eScholarship@UMMS

BACKGROUND: Certain post-translational modifications to histones, including H3K4me3, as well as binding sites for the transcription factor STAT1, predict the site of integration of exogenous gamma-retroviruses with great accuracy and cell-type specificity. Statistical methods that were used to identify chromatin features that predict exogenous gamma-retrovirus integration site selection were exploited here to determine whether cell type-specific chromatin markers are enriched in the vicinity of endogenous retroviruses (ERVs).

RESULTS: Among retro-elements in the human genome, the gamma-retrovirus HERV-H was highly associated with H3K4me3, though this association was only observed in embryonic stem (ES) cells (p < 10-300) and, to a lesser extent, in induced pluripotent stem (iPS) cells. No significant association was observed in nearly 40 differentiated cell types, nor was any association observed with other retro-elements. Similar strong association was observed between HERV-H and the binding sites within ES cells for the pluripotency transcription factors NANOG, OCT4, and SOX2. NANOG binding sites were located within the HERV-H 5'LTR itself. OCT4 and SOX2 binding sites were within 1 kB and 2 kB of the 5'LTR, respectively. In keeping with these observations, HERV-H RNA constituted 2% of all poly A RNA in ES cells. As ES cells progressed down a differentiation pathway, the levels of HERV-H RNA decreased progressively. RNA-Seq datasets showed HERV-H transcripts to be over 5 kB in length and to have the structure 5'LTR-gag-pro-3'LTR, with no evidence of splicing and no intact open reading frames.

CONCLUSION: The developmental regulation of HERV-H expression, the association of HERV-H with binding sites for pluripotency transcription factors, and the extremely high levels of HERV-H RNA in human ES cells suggest that HERV-H contributes to pluripotency in human cells. Proximity of HERV-H to binding sites for pluripotency transcription factors within ES cells might be due to retention of the same chromatin features that determined the site of integration of the ancestral, exogenous, gamma-retrovirus that gave rise to HERV-H in the distant past. Retention of these markers, or, alternatively, recruitment of them to the site of the established provirus, may have acted post-integration to fix the provirus within the germ-line of the host species. Either way, HERV-H RNA provides a specific marker for pluripotency in human cells.

BACKGROUND: Errors during meiosis that affect synapsis and recombination between homologous chromosomes contribute to aneuploidy and infertility in humans. Despite the clinical relevance of these defects, we know very little about the mechanisms by which homologous chromosomes interact with one another during mammalian meiotic prophase. Further, we remain ignorant of the way in which chromosomal DNA complexes with the meiosis-specific structure that tethers homologs, the synaptonemal complex (SC), and whether specific DNA elements are necessary for this interaction.

RESULTS: In the present study we utilized chromatin immunoprecipitation (ChIP) and DNA sequencing to demonstrate that the axial elements of the mammalian SC are markedly enriched for a specific family of interspersed repeats, short interspersed elements (SINEs). Further, we refine the role of the repeats to specific sub-families of SINEs, B1 in mouse and AluY in old world monkey (Macaca mulatta).

CONCLUSIONS: Because B1 and AluY elements are the most actively retrotransposing SINEs in mice and rhesus monkeys, respectively, our observations imply that they may serve a dual function in axial element binding; i.e., as the anchoring point for the SC but possibly also as a suppressor/regulator of retrotransposition.

BACKGROUND: A proline-to-serine substitution at position-56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) causes a form of dominantly inherited motor neuron disease (MND), including typical and atypical amyotrophic lateral sclerosis (ALS) and a mild late-onset spinal muscular atrophy (SMA). VAPB is an integral endoplasmic reticulum (ER) protein and has been implicated in various cellular processes, including ER stress, the unfolded protein response (UPR) and Ca2+ homeostasis. However, it is unclear how the P56S mutation leads to neurodegeneration and muscle atrophy in patients. The formation of abnormal VAPB-positive inclusions by mutant VAPB suggests a possible toxic gain of function as an underlying mechanism. Furthermore, the amount of VAPB protein is reported to be reduced in sporadic ALS patients and mutant SOD1G93A mice, leading to the hypothesis that wild type VAPB plays a role in the pathogenesis of ALS without VAPB mutations.

RESULTS: To investigate the pathogenic mechanism in vivo, we generated human wild type (wtVAPB) and mutant VAPB (muVAPB) transgenic mice that expressed the transgenes broadly in the CNS. We observed robust VAPB-positive aggregates in the spinal cord of muVAPB transgenic mice. However, we failed to find an impairment of motor function and motor neuron degeneration. We also did not detect any change in the endogenous VAPB level or evidence for induction of the unfolded protein response (UPR) and coaggregation of VAPA with muVAPB. Furthermore, we crossed these VAPB transgenic mice with mice that express mutant SOD1G93A and develop motor neuron degeneration. Overexpression of neither wtVAPB nor muVAPB modulated the protein aggregation and disease progression in the SOD1G93A mice.

CONCLUSION: Overexpression of VAPBP56S mutant to approximately two-fold of the endogenous VAPB in mouse spinal cord produced abundant VAPB aggregates but was not sufficient to cause motor dysfunction or motor neuron degeneration. Furthermore, overexpression of either muVAPB or wtVAPB does not modulate the course of ALS in SOD1G93A mice. These results suggest that changes in wild type VAPB do not play a significant role in ALS cases that are not caused by VAPB mutations. Furthermore, these results suggest that muVAPB aggregates are innocuous and do not cause motor neuron degeneration by a gain-of-toxicity, and therefore, a loss of function may be the underlying mechanism.

Pathogenic bacteria resistant to many or all antibiotics already exist. With the decline in microbiological research at pharmaceutical companies, the high rate at which resistance has evolved and spread has demanded a novel approach to addressing this critical human health issue. In the present paper, we propose a new paradigm in antibiotic discovery and development, one that applies ecological and evolutionary theory to design antimicrobial drugs that are more difficult and/or more costly to resist. In essence, we propose to simply adopt the strategies invented and applied by bacteria for hundreds of millions of years. Our research focuses on bacteriocins, powerful biological weapons, and their use as alternative therapeutics in human health.

The World Health Organization has estimated that 10% of the world’s population (650 million people) has a disability. Assistive Technology (AT) has the potential to improve function for individuals with disabilities. Research and development must to focus both on universal design approaches for the population, as well as customization to meet individual functional demands. This mini-symposium will present the trends driving the need for AT, case studies demonstrating solutions to functional challenges, and evidence-based policy measures that are being implemented to meet the needs of people with disabilities living in the community.

Since 1991, UMass Lowell has operated an AT Program through which individuals with disabilities and community organizations meet with teams of students and faculty to design customized solutions. Symposium participants will discuss the development of population-level measures and examine indicators linking AT device use to psychosocial well-being: ultimately informing AT policies regarding access and provision. Participants will also to discuss challenges in translation of AT research due to the diversity of users and the functional implementation of AT solutions. Ultimately, participants will recognize the complex nature of AT solutions for persons with disabilities, and provide input on a strategy for a multidisciplinary collaboration to foster a novel person-center approach to research in this area.

Discussion of clinical and translational science in the context of Dr. Ridker's research on inflammation, atherothrombosis, and cardiovascular disease prevention.

Recent studies in mammals have documented the neural expression and mobility of retrotransposons and have suggested that neural genomes are diverse mosaics. We found that transposition occurs among memory-relevant neurons in the Drosophila brain. Cell type-specific gene expression profiling revealed that transposon expression is more abundant in mushroom body (MB) αβ neurons than in neighboring MB neurons. The Piwi-interacting RNA (piRNA) proteins Aubergine and Argonaute 3, known to suppress transposons in the fly germline, are expressed in the brain and appear less abundant in αβ MB neurons. Loss of piRNA proteins correlates with elevated transposon expression in the brain. Paired-end deep sequencing identified more than 200 de novo transposon insertions in αβ neurons, including insertions into memory-relevant loci. Our observations indicate that genomic heterogeneity is a conserved feature of the brain.

Child Health Improvement through Computer Automation (CHICA) is a computer decision support system (CDSS) that interfaces with existing electronic medical record systems (EMRS) and delivers "just in time" patient-relevant guidelines to physicians during the clinical encounter and accurately captures structured data from all who interact with the system. “Delivering Geospatial Intelligence to Health Care Professionals (CHICA-GIS)” (1R01LM010923-01) expands the medical application of Geographic Information Systems (GIS) by integrating a geographic information system with CHICA. To provide knowledge management support for CHICA-GIS, three informationists at the Indiana University School of Medicine were awarded a supplement from the National Library Medicine. The informationists will enhance CHICA-GIS by: improving the accuracy and accessibility of information, managing and mapping the knowledge which undergirds the CHICA-GIS decision support tool, supporting community engagement and consumer health information outreach, and facilitating the dissemination of new CHICA-GIS research results and services.

Two supplements were awarded to the New York University Health Sciences Libraries from the National Library of Medicine's informationist grant program. These supplements funded research support in a number of areas, including data management and bioinformatics, two fields that the library had recently begun to explore. As such, the supplements were of particular value to the library as a testing ground for these newer services.

This paper will discuss a supplement received in support of a grant from the National Institute of Dental and Craniofacial Research (PI: Brian Schmidt) on the role of proteases and peptides in cancer pain. A number of barriers were preventing the research team from maximizing the efficiency and effectiveness of their work. A critical component of the research was to identify which proteins, from among hundreds identified in collected samples, to include in preclinical testing. This selection involved laborious and prohibitively time-consuming manual searching of the literature on protein function. Additionally, the research team encompassed ten investigators working in two different cities, which led to issues around the sharing and tracking of both data and citations.

The supplement outlined three areas in which the informationists would assist the researchers in overcoming these barriers: 1) creating an automated literature searching system for protein function discovery, 2) introducing tools and associated workflows for sharing citations, and 3) introducing tools and workflows for sharing data and specimens.

In 2012 the National Library of Medicine awarded several academic medical libraries informationist grants to become embedded with a research team for the purposes of data management. The University of Rochester Medical Center was among those recipients. This article will give background on the research project and team that won the grant, discuss the process of applying for the grant, identify the data management role that the informationist librarians have agreed to work on, how they embedded into the research team, and relay lessons learned thus far in the project.

Informationists at NYU Health Sciences Libraries (NYUHSL) successfully applied for a NLM supplement to a translational research grant obtained by PIs in the NYU School of Medicine Department of Otolaryngology titled, “Clinical Management of Cochlear Implant Patients with Contralateral Hearing Aids”. The grant involves development of evidence-based guidelines for post-implant management of patients with bimodal cochlear implants. The PIs are also seeking to acquire new data sets to merge with grant-generated data. In light of the shifting data requirements, and the potential introduction of additional datasets, informationists will evaluate and restructure the data model and data entry tool. Report queries will be refined for the new data model and options for a query tool appropriate for users unfamiliar with query languages will be assessed and implemented. The services offered through this supplement represent the deepest and most detailed data management support offered by NYUHSL to date. The components of the supplement are being analyzed as a pilot of a broader offering of these data management services.

In 2012, the Lamar Soutter Library (LSL), University of Massachusetts Medical School, successfully collaborated with two principal investigators at UMMS, as well as their research team, to receive a supplemental grant from the National Library of Medicine. The award, an “NLM Administrative Supplements for Informationist Services in NIH-funded Research Projects”, was one of eight awarded nationally. It provides funding to support an informationist, or in-context information specialist, who serves the research team by offering expertise in the areas of data and information management.

For 18 months, the informationist is serving as a member of the research team on the grant, “Promoting Breast Cancer Screening in Non-Adherent Women” (R01 CA-132935, National Cancer Institute, National Institutes of Health), working to develop data management tools, providing an in-depth literature review and report on the issues facing researchers and internet technology professionals when building and implementing research tools, assisting with a systematic review on the effectiveness of telephone intervention protocols for preventive screenings, and instructing the members of the team in advanced searching techniques and bibliographic management.

This role serves as a new model of embedded librarianship for the LSL. It also provides opportunities for new services from the Library in the role of data and information management. Further, the acceptance of an informationist into a well-funded research team demonstrates a level of commitment by researchers to receiving research support from the Library that it has not experienced to date. This brief paper describes the study and the accomplishments to date.

With the announcement of the NLM Administrative Supplement Grant, the informationists at the Welch Medical Library found an interested and enthusiastic Principal Investigator (PI) in the Department of Radiology at The Johns Hopkins School of Medicine. Although the PI had not used the services of a Welch informationist before, he was eager to collaborate with an informationist on the grant “Dose-Response in Radionuclide Therapy,” (Parent Grant Number: 5R01CA116477-07) and had self-identified the need for “a literature review by experts” to fulfill his funded work.

Targeted radionuclide therapy is an emerging modality for cancer therapy that involves the delivery of radioactive atoms using carriers that preferentially bind to tumor cells. Such treatment is best implemented with patient-specific dosimetry calculations. This mutually beneficial partnership brings the specialized skill set, knowledge base and expertise of an informationist to the biomedical research team to assist in accomplishing the broader work of improving RPT delivery in metastatic cancer patients.

The informationist will carry out multiple tasks to produce an effective and efficient workflow that facilitates the dissemination of the information to a globally dispersed research team. This collaboration will be evaluated both quantitatively and qualitatively, and the important role of the informationist in the success of this project will demonstrate the value of including an informationist in the research team. This demonstrated value will assist Welch Library in continuing to promote the embedded informationist program to other interested researchers throughout the institution.

Libraries have provided services to researchers for many years. Changes in technology and new publishing models provide opportunities for libraries to be more involved in the research enterprise. Within this article, the author reviews traditional library services, briefly describes the eScience and publishing landscape as it relates to libraries, and explores possible library programs in support of research. Many of the new opportunities require new partnerships, both within the institution and externally.

In this video article, Lisa Federer, Research Informationist at the UCLA Louise M. Darling Biomedical Library, describes her experience as a research informationist for a National Institutes of Health-funded research team at the University of California, Los Angeles.

Valerie Florance of the National Library of Medicine (NLM) discusses NLM's support programs to encourage new roles for health sciences librarians, specifically the NLM Administrative Supplements for Informationist Services in NIH-funded Research Projects program.

JESLIB Editor Elaine R. Martin introduces the papers in Volume 2, Issue 1 (2013), which focuses on the role of and the Informationist or Embedded Librarian in the scientific research process. As biomedical science becomes more data intensive, researchers are faced with a range of data management challenges, problems, and needs. Health sciences librarians are ideal partners for offering scientists at their institutions a range of data management services.

Discusses the development and execution of a Leadership Speaker Series by the University of Massachusetts Medical School’s Office of Faculty Affairs.

The mission of the Women’s Faculty Committee (WFC), of the University of Massachusetts Medical School (UMMS), and its clinical partner UMass Memorial Health Care (UMMHC), is to address the needs of women faculty and to promote the status of women in the UMMS and UMMHC systems. For the past 12 consecutive years, one of the mechanisms by which the WFC identifies, recognizes, and supports accomplished women clinicians, researchers, educators, leaders and mentors of our community, is through an annual awards luncheon.

OBJECTIVE: Several conditions are associated with increased preeclampsia (PE) risk. Whether altered maternal angiogenic factor levels contribute to risk in these conditions is unknown. Our objective was to compare angiogenic biomarker patterns in high-risk pregnancies and low-risk controls.

STUDY DESIGN: We conducted a planned secondary analysis of a 2-center observational study of angiogenic biomarkers in high-risk women. A total of 156 pregnant women with a PE risk factor and 59 low-risk controls were studied. Serial maternal serum samples were collected during 3 gestational windows: 23-27 weeks, 28-31 weeks, and 32-35 weeks. Soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) were measured by enzyme-linked immunosorbent assay. Geometric mean angiogenic biomarker levels and angiogenic ratio (sFlt1 + sEng):PlGF were compared with low-risk controls for each risk group, at each gestational window.

RESULTS: Gestational biomarker patterns differed in PE risk groups as compared with low-risk controls. Women with multiple gestations had markedly higher sFlt1 and sEng at all gestational windows. Women with prior PE had higher sFlt1 and angiogenic ratio, and lower PlGF, from 28 weeks onward. Women with chronic hypertension had significantly higher angiogenic ratio for all 3 gestational windows, but differences disappeared when women with PE were excluded. Obese and nulliparous women had significantly lower PlGF, but no differences in the angiogenic ratio.

CONCLUSION: High-risk groups have altered angiogenic biomarker patterns compared with controls, suggesting that altered production or metabolism of these factors may contribute to PE risk, particularly in women with multiple gestations and prior PE.