Trypacidin, a Spore-Borne Toxin from Aspergillus fumigatus, Is Cytotoxic to Lung Cells

Inhalation of Aspergillus fumigatus conidia can cause severe aspergillosis in immunosuppressed people. A. fumigatus produces a large number of secondary metabolites, some of which are airborne by conidia and whose toxicity to the respiratory tract has not been investigated. We found that spores of A. fumigatus contain five main compounds, tryptoquivaline F, fumiquinazoline C, questin, monomethylsulochrin and trypacidin. Fractionation of culture extracts using RP-HPLC and LC-MS showed that samples containing questin, monomethylsulochrin and trypacidin were toxic to the human A549 lung cell line. These compounds were purified and their structure verified using NMR in order to compare their toxicity against A549 cells. Trypacidin was the most toxic, decreasing cell viability and triggering cell lysis, both effects occurring at an IC50 close to 7 µM. Trypacidin toxicity was also observed in the same concentration range on human bronchial epithelial cells. In the first hour of exposure, trypacidin initiates the intracellular formation of nitric oxide (NO) and hydrogen peroxide (H2O2). This oxidative stress triggers necrotic cell death in the following 24 h. The apoptosis pathway, moreover, was not involved in the cell death process as trypacidin did not induce apoptotic bodies or a decrease in mitochondrial membrane potential. This is the first time that the toxicity of trypacidin to lung cells has been reported

A Novel Classification of Lung Cancer into Molecular Subtypes

The remarkably heterogeneous nature of lung cancer has become more apparent over the last decade. In general, advanced lung cancer is an aggressive malignancy with a poor prognosis. The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, however, has created new opportunities for targeted therapy and improved outcome. In this paper, we define “molecular subtypes” of lung cancer based on specific actionable genetic aberrations. Each subtype is associated with molecular tests that define the subtype and drugs that may potentially treat it. We hope this paper will be a useful guide to clinicians and researchers alike by assisting in therapy decision making and acting as a platform for further study. In this new era of cancer treatment, the ‘one-size-fits-all’ paradigm is being forcibly pushed aside—allowing for more effective, personalized oncologic care to emerge

HIV Replication Enhances Production of Free Fatty Acids, Low Density Lipoproteins and Many Key Proteins Involved in Lipid Metabolism: A Proteomics Study

BACKGROUND: HIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood. RESULTS: Since many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism. CONCLUSIONS: We conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways

Creatinine-Iron Complex and Its Use in Electrochemical Measurement of Urine Creatinine

A non-enzymatic electrochemical technique for creatinine sensing is presented, exploiting iron binding property of creatinine. Disposable carbon printed electrodes layered with FeCl3 coated cotton fiber membranes are used to sense creatinine from 10 to 245 mg/dl, on clinical urine samples. The energy-dispersive X-ray spectroscopy analysis confirms the presence of Fe(III) dry chemistry on cotton membrane. Creatinine binding with Fe(III) is verified with UV analysis, with a corresponding decrease in Fe(III) reduction current in cyclic voltammetry. The disposable test strips are interfaced with multi-potentiostat point of care (POC) hand-held device, working in amperometry mode. The results obtained on POC biosensors demonstrate good correlation (R-2 = 0.91) with Jaffe method laboratory gold standard. The intra-assay variability is less than 7.1%. The statistical bias as revealed from the Bland-Altman analysis indicates that the POC results are within 95% confidence interval. This POC device does not require any sample preparation step and provides sample to result in less than a minute. FeCl3 sensing chemistry is robust against urine albumin interference, which is especially significant for accurate estimation of albumin to creatinine ratio. The non-enzymatic nature of disposable test strips results in highly stable and robust operation of the POC device over a large range of temperature variations

The palaeolimnological record from lake Cullulleraine, lower Murray River (south-east Australia): implications for understanding riverine histories

Australia’s largest river system, the Murray-Darling Basin, is the focus of scientific and political attention, due mainly to the competing issues of economic productivity versus environmental flows. Central to this dialogue is the need to know about the Basin’s natural condition and the degree to which the system has deviated from this pre-disturbance, baseline status. This study examines the patterns of ecological change in Lake Cullulleraine, a permanently connected artificial wetland adjacent to Lock Nine on the Murray River, south-east Australia. A 43-cm sediment core was collected in January 1998 and diatoms were analysed at 1-cm intervals for use as aquatic ecological indicators. The sediment core was dated using ²¹⁰Pb. Changes in the diatom community have occurred since the time of lake formation in 1926, particularly shifts between Aulacoseira subborealis, Staurosira construens var. venter, Aulacoseira granulata, Staurosirella pinnata and Pseudostaurosira brevistriata. An electrical conductivity (EC) transfer function was applied to the fossil diatom assemblages and inferred EC values were compared to long-term, historical EC data from the River. Despite the presence of good analogues between fossil and modern diatom assemblages, inferred EC did not reflect measured EC accurately. In recent decades, patterns in the two data sets were reversed. Despite clear changes in the fossil record, quantitative palaeo-environmental interpretation was limited because the dominant taxa occupy broad ecological niches. Despite these limitations, changes in the Lake Cullulleraine record, particularly in the planktonic taxa, can be interpreted in terms of landscape change. Furthermore, because of the good chronology from the site, the record may be useful for dating changes observed in sites with poor chronological control.Jennie Fluin, John Tibby and Peter Gel