Transforming and extending library services by embracing technology and collaborations: A case study.

Technology advances and collaborations with information technology and computer science groups have enabled library services to expand into new domains. Listening to user needs, eliminating administrative burden and saving users time remain strong foundations on which to build new library services enabled by technology. Examples of what is now possible is described, including service to user groups, successes, failures and challenges. Although technology advances have enabled library service enhancements to all user groups, special emphasis on new library services in support of the research enterprise is discussed. As Lindberg and Humphreys predicted in 2015, the research enterprise's need for responsible curation of research data has created new opportunities for library services and examples of those services are discussed. As technology continues to advance, new library services are expected to emerge. These may include regulatory and compliance services. By developing these services with user feedback to save users time and expedite their work, and in collaboration with technology experts, libraries can expect to offer sustainable and valued services for years to come.

ReCiter: An open source, identity-driven, authorship prediction algorithm optimized for academic institutions.

Academic institutions need to maintain publication lists for thousands of faculty and other scholars. Automated tools are essential to minimize the need for direct feedback from the scholars themselves who are practically unable to commit necessary effort to keep the data accurate. In relying exclusively on clustering techniques, author disambiguation applications fail to satisfy key use cases of academic institutions. Algorithms can perfectly group together a set of publications authored by a common individual, but, for them to be useful to an academic institution, they need to programmatically and recurrently map articles to thousands of scholars of interest en masse. Consistent with a savvy librarian's approach for generating a scholar's list of publications, identity-driven authorship prediction is the process of using information about a scholar to quantify the likelihood that person wrote certain articles. ReCiter is an application that attempts to do exactly that. ReCiter uses institutionally-maintained identity data such as name of department and year of terminal degree to predict which articles a given scholar has authored. To compute the overall score for a given candidate article from PubMed (and, optionally, Scopus), ReCiter uses: up to 12 types of commonly available, identity data; whether other members of a cluster have been accepted or rejected by a user; and the average score of a cluster. In addition, ReCiter provides scoring and qualitative evidence supporting why particular articles are suggested. This context and confidence scoring allows curators to more accurately provide feedback on behalf of scholars. To help users to more efficiently curate publication lists, we used a support vector machine analysis to optimize the scoring of the ReCiter algorithm. In our analysis of a diverse test group of 500 scholars at an academic private medical center, ReCiter correctly predicted 98% of their publications in PubMed.

Inflammatory disease and the human microbiome.

The human body is a superorganism in which thousands of microbial genomes continually interact with the human genome. A range of physical and neurological inflammatory diseases are now associated with shifts in microbiome composition. Seemingly disparate inflammatory conditions may arise from similar disruption of microbiome homeostasis. Intracellular pathogens long associated with inflammatory disease are able to slow the innate immune response by dysregulating activity of the VDR nuclear receptor. This facilitates the ability of other species to gradually accumulate in tissue and blood, where they generate proteins and metabolites that significantly interfere with the body's metabolic processes. The microbes that contribute to this dysfunction are often inherited from family members. Immunosuppressive therapies for inflammatory disease allow pathogens driving these processes to spread with greater ease. In contrast to immunosuppression, treatments that stimulate the immune system seem to allow for reversal of this pathogen-induced genomic dysregulation.

Automatic generation of investigator bibliographies for institutional research networking systems.

OBJECTIVE: Publications are a key data source for investigator profiles and research networking systems. We developed ReCiter, an algorithm that automatically extracts bibliographies from PubMed using institutional information about the target investigators. METHODS: ReCiter executes a broad query against PubMed, groups the results into clusters that appear to constitute distinct author identities and selects the cluster that best matches the target investigator. Using information about investigators from one of our institutions, we compared ReCiter results to queries based on author name and institution and to citations extracted manually from the Scopus database. Five judges created a gold standard using citations of a random sample of 200 investigators. RESULTS: About half of the 10,471 potential investigators had no matching citations in PubMed, and about 45% had fewer than 70 citations. Interrater agreement (Fleiss' kappa) for the gold standard was 0.81. Scopus achieved the best recall (sensitivity) of 0.81, while name-based queries had 0.78 and ReCiter had 0.69. ReCiter attained the best precision (positive predictive value) of 0.93 while Scopus had 0.85 and name-based queries had 0.31. DISCUSSION: ReCiter accesses the most current citation data, uses limited computational resources and minimizes manual entry by investigators. Generation of bibliographies using named-based queries will not yield high accuracy. Proprietary databases can perform well but requite manual effort. Automated generation with higher recall is possible but requires additional knowledge about investigators.

Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis.

Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) has long been associated with the presence of infectious agents, but no single pathogen has been reliably identified in all patients with the disease. Recent studies using metagenomic techniques have demonstrated the presence of thousands of microbes in the human body that were previously undetected and unknown to science. More importantly, such species interact together by sharing genes and genetic function within communities. It follows that searching for a singular pathogen may greatly underestimate the microbial complexity potentially driving a complex disease like CFS/ME. Intracellular microbes alter the expression of human genes in order to facilitate their survival. We have put forth a model describing how multiple species-bacterial, viral, and fungal-can cumulatively dysregulate expression by the VDR nuclear receptor in order to survive and thus drive a disease process. Based on this model, we have developed an immunostimulatory therapy that is showing promise inducing both subjective and objective improvement in patients suffering from CFS/ME.

The human microbiome and autoimmunity.

PURPOSE OF REVIEW: To demonstrate how dysbiosis of the human microbiome can drive autoimmune disease. RECENT FINDINGS: Humans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens. SUMMARY: The catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis - the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities. We can stimulate innate immune defenses and allow patients to target pathogens, but cell death results in immunopathology.

Immunostimulation in the era of the metagenome.

Microbes are increasingly being implicated in autoimmune disease. This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated. The standard of care for autoimmune disease remains the use of medications that slow the immune response, while treatments aimed at eradicating microbes seek the exact opposite-stimulation of the innate immune response. Immunostimulation is complicated by a cascade of sequelae, including exacerbated inflammation, which occurs in response to microbial death. Over the past 8 years, we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease. This intervention, designed to stimulate the innate immune response, has required a reevaluation of disease progression and amelioration. Paramount is the inherent conflict between palliation and microbicidal efficacy. Increased microbicidal activity was experienced as immunopathology-a temporary worsening of symptoms. Further studies are needed, but they will require careful planning to manage this immunopathology.

Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women.

Researchers have noted that the incidence of autoimmune diseases, such as Hashimoto's thyroiditis, is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The vitamin D nuclear receptor (VDR) is expressed in the human cycling endometrium. Because the VDR controls expression of the cathelicidin and beta-defensin antimicrobial peptides (AmPs), dysregulation of the receptor greatly compromises the innate immune response. Increasing evidence indicates the presence of a chronic, intraphagocytic, metagenomic microbiota in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation, in turn, prevents the breakdown of the active vitamin D metabolite 1,25-hydroxyvitamin D (1,25-D) by CYP24. In silico data suggest that when 1,25-D rises above its normal range, it binds the alpha/beta thyroid receptors, the glucocorticoid receptor (GCR), and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from alpha-thyroid, thyroiditis may result. Because the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25-D. The end result is a system-wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptor dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25-D levels rise by 40%.

Vitamin D metabolites as clinical markers in autoimmune and chronic disease.

Recent research has implicated vitamin D deficiency (serum levels of 25-hydroxyvitamin D <50 nmol/L) with a number of chronic conditions, including autoimmune conditions such as multiple sclerosis, lupus, and psoriasis, and chronic conditions such as osteoporosis, osteoarthritis, metabolic syndrome, fibromyalgia and chronic fatigue syndrome. It has been assumed that low levels of 25-hydroxyvitamin D (25-D) accurately indicate vitamin D storage and vitamin D receptor (VDR)-mediated control of calcium metabolism and innate immunity. To evaluate this assumption, 25-D and 1,25-dihydroxyvitamin D3 (1,25-D) levels were measured in 100 Canadian patients with these conditions. Additionally, other inflammatory markers (CK, CRP) were measured. Results showed a strong positive association between these autoimmune conditions and levels of 1,25-D >110 pmol/L. However, there was little association with vitamin D deficiency or the other inflammatory markers, meaning that the results challenge the assumption that serum levels of 25-D are a sensitive measure of the autoimmune disease state. Rather, these findings support the use of 1,25-D as a clinical marker in autoimmune conditions. High levels of 1,25-D may result when dysregulation of the VDR by bacterial ligands prevents the receptor from expressing enzymes necessary to keep 1,25-D in a normal range.

Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease.

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Autoimmune disease in the era of the metagenome.

Studies of autoimmune disease have focused on the characteristics of the identifiable antibodies. But as our knowledge of the genes associated with the disease states expands, we understand that humans must be viewed as superorganisms in which a plethora of bacterial genomes - a metagenome - work in tandem with our own. The NIH has estimated that 90% of the cells in Homo sapiens are microbial and not human in origin. Some of these microbes create metabolites that interfere with the expression of genes associated with autoimmune disease. Thus, we must re-examine how human gene transcription is affected by the plethora of microbial metabolites. We can no longer assume that antibodies generated in autoimmune disease are created solely as autoantibodies to human DNA. Evidence is now emerging that the human microbiota accumulates during a lifetime, and a variety of persistence mechanisms are coming to light. In one model, obstruction of VDR nuclear-receptor-transcription prevents the innate immune system from making key antimicrobials, allowing the microbes to persist. Genes from these microbes must necessarily impact disease progression. Recent efforts to decrease this VDR-perverting microbiota in patients with autoimmune disease have resulted in reversal of autoimmune processes. As the NIH Human Microbiome Project continues to better characterize the human metagenome, new insights into autoimmune pathogenesis are beginning to emerge.

Vitamin D: the alternative hypothesis.

Early studies on vitamin D showed promise that various forms of the "vitamin" may be protective against chronic disease, yet systematic reviews and longer-term studies have failed to confirm these findings. A number of studies have suggested that patients with autoimmune diagnoses are deficient in 25-hydroxyvitamin D (25-D) and that consuming greater quantities of vitamin D, which further elevates 25 D levels, alleviates autoimmune disease symptoms. Some years ago, molecular biology identified 25 D as a secosteroid. Secosteroids would typically be expected to depress inflammation, which is in line with the reports of symptomatic improvement. The simplistic first-order mass-action model used to guide the early vitamin studies is now giving way to a more complex description of action. When active, the Vitamin D nuclear receptor (VDR) affects transcription of at least 913 genes and impacts processes ranging from calcium metabolism to expression of key antimicrobial peptides. Additionally, recent research on the Human Microbiome shows that bacteria are far more pervasive than previously thought, increasing the possibility that autoimmune disease is bacterial in origin. Emerging molecular evidence suggests that symptomatic improvements among those administered vitamin D is the result of 25-D's ability to temper bacterial-induced inflammation by slowing VDR activity. While this results in short-term palliation, persistent pathogens that may influence disease progression, proliferate over the long-term.

Chemoreception of sucrose and amino acids in second and fourth instars of the spruce budworm Choristoneura fumiferana (Clem.) (Lepidoptera: Tortricidae).

We examined the responses of some gustatory neurons in various contact-chemoreceptor sensilla of second-instar larvae of the spruce budworm. These included the L1 and L2 sensilla on the maxillary palp, and the LST and MST sensilla on the galea. Our objective was to determine whether there were differences in the physiological characteristics of individual neurons between the early and late larval instars. Changes were observed in both some sugar-sensitive and amino acid-sensitive neurons. We also confirmed the presence of a water-sensitive neuron in the L2 sensillum. Our findings are discussed in relation to changes that occur during the development of both the host plant and the insect. To our knowledge, this is the first paper to examine the responses from contact-chemoreceptor sensilla of very young second-instar caterpillar larvae.

Kinases, intracellular calcium, and apolipophorin-III influence the adhesion of larval hemocytes of the lepidopterous insect, Galleria mellonella.

Based on the results from the use of selective inhibitors and activators, active protein kinase A, protein tyrosine kinase, and protein kinase C (PKC) isoforms decreased the adhesion of larval Galleria mellonella hemocytes to glass slides. The protein kinase A inhibitor at all concentrations increased granular cell adhesion only whereas protein tyrosine kinase elevated both granular and plasmatocyte attachment at the lowest concentration. Active, Ca(2+)- and lipid-dependent PKC isoforms limited plasmatocyte and granular cell adhesion whereas PKC that was inhibited by selected compounds (with differed modes of PKC inhibition) enhanced hemocyte attachment. The granular cells were more sensitive to the PKC inhibitors than were plasmatocytes. Phospholipase C and its diacylglyceride product were necessary to reduce hemocyte adhesion and maintain PKC activity. Extracellular Ca(2+), possibly transported through L-channels, was required for plasmatocyte attachment. In contrast, lowering the levels of cytosolic Ca(2+) was associated with decreased PKC activity and was required for hemocyte adhesion.

Apolipophorin-III affects the activity of the haemocytes of Galleria mellonella larvae.

Apolipophorin-III (apoLp-III) impaired the adhesion of plasmatocytes and a granular cell-subpopulation of larval Galleria mellonella to glass slides. The protein bound to haemocytes, limited the responses of the plasmatocytes to Bacillus subtilis and increased the percentage of a subgroup of granular cells with adhering bacteria. The total number of bacteria adhering to all the haemocytes on the slides declined. Injections of apoLp-III slowed bacterial removal from the haemolymph without affecting total haemocyte counts and impaired haemocyte attachment to glass slides. Purified apoLp-III bound to B. subtilis. ApoLp-III in serum bound to bacteria within 5 min, peaked at 15 min and was either shed or dissociated by 60 min. ApoLp-III bound to B. subtilis lowered the adhesion of the bacteria to the haemocytes and slowed the removal of the bacteria from the haemolymph.