What’s Past Is . . . Still Messing With Our Workflows

Scholars Portal has been aggregating locally loaded e-books for Ontario universities on an ebrary-backed platform since 2009—eons ago in the world of library technology! Over the last year, Scholars Portal Books has received a rewrite from the ground up, and this time the focus is on building a platform that anticipates the future of e-book access and usage. No surprise that there have been many challenges along the way, and most of them are unique to consortia: How do we handle corrections to old PDFs? What do we do with six ISBNs? More broadly, how do we support local scholarship at scale, and how can we make space for the open educational resources increasingly being integrated into higher education? This session looked at the complex e-book landscape through a consortial lens—from licensing and entitlements management, to wrangling a dozen XML schemas and implementing ever-changing DRM restrictions, toward the ultimate goal of preserving Ontario universities’ books content for the long term

Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer

The epigenetic regulator BMI1 is upregulated progressively in a wide variety of human tumors including colorectal cancer. In this study, we assessed the requirement for Bmi1 in intestinal tumorigenesis using an autochthonous mouse model in which Apc was conditionally ablated in the intestinal epithelium. Germline mutation of Bmi1 significantly reduced both the number and size of small intestinal adenomas arising in this model, and it acted in a dose-dependent manner. Moreover, in contrast to wild-type controls, Bmi1[superscript −/−] mice showed no increase in median tumor size, and a dramatic decrease in tumor number, between 3 and 4 months of age. Thus, Bmi1 is required for both progression and maintenance of small intestinal adenomas. Importantly, Bmi1 deficiency did not disrupt oncogenic events arising from Apc inactivation. Instead, the Arf tumor suppressor, a known target of Bmi1 epigenetic silencing, was upregulated in Bmi1 mutant tumors. This was accompanied by significant upregulation of p53, which was confirmed by sequencing to be wild-type, and also elevated apoptosis within the smallest Bmi1[superscript −/−] adenomas. By crossing Arf into this cancer model, we showed that Arf is required for the induction of both p53 and apoptosis, and it is a key determinant of the ability of Bmi1 deficiency to suppress intestinal tumorigenesis. Finally, a conditional Bmi1 mutant strain was generated and used to determine the consequences of deleting Bmi1 specifically within the intestinal epithelium. Strikingly, intestinal-specific Bmi1 deletion suppressed small intestinal adenomas in a manner that was indistinguishable from germline Bmi1 deletion. Thus, we conclude that Bmi1 deficiency impairs the progression and maintenance of small intestinal tumors in a cell autonomous and highly Arf-dependent manner.Virginia and D.K. Ludwig Fund for Cancer ResearchNational Science Foundation (U.S.)National Cancer Institute (U.S.

The problems of offenders with mental disorders: A plurality of perspectives within a single mental health care organisation

Managers, doctors, nurses, occupational therapists, social workers, psychologists, unqualified staff and service users were interviewed for a qualitative study of risk management and rehabilitation in an inner city medium secure forensic mental health care unit. Different professional orientations to service user problems were identified. Doctors focused primarily on the diagnosis of mental disorder, which they managed mainly through pharmaceutical interventions. Psychologists were principally concerned with personal factors, for example service user insight into their biographical history. Occupational therapists concentrated mainly on daily living skills, and social workers on post-discharge living arrangements. Some front line nurses, held accountable for security lapses, adopted a criminogenic approach. Service users were more likely than professionals to understand their needs in terms of their wider life circumstances. These differences are explored qualitatively in relation to four models of crossdisciplinary relationships: monoprofessional self-organisation combined with restricted communication; hermeneutic reaching out to other perspectives; the establishment of interdisciplinary sub-systems; and transdisciplinary merger. Relationships between professions working in this unit, as portrayed in qualitative interviews, corresponded mainly to the first model of monoprofessional self-organisation. Reasons for restricted crossdisciplinary understanding, particularly the wide power/status differences between the medical and other professions, and between staff and patients, are discussed

Questioning context: a set of interdisciplinary questions for investigating contextual factors affecting health decision making

Objective  To combine insights from multiple disciplines into a set of questions that can be used to investigate contextual factors affecting health decision making. Background  Decision‐making processes and outcomes may be shaped by a range of non‐medical or ‘contextual’ factors particular to an individual including social, economic, political, geographical and institutional conditions. Research concerning contextual factors occurs across many disciplines and theoretical domains, but few conceptual tools have attempted to integrate and translate this wide‐ranging research for health decision‐making purposes. Methods  To formulate this tool we employed an iterative, collaborative process of scenario development and question generation. Five hypothetical health decision‐making scenarios (preventative, screening, curative, supportive and palliative) were developed and used to generate a set of exploratory questions that aim to highlight potential contextual factors across a range of health decisions. Findings  We present an exploratory tool consisting of questions organized into four thematic domains – Bodies, Technologies, Place and Work (BTPW) – articulating wide‐ranging contextual factors relevant to health decision making. The BTPW tool encompasses health‐related scholarship and research from a range of disciplines pertinent to health decision making, and identifies concrete points of intersection between its four thematic domains. Examples of the practical application of the questions are also provided. Conclusions  These exploratory questions provide an interdisciplinary toolkit for identifying the complex contextual factors affecting decision making. The set of questions comprised by the BTPW tool may be applied wholly or partially in the context of clinical practice, policy development and health‐related research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86973/1/j.1369-7625.2010.00618.x.pd

Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern)

AbstractThreshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual ‘dose’ applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool

Phosphorylation regulates targeting of cytoplasmic dynein to kinetochores during mitosis

Cytoplasmic dynein functions at several sites during mitosis; however, the basis of targeting to each site remains unclear. Tandem mass spectrometry analysis of mitotic dynein revealed a phosphorylation site in the dynein intermediate chains (ICs) that mediates binding to kinetochores. IC phosphorylation directs binding to zw10 rather than dynactin, and this interaction is needed for kinetochore dynein localization. Phosphodynein associates with kinetochores from nuclear envelope breakdown to metaphase, but bioriented microtubule (MT) attachment and chromosome alignment induce IC dephosphorylation. IC dephosphorylation stimulates binding to dynactin and poleward streaming. MT depolymerization, release of kinetochore tension, and a PP1-γ mutant each inhibited IC dephosphorylation, leading to the retention of phosphodynein at kinetochores and reduced poleward streaming. The depletion of kinetochore dynactin by moderate levels of p50(dynamitin) expression disrupted the ability of dynein to remove checkpoint proteins by streaming at metaphase but not other aspects of kinetochore dynein activity. Together, these results suggest a new model for localization of kinetochore dynein and the contribution of kinetochore dynactin

Family and Gender Values in China

Previous research has reported on structural changes in Chinese families. However, questions remain as to whether/how social change has influenced family and gender values and how this differs across generations, regions, and gender in China. Drawing on 2006 data from the China General Social Survey, we find that values pertaining to filial piety are traditional, whereas patrilineal and gender values are less traditional. Historic events/policies provide the context for how social change can shape differential generational, geographic, and gender perspectives. Our hypothesis that generation, region, and gender associations will differ across the various ideational domains is confirmed. We find significant interaction effects in how generation and geography differ by gender in patrilineal, filial piety, and gender values; and higher education erodes patrilineal and traditional gender values but enhances filial piety. Such findings indicate that family values should be understood in the specific sociocultural contexts governing Chinese families across time and place.</jats:p

CaMKK2 as an emerging treatment target for bipolar disorder

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue