Protecting open lands in farms and ranches from development through conservation easements

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REC, Drosophila MCM8, Drives Formation of Meiotic Crossovers

Crossovers ensure the accurate segregation of homologous chromosomes from one another during meiosis. Here, we describe the identity and function of the Drosophila melanogaster gene recombination defective (rec), which is required for most meiotic crossing over. We show that rec encodes a member of the mini-chromosome maintenance (MCM) protein family. Six MCM proteins (MCM2–7) are essential for DNA replication and are found in all eukaryotes. REC is the Drosophila ortholog of the recently identified seventh member of this family, MCM8. Our phylogenetic analysis reveals the existence of yet another family member, MCM9, and shows that MCM8 and MCM9 arose early in eukaryotic evolution, though one or both have been lost in multiple eukaryotic lineages. Drosophila has lost MCM9 but retained MCM8, represented by REC. We used genetic and molecular methods to study the function of REC in meiotic recombination. Epistasis experiments suggest that REC acts after the Rad51 ortholog SPN-A but before the endonuclease MEI-9. Although crossovers are reduced by 95% in rec mutants, the frequency of noncrossover gene conversion is significantly increased. Interestingly, gene conversion tracts in rec mutants are about half the length of tracts in wild-type flies. To account for these phenotypes, we propose that REC facilitates repair synthesis during meiotic recombination. In the absence of REC, synthesis does not proceed far enough to allow formation of an intermediate that can give rise to crossovers, and recombination proceeds via synthesis-dependent strand annealing to generate only noncrossover products

Oral vitamin B(12 )therapy in the primary care setting: a qualitative and quantitative study of patient perspectives

BACKGROUND: Although oral replacement with high doses of vitamin B(12 )is both effective and safe for the treatment of B(12 )deficiency, little is known about patients' views concerning the acceptability and effectiveness of oral B(12). We investigated patient perspectives on switching from injection to oral B(12 )therapy. METHODS: This study involved a quantitative arm using questionnaires and a qualitative arm using semi-structured interviews, both to assess patient views on injection and oral therapy. Patients were also offered a six-month trial of oral B(12 )therapy. One hundred and thirty-three patients who receive regular B(12 )injections were included from three family practice units (two hospital-based academic clinics and one community health centre clinic) in Toronto. RESULTS: Seventy-three percent (63/86) of respondents were willing to try oral B(12). In a multivariate analysis, patient factors associated with a "willingness to switch" to oral B(12 )included being able to get to the clinic in less than 30 minutes (OR 9.3, 95% CI 2.2–40.0), and believing that frequent visits to the health care provider (OR 5.4, 95% CI 1.1–26.6) or the increased costs to the health care system (OR 16.7, 95% CI 1.5–184.2) were disadvantages of injection B(12). Fifty-five patients attempted oral therapy and 52 patients returned the final questionnaire. Of those who tried oral therapy, 76% (39/51) were satisfied and 71% (39/55) wished to permanently switch. Factors associated with permanently switching to oral therapy included believing that the frequent visits to the health care provider (OR 35.4, 95% CI 2.9–432.7) and travel/parking costs (OR 8.7, 95% CI 1.2–65.3) were disadvantages of injection B(12). Interview participants consistently cited convenience as an advantage of oral therapy. CONCLUSION: Switching patients from injection to oral B(12 )is both feasible and acceptable to patients. Oral B(12 )supplementation is well received largely due to increased convenience. Clinicians should offer oral B(12 )therapy to their patients who are currently receiving injections, and newly diagnosed B(12)-deficient patients who can tolerate and are compliant with oral medications should be offered oral supplementation

Scientific imperatives, clinical implications, and theoretical underpinnings for the investigation of the relationship between genetic variables and patient-reported quality-of-life outcomes

Objectives There is emerging evidence for a genetic basis of patient-reported quality-of-life (QOL) outcomes that can ultimately be incorporated into clinical research and practice. Objectives are (1) to provide arguments for the timeliness of investigating the genetic basis of QOL given the scientific advances in genetics and patient-reported QOL research; (2) to describe the clinical implications of such investigations; (3) to present a theoretical foundation for investigating the genetic underpinnings of QOL; and (4) to describe a series of papers resulting from the GENEQOL Consortium that was established to move this work forward. Methods Discussion of scientific advances based on relevant literature. Results In genetics, technological advances allow for increases in speed and efficiency and decreases in costs in exploring the genetic underpinnings of disease processes, drug metabolism, treatment response, and survival. In patient-based research, advances yield empirically based and stringent approaches to measurement that are scientifically robust. Insights into the genetic basis of QOL will ultimately allow early identification of patients susceptible to QOL deficits and to target care. The Wilson and Cleary model for patient-reported outcomes was refined by incorporating the genetic underpinnings of QOL. Conclusions This series of papers provides a path for QOL and genetics researchers to work together to move this field forward and to unravel the intricate interplay of the genetic underpinnings of patient-reported QOL outcomes. The ultimate result will be a greater understanding of the process relating disease, patient, and doctor that will have the potential to lead to improved survival, QOL, and health services deliver

Relationship of Optimism and Suicidal Ideation in Three Groups of Patients at Varying Levels of Suicide Risk

Optimism has been associated with reduced suicidal ideation, but there have been few studies in patients at high suicide risk. We analyzed data from three study populations (total N=319) with elevated risk of suicide: (1) patients with a recent acute cardiovascular event, (2) patients hospitalized for heart disease who had depression or an anxiety disorder, and (3) patients psychiatrically hospitalized for suicidal ideation or following a suicide attempt. For each study we analyzed the association between optimism (measured by the Life-Orientation Test-Revised) and suicidal ideation, and then completed an exploratory random effects meta-analysis of the findings to synthesize this data. The meta-analysis of the three studies showed that higher levels of self-reported optimism were associated with a lower likelihood of suicidal ideation (odds ratio [OR]=.89, 95% confidence interval [CI]=.85-.95, z=3.94, pz=3.57, pz=3.61,

The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

10.1371/journal.pone.0075483PLoS ONE810-POLN

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

Alliance of Genome Resources Portal: unified model organism research platform

The Alliance of Genome Resources (Alliance) is a consortium of the major model organism databases and the Gene Ontology that is guided by the vision of facilitating exploration of related genes in human and well-studied model organisms by providing a highly integrated and comprehensive platform that enables researchers to leverage the extensive body of genetic and genomic studies in these organisms. Initiated in 2016, the Alliance is building a central portal (www.alliancegenome.org) for access to data for the primary model organisms along with gene ontology data and human data. All data types represented in the Alliance portal (e.g. genomic data and phenotype descriptions) have common data models and workflows for curation. All data are open and freely available via a variety of mechanisms. Long-term plans for the Alliance project include a focus on coverage of additional model organisms including those without dedicated curation communities, and the inclusion of new data types with a particular focus on providing data and tools for the non-model-organism researcher that support enhanced discovery about human health and disease. Here we review current progress and present immediate plans for this new bioinformatics resource

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival