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.

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: 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.

Sanitation improvements have had limited effectiveness in reducing the spread of fecal pathogens into the environment. We conducted environmental measurements within a randomized controlled trial in Bangladesh that implemented individual and combined water treatment, sanitation, handwashing (WSH) and nutrition interventions (WASH Benefits, NCT01590095). Following approximately 4 months of intervention, we enrolled households in the trial's control, sanitation and combined WSH arms to assess whether sanitation improvements, alone and coupled with water treatment and handwashing, reduce fecal contamination in the domestic environment. We quantified fecal indicator bacteria in samples of drinking and ambient waters, child hands, food given to young children, courtyard soil and flies. In the WSH arm, Escherichia coli prevalence in stored drinking water was reduced by 62% (prevalence ratio = 0.38 (0.32, 0.44)) and E. coli concentration by 1-log (Δlog10 = -0.88 (-1.01, -0.75)). The interventions did not reduce E. coli along other sampled pathways. Ambient contamination remained high among intervention households. Potential reasons include noncommunity-level sanitation coverage, child open defecation, animal fecal sources, or naturalized E. coli in the environment. Future studies should explore potential threshold effects of different levels of community sanitation coverage on environmental contamination.

The envelope glycoprotein (Env) plays a crucial role in the retroviral life cycle by mediating primary interactions with the host cell. As described previously and expanded on in this paper, Env mediates the trafficking of immature Mason-Pfizer monkey virus (M-PMV) particles to the plasma membrane (PM). Using a panel of labeled RabGTPases as endosomal markers, we identified Env mostly in Rab7a-and Rab9a-positive endosomes. Based on an analysis of the transport of recombinant fluorescently labeled M-PMV Gag and Env proteins, we propose a putative mechanism of the intracellular trafficking of M-PMV Env and immature particles. According to this model, a portion of Env is targeted from the trans-Golgi network (TGN) to Rab7a-positive endosomes. It is then transported to Rab9a-positive endosomes and back to the TGN. It is at the Rab9a vesicles where the immature particles may anchor to the membranes of the Env-containing vesicles, preventing Env recycling to the TGN. These Gag-associated vesicles are then transported to the plasma membrane.

Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH-mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine.

Memory B cells and plasma cells are antigen-experienced cells tasked with the maintenance of humoral protection. Despite these prominent functions, definitive cell surface markers have not been identified for these cells. We report here the isolation and characterization of the monoclonal variable lymphocyte receptor B (VLRB) N8 antibody from the evolutionarily distant sea lamprey that specifically recognizes memory B cells and plasma cells in humans. Unexpectedly, we determined that VLRB N8 recognizes the human leukocyte antigen-I (HLA-I) antigen in a tyrosine sulfation-dependent manner. Furthermore, we observed increased binding of VLRB N8 to memory B cells in individuals with autoimmune disorders multiple sclerosis and systemic lupus erythematosus. Our study indicates that lamprey VLR antibodies uniquely recognize a memory B cell- And plasma cell-specific posttranslational modification of HLA-I, the expression of which is up-regulated during B cell activation.

The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.

CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.

Introduction: Although rare, perinatal HIV transmission still occurs in the United States and most transmissions are preventable. We aim to identify patient barriers to antiretroviral therapy (ART) adherence during pregnancy and assess patient understanding of perinatal transmission. Methods: This cross-sectional survey recruited HIV positive postpartum women at a large safety net hospital in Atlanta, Georgia, between January 2016 and February 2018. Survey questions included demographic characteristics, HIV history, knowledge of perinatal transmission, and ART adherence. Perinatal and HIV outcomes were assessed using chart abstraction. Results: Of the 70 HIV infected postpartum women delivered at a large safety net hospital in Atlanta, GA, 45 women were eligible and consented to participate. Participating women were aged 18 to 40 years with an average age of 29 years old, 93% of participants were African-American, and 68% had ≥3 pregnancies. The majority of participants (75%) reported daily ART adherence. "Forgetting" was the most frequent reason for missing pills (57%). Thirteen women had a detectable viral load at the time of delivery and nine of those women had a viral load greater than 1000 copies/mL. Approximately 85% of women who correctly stated ART medications decrease perinatal transmission risk reported daily adherence compared with 50% of women without that knowledge (OR 5.6, 95% CI 1.17, 26.7). Almost half of women (40%) either did not know or believed a vaginal delivery, regardless of viral load, would increase their risk of perinatal transmission. Conclusion: Overall, women who were diagnosed with HIV during the current pregnancy, those with planned pregnancies, and those who were on medications prior to pregnancy were more likely to report daily ART adherence. Detectable viral load at delivery is the greatest risk factor for perinatal transmission; therefore strategies to increase ART adherence are needed.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

Background: We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. Results: Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. Conclusions: Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. Trial registration: NCT01018992. Registered 6 November 2009.

The standard treatment for patients diagnosed with glioblastoma is surgical resection of tumor followed by high dose radiation and chemotherapy with temozolomide. For patients who experience allergic reactions to temozolomide despite desensitization protocols, alternative therapies must be considered. In this report, we present such a patient who then received treatment with an epidermal growth factor receptor inhibitor, erlotinib, concurrent with a tumor-treating field device, Optune. Through this combination of a targeted molecular therapy and the Optune device, the patient has been able to achieve stable disease 9 months after completing radiation.