Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation

Alport syndrome (AS) is a clinically and genetically heterogeneous renal disorder, predominantly affecting the type IV collagen alpha 3/alpha 4/alpha 5 network of the glomerular basement membrane (GBM). AS can be caused by mutations in any of the three genes encoding these type IV collagen chains. The majority of AS families (85%) are X-linked (XL-AS) involving mutations in the COL4A5 gene. Mutations in the COL4A3 and COL4A4 genes cause autosomal recessive AS (AR-AS), accounting for approximately 14% of the cases. Recently, autosomal dominant AS (AD-AS) was linked to the COL4A3/COL4A4 locus in a large family.

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).

Optimizing the balance between false positive and false negative error probabilities of confirmatory methods for the detection of veterinary drug residues

GC-MS data on veterinary drug residues in bovine urine are used for controlling the illegal practice of fattening cattle. According to current detection criteria, peak patterns of preferably four ions should agree within 10 or 20% from a corresponding standard pattern. These criteria are rigid, rather arbitrary and do not match daily practice. A new model, based on multivariate modeling of log peak abundance ratios, provides a theoretical basis for the identification of analytes and optimizes the balance between the avoidance of false positives and false negatives. The performance of the model is demonstrated on data provided by five laboratories, each supplying GC-MS measurements on the detection of clenbuterol, dienestrol and 19 beta-nortestosterone in urine. The proposed model shows a better performance than confirmation by using the current criteria and provides a statistical basis for inspection criteria in terms of error probabilities.

A framework for designing robust food supply chains

After years of emphasis on leanness and responsiveness businesses are now experiencing their vulnerability to supply chain disturbances. Although more literature is appearing on this subject, there is a need for an integrated framework to support the analysis and design of robust food supply chains. In this chapter we present such a framework. We define the concept of robustness and classify supply chain disturbances, sources of food supply chain vulnerability, and adequate redesign principles and strategies to achieve robust supply chain performances. To test and illustrate its applicability, the research framework is applied to a meat supply chain.

Using vulnerability performance indicators to attain food supply chain robustness

High effectiveness and leanness of modern supply chains (SCs) increase their vulnerability, i.e. susceptibility to disturbances reflected in non-robust SC performances. Both the SC management literature and SC professionals indicate the need for the development of SC vulnerability assessment tools. In this article, a new method for vulnerability assessment, the VULA method, is presented. The VULA method helps to identify how much a company would underperform on a specific Key Performance Indicator in the case of a disturbance, how often this would happen and how long it would last. It ultimately informs the decision about whether process redesign is appropriate and what kind of redesign strategies should be used in order to increase the SC's robustness. The applicability of the VULA method is demonstrated in the context of a meat SC using discrete-event simulation to conduct the performance analysis.

Atomic harmonic generation in time-dependent R-matrix theory

We have developed the capability to determine accurate harmonic spectra for multielectron atoms within time-dependent R-matrix (TDRM) theory. Harmonic spectra can be calculated using the expectation value of the dipole length, velocity, or acceleration operator. We assess the calculation of the harmonic spectrum from He irradiated by 390-nm laser light with intensities up to 4 x 10(14) W cm(-2) using each form, including the influence of the multielectron basis used in the TDRM code. The spectra are consistent between the different forms, although the dipole acceleration calculation breaks down at lower harmonics. The results obtained from TDRM theory are compared with results from the HELIUM code, finding good quantitative agreement between the methods. We find that bases which include pseudostates give the best comparison with the HELIUM code, but models comprising only physical orbitals also produce accurate results.

Multi-Modal CTL:Completeness, Complexity, and an Application

We define a multi-modal version of Computation Tree Logic (ctl) by extending the language with path quantifiers E and A where d denotes one of finitely many dimensions, interpreted over Kripke structures with one total relation for each dimension. As expected, the logic is axiomatised by taking a copy of a ctl axiomatisation for each dimension. Completeness is proved by employing the completeness result for ctl to obtain a model along each dimension in turn. We also show that the logic is decidable and that its satisfiability problem is no harder than the corresponding problem for ctl. We then demonstrate how Normative Systems can be conceived as a natural interpretation of such a multi-dimensional ctl logic. © 2009 Springer Science+Business Media B.V.

Climate-related changes in peatland carbon accumulation during the last millennium

Peatlands are a major terrestrial carbon store and a persistent natural carbon sink during the Holocene, but there is considerable uncertainty over the fate of peatland carbon in a changing climate. It is generally assumed that higher temperatures will increase peat decay, causing a positive feedback to climate warming and contributing to the global positive carbon cycle feedback. Here we use a new extensive database of peat profiles across northern high latitudes to examine spatial and temporal patterns of carbon accumulation over the past millennium. Opposite to expectations, our results indicate a small negative carbon cycle feedback from past changes in the long-term accumulation rates of northern peatlands. Total carbon accumulated over the last 1000 yr is linearly related to contemporary growing season length and photosynthetically active radiation, suggesting that variability in net primary productivity is more important than decomposition in determining long-term carbon accumulation. Furthermore, northern peatland carbon sequestration rate declined over the climate transition from the Medieval Climate Anomaly (MCA) to the Little Ice Age (LIA), probably because of lower LIA temperatures combined with increased cloudiness suppressing net primary productivity. Other factors including changing moisture status, peatland distribution, fire, nitrogen deposition, permafrost thaw and methane emissions will also influence future peatland carbon cycle feedbacks, but our data suggest that the carbon sequestration rate could increase over many areas of northern peatlands in a warmer future.

Influence of multiple ionization thresholds on harmonic generation from Ar+

We apply time-dependent R-matrix theory to investigate harmonic generation from ground-state Ar+ with M = 0 at a wavelength of 390 nm. Contributions associated with the different 3s(2)3p(4) ionization thresholds are assessed, including the interference between these. The dominant contribution originates from the second ionization threshold, 3s(2)3p(4 1)D. Changes to the harmonic yields arising from the higher 3s3p(5) thresholds are also assessed. We further confirm that Ar+ has a higher harmonic yield than He for the same laser pulse, despite having a higher ionization threshold. 

Fumonisin B-1 as a Urinary Biomarker of Exposure in a Maize Intervention Study Among South African Subsistence Farmers

Background: The consumption of maize highly contaminated with carcinogenic fumonisins has been linked to high oesophageal cancer rates. The aim of this study was to validate a urinary fumonisin B-1 (UFB1) biomarker as a measure of fumonisin exposure and to investigate the reduction in exposure following a simple and culturally acceptable intervention.

Methods: At baseline home-grown maize, maize-based porridge, and first-void urine samples were collected from female participants (n = 22), following their traditional food practices in Centane, South Africa. During intervention the participants were trained to recognize and remove visibly infected kernels, and to wash the remaining kernels. Participants consumed the porridge prepared from the sorted and washed maize on each day of the two-day intervention. Porridge, maize, and urine samples were collected for FB1 analyses.

Results: The geometric mean (95% confidence interval) for FB1 exposure based on porridge (dry weight) consumption at baseline and following intervention was 4.84 (2.87-8.14) and 1.87 (1.40-2.51) mg FB1/kg body weight/day, respectively, (62% reduction, P < 0.05). UFB1C, UFB1 normalized for creatinine, was reduced from 470 (295-750) at baseline to 279 (202-386) pg/mg creatinine following intervention (41% reduction, P = 0.06). The UFB1C biomarker was positively correlated with FB1 intake at the individual level (r - 0.4972, P < 0.01). Urinary excretion of FB1 was estimated to be 0.075% (0.054%-0.104%) of the FB1 intake.

Conclusion: UFB1 reflects individual FB1 exposure and thus represents a valuable biomarker for future fumonisin risk assessment.

Impact: The simple intervention method, hand sorting and washing, could positively impact on food safety and health in communities exposed to fumonisins. Cancer Epidemiol Biomarkers Prev; 20(3); 483-9. (C)2011 AACR.

Optimising sorting and washing of home-grown maize to reduce fumonisin contamination under laboratory-controlled conditions

Subsistence farming communities with low socio-economic status reliant on a mono cereal maize diet are exposed to fumonisin levels that exceed the provisional maximum tolerable daily intake of 2 mu g kg(-1) body weight day(-1) recommended by the Joint FAO/WHO Expert Committee on Food Additives. In the rural Centane magisterial district, Eastern Cape Province, South Africa, it is customary during food preparation to sort visibly infected maize kernels from good maize kernels and to wash the good kernels prior to cooking. However, this customary practice seems not to sufficiently reduce the fumonisin levels. This is the first study to optimise the reduction of fumonisin mycotoxins in home-grown maize based on customary methods of a rural population, under laboratory-controlled conditions. Maize obtained from subsistence farmers was analysed for the major naturally occurring fumonisins (FB1, FB2 and FB3) by fluorescence HPLC. Large variations were observed in the unsorted and the experimental maize batches attributable to the non-homogeneous distribution of fumonisin contamination in maize kernels. Optimised hand-sorting of maize kernels by removing the visibly infected/damaged kernels (fumonisins, 53.7 +/- 15.0 mg kg(-1), 2.5% by weight) reduced the mean fumonisins from 2.32 +/- 1.16 mg kg(-1) to 0.68 +/- 0.42 mg kg(-1). Hand washing of the sorted good maize kernels for a period of 10 min at 25 degrees C resulted in optimal reduction with no additional improvement for wash periods up to 15 h. The laboratory optimised sorting reduced the fumonisins by 71 +/- 18% and an additional 13 +/- 12% with the 10 min wash. Based on these results and on local practices and practicalities the protocol that would be recommended to subsistence farmers consists of the removal of the infected/damaged kernels from the maize followed by a 10 min ambient temperature water wash. (C) 2010 Elsevier Ltd. All rights reserved.

Simple intervention method to reduce fumonisin exposure in a subsistence maize-farming community in South Africa

In the Centane magisterial area of South Africa, high rates of oesophageal cancer have been associated with home-grown maize contaminated with fumonisins. The aim of this study was to implement a simple intervention method to reduce fumonisin exposure in a subsistence-farming community. The hand-sorting and washing procedures, based on traditional maize-based food preparation practices, were previously customised under laboratory-controlled conditions. Home-grown maize and maize-based porridge collected at baseline were analysed for fumonisin B1, B2 and B3. The geometric mean (95% confidence interval) of fumonisin contamination in the home-grown maize at baseline was 1.67 (1.21-2.32) mg kg-1 and 1.24 (0.75-2.04) mg kg -1 (dry weight) in the porridge. Fumonisin exposure was based on individual stiff porridge consumption and the specific fumonisin levels in the porridge (dry weight) consumed. Porridge (dry weight) consumption at baseline was 0.34 kg day-1 and fumonisin exposure was 6.73 (3.90-11.6) mu g kg-1 body weight day-1. Female participants (n = 22) were trained to recognise and remove visibly infected/damaged kernels and to wash the remaining maize kernels. The discarded kernels represented 3.9% by weight and the fumonisins varied from 17.1 to 76.9 mg kg-1. The customised hand-sorting and washing procedures reduced fumonisin contamination in the maize and porridge by 84 and 65%, respectively. The intervention reduced fumonisin exposure by 62% to 2.55 (1.94-3.35) mu g kg-1 body weight day-1. This simple intervention method has the potential to improve food safety and health in subsistence-farming communities consuming fumonisin-contaminated maize as their staple diet.