Molecular Determinants of S100B Oligomer Formation

Background: S100B is a dimeric protein that can form tetramers, hexamers and higher order oligomers. These forms have been suggested to play a role in RAGE activation. Methodology/Principal Findings: Oligomerization was found to require a low molecular weight trigger/cofactor and could not be detected for highly pure dimer, irrespective of handling. Imidazol was identified as a substance that can serve this role. Oligomerization is dependent on both the imidazol concentration and pH, with optima around 90 mM imidazol and pH 7, respectively. No oligomerization was observed above pH 8, thus the protonated form of imidazol is the active species in promoting assembly of dimers to higher species. However, disulfide bonds are not involved and the process is independent of redox potential. The process was also found to be independent of whether Ca 2+ is bound to the protein or not. Tetramers that are purified from dimers and imidazol by gel filtration are kinetically stable, but dissociate into dimers upon heating. Dimers do not revert to tetramer and higher oligomer unless imidazol is again added. Both tetramers and hexamers bind the target peptide from p53 with retained stoichiometry of one peptide per S100B monomer, and with high affinity (lgK = 7.360.2 and 7.260.2, respectively in 10 mM BisTris, 5 mM CaCl 2, pH 7.0), which is less than one order of magnitude reduced compared to dimer under the same buffer conditions. Conclusion/Significance: S100B oligomerization requires protonated imidazol as a trigger/cofactor. Oligomers ar

Multiscale modelling of auxin transport in the plant-root elongation zone

In the root elongation zone of a plant, the hormone auxin moves in a polar manner due to active transport facilitated by spatially distributed influx and efflux carriers present on the cell membranes. To understand how the cell-scale active transport and passive diffusion combine to produce the effective tissue-scale flux, we apply asymptotic methods to a cell-based model of auxin transport to derive systematically a continuum description from the spatially discrete one. Using biologically relevant parameter values, we show how the carriers drive the dominant tissue-scale auxin flux and we predict how the overall auxin dynamics are affected by perturbations to these carriers, for example, in knockout mutants. The analysis shows how the dominant behaviour depends on the cells' lengths, and enables us to assess the relative importance of the diffusive auxin flux through the cell wall. Other distinguished limits are also identified and their potential roles discussed. As well as providing insight into auxin transport, the study illustrates the use of multiscale (cell to tissue) methods in deriving simplified models that retain the essential biology and provide understanding of the underlying dynamics

A comparative analysis of the chemical compositions of Gaia-Enceladus/Sausage and Milky Way satellites using APOGEE

We use data from the 17th data release of the Apache Point Observatory Galactic Evolution Experiment (APOGEE 2) to contrast the chemical composition of the recently discovered Gaia Enceladus/Sausage system (GE/S) to those of ten Milky Way (MW) dwarf satellite galaxies: LMC, SMC, Boötes I, Carina, Draco, Fornax, Sagittarius, Sculptor, Sextans and Ursa Minor. Our main focus is on the distributions of the stellar populations of those systems in the [Mg/Fe]-[Fe/H] and [Mg/Mn]-[Al/Fe] planes, which are commonly employed in the literature for chemical diagnosis and where dwarf galaxies can be distinguished from in situ populations. We show that, unlike MW satellites, a GE/S sample defined purely on the basis of orbital parameters falls almost entirely within the locus of ‘accreted’ stellar populations in chemical space, which is likely caused by an early quenching of star formation in GE/S. Due to a more protracted history of star formation, stars in the metal-rich end of the MW satellite populations are characterized by lower [Mg/Mn] than those of their GE/S counterparts. The chemical compositions of GE/S stars are consistent with a higher early star formation rate than MW satellites of comparable and even higher mass, suggesting that star formation in the early universe was strongly influenced by other parameters in addition to mass. We find that the direction of the metallicity gradient in the [Mg/Mn]–[Al/Fe] plane of dwarf galaxies is an indicator of the early star formation rate of the system

Newly diagnosed incident dizziness of older patients: a follow-up study in primary care

<p>Abstract</p> <p>Background</p> <p>Dizziness is a common complaint of older patients in primary care, yet not much is known about the course of incident dizziness. The aim of the study was to follow-up symptoms, subjective impairments and needs of older patients (≥65) with incident dizziness and to determine predictors of chronic dizziness. Furthermore, we analysed general practitioners' (GPs') initial diagnoses, referrals and revised diagnoses after six months.</p> <p>Methods</p> <p>An observational study was performed in 21 primary care practices in Germany, including a four-week and six-month follow-up. A questionnaire comprising characteristic matters of dizziness and a series of validated instruments was completed by 66 participants during enrolment and follow-up (after 1 month and 6 months). After six months, chart reviews and face-to-face interviews were also performed with the GPs.</p> <p>Results</p> <p>Mean scores of dizziness handicap, depression and quality of life were not or only slightly affected, and did not deteriorate during follow-up; however, 24 patients (34.8%) showed a moderate or severe dizziness handicap, and 43 (62.3%) showed a certain disability in terms of quality of life at the time of enrolment. In multivariate analysis, n = 44 patients suffering from chronic dizziness (dependent variable, i.e. relapsing or persistent at six months) initially had a greater dizziness handicap (OR 1.42, 95%CI 1.05-1.47) than patients with transient dizziness. GPs referred 47.8% of the patients to specialists who detected two additional cases of benign paroxysmal positional vertigo (BPPV).</p> <p>Conclusions</p> <p>New-onset dizziness relapsed or persisted in a considerable number of patients within six months. This was difficult to predict due to the patients' heterogeneous complaints and characteristics. Symptom persistence does not seem to be associated with deterioration of the psychological status in older primary care patients. Management strategies should routinely consider BPPV as differential diagnosis.</p

Influence of Ni Catalyst Layer and TiN Diffusion Barrier on Carbon Nanotube Growth Rate

Dense, vertically aligned multiwall carbon nanotubes were synthesized on TiN electrode layers for infrared sensing applications. Microwave plasma-enhanced chemical vapor deposition and Ni catalyst were used for the nanotubes synthesis. The resultant nanotubes were characterized by SEM, AFM, and TEM. Since the length of the nanotubes influences sensor characteristics, we study in details the effects of changing Ni and TiN thickness on the physical properties of the nanotubes. In this paper, we report the observation of a threshold Ni thickness of about 4 nm, when the average CNT growth rate switches from an increasing to a decreasing function of increasing Ni thickness, for a process temperature of 700°C. This behavior is likely related to a transition in the growth mode from a predominantly “base growth” to that of a “tip growth.” For Ni layer greater than 9 nm the growth rate, as well as the CNT diameter, variations become insignificant. We have also observed that a TiN barrier layer appears to favor the growth of thinner CNTs compared to a SiO2 layer

Response of Quercus ilex seedlings to Phytophthora spp. root infection in a soil infestation test

[EN] Phytophthora species are the main agents associated with oak (Quercus spp.) decline, together with the changing environmental conditions and the intensive land use. The aim of this study was to evaluate the susceptibility of Quercus ilex to the inoculation with eight Phytophthora species. Seven to eight month old Q. ilex seedlings grown from acorns, obtained from two Spanish origins, were inoculated with P. cinnamomi, P. cryptogea, P. gonapodyides, P. megasperma, P. nicotianae, P. plurivora, P. psychrophila and P. quercina. All Phytophthora inoculated seedlings showed decline and symptoms including small dark necrotic root lesions, root cankers, and loss of fine roots and tap root. The most aggressive species were P. cinnamomi, P. cryptogea, P. gonapodyides, P. plurivora and P. psychrophila followed by P. megasperma., while Phytophthora quercina and P. nicotianae were the less aggressive species. Results obtained confirm that these Phytophthora species could constituted a threat to Q. ilex ecosystems and the implications are further discussed.The authors are grateful to A. Solla and his team from the Centro Universitario de Plasencia-Universidad de Extremadura (Spain) for helping in the acorns collection and to the CIEF (Centro para la Investigación y Experimentación Forestal, Generalitat Valenciana, Valencia, Spain) for providing the acorns. This research was supported by funding from the project AGL2011- 30438-C02-01 (Ministerio de Economía y Competitividad, Spain).Mora-Sala, B.; Abad Campos, P.; Berbegal Martinez, M. (2018). Response of Quercus ilex seedlings to Phytophthora spp. root infection in a soil infestation test. European Journal of Plant Pathology. https://doi.org/10.1007/s10658-018-01650-6SÁlvarez, L. A., Pérez-Sierra, A., Armengol, J., & García-Jiménez, J. (2007). 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Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer

Introduction: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance. Methods: High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data. Results: A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy number events, irrespective of subtype. Finally, SNP data from individual tumors indicated that genomic amplification in general appears as monoallelic, that is, it preferentially targets one parental chromosome in HER2-amplified tumors. Conclusions: We have delineated the genomic landscape of CNAs, amplifications, LOH, and CNN-AI in HER2-amplified breast cancer, but also demonstrated a strong association between different types of genomic aberrations and tumor aneuploidy irrespective of molecular subtype

Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris

Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p,0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p,0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p,0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that th

Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy

Introduction Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information. Methods We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation. Results Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-). Conclusion A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy