This paper discusses how the arrival of born-digital content into archives operating systems and complex digital collections, archives must build upon practices developed over recent decades in the handling of electronic records while also radically reconsidering the extent of acquisition and approaches to access. These changes are discussed within the context of the manuscripts and computers that comprise Salman Rushdie’s personal literary “papers,” which are housed in Emory University’s Manuscript, Archives, and Rare Book Library (MARBL). Early in the development of the Rushdie project, the library made a commitment to approach the material as holistically as possible, to prioritize the integration of paper and digital, and to balance the needs of donors with those of researchers. The paper will outline how the library developed researcher tools that allow concurrent exploration of the paper material and the born-digital material via emulation and item-level, database-driven searches.

Beginning with his famous 1963 lecture on Foucault, Derrida repeatedly invokes a line from Kierkegaard, often translated from his French as ‘the instant of decision is madness,’ without ever giving a precise reference or subjecting that sentence to anything like a reading in the Derridean sense. This paper tracks some of the unsuspected complexities that emerge when that sentence is located in Kierkegaard and the Pauline tradition to which Kierkegaard is appealing. It is suggested that the singular functioning of this sentence in Derrida nonetheless, in its very failure to read, shows up something of the madness, folly or stupidity at play in Kierkegaard’s thinking, and thus performs in its repetitions something of the unreadability that opens the possibility of reading itself.

Based on Micah Vandegrift’s article What is digital humanities and what’s it doing in the library? and Stewart Varner’s response to that piece, this article offers an overview of the foundational ideals where libraries and digital humanities overlap. The authors lay out practical ways for libraries to involve themselves in this evolving area, especially focused on current strengths of many libraries including commitments to resource accessibility and project development. Finally, this article proposes that the role of the research librarian is evolving in order to effectively integrate the library as a partner in the scholarship of digital humanities.

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Histone deacetylase inhibitors (HDACi) were recently identified as having significant clinical potential in reversing β-cell functional inhibition caused by inflammation, a shared precursor of Type 1 and Type 2 diabetes. However, HDACi are highly complex and little is known of their direct effect on important cell secretion pathways for blood glucose regulation. The aims of the present study were to investigate the effect of HDACi on insulin secretion from β-cells, GLP-1 secretion from L-cells, and recombinant insulin secretion from engineered L-cells. The β-cell line βTC-tet, L-cell line GLUTag, or recombinant insulin-secreting L-cell lines were exposed to Trichostatin A for 24. h. Effects on insulin or GLP-1 mRNA, intracellular protein content, processing efficiency, and secretion were measured by real-time PCR, ELISA, and radioimmunoassay. HDACi increased secretion per viable cell in a dose-dependent manner for all cell types. Effects on mRNA levels were variable, but enhanced intracellular polypeptide content and secretion were comparable among cell types. Enhanced recombinant insulin secretion was sustained for seven days in alginate microencapsulated L-cells. HDACi enhances β- and L-cell secretion fluxes in a way that could significantly improve blood glucose regulation in diabetes patients and holds potential as a novel method for enhancing insulin-secreting non-β or β-cell grafts.

CRISPR-Cas9 is a powerful new tool for genome editing, but this technique creates mosaic mutations that affect the efficiency and precision of its ability to edit the genome. Reducing mosaic mutations is particularly important for gene therapy and precision genome editing. Although the mechanisms underlying the CRSIPR/Cas9-mediated mosaic mutations remain elusive, the prolonged expression and activity of Cas9 in embryos could contribute to mosaicism in DNA mutations. Here we report that tagging Cas9 with ubiquitin-proteasomal degradation signals can facilitate the degradation of Cas9 in non-human primate embryos. Using embryo-splitting approach, we found that shortening the half-life of Cas9 in fertilized zygotes reduces mosaic mutations and increases its ability to modify genomes in non-human primate embryos. Also, injection of modified Cas9 in one-cell embryos leads to live monkeys with the targeted gene modifications. Our findings suggest that modifying Cas9 activity can be an effective strategy to enhance precision genome editing.

HIV-1 Env glycoprotein-mediated fusion is initiated upon sequential binding of Env to CD4 and the coreceptor CXCR4 or CCR5. Whereas these interactions are thought to be necessary and sufficient to promote HIV-1 fusion, other host factors can modulate this process. Previous studies reported potent inhibition of HIV-1 fusion by selective P2X1 receptor antagonists, including NF279, and suggested that these receptors play a role in HIV-1 entry. Here we investigated the mechanism of antiviral activity of NF279 and found that this compound does not inhibit HIV-1 fusion by preventing the activation of P2X1 channels but effectively blocks the binding of the virus to CXCR4 or CCR5. The notion of an off-target effect of NF279 on HIV-1 fusion is supported by the lack of detectable expression of P2X1 receptors in cells used in fusion experiments and by the fact that the addition of ATP or the enzymatic depletion of ATP in culture medium does not modulate viral fusion. Importantly, NF279 fails to inhibit HIV-1 fusion with cell lines and primary macrophages when added at an intermediate stage downstream of Env-CD4-coreceptor engagement. Conversely, in the presence of NF279, HIV-1 fusion is arrested downstream of CD4 binding but prior to coreceptor engagement. NF279 also antagonizes the signaling function of CCR5, CXCR4, and another chemokine receptor, as evidenced by the suppression of calcium responses elicited by specific ligands and by recombinant gp120. Collectively, our results demonstrate that NF279 is a dual HIV-1 coreceptor inhibitor that interferes with the functional engagement of CCR5 and CXCR4 by Env.

Background: This study sought to systematically investigate the derivation of late outgrowth endothelial progenitor cells (late EPC) and mesenchymal stem cells (MSC) from umbilical cord blood (UCB) and to examine their therapeutic effects on myocardial infarction (MI). Methods: The expression of angiogenic genes were determined by qRT-PCR. Myocardial infarction (MI) was induced in rats, and cells were directly transplanted into the border regions of ischemic heart tissue. Results: Culture of UCB mononuclear cells yielded two distinct types of cells by morphology after 2 weeks in the same culture conditions. These cells were identified as late EPC and MSC, and each was intramyocardially injected into rat hearts after induction of MI. Echocardiography and histologic analyses demonstrated that both EPC and MSC improved cardiac function and enhanced vascularization, although fibrosis was reduced only in the EPC transplanted hearts. Different paracrine factors were enriched in EPC and MSC. However, once injected into the hearts, they induced similar types of paracrine factors in the heart. Transplanted EPC or MSC were mostly localized at the perivascular areas. This study demonstrated that EPC and MSC can be simultaneously derived from UCB under the same initial culture conditions, and that common paracrine factors are involved in the repair of MI. Conclusion: Late EPC and MSC are effective for infarct repair, apparently mediated through common humoral mechanisms.

Objective and sources We reviewed the epidemiologic literature for PFOA. Data synthesis Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood. PFOA has been used to manufacture such products as Gore-Tex and Teflon. PFOA does not break down in the environment; the human half-life is estimated at about 3 years. PFOA is not metabolized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems. Data on the human health effects of PFOA are sparse. There is relatively consistent evidence of modest positive associations with cholesterol and uric acid, although the magnitude of the cholesterol effect is inconsistent across different exposure levels. There is some but much less consistent evidence of a modest positive correlation with liver enzymes. Most findings come from cross-sectional studies, limiting conclusions. Two occupational cohort studies do not provide consistent evidence for chronic disease; both are limited by sample size and reliance on mortality data. Reproductive data have increased recently but are inconsistent, and any observed adverse effects are modest. Conclusions Epidemiologic evidence remains limited, and to date data are insufficient to draw firm conclusions regarding the role of PFOA for any of the diseases of concern.

Background: The 7th AJCC T-stage system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. Method: Patients undergoing curative-intent resections for ACC from 1993 to 2014 at 13 institutions comprising the US ACC Group were included. Primary outcome was disease-specific survival (DSS). Results: Of the 265 patients with ACC, 149 were included for analysis. The current T-stage system failed to differentiate patients with T2 versus T3 disease (p = 0.10). Presence of LVI was associated with worse DSS versus no LVI (36 mo vs. 168 mo; p = 0.001). After accounting for the individual components of the current T-stage system (size, extra-adrenal invasion), LVI remained a poor prognostic factor on multivariable analysis (hazard ratio 2.14, 95% confidence interval 1.05–4.38, p = 0.04). LVI positivity further stratified patients with T2 and T3 disease (T2: 37 mo vs. median not reached; T3: 36 mo vs. 96 mo; p = 0.03) but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: ≤ 5 cm, (−)local invasion, (+/−)LVI; T2: > 5 cm, (−)local invasion, (−)LVI OR any size, (+)local invasion, (−)LVI; T3: > 5 cm, (−)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/−)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167 mo; T2: 96 mo; T3: 37 mo; T4: 15 mo; p < 0.001). Conclusions: Compared with the current T-stage system, the proposed T-stage system, which incorporates LVI, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this T-stage classification should be considered for future AJCC staging systems.

Although there is great interest in the improving the ability to track patients' change over time in routine clinical care settings, no standardized transdiagnostic measure is currently available for busy clinicians to apply. The Clinical Global Impression (CGI) scales are simple measures widely used as outcomes in psychiatric clinical trials. However, the CGI suffers from poorly defined scoring anchors. Efforts to improve the anchors by enhancing the anchor descriptions have proven useful but are limited by being disease-specific, thereby acting as a barrier to the routine clinical adoption of the CGI. To inform the development of more broadly applicable CGI scoring anchors, we surveyed 24 clinical trial investigators, asking them to rank-order seven elements that inform their CGI-Severity (CGI-S) scoring. Symptom severity emerged as the most important element in determining CGI-S scores; the functional status of the patient emerged as a second element. Less importance was given to self-report symptom scores, staff observations, or side effects. Relative rankings of the elements' importance did not differ by investigators' experience nor time usually spent with patients. We integrated these results with published illness-specific CGI anchors to develop the Transdiagnostic CGI (T-CGI), which employs standardized scoring anchors applicable across psychiatric illnesses. Pending validity and reliability evaluations, the T-CGI may prove well-suited for inclusion in routine clinical settings and for incorporation into electronic medical records as a simple and useful measure of treatment efficacy.

Depression is one of the world's most prevalent mental health problems, with as many as 350 million sufferers worldwide and close to 20 million sufferers in the US. While neuroimaging applications for identifying various types of depression have made enormous strides in recent years, no findings have been sufficiently replicated or considered significant enough to warrant application in clinical settings. Our authors are well equipped to tell us what the future may bring.

Our goal was to ascertain how fatigue affects performance in reading computed tomography (CT) examinations of patients with multiple injuries. CT images with multiple fractures from a previous study of satisfaction of search (SOS) were read by radiologists after a day of clinical work. Performance in this study with fatigued readers was compared to a previous study in which readers were not fatigued. Detection accuracy for obvious injuries was not affected by fatigue, but accuracy for subtle fractures was reduced ([Formula: see text]). An SOS effect on decision thresholds was evident mirroring recent studies. Without fatigue, readers spent more time interpreting and reporting findings as the number of the injuries increased. When fatigued, readers did not increase reading time as fracture number increased. Without fractures, reading time for not-fatigued and fatigued readers was the same ([Formula: see text]) but was significant ([Formula: see text]) with an added subtle fracture. The difference increased with a major injury ([Formula: see text]) and increased further with both a major injury and subtle fracture ([Formula: see text]). Fatigue and multiple abnormalities have independent effects on detection performance but do interact in determining search time.

© 2018 The Author(s) In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn’s disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher’s exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

© 2018 Tian S et al. The emerging field of pathway-based feature selection that incorporates biological information conveyed by gene sets/pathways to guide the selection of relevant genes has become increasingly popular and widespread. In this study, we adapt a gene set analysis method – the significance analysis of microarray gene set reduction (SAMGSR) algorithm to carry out feature selection for longitudinal microarray data, and propose a pathway-based feature selection algorithm – the two-level SAMGSR method. By using simulated data and a real-world application, we demonstrate that a gene’s expression profiles over time can be considered as a gene set. Thus a suitable gene set analysis method can be utilized or modified to execute the selection of relevant genes for longitudinal omics data. We believe this work paves the way for more research to bridge feature selection and gene set analysis with the development of novel pathway-based feature selection algorithms.

Angiotensin II (Ang II), part of the renin-angiotensin-aldosterone system (RAS), is a potent vasoconstrictor and has been recently approved for use by the US Food and Drug Administration in high-output shock. Though not a new drug, the recently published Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial, as well as a number of retrospective analyses have sparked renewed interest in the use of Ang II, which may have a role in treating refractory shock. We describe refractory shock, the unique mechanism of action of Ang II, RAS dysregulation in shock, and the evidence supporting the use of Ang II to restore blood pressure. Evidence suggests that Ang II may preferentially be of benefit in acute kidney injury and acute respiratory distress syndrome, where the RAS is known to be disrupted. Additionally, there may be a role for Ang II in cardiogenic shock, angiotensin converting enzyme inhibitor overdose, cardiac arrest, liver failure, and in settings of extracorporeal circulation.

Inflammatory bowel disease (IBD) can be divided into two major categories, ulcerative colitis (UC) and Crohn disease (CD). While the main cause(s) of IBD remain unknown, a number of interventional and preventive strategies have been proposed for use against CD and UC. Many reports have focused on the use of alternative natural medicines as potential therapeutic interventions in IBD patients with minimal side effects. While the use of alternative medicines may be effective in IBD patients that are refractory to corticosteroids or thiopurins, alternative treatment strategies are limited and require extensive clinical testing before being optimized for use in patients.

© 2018, The Author(s). The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.