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Supplementary Figures S1-S14. p53 levels in p53 knockdown GBM cells (S1); TMZR3 cells obtained from a p53 deficient background display increased ploidy (S2); H2AX activation in temozolomide treated parental and TMZR3 GBM cells (S3); In-cell Host cell reactivation (HCR) assays used to assess the MGMT and MMR repair capacity of GBM cells (S4); MSH6 and MSH2 levels in MSH6 and MSH2 knockdown GBM cells (S5); Cell cycle profiles and quantitation of cell cycle changes in TMZ-treated MSH6 knockdown cells two cell cycle times post-TMZ treatment (S6); Cell cycle profiles and quantitation of cell cycle changes in TMZ-treated MSH2 knockdown cells two cell cycle times post-TMZ treatment (S7); Minor decreases in MSH2 levels correlate with acquired TMZ resistance in LN229 and A172 GBM cells (S8); Effects of MSH6 or MSH2 knockdown on the protein level of its dimerization partner (S9); Msh2 knockdown in GL261 glioblastoma cells (S10); Moderate decreases in Msh2 confer a growth advantage to GL261 GBM cells after TMZ, but not BCNU, exposure in vitro (S11); Distribution of patient survival in TMZ treated TCGA GBM patients and effects of MSH2 transcript levels on the survival of TMZ treated patients in the 95th percentile for patient survival after TMZ therapy (S12); Overall survival of GBM patients stratified by MSH3, MLH1 and PMS2 tumor transcript levels (S13); PMS2 transcript levels correlate with increased chromosome 7 copy number (S14).

Supplementary Tables S1-S2. O6-methylguanine adducts levels in parental and TMZR3 GBM cells 3 hours post-TMZ exposure (S1); shRNA constructs used in this study (S2).

Supplementary Methods and Discussion. Description of additional methods and procedures used in the study. Also includes Supplementary References.

Activating germline K-ras mutations cause Noonan syndrome (NS), which is characterized by several developmental deficits including cardiac defects, cognitive delays and skeletal abnormalities. NS patients have increased signaling through the MAPK pathway. To model NS skeletal defects and understand the effect of hyperactive K-ras signaling on normal limb development, we generated a mouse model in which activated K-rasG12D was expressed specifically in mesenchymal progenitors of the limb bud. These mice display short, abnormally mineralized long bones that phenocopy those of NS patients. This defect was first apparent at E14.5, and was characterized by a delay in bone collar formation. Coincident mutation of p53 had no effect on the K-rasG12D induced bone defect, arguing that it is does not result from senescence or apoptosis. Instead, our data revealed profound defects in the development of the committed osteoblasts; their appearance is delayed, concordant with the delay in bone collar formation, and they display an aberrant localization outside of the bone shaft. Additionally, we see growth plate defects including a reduction in the hypertrophic chondrocyte layer. Most importantly, we found that in utero delivery of a MEK inhibitor between E10.5 and E14.5 is sufficient to completely suppress the ability of activated K-ras to induce NS-like long bone defects in embryogenesis. These data define a critical point in mid-gestation in which elevated MAPK signaling impairs growth plate and bone collar formation and yield NS-like limb defects. Moreover, they offer insight into possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.SIGNIFICANCE STATEMENTNoonan syndrome is a genetic condition that is characterized by various developmental defects including skeletal abnormalities that lead to short stature. These patients carry mutations that activate Ras/MAPK signaling. We have generated a mouse model that recapitulates these Noonan Syndrome-like bone defects. Analysis of these animals establishes the developmental window in which bone formation goes awry, and reveals disruption of an early event that is critical for the longitudinal growth of bones. Additionally, we show that treatment with an inhibitor of Ras/MAPK signaling during this key developmental window is sufficient to completely suppress these Noonan Syndrome-like bone defects. This offers possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.

The sewage sludge from wastewater treatment plant of Iasi, a city with 300,000 inhabitants, for domestic and industrial origin, was stored in a mud pond arranged on an area of 18,920 m2. Chemical analyzes of the sludge showed that, of all the chemical elements determined, only Zn is found at pollutant level (5739 mg∙kg-1), i.e. almost 30 times more than the maximum allowable limit for Zn in soil and 45 times more than the Zn content of the soil on which the mud pond has been set. Over time, the content of Zn in the mud pond, but also from soil to which it has been placed, has become upper the normal content of the surrounding soil up to a depth of 260 cm. On the other hand, the vegetation installed on sewage sludge in the process of mineralization, composed predominantly of Phragmites, Rumex, Chenopodium, and Aster species had accumulated in roots, stems and leaves Zn quantities equivalent to 1463 mg Kg-1, 3988 mg Kg-1, 1463 mg Kg-1, respectively, 1120 mg∙Kg-1. The plants in question represents the natural means of phytoremediation, and sewage sludge as such may constitute a fertilizer material for soils in the area, on which Zn deficiency in maize has been recorded. In addition, the ash resulted from the incineration of plants loaded with zinc may constitute, in its turn, a good material for fertilizing of the soils that are deficient in zinc.

Selenium mobility in soil depends on a multitude of physical and chemical factors. The present paper highlights the selenium solubilization degree out of the total soil content in relation with its agrochemical properties. Soils samples were considered collected from different agricultural areas of the Country, with or without certain natural handicaps, from soils under industrial impact and long term agrochemical experiments. The selenium solubilization percentages out of the soil total content ranged between 3.57 and 8.15%. No solubilization percentage was calculated for Central and Southern Dobrudja and the South-Eastern Romanian Plane, because the total selenium quantities in these areas are lower and mobile selenium values are very low. The statistical analysis of the calculated percentage values highlighted homogeneous areas and areas with a higher scattering degree. Thus, in agricultural land, in acknowledged agrarian areas and in long term agricultural experiments, the percentage values are better grouped, showing (expectable) soil homogeneousness, on one hand, and a significant soil selenium supply and its adequate solubilization for plant nutrition, on the other. The most scattered values occurred in the Călmăţui and Buzău valleys area in halomorphic soils, and in the Făgăraş Depression which is under the industrial polluting influence of chemical works. Among the causes for these differences is the uniformity or non-uniformity of the terrains, induced by land use and the existence or not of a handicap (polluting impact or halomorphic soils, for example). In general, there are no significant differences between the selenium mobility values and their grouping or scattering degree in the soil depth. A single exception stands out, namely in the Făgăraş Depression, where the selenium solubilization degree tends to increase with soil depth, as well as the scattering degree. In the Danube Delta diked areas Sireasa and Pardina very significant correlations have been computed, direct between the selenium solubilization degree and soil reaction and indirect with the humus, total nitrogen, mobile phosphorus and potassium contents. In the other areas the soils agrochemical properties don’t seem to influence selenium solubilization, not directly anyway.

The paper presents the results of an experiment carried out in controlled conditions, regarding triticale plants growth on a nutritive layer consisting of a mixture of red mud, acid rock and compost, in different proportions. The analytical results highlighted the strongly alkaline reaction of the layer, high organic carbon, mobile phosphorus and potassium contents and low nitrogen contents. The layer has a high salinity and sodium salts are predominant. The total microelements and heavy metals contents are generally acceptable. The triticale plants grew in these conditions up to 10-15 cm height, when the experiment was stopped. The plants accumulated normal nitrogen, calcium and magnesium quantities, low potassium ones, high phosphorus and very high sodium contents. The metallic microelements (copper, iron, manganese, zinc) accumulated at relatively normal levels, but the heavy metals (cadmium, cobalt, chromium, nickel, lead) concentrated up to values several tens of times higher than the normal contents. Introducing the obtained vegetal mass in the nutritive layer will contribute to enhancing its fertility for the next vegetation cycles.

Backgound Polymyxin B is not included in most standard contact allergen series. The aim of this study was to determine the prevalence of contact sensitization to polymyxin B in a population of patients referred for patch testing. Methods A retrospective cohort study design was used to collect data on 795 patients referred to the contact dermatitis clinic of the McGill University Health Centre, as well as to the office of one of the authors (L.M.), between March 2014 and November 2015. Patients were patch tested to the North American Contact Dermatitis Group baseline series and polymyxin B sulfate 3% in petrolatum. Results Out of 795 tested individuals, 18 were allergic to polymyxin B, for a prevalence of 2.3%. The eruptions affected almost all body parts, but mostly the face. The degree of reaction ranged from 1+ to 2+. Isolated reactions to polymyxin B occurred in 9 (50%) patients, whereas reactions to bacitracin and polymyxin B were seen in the other 9. Only 1 patient reacted to bacitracin, polymyxin B, and neomycin (11.1%). Most reactions (12/18) were from past exposure to polymyxin B. Conclusions Allergic reactions to polymyxin B are not rare, and this antibiotic warrants inclusion in the standard patch testing series.

Researches have been carried out with medicinal herbs in the frame of a National project financed by CNCSIS through the Partnership Program. Ecologic and conventional technologies were applied. The project aimed to implement a standardization system of the vegetal raw materials which can be used in the cosmetic industry. Sage, basilicum, and savory were subject of the experiments, at Jucu, Cluj County, Ungureni – Butimanu, Dâmboviţa County, and Secuieni, Neamţ County. The dominant soils in these areas are Fluvisols and Haplic Chernozems in the Jucu area, Chromic Luvisol in the Ungureni – Butimanu area, and Calcic Chernozem in the Secuieni area. The agrochemical analysis of the soils from the experimental fields highlighted soil fertility properties conservation both under ecologic and conventional growing technologies.

Selenium contents were determined in the A horizon of the Salsodisols (Solonchaks and Solonetz)placed along the Călmăţui and Buzău Valleys. The total selenium content oscillated between 480 and 1140g·kg-1, with an average value of 800 g·kg-1. This value is 2.1 times higher than the selenium total content inthe upper horizon of the World’s non-halomorphic soils. It is also higher than the selenium total content in the upper horizon of the soils from Dobrogea and the South-Eastern Romanian Plain, 5.6 respectively 3.4 times. The mobile selenium content, soluble in the EDTA-CH3COONH4 solution at pH = 7, ranged in the 13-25 g·kg-1 interval, with an average value of 18 g·kg-1, 4 times higher than the mobile selenium contents of the Dobrogea soils upper horizon and 1.2 times higher than the ones in the South-Eastern part of the Romanian Plain. Between the selenium total contents and some Salsodisols physical and chemical properties proportionality relations were established, statistically ensured. Most of these soils’ selenium content is to be found as calcium, sodium, or magnesium (secondary) selenates. The presence of the same cations’ selenites is not excluded.

More than 20 years later, a new research on heavy metals (cadmium, cobalt, chromium, copper) contents in the soil cover of the Pantelimon – Brăneşti area located East of the Bucharest Municipality and exposed for several decades to the influence of industrial emissions from two non-ferrous metallurgy plants is presented. A 5,912.72 ha area was investigated, 544 samples taken by geometric horizons (0-20; 20-40; 40-60 cm) from 215 points have been analyzed.The dominant soils are: Preluvosols, Chernozems, Phaeozems. The analytical data showed that all the heavy metals contents are below the maximum allowable limits and of the alarm thresholds. Higher cadmium and copper concentrations have been registered in the 40-60 cm layer and higher chromium and copper concentrations in the 0-20 cm layer. Cadmium and cobalt distributions are non-central, with a right asymmetry, and the chromium and copper ones are slightly symmetric. The surface distribution of the heavy metals shows the presence of some high contents areas distributed insularly, with a higher frequency around the industrial units. The geochemical abundance indexes are higher than 1 for cadmium and lower for cobalt, chromium, and copper, and the pedo-geochemical abundance indexes are lower than 1 only for chromium.

In the last several years, a number of studies have described large-scale structural variation in several genomes. Traditionally, such methods have used whole-genome array comparative genome hybridization or single-nucleotide polymorphism arrays to detect large regions subject to copy-number variation. Later techniques have been based on paired-end mapping of Sanger sequencing data, providing better resolution and accuracy. With the advent of next-generation sequencing, a new generation of methods is being developed to tackle the challenges of short reads, while taking advantage of the high coverage the new sequencing technologies provide. In this survey, we describe these methods, including their strengths and their limitations, and future research directions.

Background: Calciphylaxis is a rare syndrome of vascular calcification with subsequent cutaneous and tissue necrosis. It usually manifests as a complication of end-stage renal failure, affecting 1 to 4% of long-term dialysis patients. Very exceptionally, it can occur without chronic renal failure. Objective: The goal of this study was to discuss an exceptional case of extensive calciphylaxis in the absence of chronic renal failure and its successful management. Methods: We present a case of a 31-year-old woman with extensive proximal, ulcerated calciphylaxis without associated chronic renal failure. Our patient had quite a few risk factors associated with the pathogenesis of calciphylaxis, such as obesity, malnutrition, and a transient episode of acute renal failure. Results: She was successfully treated with sodium thiosulfate, extensive wound débridement (more than 30% total body surface), and subsequent skin grafts. The patient has miraculously survived this often fatal condition. Conclusion: Calciphylaxis can occur even in the absence of chronic renal failure. This often fatal condition can be managed successfully with a combination of aggressive wound control and the fairly newly described sodium thiosulfate therapy.

Continuous use of traditional tillage system (conventional) resulted in a gradual harvest increase, but gave rise to some worrying negative phenomenon regarding the most important supply of the agricultural production - soil, by its chemical and physical degradation.This paper aims to assess soil degradation processes, based on pedo-transfer rules and is based on of expeditionary studies regarding assessment and characterization of soil fertility, under the practice of various farming systems: conventional tillage and minimum tillage. The study carried out the effects of moderat conservative tillage on physical and chemical soil properties comparative with conventional soil technology on an argic chernozem, belongs to the agricultural Caracal area. Agricultural area is affected by a relatively high variability of the limiting factors and soil degradation processes, which require adaptation of technology systems to protection of soil and plants. Because of all limiting factors, natural and antropic, in this expeditionary study we compare the moderat conservative tillage effects, with conventional technology effects and impact of those both soil technology, on physical, chemical and biological properties. Results of study show the potential depth of aeration conditions are moderately favorable, being determined particularly by intense state of compactness of the soil as a natural consequence of it. Macroporosity decrease in depth, has negative consequences not only on the normal performance of the processes of aeration, and water penetration and infiltration, but for the accumulation of water available for plants. Content of structural microagregates water-stable or soil dispersion is high, which shows that the formation of structural macroagregates occurred more mechanical factors such as compaction or natural processes. The numerical values of the degree of compaction of 15-20 cm in depth up to the 15-18% v / v in both phases of observation. Deep compaction is undoubtedly due to the technological system applied to the greatest extent, and only a small part pedogenetical natural factors.

Many cutaneous conditions have associated ophthalmologic findings, which are important to recognize for both dermatologists and ophthalmologists. This review highlights some important ophthalmologic manifestations associated with neurocutaneous syndromes and inherited connective tissue diseases.

In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC). We previously showed that sublytic concentration of C5b-9 triggers a variety of biological events in GEC. In the current study, we demonstrate that complement activates p38 MAPK in GEC and address the role of p38 in complement-mediated cell injury. When cultured rat GEC were stimulated with complement, p38 kinase activity and phosphorylation were increased by ∼2.4-fold, compared with control. Treatment with p38 inhibitors significantly augmented complement-mediated cytotoxicity. In contrast, when the constitutively active mutant of transforming growth factor-β-activated kinase 1 (TAK1), a kinase upstream of p38, was expressed in GEC in an inducible manner, cytotoxicity was significantly reduced, compared with uninduced cells. p38 inhibitors abolished the protective effect of TAK1 expression. By analogy to cultured cells, p38 activity was also increased in glomeruli from rats with PHN and treatment with the p38 inhibitor FR-167653 increased proteinuria. Complement induced phosphorylation of MAPK-associated protein kinase-2 (MAPKAPK-2), a kinase downstream of p38 in GEC. Heat shock protein (HSP27) is a cytoskeleton-interacting substrate of MAPKAPK-2. Overexpression of the wild-type HSP27, but not a non-phosphorylatable mutant, markedly reduced complement-mediated GEC injury. In summary, complement activates p38 MAPK in GEC in vitro and in glomeruli from rats with PHN. The activation of p38 MAPK appears to be cytoprotective for GEC against complement-mediated GEC injury. Phosphorylation of HSP27 may mediate this cytoprotection.

Our aim is to construct a perfect (i.e. minimal and optimal) ILP refinement operator for hypotheses spaces bounded below by a most specific clause and subject to syntactical restrictions in the form of input/output variable declarations (like in Progol). Since unfortunately no such optimal refinement operators exist, we settle for a weaker form of optimality and introduce an associated weaker form of subsumption which exactly captures a first incompleteness of Progol's refinement operator. We argue that this sort of incompleteness is not a drawback, as it is justified by the examples and the MDL heuristic. A second type of incompleteness of Progol (due to subtle interactions between the requirements of non-redundancy, completeness and the variable dependencies) is more problematic, since it may sometimes lead to unpredictable results. We remove this incompleteness by constructing a sequence of increasingly more complex refinement operators which eventually produces the first (weakly) perfect refinement operator for a Progol-like ILP system.