Natural variation and dosage of the HEI10 meiotic E3 ligase control Arabidopsis crossover recombination

During meiosis, homologous chromosomes undergo crossover recombination, which creates genetic diversity and balances homolog segregation. Despite these critical functions, crossover frequency varies extensively within and between species. Although natural crossover recombination modifier loci have been detected in plants, causal genes have remained elusive. Using natural Arabidopsis thaliana accessions, we identified two major recombination quantitative trait loci (rQTLs) that explain 56.9% of crossover variation in ColxLer F2 populations. We mapped rQTL1 to semidominant polymorphisms in HEI10, which encodes a conserved ubiquitin E3 ligase that regulates crossovers. Null hei10 mutants are haploinsufficient, and, using genome-wide mapping and immunocytology, we show that transformation of additional HEI10 copies is sufficient to more than double euchromatic crossovers. However, heterochromatic centromeres remained recombination-suppressed. The strongest HEI10-mediated crossover increases occur in subtelomeric euchromatin, which is reminiscent of sex differences in Arabidopsis recombination. Our work reveals that HEI10 naturally limits Arabidopsis crossovers and has the potential to influence the response to selection

Structure and magnetism in the bond-frustrated spinel ZnCr2Se4ZnCr_2Se_4

The crystal and magnetic structures of stoichiometric $ZnCr_2Se_4$ have been investigated using synchrotron x-ray and neutron powder diffraction, muon spin relaxation ($μSR$), and inelastic neutron scattering. Synchrotron x-ray diffraction shows a spin-lattice distortion from the cubic $Fd\bar3m$ spinel to a tetragonal $I4_1/amd$ lattice below $T_N = 21 K$, where powder neutron diffraction confirms the formation of a helical magnetic structure with magnetic moment of $3.04(3) μ_B$ at 1.5 K, close to that expected for high-spin $Cr^{3+}$. $μSR$ measurements show prominent local spin correlations that are established at temperatures considerably higher (100 μs^{-1}\)) muon relaxation rates are suggestive of rapid site hopping of the muons in static field. Inelastic neutron scattering measurements show a gapless mode at an incommensurate propagation vector of k = [000.4648(2)] in the low-temperature magnetic ordered phase that extends to 0.8 meV. The dispersion is modeled by a two-parameter Hamiltonian, containing ferromagnetic nearest-neighbor and antiferromagnetic next-nearest-neighbor interactions with a $J_{nnn}/J_{nn} = -0.337$

Investigating the role of the interleukin-23/-17A axis in rheumatoid arthritis

Objective. IL-23 is a pro-inflammatory cytokine proposed to be central to the development of autoimmune disease. We investigated whether IL-23, together with the downstream mediator IL-17A, was present and functional in RA in humans

Positioning pharmacists’ roles in primary health care: a discourse analysis of the compensation plan in Alberta, Canada

Abstract Background A comprehensive Compensation Plan for pharmacy services delivered by community pharmacists was implemented in Alberta, Canada in July 2012. Services covered by the Compensation Plan include care planning services, prescribing services such as adapting prescriptions, and administering a drug or publicly-funded vaccine by injection. Understanding how the Compensation Plan was framed and communicated provides insight into the roles of pharmacists and the potential influence of language on the implementation of services covered by the Compensation Plan by Albertan pharmacists. The objective of this study is to examine the positioning of pharmacists’ roles in documents used to communicate the Compensation Plan to Albertan pharmacists and other audiences. Methods Publicly available documents related to the Compensation Plan, such as news releases or reports, published between January 2012 and December 2015 were obtained from websites such as the Government of Alberta, Alberta Blue Cross, the Alberta College of Pharmacists, the Alberta Pharmacists’ Association, and the Blueprint for Pharmacy. Searches of the Canadian Newsstand database and Google identified additional documents. Discourse analysis was performed using social positioning theory to explore how pharmacists’ roles were constructed in communications about the Compensation Plan. Results In total, 65 publicly available documents were included in the analysis. The Compensation Plan was put forward as a framework for payment for professional services and formal legitimization of pharmacists’ changing professional roles. The discourse associated with the Compensation Plan positioned pharmacists’ roles as: (1) expanding to include services such as medication management for chronic diseases, (2) contributing to primary health care by providing access to services such as prescription renewals and immunizations, and (3) collaborating with other health care team members. Pharmacists’ changing roles were positioned in alignment with the aims of primary health care. Conclusions Social positioning theory provides a useful lens to examine the dynamic and evolving roles of pharmacists. This study provides insight into how communications regarding the Compensation Plan in Alberta, Canada positioned pharmacists’ changing roles in the broader context of changes to primary health care delivery. Our findings may be useful for other jurisdictions considering implementation of remunerated clinical services provided by pharmacists

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.</p> <p>Methods</p> <p>In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the <it>NBN </it>gene in our cohort of 97 high-risk non-<it>BRCA1 </it>and -<it>BRCA2 </it>breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. <it>In silico </it>programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.</p> <p>Results</p> <p>Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.</p> <p>Conclusion</p> <p>Our analysis of <it>NBN </it>sequence variations indicated that potential <it>NBN </it>alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in <it>NBN </it>promoter region.</p

Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>NBS1 is a key DNA repair protein in the homologous recombination repair pathway and a signal modifier in the intra-S phase checkpoint that plays important roles in maintaining genomic stability. The <it>NBS1 </it>8360G>C (<it>Glu185Gln</it>) is one of the most commonly studied polymorphisms of the gene for their association with risk of cancers, but the results are conflicting.</p> <p>Methods</p> <p>We performed a meta-analysis using 16 eligible case-control studies (including 17 data sets) with a total of 9,734 patients and 10,325 controls to summarize the data on the association between the <it>NBS1 </it>8360G>C (E185Q) polymorphism and cancer risk.</p> <p>Results</p> <p>Compared with the common 8360GG genotype, the carriers of variant genotypes (i.e., 8360 GC/CC) had a 1.06-fold elevated risk of cancer (95% CI = 1.00–1.12, <it>P </it>= 0.05) in a dominant genetic model as estimated in a fixed effect model. However, the association was not found in an additive genetic model (CC <it>vs </it>GG) (odds ratio, OR = 0.98, 95% CI = 0.85–1.13, <it>P </it>= 0.78) nor in a recessive genetic model (CC <it>vs </it>GC +GG) (OR = 0.94, 95% CI = 0.82–1.07, <it>P </it>= 0.36). The effect of the 8360G>C (E185Q) polymorphism was further evaluated in stratification analysis. It was demonstrated that the increased risk of cancer associated with 8360G>C variant genotypes was more pronounced in the Caucasians (OR = 1.07, 95% CI = 1.01–1.14, <it>P </it>= 0.03).</p> <p>Conclusion</p> <p>Our meta-analysis suggests that the <it>NBS1 </it>E185Q variant genotypes (8360 <it>GC/CC</it>) might be associated with an increased risk of cancer, especially in Caucasians.</p

Investigation of Griffithsin's Interactions with Human Cells Confirms Its Outstanding Safety and Efficacy Profile as a Microbicide Candidate

Many natural product-derived lectins such as the red algal lectin griffithsin (GRFT) have potent in vitro activity against viruses that display dense clusters of oligomannose N-linked glycans (NLG) on their surface envelope glycoproteins. However, since oligomannose NLG are also found on some host proteins it is possible that treatment with antiviral lectins may trigger undesirable side effects. For other antiviral lectins such as concanavalin A, banana lectin and cyanovirin-N (CV-N), interactions between the lectin and as yet undescribed cellular moieties have been reported to induce undesirable side effects including secretion of inflammatory cytokines and activation of host T-cells. We show that GRFT, unlike CV-N, binds the surface of human epithelial and peripheral blood mononuclear cells (PBMC) through an exclusively oligosaccharide-dependent interaction. In contrast to several other antiviral lectins however, GRFT treatment induces only minimal changes in secretion of inflammatory cytokines and chemokines by epithelial cells or human PBMC, has no measureable effect on cell viability and does not significantly upregulate markers of T-cell activation. In addition, GRFT appears to retain antiviral activity once bound to the surface of PBMC. Finally, RNA microarray studies show that, while CV-N and ConA regulate expression of a multitude of cellular genes, GRFT treatment effects only minimal alterations in the gene expression profile of a human ectocervical cell line. These studies indicate that GRFT has an outstanding safety profile with little evidence of induced toxicity, T-cell activation or deleterious immunological consequence, unique attributes for a natural product-derived lectin

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

<p>Abstract</p> <p>Background</p> <p>Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.</p> <p>Methods</p> <p>We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].</p> <p>Results</p> <p>The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.</p> <p>Conclusion</p> <p>Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.</p

Single-lens mass measurement in the high-magnification microlensing event Gaia 19bld located in the Galactic disc

CONTEXT: Microlensing provides a unique opportunity to detect non-luminous objects. In the rare cases that the Einstein radius θ_{E} and microlensing parallax π_{E} can be measured, it is possible to determine the mass of the lens. With technological advances in both ground- and space-based observatories, astrometric and interferometric measurements are becoming viable, which can lead to the more routine determination of θ_{E} and, if the microlensing parallax is also measured, the mass of the lens. AIMS: We present the photometric analysis of Gaia19bld, a high-magnification (A ≈ 60) microlensing event located in the southern Galactic plane, which exhibited finite source and microlensing parallax effects. Due to a prompt detection by the Gaia satellite and the very high brightness of I = 9.05 mag at the peak, it was possible to collect a complete and unique set of multi-channel follow-up observations, which allowed us to determine all parameters vital for the characterisation of the lens and the source in the microlensing event. METHODS: Gaia19bld was discovered by the Gaia satellite and was subsequently intensively followed up with a network of ground-based observatories and the Spitzer Space Telescope. We collected multiple high-resolution spectra with Very Large Telescope (VLT)/X-shooter to characterise the source star. The event was also observed with VLT Interferometer (VLTI)/PIONIER during the peak. Here we focus on the photometric observations and model the light curve composed of data from Gaia, Spitzer, and multiple optical, ground-based observatories. We find the best-fitting solution with parallax and finite source effects. We derived the limit on the luminosity of the lens based on the blended light model and spectroscopic distance. RESULTS: We compute the mass of the lens to be 1.13 ± 0.03 M_{⊙} and derive its distance to be 5.52_{−0.64}^{+0.35} kpc. The lens is likely a main sequence star, however its true nature has yet to be verified by future high-resolution observations. Our results are consistent with interferometric measurements of the angular Einstein radius, emphasising that interferometry can be a new channel for determining the masses of objects that would otherwise remain undetectable, including stellar-mass black holes