Population genomic analysis reveals geographic structure and climatic diversification for Macrophomina phaseolina isolated from soybean and dry bean across the United States, Puerto Rico, and Colombia

Macrophomina phaseolina causes charcoal rot, which can significantly reduce yield and seed quality of soybean and dry bean resulting from primarily environmental stressors. Although charcoal rot has been recognized as a warm climate-driven disease of increasing concern under global climate change, knowledge regarding population genetics and climatic variables contributing to the genetic diversity of M. phaseolina is limited. This study conducted genome sequencing for 95 M. phaseolina isolates from soybean and dry bean across the continental United States, Puerto Rico, and Colombia. Inference on the population structure using 76,981 single nucleotide polymorphisms (SNPs) revealed that the isolates exhibited a discrete genetic clustering at the continental level and a continuous genetic differentiation regionally. A majority of isolates from the United States (96%) grouped in a clade with a predominantly clonal genetic structure, while 88% of Puerto Rican and Colombian isolates from dry bean were assigned to a separate clade with higher genetic diversity. A redundancy analysis (RDA) was used to estimate the contributions of climate and spatial structure to genomic variation (11,421 unlinked SNPs). Climate significantly contributed to genomic variation at a continental level with temperature seasonality explaining the most variation while precipitation of warmest quarter explaining the most when spatial structure was accounted for. The loci significantly associated with multivariate climate were found closely to the genes related to fungal stress responses, including transmembrane transport, glycoside hydrolase activity and a heat-shock protein, which may mediate climatic adaptation for M. phaseolina. On the contrary, limited genome-wide differentiation among populations by hosts was observed. These findings highlight the importance of population genetics and identify candidate genes of M. phaseolina that can be used to elucidate the molecular mechanisms that underly climatic adaptation to the changing climate

Preclinical Evaluation of the Novel, Orally Bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Spontaneous Canine Cancer: Results of a Phase I Study

The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer

The genetic composition of feeding aggregations of the Atlantic mackerel (Scomber scombrus) in the central north Atlantic: a microsatellite loci approach

The impacts of climate change on marine ecosystems can be seen in the changing distribution, migration, and abundance of species in the oceans. For some species this changing environment may be beneficial and can support population expansions. In the northeast Atlantic (NEA), the Atlantic mackerel (Scomber scombrus) is undergoing an increase in stock size accompanied by changing summer migration patterns, which have resulted in an expansion further north and north west than previously recorded. This study uses microsatellite loci to confirm the differentiation among NEA and northwest Atlantic (NWA) mackerel spawning populations and to assess the level of structuring within these populations. In addition, to enable population-specific exploitation rates to be factored into fisheries management, we identified the origin of individuals composing the expanding feeding aggregations in the central north Atlantic (Greenland, Iceland, Faroes), with all aggregations tested originating from spawning populations in the NEA. This study showed that microsatellite loci were useful to assess the contribution of NEA and NWA populations to mixed feeding aggregations across the north Atlantic for large pelagic fish stocks but were not powerful enough to evaluate the specific contribution of known stocks within NEA and NWA

Biologic activity of SINE compounds against canine tumor cell lines.

<p>Canine tumor cell lines C2 (mast cell), OSA16 (osteosarcoma) and 323610-3 were cultured in 96 well plates in triplicate with serial dilutions of KPT-214 for 92 hours after which the plates were collected, media removed, and the plates were frozen at −80°C. Analysis for effects on cell proliferation was then performed using the CyQUANT assay according to the manufacturer’s specifications. Experiments were repeated three times; the IC₅₀ for each cell line is shown.</p

Pharmacokinetics of KPT-335 in healthy dogs.

<p>Pharmacokinetics of KPT-335 in healthy dogs.</p

Constitutional and gastrointestinal toxicities.

<p>Constitutional and gastrointestinal toxicities.</p

Hepatic and hematologic toxicities.

<p>Hepatic and hematologic toxicities.</p

Subject demographics.

<p>Subject demographics.</p

Trends in quality of life in dogs treated with KPT-335.

<p>An overall score was created based on answers to questions on the quality of life questionnaire. The scores from each question were summed resulting in an overall quality of life score which could range from 23 to 115. These are represented graphically in the figure above where scores for each patient are graphed over time (each line represents a patient). Trends in quality of life during the study were examined using linear mixed models. The overall quality of life did not change significantly in dogs treated in either the (A) dose escalation study (p = 0.64) or (B) dose expansion study (p = 0.47).</p

IC₅₀ (± S.D.) of SINE for human and canine lymphoma cells.

<p>IC₅₀, 50% inhibitory concentration; DLBCL, diffuse large B-cell lymphoma;</p><p>NP, not performed.</p