Investigating the Use of Support Vector Machine Classification on Structural Brain Images of Preterm–Born Teenagers as a Biological Marker

Preterm birth has been shown to induce an altered developmental trajectory of brain structure and function. With the aid support vector machine (SVM) classification methods we aimed to investigate whether MRI data, collected in adolescence, could be used to predict whether an individual had been born preterm or at term. To this end we collected T1–weighted anatomical MRI data from 143 individuals (69 controls, mean age 14.6y). The inclusion criteria for those born preterm were birth weight ≤ 1500g and gestational age < 37w. A linear SVM was trained on the grey matter segment of MR images in two different ways. First, all the individuals were used for training and classification was performed by the leave–one–out method, yielding 93% correct classification (sensitivity = 0.905, specificity = 0.942). Separately, a random half of the available data were used for training twice and each time the other, unseen, half of the data was classified, resulting 86% and 91% accurate classifications. Both gestational age (R = –0.24, p<0.04) and birth weight (R = –0.51, p < 0.001) correlated with the distance to decision boundary within the group of individuals born preterm. Statistically significant correlations were also found between IQ (R = –0.30, p < 0.001) and the distance to decision boundary. Those born small for gestational age did not form a separate subgroup in these analyses. The high rate of correct classification by the SVM motivates further investigation. The long–term goal is to automatically and non–invasively predict the outcome of preterm–born individuals on an individual basis using as early a scan as possible

Germline tp53 testing in breast cancers: Why, when and how?

Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first-or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.D.G.E. and E.R.W. are supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007)

Phase-Changing Glauber Salt Solution for Medical Applications in the 28-32 °C Interval

(1) Background: The field of medicine requires simple cooling materials. However, there is little knowledge documented about phase change materials (PCM) covering the range of 28 to 40 degrees Celsius, as needed for medical use. Induced mild hypothermia, started within 6 h after birth, is an emerging therapy for reducing death and severe disabilities in asphyxiated infants. Currently, this hypothermia is accomplished with equipment that needs a power source and a liquid supply. Neonatal cooling is more frequent in low-resource settings, where ~1 million deaths are caused by birth-asphyxia. (2) Methods: A simple and safe cooling method suitable for medical application is needed for the 28 to 37.5 °C window. (3) Results: Using empirical experiments in which the ingredients in Glauber salt were changed, we studied the effects of temperature on material in the indicated temperature range. The examination, in a controlled manner, of different mixtures of NaCl, Na2SO4 and water resulted in a better understanding of how the different mixtures act and how to compose salt solutions that can satisfy clinical cooling specifications. (4) Conclusions: Our Glauber salt solution is a clinically suited PCM in the temperature interval needed for the cooling of infants suffering from asphyxia

Effects of Preterm Birth on Cortical Thickness Measured in Adolescence

Despite the extensive research into brain development after preterm birth, few studies have investigated its long-term effects on cortical thickness. The Stockholm Neonatal Project included infants between 1988 and 1993 with birth weight (BW) ≤1500 g. Using a previously published method, cortical thickness was estimated on T1-weighted 3D anatomical images acquired from 74 ex-preterm and 69 term-born adolescents (mean age 14.92 years). The cortex was significantly thinner in ex-preterm individuals in focal regions of the temporal and parietal cortices as indicated by voxel-wise t-tests. In addition, large regions around the central sulcus and temporal lobe as well as parts of the frontal and occipital lobes tended also to be thinner in the ex-preterm group. Although these results were not significant on voxel-wise tests, the spatially coherent arrangement of the thinning in ex-preterm individuals made it notable. When the group of ex-preterm individuals was divided by gestational age or BW, the thinning tended to be more pronounced in the anterior and posterior poles in those born nearer term or with a BW closer to 1500 g. These results support the notion that preterm birth is a risk factor for long-term development of cortical thickness

Characterization of variable EST SSR markers for Norway spruce (Picea abies L.)

<p>Abstract</p> <p>Background</p> <p>Norway spruce is widely distributed across Europe and the predominant tree of the Alpine region. Fast growth and the fact that timber can be harvested cost-effectively in relatively young populations define its status as one of the economically most important tree species of Northern Europe. In this study, EST derived simple sequence repeat (SSR) markers were developed for the assessment of putative functional diversity in Austrian Norway spruce stands.</p> <p>Results</p> <p>SSR sequences were identified by analyzing 14,022 publicly available EST sequences. Tri-nucleotide repeat motifs were most abundant in the data set followed by penta- and hexa-nucleotide repeats. Specific primer pairs were designed for sixty loci. Among these, 27 displayed polymorphism in a testing population of 16 <it>P. abies </it>individuals sampled across Austria and in an additional screening population of 96 <it>P. abies </it>individuals from two geographically distinct Austrian populations. Allele numbers per locus ranged from two to 17 with observed heterozygosity ranging from 0.075 to 0.99.</p> <p>Conclusions</p> <p>We have characterized variable EST SSR markers for Norway spruce detected in expressed genes. Due to their moderate to high degree of variability in the two tested screening populations, these newly developed SSR markers are well suited for the analysis of stress related functional variation present in Norway spruce populations.</p

Genic Microsatellite Markers in Brassica rapa: Development, Characterization, Mapping, and Their Utility in Other Cultivated and Wild Brassica Relatives

Genic microsatellite markers, also known as functional markers, are preferred over anonymous markers as they reveal the variation in transcribed genes among individuals. In this study, we developed a total of 707 expressed sequence tag-derived simple sequence repeat markers (EST-SSRs) and used for development of a high-density integrated map using four individual mapping populations of B. rapa. This map contains a total of 1426 markers, consisting of 306 EST-SSRs, 153 intron polymorphic markers, 395 bacterial artificial chromosome-derived SSRs (BAC-SSRs), and 572 public SSRs and other markers covering a total distance of 1245.9 cM of the B. rapa genome. Analysis of allelic diversity in 24 B. rapa germplasm using 234 mapped EST-SSR markers showed amplification of 2 alleles by majority of EST-SSRs, although amplification of alleles ranging from 2 to 8 was found. Transferability analysis of 167 EST-SSRs in 35 species belonging to cultivated and wild brassica relatives showed 42.51% (Sysimprium leteum) to 100% (B. carinata, B. juncea, and B. napus) amplification. Our newly developed EST-SSRs and high-density linkage map based on highly transferable genic markers would facilitate the molecular mapping of quantitative trait loci and the positional cloning of specific genes, in addition to marker-assisted selection and comparative genomic studies of B. rapa with other related species

A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI

Neuronal networks provide rapid neuroprotection against spreading toxicity

Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients. Here, using hippocampal neurons (DIV 15-20) cultured in microfluidic devices in order to deliver a localized excitotoxic insult, we replicate secondary spreading toxicity and demonstrate that this process is driven by GluN2B receptors. In addition to the modeling of spreading toxicity, this approach has uncovered a previously unknown, fast acting, GluN2A-dependent neuroprotective signaling mechanism. This mechanism utilizes the innate capacity of surrounding neuronal networks to provide protection against both forms of spreading neuronal toxicity, synaptic hyperactivity and direct glutamate excitotoxicity. Importantly, network neuroprotection against spreading toxicity can be effectively stimulated after an excitotoxic insult has been delivered, and may identify a new therapeutic window to limit brain damage

Subcellular peptide localization in single identified neurons by capillary microsampling mass spectrometry

Single cell mass spectrometry (MS) is uniquely positioned for the sequencing and identification of peptides in rare cells. Small peptides can take on different roles in subcellular compartments. Whereas some peptides serve as neurotransmitters in the cytoplasm, they can also function as transcription factors in the nucleus. Thus, there is a need to analyze the subcellular peptide compositions in identified single cells. Here, we apply capillary microsampling MS with ion mobility separation for the sequencing of peptides in single neurons of the mollusk Lymnaea stagnalis, and the analysis of peptide distributions between the cytoplasm and nucleus of identified single neurons that are known to express cardioactive Phe-Met-Arg-Phe amide-like (FMRFamide-like) neuropeptides. Nuclei and cytoplasm of Type 1 and Type 2 F group (Fgp) neurons were analyzed for neuropeptides cleaved from the protein precursors encoded by alternative splicing products of the FMRFamide gene. Relative abundances of nine neuropeptides were determined in the cytoplasm. The nuclei contained six of these peptides at different abundances. Enabled by its relative enrichment in Fgp neurons, a new 28-residue neuropeptide was sequenced by tandem MS