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.
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.
Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate motile processes. Motility of these processes is guided by local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. Here we identified a molecular pathway in mouse and human microglia that converts ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A2A adenosine receptor coincident with P2Y12 downregulation. Thus, A2A receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.
An important challenge in prostate cancer research is to develop effective predictors of tumor recurrence following surgery to determine whether immediate adjuvant therapy is warranted. To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed, paraffin-embedded radical prostatectomy specimens with known long-term outcomes to perform DASL expression profiling with a custom panel that we designed of 522 prostate cancer–relevant genes. We identified a panel of 10 protein-coding genes and two miRNA genes (RAD23B, FBP1, TNFRSF1A, CCNG2, NOTCH3, ETV1, BID, SIM2, LETMD1, ANXA1, miR-519d, and miR-647) that could be used to separate patients with and without biochemical recurrence (P < 0.001), as well as for the subset of 42 Gleason score 7 patients (P < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of biochemical recurrence for all cases (P = 0.013) and for a subset of 19 Gleason score 7 cases (P = 0.010), both of which were adjusted for relevant clinical information including T-stage, prostate-specific antigen, and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason score 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
Background
This study determined the reliability of topographic motor cortical maps and MEP characteristics in the extensor digitorum communis (EDC) evoked by single-pulse TMS among patients with chronic stroke.
Methods
Each of ten patients was studied on three occasions. Measures included location of the EDC hotspot and center of gravity (COG), threshold of activation and average amplitude of the hotspot, number of active sites, map volume, and recruitment curve (RC) slope.
Results
Consistent intrahemispheric measurements were obtained for the three TMS mapping sessions for all measured variables. No statistically significant difference was observed between hemispheres for the number of active sites, COG distance or the RC slope. The magnitude and range of COG movement between sessions were similar to those reported previously with this muscle in able-bodied individuals. The average COG movement over three sessions in both hemispheres was 0.90 cm. The average COG movement in the affected hemisphere was 1.13 (± 0.08) cm, and 0.68 (± 0.04) cm) for the less affected hemisphere. However, significant interhemispheric variability was seen for the average MEP amplitude, normalized map volume, and resting motor threshold.
Conclusion
The physiologic variability in some TMS measurements of EDC suggest that interpretation of TMS mapping data derived from hemiparetic patients in the chronic stage following stroke should be undertaken cautiously. Irrespective of the muscle, potential causes of variability should be resolved to accurately assess the impact of pharmacological or physical interventions on cortical organization as measured by TMS among patients with stroke.
In the United States, the number and proportion of HIV/AIDS cases among black/African Americans continue to highlight the need for new biomedical prevention interventions, including an HIV vaccine, microbicide, or new antiretroviral (ARV) prevention strategies such as pre-exposure prophylaxis (PrEP) to complement existing condom usage, harm reduction methods, and behavioral change strategies to stem the HIV epidemic. Although black/African Americans are disproportionately impacted by HIV/AIDS, their participation in HIV clinical research continues to have unique challenges. We theorize that interaction among multilevel factors creates ideal alignment for minority participation in HIV clinical studies. Thus, we initially set out to test an extended model of reasoned action with 362 participants to understand the interplay of sociopsychological and network-level considerations influencing minority participation in HIV prevention research efforts. In this study, we linked the intrapersonal dimensions of attitudes, beliefs, and normative concerns to community-level components, appraisal of involvement with the clinical research organization, an entity which operates within a networked structure of community partner agencies, and identification with coalition advocacy aims. Various participatory outcomes were explored including involvement in future HIV vaccine community functions, participation in community promotion of HIV vaccine research, and community mobilization. Three-stage least squares estimates indicated similar findings across three models. Significant effects demonstrate the importance of positive attitudes toward HIV vaccine research, favorable health research beliefs, perceived social support for participation, HIV/AIDS issue engagement, and perceived relevance of the clinical research site’s mission and values. Identification of these nuanced pathway effects provides implications for tailored community program development.
by
James J Kohler;
Seyed H. Hosseini;
Elgin Green;
Amy Hoying-Brandt;
Ioan Cucoranu;
Chad P. Haase;
Rodney Russ;
Jaya Srivastava;
Kristopher Ivey;
Tomika Ludaway;
Victor Kapoor;
Allison Abuin;
Alexsey Shapoval;
Robert Santoianni;
Ann Saada;
Orly Elpeleg;
William Lewis
Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (pol γ) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol γ and mtDNA replication. Cardiac “dominant negative” murine transgenes (TGs; Pol γ Y955G, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in “2 × 2” studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs (∼50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass (≈50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.
Background: Exposure measurement error in copollutant epidemiologic models has the potential to introduce bias in relative risk (RR) estimates. A simulation study was conducted using empirical data to quantify the impact of correlated measurement errors in time-series analyses of air pollution and health.
Methods: ZIP-code level estimates of exposure for six pollutants (CO, NOx, EC, PM2.5, SO4, O3) from 1999 to 2002 in the Atlanta metropolitan area were used to calculate spatial, population (i.e. ambient versus personal), and total exposure measurement error.
Empirically determined covariance of pollutant concentration pairs and the associated measurement errors were used to simulate true exposure (exposure without error) from observed exposure. Daily emergency department visits for respiratory diseases were simulated using a Poisson time-series model with a main pollutant RR = 1.05 per interquartile range, and a null association for the copollutant (RR = 1). Monte Carlo experiments were used to evaluate the impacts of correlated exposure errors of different copollutant pairs.
Results: Substantial attenuation of RRs due to exposure error was evident in nearly all copollutant pairs studied, ranging from 10 to 40% attenuation for spatial error, 3–85% for population error, and 31–85% for total error. When CO, NOx or EC is the main pollutant, we demonstrated the possibility of false positives, specifically identifying significant, positive associations for copollutants based on the estimated type I error rate.
Conclusions: The impact of exposure error must be considered when interpreting results of copollutant epidemiologic models, due to the possibility of attenuation of main pollutant RRs and the increased probability of false positives when measurement error is present.
Objective: This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule.
Materials and Methods: In this single-arm, open label, dose-escalation study, we administered topotecan (0.75–1.5 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors.
Results: The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m2/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3–4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1).
Conclusions: Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).
Objective: To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.
Design: Collaborative case-control study conducted from July 2001 to December 2005.
Setting: A heterogeneous population of patients from 12 USA intensive care units (ICUs) represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive.
Patients: Eight hundred and fifty-four patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the ICU without evidence of any infection (matched nonseptic controls).
Measurements and Main Results: We developed assays for six functional single nucleotide polymorphisms (SNPs) present before the first codon of TNF at −308, IL1B at −511, IL6 at −174, IL10 at −819, and CD14 at −159, and in the first intron of LTA (also known as TNF-β) at +252 (LTA(+252)). The Project IMPACT™ critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics, Inc. and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3 % and 6.4 % of Caucasian and African American racial types, respectively. Overall mortality was 35.1 % in both severe sepsis (SS) and matched nonseptic control (MC) patients group. Average ages (SD) of the SS and MC patients were 63.0 (16.05) and 65.0 (15.58) years old, respectively. Among the 6 SNPs, LTA(+252) was most over-represented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, P = .005). Moreover, the genetic risk effect was most pronounced in males, age > 60 yrs (P = .005).
Conclusions: LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.
Background: Patients with cystic fibrosis (CF) may be at risk for micronutrient depletion, particularly during periods of illness and infection. The purpose of this study was to investigate serum micronutrient status over time in adults with CF initially hospitalized with a pulmonary exacerbation.
Materials and Methods: This was an ancillary study of a multicenter trial investigating the role of high-dose vitamin D supplementation in 24 adults with CF (mean age, 29.6 ± 7.3 years). We measured serum concentrations of copper (Cu), iron (Fe), calcium (Ca), magnesium (Mg), potassium (K), and sulfur (S) in subjects at the beginning of a pulmonary exacerbation and again at 3 months.
Results: Serum concentrations of Cu, Fe, and Ca were significantly lower at baseline compared with 3 months following the pulmonary exacerbation (Cu: baseline, 1.5 ± 0.6 vs 3 months, 1.6 ± 0.6 μg/mL, P = .027; Fe: 0.8 ± 0.3 vs 1.3 ± 1.1 μg/mL, P = .026; Ca: 9.7 ± 0.8 vs 10.8 ± 2.0 mg/dL, P = .024). Serum concentrations of K, Mg, and S did not change over time (K: baseline, 4.9 ± 0.3 vs 3 months, 5.1 ± 0.5 mEq/L; Mg: 1.8 ± 0.2 vs 2.0 ± 0.3 mg/dL; S: 1288.6 ± 343 vs 1309.9 ± 290 μg/mL; P > .05 for all).
Conclusion: Serum concentrations of Cu, Fe, and Ca increased significantly several months following recovery from acute pulmonary exacerbation in adults with CF. This may reflect decreased inflammation, improved food intake, and/or increased absorption following recovery.
The biomechanical environment within the eye is of interest in both the regulation of intraocular pressure and the loss of retinal ganglion cell axons in glaucomatous optic neuropathy. Unfortunately, this environment is complex and difficult to determine. Here we provide a brief introduction to basic concepts of mechanics (stress, strain, constitutive relationships) as applied to the eye, and then describe a variety of experimental and computational approaches used to study ocular biomechanics. These include finite element modeling, direct experimental measurements of tissue displacements using optical and other techniques, direct experimental measurement of tissue microstructure, and combinations thereof. Thanks to notable technical and conceptual advances in all of these areas, we are slowly gaining a better understanding of how tissue biomechanical properties in both the anterior and posterior segments may influence the development of, and risk for, glaucomatous optic neuropathy. Although many challenging research questions remain unanswered, the potential of this body of work is exciting; projects underway include the coupling of clinical imaging with biomechanical modeling to create new diagnostic tools, development of IOP control strategies based on improved understanding the mechanobiology of the outflow tract, and attempts to develop novel biomechanically-based therapeutic strategies for preservation of vision in glaucoma.
Central nervous system (CNS) tissue motion of the brain occurs over 30 million cardiac cycles per year due to intracranial pressure differences caused by the pulsatile blood flow and cerebrospinal fluid (CSF) motion within the intracranial space. This motion has been found to be elevated in type 1 Chiari malformation. The impact of CNS tissue motion on CSF dynamics was assessed using a moving-boundary computational fluid dynamics (CFD) model of the cervical-medullary junction (CMJ). The cerebellar tonsils and spinal cord were modeled as rigid surfaces moving in the caudocranial direction over the cardiac cycle. The CFD boundary conditions were based on in vivo MR imaging of a 35-year old female Chiari malformation patient with ~150–300 µm motion of the cerebellar tonsils and spinal cord, respectively. Results showed that tissue motion increased CSF pressure dissociation across the CMJ and peak velocities up to 120 and 60%, respectively. Alterations in CSF dynamics were most pronounced near the CMJ and during peak tonsillar velocity. These results show a small CNS tissue motion at the CMJ can alter CSF dynamics for a portion of the cardiac cycle and demonstrate the utility of CFD modeling coupled with MR imaging to help understand CSF dynamics.
Planned interventions and/or natural conditions often effect change on an ordinal categorical outcome (e.g., symptom severity). In such scenarios, it is sometimes desirable to assign a priori scores to observed changes in status, typically giving higher weight to changes of greater magnitude. We define change indices for such data based upon a multinomial model for each row of a c × c table, where the rows represent the baseline status categories. We distinguish an index designed to assess conditional changes within each baseline category from two others designed to capture overall change. One of these overall indices measures expected change across a target population. The other is scaled to capture the proportion of total possible change in the direction indicated by the data, so that it ranges from -1 (when all subjects finish in the least favorable category) to +1 (when all finish in the most favorable category). The conditional assessment of change can be informative regardless of how subjects are sampled into the baseline categories. In contrast, the overall indices become relevant when subjects are randomly sampled at baseline from the target population of interest, or when the investigator is able to make certain assumptions about the baseline status distribution in that population. We use a Dirichlet-multinomial model to obtain Bayesian credible intervals for the conditional change index that exhibit favorable small-sample frequentist properties. Simulation studies illustrate the methods, and we apply them to examples involving changes in ordinal responses for studies of sleep deprivation and activities of daily living.
Emerging evidence indicates impairments in somatosensory function may be a major contributor to motor dysfunction associated with neurologic injury or disorders. However, the neuroanatomical substrates underlying the connection between aberrant sensory input and ineffective motor output are still under investigation. The primary somatosensory cortex (S1) plays a critical role in processing afferent somatosensory input and contributes to the integration of sensory and motor signals necessary for skilled movement. Neuroimaging and neurostimulation approaches provide unique opportunities to non-invasively study S1 structure and function including connectivity with other cortical regions. These research techniques have begun to illuminate casual contributions of abnormal S1 activity and connectivity to motor dysfunction and poorer recovery of motor function in neurologic patient populations. This review synthesizes recent evidence illustrating the role of S1 in motor control, motor learning and functional recovery with an emphasis on how information from these investigations may be exploited to inform stroke rehabilitation to reduce motor dysfunction and improve therapeutic outcomes.
Raman and Raman optical activity (ROA) spectra were collected for four RNA oligonucleotides based on the EMCV IRES Domain I to assess the contributions of helix, GNRA tetraloop, U·C mismatch base pair and pyrimidine-rich bulge structures to each. Both Raman and ROA spectra show overall similarities for all oligonucleotides, reflecting the presence of the same base paired helical regions and GNRA tetraloop in each. Specific bands are sensitive to the effect of the mismatch and asymmetric bulge on the structure of the RNA. Raman band changes are observed that reflect the structural contexts of adenine residues, disruption of A-form helical structure, and incorporation of pyrimidine bases in non-helical regions. The ROA spectra are also sensitive to conformational mobility of ribose sugars, and verify a decrease in A-type helix content upon introduction of the pyrimidine-rich bulge. Several Raman and ROA bands also clearly show cooperative effects between the mismatch and pyrimidine-rich bulge motifs on the structure of the RNA. The complementary nature of Raman and ROA spectra provides detailed and highly sensitive information about the local environments of bases, and secondary and tertiary structures, and has the potential to yield spectral signatures for a wide range of RNA structural motifs.
The X-ray crystal structure of a single-chain monellin protein (MNEI) has been determined at 1.15 Å resolution. The model was refined to convergence employing anisotropic displacement parameters and riding H atoms to produce a final model with Rwork and Rfree values of 0.132 and 0.162, respectively. The crystal contains a single MNEI protein in the asymmetric unit and unusually lacks the dimer interface observed in all previous crystal structures of monellin and its single-chain derivatives. The high resolution allowed a more detailed view of MNEI than previously possible, with 38 of the 96 residues modelled with alternative side-chain conformations, including four core residues Thr12, Cys41, Leu62 and Ile75. Four stably bound negative ions were also located, providing new insight into potential electrostatic interactions of MNEI with the largely negatively charged surface of the sweet taste receptor T1R2-T1R3.