Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This ...unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes. Due to the synthetic complexity of the compound, as well as the low yield from the producing organism, analogs are sought to create synthetically accessible alternatives. As a T-cell lymphoma drug, romidepsin offers a valuable new treatment for diseases with few effective therapies.
Variation in the growing environment can have significant impacts on the quantity and diversity of fungal secondary metabolites. In the industrial setting, optimization of growing conditions can lead ...to significantly increased production of a compound of interest. Such optimization becomes challenging in a drug-discovery screening situation, as the ideal conditions for one organism may induce poor metabolic diversity for a different organism. Here, the impact of different media types, including six liquid media and five solid media, on the secondary metabolite production of three fungal strains was examined in the context of the drug-discovery screening process. The relative production of marker compounds was used to evaluate the usefulness and reliability of each medium for the purpose of producing secondary metabolites.
There is increasing interest among scholars in producing information that is useful and usable to land and natural resource managers in a changing climate. This interest has prompted transitions from ...scientist- to stakeholder-driven or collaborative approaches to climate science. A common indicator of successful collaboration is whether stakeholders use the information resulting from the projects in which they are engaged. However, detailed examples of how stakeholders use climate information are relatively scarce in the literature, leading to a challenge in understanding what researchers can and should expect and plan for in terms of stakeholder use of research findings. Drawing on theoretical, typological, and evaluation insights from the field of information use, we examine stakeholder use of climate information emerging from 13 collaborative climate science projects conducted in the western United States between 2012 and 2016. Three primary types of use emerge from our findings—conceptual, instrumental, and justification—reflecting common typologization of information use. Conceptual use was the most predominant. We suggest that researcher awareness of this typology can enable more systematic understanding of what project outputs stakeholders use and impacts of those outputs, giving way to new areas of inquiry and aiding in the conceptualization and design of climate information products for land and natural resource managers.
Cell division is often regulated by extracellular signaling networks to ensure correct patterning during development. In Arabidopsis, the SHORT-ROOT (SHR)/SCARECROW (SCR) transcription factor dimer ...activates CYCLIND6;1 (CYCD6;1) to drive formative divisions during root ground tissue development. Here, we show plasma-membrane-localized BARELY ANY MERISTEM1/2 (BAM1/2) family receptor kinases are required for SHR-dependent formative divisions and CYCD6;1 expression, but not SHR-dependent ground tissue specification. Root-enriched CLE ligands bind the BAM1 extracellular domain and are necessary and sufficient to activate SHR-mediated divisions and CYCD6;1 expression. Correspondingly, BAM-CLE signaling contributes to the restriction of formative divisions to the distal root region. Additionally, genetic analysis reveals that BAM-CLE and SHR converge to regulate additional cell divisions outside of the ground tissues. Our work identifies an extracellular signaling pathway regulating formative root divisions and provides a framework to explore this pathway in patterning and evolution.
Background Quantitative fetal fibronectin testing has demonstrated accuracy for prediction of spontaneous preterm birth in asymptomatic women with a history of preterm birth. Predictive accuracy in ...women with previous cervical surgery (a potentially different risk mechanism) is not known. Objective We sought to compare the predictive accuracy of cervicovaginal fluid quantitative fetal fibronectin and cervical length testing in asymptomatic women with previous cervical surgery to that in women with 1 previous preterm birth. Study Design We conducted a prospective blinded secondary analysis of a larger observational study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women measured with a Hologic 10Q system (Hologic, Marlborough, MA). Prediction of spontaneous preterm birth (<30, <34, and <37 weeks) with cervicovaginal fluid quantitative fetal fibronectin concentration in primiparous women who had undergone at least 1 invasive cervical procedure (n = 473) was compared with prediction in women who had previous spontaneous preterm birth, preterm prelabor rupture of membranes, or late miscarriage (n = 821). Relationship with cervical length was explored. Results The rate of spontaneous preterm birth <34 weeks in the cervical surgery group was 3% compared with 9% in previous spontaneous preterm birth group. Receiver operating characteristic curves comparing quantitative fetal fibronectin for prediction at all 3 gestational end points were comparable between the cervical surgery and previous spontaneous preterm birth groups (34 weeks: area under the curve, 0.78 95% confidence interval 0.64-0.93 vs 0.71 95% confidence interval 0.64-0.78; P = .39). Prediction of spontaneous preterm birth using cervical length compared with quantitative fetal fibronectin for prediction of preterm birth <34 weeks of gestation offered similar prediction (area under the curve, 0.88 95% confidence interval 0.79-0.96 vs 0.77 95% confidence interval 0.62-0.92, P = .12 in the cervical surgery group; and 0.77 95% confidence interval 0.70-0.84 vs 0.74 95% confidence interval 0.67-0.81, P = .32 in the previous spontaneous preterm birth group). Conclusion Prediction of spontaneous preterm birth using cervicovaginal fluid quantitative fetal fibronectin in asymptomatic women with cervical surgery is valid, and has comparative accuracy to that in women with a history of spontaneous preterm birth.
As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Here we ...explore in vitro gene expression as well receptor binding and enzyme activity as alternative assays to inform on developmental and reproductive toxicity (DART) relevant modes of action, since DART data gaps are common for botanicals. Specifically, botanicals suspected to have DART effects, in addition to those with a significant history of use, were tested in these assays. Gene expression changes in a number of different cell types were analysed using the connectivity mapping approach (CMap) to identify modes of action through a functional read across approach. Taken together with ligand affinity data obtained using a set of molecular targets customised towards known DART relevant modes of action, it was possible to inform DART risk using functional analogues, potency comparisons and a margin of internal exposure approach.
•Botanical mode of action can be informed by high content and high throughput in vitro data.•Orthogonal data streams utilising the CMap approach and affinity for molecular targets underpin confidence in MoA predictions.•DART risk can be inferred using functional analogues, potency comparisons and a margin of internal exposure approach.
Abstract
Background
Coexisting moderate aortic stenosis and regurgitation (MAVD) is common. The haemodynamic effect of MAVD is poorly understood with sparse data to guide risk stratification.
Purpose
...This study aims to compare all-cause mortality in moderate MAVD with matched controls and identify markers associated with prognosis.
Methods
Patients with both moderate aortic stenosis (aortic valve area AVA 1.0-1.5cm2) and regurgitation (vena contracta VC 0.3-0.6cm) were identified from a multicentre registry. All-cause mortality was compared to an age and sex matched UK population. The association between echocardiographic and clinical metrics with all-cause mortality was evaluated.
Results
207 patients were included, age 78 66-84 years and moderate MAVD (AVA 1.2 1.1- 1.4cm2 and VC 0.4 0.4-0.5cm). Over a median follow up of 3.2 years, 75/207 (36.2%) patients died. Patients with moderate MAVD had a significantly higher mortality compared to age and sex matched controls (36% versus 14.3%), p<0.001. Peak aortic jet velocity (Vmax) was the only haemodynamic metric independently associated with mortality hazard ratio (HR): 0.61, 95% confidence interval (CI): 0.39-0.93; p=0.02 in a multivariate model along with age, creatinine and previous cerebrovascular accident. Compared to patients with Vmax >3m/sec, those with Vmax ≤3.0m/s had lower LVEF and stroke volume and a higher mortality (HR: 1.76, 95% CI: 1.10-2.80; p=0.017).
Conclusions
Moderate MAVD is associated with reduced survival compared to age and sex matched controls. Patients with discordant low Vmax ≤3 m/sec, have disproportionately worse outcome and may represent a high risk ‘low flow’ phenotype.Figure 1
Despite growing popularity in dietary supplements, many medicinal mushrooms have not been evaluated for their safe human consumption using modern techniques. The multifaceted approach described here ...relies on five key principles to evaluate the safety of non-culinary fungi for human use: (1) identification by sequencing the nuclear ribosomal internal transcribed spacer (ITS) region (commonly referred to as ITS barcoding), (2) screening an extract of each fungal raw material against a database of known fungal metabolites, (3) comparison of these extracts to those prepared from grocery store-bought culinary mushrooms using UHPLCPDA-ELS-HRMS, (4) review of the toxicological and chemical literature for each fungus, and (5) evaluation of data establishing presence in-market. This weight-of-evidence approach was used to evaluate seven fungal raw materials and determine safe human use for each. Such an approach may provide an effective alternative to conventional toxicological animal studies (or more efficiently identifies when studies are necessary) for the safety assessment of fungal dietary ingredients.
•A weight-of-evidence approach provides an alternative to animal studies for the safety assessment of fungal ingredients.•Positive identification using DNA methods is a critical first step in the safety review of fungal raw material.•Comparing to culinary mushrooms using UHPLC-PDA-ELS-HRMS provides a baseline of innocuous shared components.•When toxicological literature is scarce, in-market data on fungal ingredients can supplement the body of evidence.
PDF
