequence of its cross-cultural make-up, recognising that the mismatches in knowledge in this borderland take place not just at the level of the practical, theoretical, or epistemological, but also at the cultural level too. The trend in big, interdisciplinary science is towards multiple authors on a single paper; in bioinformatics this has created hybrid or fractional scientists who find they are being positioned not just in-between established disciplines but also in-between as middle authors or, worse still, left off papers altogether

Time trends in municipal distribution patterns of cancer mortality in Spain

BACKGROUND: New disease mapping techniques widely used in small-area studies enable disease distribution patterns to be identified and have become extremely popular in the field of public health. This paper reports on trends in the geographical mortality patterns of the most frequent cancers in Spain, over a period of 20 years. METHODS: We studied the municipal spatial pattern of stomach, colorectal, lung, breast, prostate and urinary bladder cancer mortality in Spain across four quinquennia, spanning the period 1989-2008. Case data were broken down by town (8073 municipalities), period and sex. Expected cases for each town were calculated using reference rates for each five-year period. For map plotting purposes, smoothed municipal relative risks were calculated using the conditional autoregressive model proposed by Besag, York and Mollié, with independent data for each quinquennium. We evaluated the presence of spatial patterns in maps on the basis of models, calculating the variance in relative risk corresponding to the structured spatial component and the unstructured component, as well as the proportion of variance explained by the structured spatial component. RESULTS: The mortality patterns observed for stomach, colorectal and lung cancer were maintained over the 20 years covered by the study. Prostate cancer and the tumours studied in women showed no defined spatial pattern, with the single exception of stomach cancer. The trend in spatial fractional variance indicated the possibility of a change in the spatial pattern in breast, bladder and colorectal cancer in women during the last five-year period. The paper goes on to discuss ways in which spatio-temporal data are depicted in the case of cancer, and review the risk factors that may possibly influence the respective tumours’ spatial patterns. CONCLUSION: In men, the marked geographical patterns of stomach, colorectal, lung and bladder cancer remained stable over time. Breast, colorectal and bladder cancer in women show signs of the possible appearance of a spatial pattern in Spain and should therefore be monitored. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-535) contains supplementary material, which is available to authorized users