The availability of entire genome sequences has triggered the development of microarrays for clinical diagnostics that measure the expression levels of specific genes. Methods that involve labelling ...can achieve picomolar detection sensitivity, but they are costly, labour-intensive and time-consuming. Moreover, target amplification or biochemical labelling can influence the original signal. We have improved the biosensitivity of label-free cantilever-array sensors by orders of magnitude to detect mRNA biomarker candidates in total cellular RNA. Differential gene expression of the gene 1-8U, a potential marker for cancer progression or viral infections, has been observed in a complex background. The measurements provide results within minutes at the picomolar level without target amplification, and are sensitive to base mismatches. This qualifies the technology as a rapid method to validate biomarkers that reveal disease risk, disease progression or therapy response. We foresee cantilever arrays being used as a tool to evaluate treatment response efficacy for personalized medical diagnostics.
We report the specific transduction, via surface stress changes, of DNA hybridization and receptor-ligand binding into a direct nanomechanical response of microfabricated cantilevers. Cantilevers in ...an array were functionalized with a selection of biomolecules. The differential deflection of the cantilevers was found to provide a true molecular recognition signal despite large nonspecific responses of individual cantilevers. Hybridization of complementary oligonucleotides shows that a single base mismatch between two 12-mer oligonucleotides is clearly detectable. Similar experiments on protein A-immunoglobulin interactions demonstrate the wide-ranging applicability of nanomechanical transduction to detect biomolecular recognition.
In mammals, excess energy is stored primarily as triglycerides, which are mobilized when energy demands arise and cannot be covered by feed intake. This review mainly focuses on the role of long ...chain fatty acids in disturbed energy metabolism of the bovine species. Long chain fatty acids regulate energy metabolism as ligands of peroxisome proliferator-activated receptors. Carnitine acts as a carrier of fatty acyl groups as long-chain acyl-CoA derivatives do not penetrate the mitochondrial inner membrane. There are two different types of disorders in lipid metabolism which can occur in cattle, namely the hypoglycaemic-hypoinsulinaemic and the hyperglycaemic-hyperinsulinaemic type with the latter not always associated with ketosis. There is general agreement that fatty acid β-oxidation capability is limited in the liver of (ketotic) cows. In accord, supplemental L-carnitine decreased liver lipid accumulation in periparturient Holstein cows. Of note, around parturition concurrent oxidation of fatty acids in skeletal muscle is highly activated. Also peroxisomal β-oxidation in liver of dairy cows may be part of the hepatic adaptations to a negative energy balance (NEB) to break down fatty acids. An elevated blood concentration of nonesterified fatty acids is one of the indicators of NEB in cattle among others like increased β-hydroxy butyrate concentration, and decreased concentrations of glucose, insulin, and insulin-like growth factor-I. Assuming that liver carnitine concentrations might limit hepatic fatty acid oxidation capacity in dairy cows, further study of the role of acyl-CoA dehydrogenases and/or riboflavin in bovine ketosis is warranted.
The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of ...scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.
With the second highest gross domestic product in Africa, South Africa is known to have a high pesticide usage, including the highly persistent and banned group of organochlorine pesticides (OCPs). ...South Africa is also one of few countries to still actively spray DDT as malaria vector control. The aim of the study was to determine the degree to which aquatic biota in selected rivers of the world renowned Kruger National Park (KNP) are exposed to by use of OCPs in the catchments outside the KNP and how this exposure relates to human health. Tigerfish (Hydrocynus vittatus) are economically important apex predators and was selected as bioindicator for this study. Fish were sampled from the KNP sections of the Luvuvhu, Letaba and Olifants rivers during the high and low flow periods from 2010 to 2011 within the KNP and 19 OCPs were determined in muscle tissue using GC-ECD techniques. Significant flow related and spatial OCP bioaccumulation was observed. Tigerfish from the Luvuvhu River displayed the highest OCP bioaccumulation. Concentrations of the majority of the OCPs including the DDTs were the highest levels ever recorded from South African freshwater systems and in many cases the concentrations were higher than most contaminated areas from around the world. The concentrations found in H. vittatus muscle also exceeded maximum residue levels in edible fat as set by the European Union. The health risk assessment also demonstrated that the levels of OCPs pose very high cancer risks to the local populations consuming tigerfish, as high as 2 in 10 increased risk factor. This is of concern not only when managing the water resources of the conservation area but also for surrounding communities consuming freshwater fish. Contaminants enter the park from outside the borders and pose potential risks to the mandated conservation of aquatic biota within the KNP.
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•First record of OCPs in top predator tigerfish from rivers in Kruger National Park•Pesticides used for vector control bioaccumulate at very high levels in fish from conservation areas•Both rivers flowing through the Kruger National Park are polluted by OCPs originating from the catchment.•OCP bioaccumulation is the highest reported for Africa.•Significant human cancer risk is associated with the consumption of fish from these rivers.
•South Africa's largest floodplain not been assessed for OCPs for three decades.•High OCP concentration found in other aquatic ecosystems of eastern South Africa.•OCPs and stable isotopes assessed in ...ecologically and economically important fishes.•High levels of γ-HCH (Lindane) in all species sampled•Trophic transfer of DDT demonstrated major ecological and human health risks.
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Anthropogenic activities, including combustion of fossil fuels, coal, and gold mining, are significant sources of mercury (Hg) emissions into aquatic ecosystems. South Africa is a major contributor ...to global Hg emissions (46.4 tons Hg in 2018), with coal-fired power stations as the main source. Atmospheric transport of Hg emissions is the dominant cause of contamination, especially on the east coast of southern Africa where the Phongolo River Floodplain (PRF) is located. The PRF is the largest floodplain system in South Africa, with unique wetlands and high biodiversity, and provides essential ecosystem services to local communities who rely on fish as a protein source. We assessed the bioaccumulation of Hg in various biota, the trophic positions and food webs, as well as the biomagnification of Hg through the food webs in the PRF. Elevated Hg concentrations were found in sediments, macroinvertebrates and fish from the main rivers and associated floodplains in the PRF. Mercury biomagnification was observed through the food webs, with the apex predator tigerfish, Hydrocynus vittatus, having the highest Hg concentration. Our study shows that Hg in the PRF is bioavailable, accumulates in biota and biomagnifies in food webs.
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•First study to report Hg in different matrices in South Africa's largest floodplain.•Bioaccumulation and biomagnification associated with Hg in rivers and wetlands.•Trophic magnification occurred with highest Hg levels in apex predator H. vittatus.•Changes in tropic position in intraspecific species among sampling sites.•Aerial deposition major contributor of elevated Hg levels in Phongolo River Floodplain.
Global declines in elasmobranch populations resulting from several stressors raises conservation concern. Additionally, apex predators bioaccumulate high concentrations of total mercury (THg), due to ...biomagnification. Although South Africa is considered one of the top ten contributors of Hg emissions globally, information on Hg concentrations in elasmobranchs is limited. The aim of this study was to evaluate the THg concentrations in 22 species of elasmobranchs along the South African coastline. Concentrations ranged between 0.22 and 5.8 mg/kg in Haploblepharus pictus (dark shysharks) and Rostroraja alba (white skates) on the south coast, respectively. Along the east coast it ranged between 0.21 and 17.8 mg/kg in Mobula kuhlii (shortfin devil rays) and Sphyrna lewini (scalloped hammerheads), respectively. Mercury concentrations on the east coast were in the same range or higher compared to the same species sampled between 2005–10 from the same region, with generally higher concentrations compared to the same species sampled globally.
•East coast THg concentrations are higher than the south coast of South Africa.•Higher trophic position elasmobranchs exhibit higher THg concentrations.•Foraging depth did not play a significant role in THg bioaccumulation.•Current THg concentrations are higher than those reported in 2005–10.•Highest THg concentrations for Sphyrna lewini reported globally
In the RIP1-Tag2 mouse model of pancreatic islet carcinoma, angiogenesis is switched on in a discrete premalignant stage of tumor development, persisting thereafter. Signaling through VEGF receptor ...tyrosine kinases is a well-established component of angiogenic regulation. We show that five VEGF ligand genes are expressed in normal islets and throughout islet tumorigenesis. To begin dissecting their contributions, we produced an islet β cell specific knockout of VEGF-A, resulting in islets with reduced vascularity but largely normal physiology. In RIP1-Tag2 mice wherein most oncogene-expressing cells had deleted the VEGF-A gene, both angiogenic switching and tumor growth were severely disrupted, as was the neovasculature. Thus, VEGF-A is crucial for angiogenesis in a prototypical model of carcinogenesis, whose loss is not readily compensated.
The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients ...with advanced NSCLC.
Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models.
A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate.
Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.
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