The dual role of group V secretory phospholipase A 2 in pancreatic β-cells

Abstract

Purpose

Group X (GX) and group V (GV) secretory phospholipase A₂ (sPLA₂) potently release arachidonic acid (AA) from the plasma membrane of intact cells. We previously demonstrated that GX sPLA₂ negatively regulates glucose-stimulated insulin secretion (GSIS) by a prostaglandin E2 (PGE2)-dependent mechanism. In this study we investigated whether GV sPLA₂ similarly regulates GSIS.

Methods

GSIS and pancreatic islet-size were assessed in wild-type (WT) and GV sPLA₂-knock out (GV KO) mice. GSIS was also assessed ex vivo in isolated islets and in vitro using MIN6 pancreatic beta cell lines with or without GV sPLA₂ overexpression or silencing.

Results

GSIS was significantly decreased in islets isolated from GV KO mice compared to WT mice and in MIN6 cells with siRNA-mediated GV sPLA₂ suppression. MIN6 cells overexpressing GV sPLA₂ (MIN6-GV) showed a significant increase in GSIS compared to control cells. Though the amount of AA released into the media by MIN6-GV cells was significantly higher, PGE2 production was not enhanced or cAMP content decreased compared to control MIN6 cells. Surprisingly, GV KO mice exhibited a significant increase in plasma insulin levels following i.p. injection of glucose compared to WT mice. This increase in GSIS in GV KO mice was associated with a significant increase in pancreatic islet size and number of proliferating cells in β-islets compared to WT mice.

Conclusions

Deficiency of GV sPLA₂ results in diminished GSIS in isolated pancreatic beta-cells. However, the reduced GSIS in islets lacking GV sPLA₂ appears to be compensated by increased islet mass in GV KO mice.

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Learning path recommendation based on modified variable length genetic algorithm

Abstract

With the rapid advancement of information and communication technologies, e-learning has gained a considerable attention in recent years. Many researchers have attempted to develop various e-learning systems with personalized learning mechanisms for assisting learners so that they can learn more efficiently. In this context, curriculum sequencing is considered as an important concern for developing more efficient personalized e-learning systems. A more effective personalized e-learning recommender system should recommend a sequence of learning materials called learning path, in an appropriate order with a starting and ending point, rather than a sequence of unordered learning materials. Further the recommended sequence should also match the learner preferences for enhancing their learning capabilities. Moreover, the length of recommended sequence cannot be fixed for each learner because these learners differ from one another in their preferences such as knowledge levels, learning styles, emotions, etc. In this paper, we present an effective learning path recommendation system (LPRS) for e-learners through a variable length genetic algorithm (VLGA) by considering learners' learning styles and knowledge levels. Experimental results are presented to demonstrate the effectiveness of the proposed LPRS in e-learning environment.

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An analysis of first year engineering students’ satisfaction with a support distance learning program in mathematics

Abstract

An online support distance-learning program in Mathematics was developed to aid first year engineering students for their transition from the secondary to the tertiary education in order to reinforce deficiencies they may have in mathematical knowledge. The aim of the present study is to examine, firstly, to what extent the attendance of such a program helped students to familiarize themselves with distance learning programs. In addition, the students' satisfaction with the material of the program was examined as well as their attitudes towards a conventional support learning program in Mathematics. The structure and part of the material developed is presented in detail. The basic methodological tool was an appropriately structured questionnaire. The results indicate that students responded positively to the program, which was a basic way of acquainting themselves with distance learning, and were satisfied with the material. The students' attitudes towards a conventional program was found to be related to their prior experience in distance learning programs. Statistical analysis of the research data yielded 4 basic factors related to the students' beliefs regarding the support online learning program in Mathematics. These factors were student's development and progress, satisfaction with the parts of the online support program, their attitudes towards a conventional program while being in the online support program and their familiarization with online distance education. These factors as well as the targeted identification of the students' needs should be taken under consideration while designing and implementing support online distance learning programs in Mathematics.

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Chryseobacterium ginsengiterrae sp. nov., with Beta-Glucosidase Activity Isolated from Soil of a Ginseng Field

Abstract

The isolated Chryseobacterium ginsengiterrae sp. nov DCY68^T was found to be Gram-negative, aerobic, non-motile, non-flagellate and rod-shaped. Their size was approximately 0.40–0.46 × 1.0–1.27 μm. The colonies were yellow-pigmented, convex, circular and 0.5–1.3 mm in diameter when grown on R2A agar for 2 days. DNA, esculin, skim milk, gelatine, starch, Tween 20, and Tween 80 were hydrolyzed, but not cellulose. The cells grew on R2A, TSA, and NA but not on MacConkey agars. Growth occured at 4–33 °C (optimum, 30 °C), at pH 5.0–8.0 (optimum, pH 6.5), and 0–2.5% NaCl. Nitrate was not reduced to nitrite. Oxidase and catalase activity were positive. Strain DCY68^T contained β–glucosidase activity in which ginsenoside Rb1 was enzymatically converted to ginsenoside F2. Analysis of the16S rRNA gene sequence revealed that strain C. ginsengiterrae sp. nov DCY68^T belonged to the family Flavobacteriaceae and was most closely related to C. limigenitum SUR2^T (97.4%). The genomic DNA G+C content was 42.0 mol%. The predominant quinones were MK-6 (74.5%) and MK-7 (25.5%). The major fatty acids were iso-C_15:0, summed feature 3 (containing C_16:1ω7c and/or C_16:1ω6c) and iso-C_17:0 3-OH. On the basis of these phenotypic, genotypic and chemotaxonomic studies, strain DCY68^T represents a novel species of the genus Chryseobacterium, for which name C. ginsengiterrae sp. nov. is proposed. The type strain is DCY68^T (=KCTC 32089^T = JCM 18517^T).

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Priapism due to essential thrombocythaemia: a rare causation

Priapism is rarely caused by essential thrombocytosis, a disorder characterised by increased number of megakaryocytes. We report a case of a 21-year-old man who presented with priapism and on investigation was found to have essential thrombocytosis as the cause.

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Renal cell carcinoma presenting as a cutaneous horn and nodules on the gingiva and scalp

A 63-year-old man presented with a pulsatile cutaneous horn on the nose and multiple angiomatous nodules on the gingiva and scalp, which appeared over 2 months. He had severe hypercalcaemia, lytic lesions in multiple bones and acute kidney injury. Excision biopsy from the gingival nodule showed a clear cell neoplasm. The bone marrow showed atypical cells with similar morphology. Imaging showed a 7 cmx7.5 cm mass at the upper pole of the left kidney with metastases to the bones, liver and lung. Immunohistochemistry was consistent with metastatic renal cell carcinoma. Renal cell carcinoma presenting as a cutaneous horn is extremely rare and to the best of our knowledge only one other case was found in the literature. There was visible regression in the size of the cutaneous horn and nodules following initiation of pazopanib therapy. However, he succumbed to his illness a month later.

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Bilateral optic disc coloboma

Description

A 5-month-old male child was brought with the history of right-sided corneal opacity noticed for the past 2 months. The baby was immunised until now with an uneventful antenatal and peripartum history. Ocular examination showed normal sized cornea having a paracentral nebular opacity along the inferior and nasal aspect without any discharge or significant exposure keratopathy. The baby was able to fix at the light with each eye separately, the anterior chamber in both the eyes was of normal depth having a clear lens and retinal examination showed a well-defined posteriorly excavated area along the inferior portion of the optic disc in both the eyes. Sleeping intraocular pressures were 10 and 12 mm Hg in right eye and left eye, respectively. Posterior segment B-scan ultrasound showed a well-defined symmetric excavation along the inferior aspect of the optic disc in both the eyes with an axial length of 20 mm...

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Idiopathic spontaneous lesser sac haematoma: a perplexing case of abdominal apoplexy

A 37-year-old woman presented with a 3-hour history of back pain, nausea and vomiting and an episode of syncope. A fluid collection in the lesser sac was detected on ultrasound and CT scan. Emergency laparoscopy and subsequent laparotomy were performed and a large blood clot was evacuated from the lesser sac. No identifiable source or predisposition to bleeding was found. She made a full recovery postoperatively. There are few reported cases of spontaneous intraperitoneal haemorrhage. In a third of cases, there is no identifiable source of bleeding. Unfortunately, patients present late with non-specific symptoms and a prompt diagnosis is difficult to make. The case reiterates the importance of awareness of lesser sac haematoma formation; an unusual clinical entity with a high morbidity and mortality rate. A high index of suspicion, radiological adjuncts and appropriate surgical intervention, especially in unstable patients, is essential for a good outcome.

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Successful treatment of direct carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV without arterial puncture: the transvenous triple-overlay embolization (TAILOREd) technique

We report successful transvenous treatment of direct carotid–cavernous fistula in a patient with Ehlers–Danlos syndrome type IV using a novel triple-overlay embolization (TAILOREd) technique without the need for arterial puncture, which is known to be highly risky in this patient group. The TAILOREd technique allowed for successful treatment using preoperative MR angiography as a three-dimensional overlay roadmap combined with cone beam CT and live fluoroscopy, precluding the need for an arterial puncture.

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Duration of Adjuvant Trastuzumab in HER2 Positive Breast Cancer: Overall and Disease Free Survival Results from Meta-Analyses of Randomized Controlled Trials

Publication date: Available online 19 August 2017
Source:Cancer Treatment Reviews
Author(s): Bishal Gyawali, Saroj Niraula
BackgroundOne year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities.MethodsMedline, Embase, and major conference proceedings were searched systematically in June, 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratios for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter-study heterogeneity and sub-group difference (based on hormone-receptors and node-positivity) were assessed using I², and chi² statistics, respectively.ResultsFour studies (n=7,614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p=0.04), and DFS (HR 1.24, p=0.005) with 1 year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1 year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9 weeks versus 6 months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub-group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65(p<0.001) favoring shorter duration.ConclusionOne year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment.



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Throat cancer: New surgical technique helps you recover faster - WVU Medicine (press release)

WVU Medicine (press release)

Throat cancer: New surgical technique helps you recover faster WVU Medicine (press release) This surgical approach uses a guided endoscope (a tubular instrument that can look deep into the body) to provide 3D images of tumors in the throat, base of the tongue, and tonsils. These tumors were previously challenging to reach with traditional tools.

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Large-scale proteomics combined with transgenic experiments demonstrates an important role of jasmonic acid in potassium deficiency response in wheat and rice [Research]

Potassium (K+) is the most abundant inorganic cation in plants, and molecular dissection of K+ deficiency has received considerable interest in order to minimize K+ fertilizer input and develop high quality K+-efficient crops. However, the molecular mechanism of plant responses to K+ deficiency is still poorly understood. In this study, two-week-old bread wheat seedlings grown hydroponically in Hoagland solution were transferred to K+-free conditions for 8 d, and their root and leaf proteome profiles were assessed using the iTRAQ proteome method. Over 4,000 unique proteins were identified, and 818 K+-responsive protein species showed significant differences in abundance. The differentially expressed protein species were associated with diverse functions and exhibited organ-specific differences. Most of the differentially expressed protein species related to hormone synthesis were involved in jasmonic acid (JA) synthesis and the upregulated abundance of JA synthesis-related enzymes could result in the increased JA concentrations. Abundance of allene oxide synthase (TaAOS), one key JA synthesis-related enzyme, was significantly increased in K+-deficient wheat seedlings, and its overexpression markedly increased concentrations of K+ and JA, altered the transcription levels of some genes encoding K+-responsive protein species, as well as enhanced the tolerance of rice plants to low K+ or K+ deficiency. Moreover, rice AOS mutant (osaos) exhibited more sensitivity to low K+ or K+ deficiency. Our findings could highlight the importance of JA in K+ deficiency, and imply a network of molecular processes underlying plant responses to K+ deficiency.

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High sensitivity quantitative proteomics using automated multidimensional nano-flow chromatography and accumulated ion monitoring on quadrupole-Orbitrap-linear ion trap mass spectrometer [Research]

Quantitative proteomics using high-resolution and accuracy mass spectrometry promises to transform our understanding of biological systems and disease. Recent development of parallel reaction monitoring (PRM) using hybrid instruments substantially improved the specificity of targeted mass spectrometry. Combined with high-efficiency ion trapping, this approach also provided significant improvements in sensitivity. Here, we investigated the effects of ion isolation and accumulation on the sensitivity and quantitative accuracy of targeted proteomics using the recently developed hybrid quadrupole-Orbitrap-linear ion trap mass spectrometer. We leveraged ultra-high efficiency nano-electrospray ionization under optimized conditions to achieve yoctomolar sensitivity with more than seven orders of linear quantitative accuracy. To enable sensitive and specific targeted mass spectrometry, we implemented an automated, two-dimensional (2D) ion exchange-reversed phase nanoscale chromatography system. We found that automated 2D chromatography improved the sensitivity and accuracy of both PRM and an intact precursor scanning mass spectrometry method, termed accumulated ion monitoring (AIM), by more than 100-fold. Combined with automated 2D nano-scale chromatography, AIM achieved sub-attomolar limits of detection of endogenous proteins in complex biological proteomes. This allowed quantitation of absolute abundance of the human transcription factor MEF2C at approximately 100 molecules/cell, and determination of its phosphorylation stoichiometry from as little as 1 μg of extracts isolated from 10,000 human cells. The combination of automated multidimensional nano-scale chromatography and targeted mass spectrometry should enable ultra-sensitive high-accuracy quantitative proteomics of complex biological systems and diseases.

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A Simple Light Isotope Metabolic labeling (SLIM-labeling) strategy: a powerful tool to address the dynamics of proteome variations in vivo [Research]

Many quantitative proteomics strategies rely on in vivo metabolic incorporation of amino acids with modified stable isotope profiles into proteins. These methods give rise to multiple ions for each peptide, with possible distortion of the isotopolog distribution, making the overall analytical process complex. We validated an alternative strategy, simple light isotope metabolic labeling (SLIM-labeling), which alleviates many of these problems. SLIM-labeling is based on the in vivo reduction of the isotopic composition of proteins using metabolic precursors with a unique light isotope composition to label all amino acids. This brings a new dimension to in-depth, high resolution MS-based quantitative proteomics. Here, we describe a ¹²C-based SLIM-labeling strategy using U-[¹²C]-glucose as the metabolic precursor of all amino acids in the pathogenic yeast Candida albicans. Monoisotopic ion intensity increased exponentially following ¹²C enrichment, substantially improving peptide identification scores and protein sequence coverage in bottom-up analyses. Multiplexing samples of ¹²C composition varying from natural abundance (98.93%) to 100% makes it possible to address relative quantification issues, keeping all the critical information for each peptide within a single isotopolog cluster. We applied this method to measure, for the first time, protein turnover at the proteome scale in Candida albicans and its modulation by inhibitors of the proteasome and vacuolar protein degradation systems.

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Researchers have created a new material that inhibits biofilm formation of a virulent superbug - Science Daily

Science Daily

Researchers have created a new material that inhibits biofilm formation of a virulent superbug Science Daily By some estimates, bacterial strains resistant to antibiotics -- so-called superbugs -- will cause more deaths than cancer by 2050. Colorado State University biomedical and chemistry researchers are using creative tactics to subvert these superbugs and ... and more »

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New imaging technique overturns longstanding textbook model of DNA folding - Science Daily

New imaging technique overturns longstanding textbook model of DNA folding Science Daily The researchers believe their discovery dovetails with their research on how tumor viruses and cancer mutations change a cell's DNA structure and organization to cause uncontrolled cell growth. It could enable the design of new drugs that manipulate ... and more »

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Cover Image

On the cover: The cover image, by Yulin Lin et al., is based on the Research Article Assessment of fracture risk in proximal tibia with tumorous bone defects by a finite element method, DOI: 10.1002/jemt.22899.

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Issue Information

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Insys agrees to pay $4.45 million to resolve Illinois opioid lawsuit - New York Daily News

Chicago Tribune

Insys agrees to pay $4.45 million to resolve Illinois opioid lawsuit New York Daily News BOSTON (Reuters) - Insys Therapeutics Inc has agreed to pay $4.45 million to resolve a lawsuit by Illinois' attorney general claiming it deceptively marketed an addictive fentanyl-based cancer pain drug for off-label uses. The settlement, announced by ... Opioid drugmaker settles with Illinois for $4.5 millionChicago Tribune all 5 news articles »

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Increased serum levels of fetuin B in patients with coronary artery disease

Abstract

Background

Recent evidence indicates a pivotal role for fetuin B, one of the cystatin superfamily of cysteine protease inhibitors, in the pathogenesis of metabolic diseases. This study investigated whether serum fetuin B levels are associated with the presence of coronary artery disease.

Methods

Serum fetuin B levels were assessed in 87 patients with coronary artery disease (41 with acute coronary syndromes and 46 with stable angina pectoris) and 87 healthy controls using an enzyme-linked immunosorbent assay. The association of serum fetuin B levels with cardiac risk factors was analyzed.

Results

Serum fetuin B levels were significantly higher in patients with coronary artery disease than those in healthy controls (90.7 ± 32.1 vs. 110.0 ± 32.7 μg/ml, P < 0.001), extremely elevated in group with acute coronary syndromes (115.0 ± 35.2 μg/ml). Pearson correlation analysis showed that serum fetuin B levels were positively associated with the levels of total cholesterol (r = 0.276, P < 0.001), low-density lipoprotein cholesterol (r = 0.363, P < 0.001), and fasting blood glucose (r = 0.159, P < 0.05). In addition, multiple logistic regression analyses revealed that fetuin B was independently associated with the presence of coronary artery disease (OR, 1.019; 95% CI, 1.009 to 1.029; P < 0.001) and acute coronary syndromes (OR, 1.017; 95% CI, 1.006 to 1.028; P < 0.01).

Conclusions

Our data revealed that high fetuin B levels are associated with the presence of coronary artery disease and acute coronary syndromes, and that fetuin B may serve as a potential biomarker for coronary artery disease.

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Effect of tetramethylpyrazin combined with cisplatin on VEGF, KLF4 and ADAMTS1 in lewis lung cancer mice

Publication date: Available online 18 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Jian-Hua Tang, He-Min Zhang, Zhi-Hua Zhang, Xiu-Long Zhang
ObjectiveTo further explore the function of combine use of tetramethylpyrazine (TMP) and cisplatin (DDP) in lung carcinoma.MethodsWe used the combination drug to treat Lewis lung cancer mice, investigated the expression level of vascular endothelial growth factor (VEGF), Kruppel-like factor 4 (KLF4) and A disintegrin and metalloproteinase with thrombospondin motifs 1(ADAMTS1) and to further explore the inhibitory effects and potential mechanism of TMP combined with DDP on tumor angiogenesis.ResultsThe tumor growth was suppressed in TMP group, DDP group and TMP combined with DDP group. Furthermore, the weights and volume of tumor, the expression level of VEGF, KLF4 and ADAMTS1 were found significantly changed between experiment group and control group. These findings suggest that TMP with DDP had additional or synergistic effects to inhibit the tumor growth effectively, might be achieved through reducing the expression of angiogenesis promoting factor VEGF and increasing expression of angiogenesis inhibitors KLF4 and ADAMTS1. Conclusion: KLF4 and ADAMTS1 may be synergically involved in the angiogenesis in mouse Lewis lung cancer through the different signal ways.



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Tetrahydrocurcumin Ameliorates Homocysteine Mediated Mitochondrial Remodeling in Brain Endothelial Cells

Abstract

Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated of fission marker (DRP-1), fusion markers (Mfn2) and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) was co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15µM) ameliorated Hcy induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction. This article is protected by copyright. All rights reserved

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Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH

Vemurafenib, a BRAF inhibitor, elicits in ∼80 % of BRAFV600E-mutant melanoma patients a transient anti-tumor response which precedes the emergence of resistance. We tested whether an acidic tumor microenvironment may favor a BRAF inhibitor resistance. A375M6 BRAFV600E melanoma cells, either exposed for a short period or chronically adapted to an acidic medium, showed traits compatible with an epithelial-mesenchymal transition, reduced proliferation and high resistance to apoptosis. Both types of acidic cells treated with vemurafenib did not change their proliferation, distribution in cell cycle and level of p-AKT, in contrast to cells grown at standard pH, which showed reduced proliferation, cell cycle arrest and ERK/AKT inhibition.

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Androgen-deprivation therapy with enzalutamide enhances prostate cancer metastasis via decreasing the EPHB6 suppressor expression

Early studies suggested that using the recently developed anti-androgen Enzalutamide (Enz, also named as MDV3100) with ADT could extend castration resistant prostate cancer (CRPC) patients' survival extra 4.8 months. Yet the therapy in most patients might eventually fail due to development of Enz-resistance. Here we found Enz might also increase some unwanted side-effects via increasing the CRPC cell invasion that might involve altering the Enz-androgen receptor (AR)/EPHB6 suppressor/JNK signaling.

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PD-1/PD-L1 and immunotherapy for pancreatic cancer

Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.

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Understanding polycystic ovary syndrome from the patient perspective: a concept elicitation patient interview study

The aim of this study was to explore the need for a new disease-specific patient reported outcome (PRO) measure for use in clinical trials of drugs designed to target the underlying causes of polycystic ovary ...

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Validity and test-retest reliability of the self-completion adult social care outcomes toolkit (ASCOT-SCT4) with adults with long-term physical, sensory and mental health conditions in England

The Adult Social Care Outcomes Toolkit (ASCOT-SCT4) is a multi-attribute utility index designed for the evaluation of long-term social care services. The measure comprises eight attributes that capture aspects...

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Efficient and sustainable water systems management toward worth living development

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Treatment of Swedish Patients with Graves' Hyperthyroidism Is Associated with Changes in Acylcarnitine Levels

Thyroid , Vol. 0, No. 0.


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GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells

Publication date: Available online 18 August 2017
Source:Experimental Cell Research
Author(s): Ningning Yan, Liang Xu, Xiaobo Wu, Le Zhang, Xiaochun Fei, Yali Cao, Fengchun Zhang
Recently, studies have been suggested that H3K27me3 is implicated with maintenance of cancer stem cells (CSCs), however, the roles of H3K27me3 in Breast cancer stem cells (BCSCs) remain poorly investigated. Here we explore the functionality of H3K27me3 on BCSCs, we identify H3K27me3 as a negative modulator of BCSCs and suggest GSKJ4 is a promising drug targeting BCSCs. We show that the H3K27me3 level is decreased in mammosphere-derived BCSCs. In breast cancer cells, we demonstrate that GSKJ4 could markedly inhibit the proliferation. Strikingly, we show that GSKJ4 could effectively suppress BCSCs including expansion, self-renewal capacity, and the expression of stemness-related markers. Additionally, our xenograft model confirms that GSKJ4 is able to effectively inhibit the tumorigenicity of MDA-MB-231. Mechanistically, the inhibition effects of GSKJ4 on BCSCs are via inhibiting demethylases JMJD3 and UTX with methyltransferase EZH2 unchanged, which enhances H3K27me3 level. H3K27me3 activating leads to reduction of BCSCs expansion, self-renewal and global level of stemness factors. Collectively, our results provide strong supports that H3K27me3 exerts a suppressive influence on BCSCs and reveal that GSKJ4 is capable to be a prospective agent targeting BCSCs.

Graphical abstract

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The adapter SASH1 acts through NOTCH1 and its inhibitor DLK1 in a 3D model of lumenogenesis involving CEACAM1

Publication date: Available online 18 August 2017
Source:Experimental Cell Research
Author(s): Kandis Stubblefield, Jennifer Chean, Tung Nguyen, Charng-jui Chen, John E. Shively
CEACAM1 transfection into breast cancer cells restores lumen formation in a 3D culture model. Among the top up-regulated genes that were associated with restoration of lumen formation, the adaptor protein SASH1 was identified. Furthermore, SASH1 was shown to be critical for lumen formation by RNAi inhibition. Upon analyzing the gene array from CEACAM1/MCF7 cells treated with SASH1 RNAi, DLK1, an inhibitor of NOTCH1 signaling, was found to be down-regulated to the same extent as SASH1. Subsequent treatment of CEACAM1/MCF7 cells with RNAi to DLK1 also inhibited lumen formation, supporting its association with SASH1. In agreement with the role of DLK1 as a NOTCH1 inhibitor, NOTCH1, as well as its regulated genes HES1 and HEY1, were down-regulated in CEACAM1/MCF7 cells by the action of DLK1 RNAi, and up-regulated by SASH1 RNAi. When CEACAM1/MCF7 cells were treated with a γ-secretase inhibitor known to inhibit NOTCH signaling, lumen formation was inhibited. We conclude that restoration of lumen formation by CEACAM1 regulates the NOTCH1 signaling pathway via the adaptor protein SASH1 and the NOTCH1 inhibitor DLK1. These data suggest that the putative involvement of NOTCH1 as a tumor-promoting gene in breast cancer may depend on its lack of regulation in cancer, whereas its involvement in normal lumen formation requires activation of its expression, and subsequently, inhibition of its signaling.



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MicroRNA-21 suppresses ox-LDL-induced human aortic endothelial cells injuries in atherosclerosis through enhancement of autophagic flux: involvement in promotion of lysosomal function

Publication date: Available online 18 August 2017
Source:Experimental Cell Research
Author(s): Feng Tang, Tian-Lun Yang, Zhen Zhang, Xiao-Gang Li, Qiao-Qing Zhong, Ting-Ting Zhao, Li Gong
Atherosclerosis is a common pathological basis of cardiovascular disease and remains the leading cause of mortality. Endothelial cell (EC) injury and autophagy dysfunction have been proved to contribute to the development of atherosclerosis. Recently, accumulating evidence confirms that microRNAs (miRNAs) have emerged as vital regulators and fine-tuners of various pathophysiological cellular impacts and molecular signaling pathways involvedin atherosclerosis. Herein, the objective of the present study was to explore the biological function of miR-21 in oxidized low-density lipoprotein (ox-LDL)-induced human aortic endothelial cells (HAECs) injury and the underlying molecular mechanism. The results showed that ox-LDL treatment significantly decreased HAECs viability, increased caspase-3 activity, apoptosis ratio and Bax protein expression, and reduced Bcl-2 protein expressionresulting in EC injuries. Simultaneously, ox-LDL treatment obviously reduced miR-21 level in a time-and dose-dependent manner. Notably, ox-LDL-induced EC injuries were abolished by miR-21 mimics transfection. In addition, miR-21 mimics alleviated ox-LDL-induced impaired autophagic flux as illustrated by the increases in LC3-II/LC3-I ratio and Beclin-1 protein expression, and the decrease in p62 protein expression in HAECs. Moreover, ox-LDL suppressed the expressions of lysosomal membrane protein (LAMP1) and cathepsin D proteins, and attenuated cathepsin D activity in HAECs, leading to lysosomal dysfunction, while these effects were also blocked by miR-21 mimics. These findings indicated that miR-21 restored impaired autophagic flux and lysosomal dysfunction, thereby attenuating ox-LDL-induced HAECs injuries.



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Analysis of temperature increase in swine gingiva after exposure to a Polywave® LED light curing unit

Publication date: Available online 18 August 2017
Source:Dental Materials
Author(s): Cristiane Maucoski, Driellen Christine Zarpellon, Fabio Andre dos Santos, Leandro Cavalcante Lipinski, Eduardo Bauml Campagnoli, Frederick Allen Rueggeberg, Cesar Augusto Galvão Arrais
ObjectiveThis study evaluated the temperature increase in swine gingival temperature after exposure to light emitted by a Polywave^® LED light curing unit (LCU, Bluephase 20i, Ivoclar Vivadent).MethodsAfter local Ethics Committee approval (protocol 711/2015), 40 pigs were subjected to general anesthesia and the LCU tip was placed 5mm from the buccal gingival tissue (GT) close to lower lateral incisors. A thermocouple probe (Thermes WFI, Physitemp) was inserted into the gingival sulcus before and immediately after exposure to light. Real-time temperature (°C) was measured after the following exposure modes were applied: High Power (20s-H, 40s-H, and 60s-H) or Turbo mode (5s-T), either with or without the presence of rubber dam (RD) interposed between the LCU tip and GT (n=10). The presence of gingival lesions after the exposures was also evaluated. Peak temperature (°C) and the temperature increase during exposure over that of the pre-exposure baseline value (ΔT) data were analyzed using 2-way ANOVA followed by Bonferroni's post-hoc test (α=5%). A binary logistic regression analysis determined the risk of gingival lesion development.ResultsWithout RD, no significant difference in ΔT was observed among 20s-H, 40s-H, and 60s-H groups, which showed the highest temperature values, while the 5s-T exposure showed the lowest ΔT, regardless of RD. RD reduced ΔT only for the 20s-H group (p=0.004). Gingival lesions were predominantly observed using 40s-H, with RD, and 60s-H, with and without RD.SignificanceExposure to a LCU light might be harmful to swine gingiva only when high radiant exposure values are delivered, regardless of the use of RD.



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Favorable residual stress induction by resin-cementation on dental porcelain

Publication date: Available online 16 August 2017
Source:Dental Materials
Author(s): Garry J.P. Fleming, Xu Cao, Dan L. Romanyk, Owen Addison
ObjectivesDespite developments in polycrystalline ceramics, glassy dental-ceramic materials provide the optimum cosmetic option in most clinical situations to mimic the natural dentition. The clinical success of glassy dental-ceramic materials is often attributed to resin-adhesive bonding techniques. In this study we explore whether shrinkage stresses generated on photo-polymerisation of the resin-cement are sufficient to induce ceramic surface defect stabilization, and we quantify the transient nature of the induced stresses.MethodsStress-induced changes in a feldspathic ceramic over a range of thicknesses (0.5–2.0mm: n=20 per thickness) were measured using a profilometric technique at baseline for each disc-shaped specimen (mean of the maximum deflection (δbaseline)) and again following polymerisation of a controlled resin-cement thickness on the contra-lateral surface. Measurements were repeated at 30, 60, 90 and 1440min following photo-polymerization (δ30, δ60, δ90 and δ1440, respectively) before bi-axial flexure strength (BFS) determination at 24h.ResultsA repeated measures ANOVA and post-hoc Bonferroni tests determined that δ1440 was significantly different from δbaseline (p=0.02), δ30 (p<0.01) and δ60 (p<0.01) but not δ90 (p=0.61). Data exploration revealed that there were differences in directionality of the independent variable (mean of the maximum deflection (δ)) with a proportion of specimens increasing in deflection and others reducing. The directionality of the effect strongly correlated with the BFS values. Where δ1440-δbaseline was low and/or negative, BFS values were also low. High BFS values were observed when δ1440-δbaseline was large and positive (indirectly inferring high shrinkage-stress-induced-deformation).SignificanceA link between shrinkage stresses associated with the photo-polymerization of dental resin-based cements and the reinforcement of dental porcelain has clearly been established.



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Proteolytic cleavage by the IMP complex or Oct1 peptidase controls the localization of the yeast peroxiredoxin Prx1 to distinct mitochondrial compartments [Bioenergetics]

Yeast Prx1 is a mitochondrial 1-Cys peroxiredoxin that catalyzes the reduction of endogenously generated H2O2. Prx1 is synthesized on cytosolic ribosomes as a preprotein with a cleavable N-terminal presequence that is the mitochondrial targeting signal, but the mechanisms underlying Prx1 distribution to distinct mitochondrial subcompartments are unknown. Here, we provide direct evidence of the following dual mitochondrial localization of Prx1: a soluble form in the intermembrane space and a form in the matrix weakly associated with the inner mitochondrial membrane. We show that Prx1 sorting into the intermembrane space likely involves the release of the protein precursor within the lipid bilayer of the inner membrane, followed by cleavage by the inner membrane peptidase (IMP). We also found that during its import into the matrix compartment, Prx1 is sequentially cleaved by mitochondrial processing peptidase (MPP) and then by octapeptidyl aminopeptidase 1 (Oct1). Oct1 cleaved eight amino acid residues from the N-terminal region of Prx1 inside the matrix, without interfering with its peroxidase activity in vitro. Remarkably, the processing of Prx proteins by Oct1 appears to be an evolutionarily conserved process since yeast Oct1 could cleave the human mitochondrial peroxiredoxin Prx3 when expressed in Saccharomyces cerevisiae. Altogether, the processing of peroxiredoxins by Imp2 or Oct1 likely represents systems that control the localization of Prxs into distinct compartments and thereby contribute to various mitochondrial redox processes..

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Two Plant-Derived Aporphinoid Alkaloids Exert Their Antifungal Activity by Disrupting Mitochondrial Iron-Sulfur Cluster Biosynthesis [Microbiology]

Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans. However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis. Several lines of evidence supported this conclusion. First, both E9591 and LMT elicited a transcriptional response indicative of iron imbalance, causing the induction of genes that are required for iron uptake and for the maintenance of cellular iron homeostasis. Second, a genome-wide fitness profile analysis showed that yeast mutants with deletions in iron homeostasis-related genes were hypersensitive to E9591 and LMT. Third, treatment of wild-type yeast cells with E9591 or LMT generated cellular defects that mimicked deficiencies in mitochondrial Fe-S cluster synthesis including an increase in mitochondrial iron levels, a decrease in the activities of Fe-S cluster enzymes, a decrease in respiratory function, and an increase in oxidative stress. Collectively, our results demonstrate that E9591 and LMT perturb mitochondrial Fe-S cluster biosynthesis; thus, these two compounds target a cellular pathway that is distinct from the pathways commonly targeted by clinically used antifungal drugs. Therefore, the identification of this pathway as a target for antifungal compounds has potential applications in the development of new antifungal therapies.

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Protein Kinase G confers survival advantage to Mycobacterium tuberculosis during latency like conditions [Signal Transduction]

Protein Kinase G (PknG), a thioredoxin-fold containing eukaryotic like serine/threonine protein kinase (STPK), is a virulence factor in the Mycobacterium tuberculosis, required for inhibition of phago-lysosomal fusion. Here, we unravelled novel functional facets of PknG during latency like conditions. We find that PknG mediates persistence under stressful conditions like hypoxia and abets drug tolerance. PknG mutant displayed minimal growth in nutrient limiting conditions suggesting its role in modulating cellular metabolism. Intracellular metabolic profiling revealed that PknG is necessary for efficient metabolic adaptation during hypoxia. Notably, PknG mutant exhibited reductive shift in mycothiol redox potential (EMSH) and compromised stress response. Exposure to antibiotics and hypoxic environment resulted in higher oxidative shift in EMSH of PknG mutant compared with the wild type. Persistence during latency like conditions required kinase activity and thioredoxin motifs of PknG and is mediated through phosphorylation of a central metabolic regulator GarA. Finally, using guinea pig model of infection, we assessed the in-vivo role of PknG in manifestation of disease pathology and established a role for PknG in stable granuloma formation, hallmark structures of latent tuberculosis. Taken together, PknG mediated GarA phosphorylation is important for maintenance of both mycobacterial physiology and redox poise, an axis which is dispensable for survival under normoxic conditions but is critical for non-replicating persistence of mycobacteria. In conclusion, we propose that PknG likely acts as modulator of latency-associated signals.

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Arȷunolic Acid, a Peroxisome Proliferator-Activated Receptor Alpha Agonist Regresses Cardiac Fibrosis by Inhibiting Non-canonical TGF-{beta} Signaling. [Signal Transduction]

Abstract: Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant Terminalia arjuna which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive T. arjuna compound, arjunolic acid (AA) in ameliorating hemodynamic load-induced cardiac fibrosis and identified its intracellular target. Our data revealed that AA significantly represses collagen expression and improves cardiac function during hypertrophy. We found that AA binds to and stabilizes the ligand binding domain of peroxisome proliferator-activated receptor alpha (PPARα) and increases its expression during cardiac hypertrophy. PPARα knockdown during AA treatment in hypertrophy samples, including angiotensinII treated adult cardiac fibroblasts and renal artery-ligated rat heart suggests that AA-driven cardioprotection primarily arises from PPARα agonism. Moreover, AA-induced PPARα upregulation leads to repression of TGF-β signaling, specifically by inhibiting TGF-β activated kinase1 (TAK1) phosphorylation. We observed that PPARα directly interacts with TAK1, predominantly via PPARα N-terminal transactivation domain (AF-1) thereby masking the TAK1 kinase domain. AA-induced PPARα-bound TAK1 level thereby shows inverse correlation with phosphorylation level of TAK1 and subsequent reduction in p38 MAPK and NF-κBp65 activation, ultimately culminating in amelioration of excess collagen synthesis in cardiac hypertrophy. In conclusion, our findings unravel the mechanism of AA action in regressing hypertrophy associated cardiac fibrosis by assigning a role of AA as a PPARα agonist that inactivates non-canonical TGF-β signaling.

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Dsc E3 ligase localization to the Golgi requires the ATPase Cdc48 and cofactor Ufd1 for activation of Sterol Regulatory Element-binding Protein in fission yeast [Protein Synthesis and Degradation]

Sterol regulatory element-binding proteins (SREBPs) in the fission yeast Schizosaccharomyces pombe regulate lipid homeostasis and the hypoxic response under conditions of low sterol or oxygen availability. SREBPs are cleaved in the Golgi through the combined action of the Dsc E3 ligase complex, the rhomboid protease Rbd2, and the essential ATPases Associated with diverse cellular Activities (AAA+) ATPase Cdc48. The soluble SREBP N-terminal transcription factor domain is then released in the cytosol to enter the nucleus and regulate gene expression. Previously, we reported that Cdc48 binding to Rbd2 is required for Rbd2-mediated SREBP cleavage. Here, using affinity chromatography and mass spectrometry experiments, we identified Cdc48-binding proteins in S. pombe, generating a list of many previously unknown potential Cdc48 binding partners. We show that the established Cdc48 cofactor Ufd1 is required for SREBP cleavage but does not interact with the Cdc48-Rbd2 complex. Cdc48-Ufd1 is instead required at a step prior to Rbd2 function, during Golgi localization of the Dsc E3 ligase complex. Together, these findings demonstrate that two distinct Cdc48 complexes - Cdc48-Ufd1 and Cdc48-Rbd2 - are required for SREBP activation and low-oxygen adaptation in S. pombe.

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Evidence based anti-osteoporosis effects of Periplaneta americana L on osteoblasts, osteoclasts, vascular endothelial cells and bone marrow derived mesenchymal stem cells

Kangfuxin (KFX) is the ethanol extract of Periplaneta americana L, which has been widely used in the Traditional Chinese Medicine for the repair and regeneration of injured organ and tissues with long history. Th...

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Hemin is able to disaggregate lysozyme amyloid fibrils into monomers

Publication date: Available online 18 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Sumalata Sonavane, Syeda Zehra Haider, Anil Kumar, Basir Ahmad
Lysozyme amyloidosis (ALys) is a disease of the gastrointestinal tract, liver and kidneys, which is caused by the accumulation of insoluble fibrils of lysozyme in the tissues of above organs. The ALys can be cured by disintegration and clearance of the fibrils from the affected tissues and organs. It is thought that protein fibrils are extremely stable. Consequently, small molecule-induced dissociation of fibrils under physiological conditions is really challenging. Here, we report kinetic and thermodynamic analyses of hemin-induced dissociation of hen egg white lysozyme amyloid fibrils. We examined the effect of hemin on the kinetics of dissociation of lysozyme fibrils. We observed that the hemin binding dissociates fibrils in a concentration dependent manner within a reasonable time. Studies of structural, morphological properties and gel filtration chromatography indicate that fibrils dissociate mainly into monomeric species. The conformational, hydrodynamic, unfolding and stability studies of the resolubilized proteins show that dissociated monomers possess characteristics of partially folded intermediate state of the protein. We also find that hemin-induced fibril dissociation mainly depends on the kinetic and thermodynamic stability of the fibrils. These results suggest that non-toxic derivatives of hemin and other porphyrins could pave a way for therapeutic intervention in amyloidosis and related pathologies.

Graphical abstract

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Colorectal cancer patient’s self-efficacy for managing illness-related problems in the first 2 years after diagnosis, results from the ColoREctal Well-being (CREW) study

Abstract

Purpose

There is a growing emphasis on self-management of cancer aftercare. Little is known about patient's self-efficacy (confidence) to manage illness-related problems and how this changes over time. This paper describes the patterns of self-efficacy for managing illness-related problems amongst colorectal cancer patients in the 2 years following diagnosis.

Methods

In this prospective cohort study, questionnaires were administered at baseline (pre-surgery), 3, 9, 15 and 24 months to 872 colorectal cancer patients. Self-efficacy (confidence to manage illness-related problems), anxiety, social support, affect, socio-demographics, physical symptoms and clinical and treatment characteristics were assessed. Group-based trajectory analysis identified trajectories of self-efficacy up to 24 months and predictors.

Results

Four trajectories of self-efficacy were identified: group 1 (very confident) 16.0% (95% confidence interval (CI) 10.7–21.3%), group 2 (confident) 45.6% (95% CI 40.3–51.0%), group 3 (moderately confident) 29.5% (95% CI 25.1–33.8%) and group 4 (low confidence) 8.9% (95% CI 6.4–11.4%). Greater deprivation, domestic status, more co-morbidities, worse fatigue and pain, lower positivity and greater negativity were significantly associated with lower self-efficacy. There was an increase in mean scores for self-efficacy over time for the whole sample, but this did not reach the cut-off for minimally important differences. At 2 years, the lowest level of confidence to manage was for symptoms or health problems.

Conclusion

Around 40% of patients had suboptimal levels of confidence to manage illness-related problems with little change from the time of diagnosis across the four groups.

Implications for cancer survivors

Screening for self-efficacy at diagnosis would enable targeted, early intervention which could in turn enhance health-related quality of life.

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Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes [Research]

Metabolic profiling of individuals with type 2 diabetes mellitus (T2DM) has previously been limited to single-time-point samples, ignoring time-of-day variation. Here, we tested our hypothesis that body mass and T2DM affect daily rhythmicity and concentrations of circulating metabolites across a 24-h day in 3 age-matched, male groups—lean, overweight/obese (OW/OB), and OW/OB with T2DM—in controlled laboratory conditions, which were not confounded by large meals. By using targeted liquid chromatography/mass spectrometry metabolomics, we quantified 130 plasma metabolites every 2 h over 24 h, and we show that average metabolite concentrations were significantly altered by increased body mass (90 of 130) and T2DM (56 of 130). Thirty-eight percent of metabolites exhibited daily rhythms in at least 1 study group, and where a metabolite was rhythmic in >1 group, its peak time was comparable. The optimal time of day was assessed to provide discriminating biomarkers. This differed between metabolite classes and study groups—for example, phospholipids showed maximal difference at 5:00 AM (lean vs. OW/OB) and at 5:00 PM (OW/OB vs. T2DM). Metabolites that were identified with both robust 24-h rhythms and significant concentration differences between study groups emphasize the importance of controlling the time of day for diagnosis and biomarker discovery, offering a significant improvement over current single sampling.—Isherwood, C. M., Van der Veen, D. R., Johnston, J. D., Skene, D. J. Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes.

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Poncet’s disease after the intravesical instillation of Bacillus Calmette–Guérin (BCG): a case report

Poncet's disease is a rare syndrome characterized by articular impairment in a form of rare tuberculid. One of the theories of its cause involves an autoimmune response induced by the intravesical administrati...

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Anal Cancer More Deadly in Black Men

Significant racial and gender-based disparities exist in outcomes among patients with squamous cell carcinoma of the anus, with black men having the lowest survival rates, according to a new study. (Source: CancerNetwork)

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Periodontal Disease Linked to Certain Cancer Types

In this interview we discuss a recent study that linked periodontal disease with an increased cancer risk, specifically melanoma and cancers of the lung, breast, esophagus, and gallbladder. (Source: CancerNetwork)

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FDA Approves New Acute Lymphoblastic Leukemia Treatment

The FDA has approved inotuzumab ozogamicin (Besponsa) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. (Source: CancerNetwork)

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Breast Nodule Found in 21-Year-Old Patient

A 21-year-old woman develops a nodule in her left breast, and a biopsy is obtained. What your diagnosis? (Source: CancerNetwork)

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Patient Presents With Skin Mass on Shoulder

A 48-year-old man presents with a skin mass on his left shoulder, and a biopsy is performed. What is your diagnosis? (Source: CancerNetwork)

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When the Damage Is Done: Selecting Patients for Head and Neck Cancer Chemoprevention Trials

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Airway Basal Cell Heterogeneity and Lung Squamous Cell Carcinoma

Basal cells are stem/progenitor cells that maintain airway homeostasis, enact repair following epithelial injury, and are a candidate cell-of-origin for lung squamous cell carcinoma. Heterogeneity of basal cells is recognized in terms of gene expression and differentiation capacity. In this Issue, Pagano and colleagues isolate a subset of immortalized basal cells that are characterized by high motility, suggesting that they might also be heterogeneous in their biophysical properties. Motility-selected cells displayed an increased ability to colonize the lung in vivo. The possible implications of these findings are discussed in terms of basal cell heterogeneity, epithelial cell migration, and modeling of metastasis that occurs early in cancer evolution. Cancer Prev Res; 10(9); 1–3. ©2017 AACR.

See related article by Pagano et al., p. 514

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'Acidic patch' regulates access to genetic information - Science Daily

Science Daily

'Acidic patch' regulates access to genetic information Science Daily Their findings may also identify a new instrument in cells' molecular repertoire of chromatin-remodeling tools and spur investigations into potential cancer therapeutic targets. "Mutations in the acidic patch are known to occur in certain types of ...

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Nivolumab-associated nausea and vomiting as an immune adverse event

Immunotherapy in the form of programmed cell death protein 1 (PD-1) inhibitors such as nivolumab have been found highly effective in treatment of several malignancies, including metastatic melanoma and squamous non-small-cell lung cancer [1,2]. Although studies suggest smaller percentages of immune-related adverse events (iAEs) with the use of PD-1 inhibitors as compared with cytotoxic T-lymphocyte–associated antigen 4 inhibitors, the increasingly wide use of these newer agents places importance on physician awareness and recognition of their side-effects [3].

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Down-regulation of the tumour suppressor κ-opioid receptor predicts poor prognosis in hepatocellular carcinoma patients

Opioid receptors have become increasingly implicated in cancer progression and long-term patient outcomes. However, the expression and significance of the κ-opioid receptor (KOR) in hepatocellular carcinoma (H...

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Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study: design of a randomized controlled trial

Following esophagectomy, esophageal cancer patients experience a clinically relevant deterioration of health-related quality of life, both on the short- and long-term. With the currently growing number of esop...

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The effect of sources and air mass transport on the variability of trace element deposition in central Poland: a cluster-based approach

Abstract

Measurements of trace element (As, Cu, Cd, Cr, Ni, Pb, Zn) deposition fluxes were conducted simultaneously in two contrasted environments, i.e., urban and forest, between April 2013 and October 2014. This was the first such project in central Poland, aimed at long-term observations of trace elements in the atmosphere and their distribution, transport, and deposition pattern. The receptor sites were different in terms of local meteorological conditions, emission potential, and distance to major anthropogenic sources. The deposition fluxes of all trace elements showed clear seasonal variations, with relatively higher values in winter than in summer. The main factors affecting interannual differences in concentrations and deposition of trace elements in central Poland were local emission from industrial and commercial sources, and changes in atmospheric conditions (wind speed and direction, boundary layer, precipitation amount, air mass origin). In this study, the impact of regional and long-range transport on trace element deposition was determined using the air back-trajectory cluster analysis. During the summertime of 2013 and 2014, the predominant SW and E advections from regional and remote anthropogenic sources in Europe were responsible for high deposition of Cd, Cr, Pb, Cu, and Zn, whereas during the wintertime of 2013/2014, we observed a significant influence of polluted air masses from southeastern regions. Based on the Pb/Zn ratio, it was found that regional sources significantly influenced the aerosol composition and rainwater chemistry within the study domain. However, the role of a long-range transport of anthropogenic pollutants was also important. In addition, a relatively small difference in the Pb/Zn ratio between both sites (urban 0.26 ± 0.18, forest 0.23 ± 0.17) may suggest (1) very similar contribution of anthropogenic sources and (2) minor importance of atmospheric transformation processes of these metals in the aqueous phase.

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New biomarker trials to detect upper gastrointestinal cancers earlier - University College London Hospitals

University College London Hospitals

New biomarker trials to detect upper gastrointestinal cancers earlier University College London Hospitals The trials are for cancer of the pancreas – a large gland behind the stomach and next to the small intestine, and cancer of the oesophagus – the tube that connects the throat to the stomach. Around 20,000 people are diagnosed with upper ... and more »

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Effect of Structure and Disorder on the Charge Transport in Defined Self-Assembled Monolayers of Organic Semiconductors

ACS Nano

DOI: 10.1021/acsnano.7b02394

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Discovery of Enhanced Magnetoelectric Coupling through Electric Field Control of Two-Magnon Scattering within Distorted Nanostructures

ACS Nano

DOI: 10.1021/acsnano.7b04653

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The 3D Printing of the Paralyzed Vocal Fold: Added Value in Injection Laryngoplasty

Three-dimensional (3D) printing has had numerous applications in various disciplines, especially otolaryngology. We report the first case of a high-fidelity 3D-printed model of the vocal cords of a patient with unilateral vocal cord paralysis in need of injection laryngoplasty.

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A Review of the Physiological Effects and Mechanisms of Singing

Daily experience suggests that singing can energize us and even provide a physical workout. A growing amount of evidence has been presented to support anecdotal claims of the benefits of singing on health and well-being. Singing has been shown to be related to numerous physiological changes. The cardiorespiratory system is utilized during persistent singing training, resulting in enhanced respiratory muscles and an optimized breathing mode. In addition, singing can also cause changes in neurotransmitters and hormones, including the upregulation of oxytocin, immunoglobulin A, and endorphins, which improves immune function and increases feelings of happiness.

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Risk Factors for Voice Disorders in University Professors in Cyprus

The purpose of this study was to investigate risk factors for voice pathologies in university professors to determine the need for a preventative vocal hygiene education program that could improve the quality of life of university faculty.

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Editorial Board

Publication date: October 2017
Source:Clinical Biochemistry, Volume 50, Issue 15





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Serum microRNA profiles in patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, or drug-induced liver injury

Publication date: Available online 18 August 2017
Source:Clinical Biochemistry
Author(s): Yu Yamaura, Naoyuki Tatsumi, Shingo Takagi, Shinsaku Tokumitsu, Tatsuki Fukami, Kazuto Tajiri, Masami Minemura, Tsuyoshi Yokoi, Miki Nakajima
PurposeSome blood biomarkers or histological examination by liver biopsy are used for the diagnosis of liver diseases in clinics. However, conventional blood biomarkers show poor specificity and sensitivity, and liver biopsy is highly invasiveness. Therefore, to overcome such disadvantages, specific/sensitive and noninvasive options are desirable. In recent years, circulating microRNAs (miRNAs) have been acknowledged for their potential as disease markers. Actually, several miRNAs have been reported to be biomarker candidates of liver diseases. However, these earlier studies were performed for one disease. Therefore, the specificity as biomarkers was not guaranteed, because they didn't study for the other types of liver injury. In this study, we examined if circulating miRNA could distinguish different types of liver diseases.MethodsSerum miRNA profiles in 28 patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis or drug-induced liver injury as well as 4 control subjects were determined by TaqMan MicroRNA Array analysis. Principal component analysis (PCA) of selected miRNAs was performed.ResultsWe identified 37 miRNAs whose levels were significantly different between any of the groups. Although individual miRNAs could not distinguish different types of liver diseases, probably because of similar liver pathology, their profiling by PCA could classify different liver disease groups.ConclusionsThe profiling of the selected miRNAs can be useful to distinguish different types of liver diseases.



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Condylar positions before and after bilateral mandibular distraction osteogenesis in children with Pierre Robin sequence

This study aimed to analyze the changes in mandibular morphology after bilateral mandibular distraction osteogenesis (BMDO) in children with Pierre Robin sequence. The positions of the condyles were analyzed in reconstructed three-dimensional craniomaxillofacial images obtained for 18 children before and 8–12 weeks after BMDO. Differences between pre- and postoperative parameters were assessed using paired t-tests. After surgery, a significant decrease in superior joint space was detected (P<0.05), but no change in anterior joint space or posterior joint space was observed.

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Validation of a non-contact screening device for the combination of sleep-disordered breathing and periodic limb movements in sleep

Abstract

Purpose

Recent studies found that the non-contact screening device SleepMinder (ResMed Sensor Technologies, Dublin, Ireland) detects sleep-disordered breathing (SDB) with high diagnostic accuracy in cohorts suspected of this disorder. However, it was reported that in patients with periodic limb movement in sleep (PLMS), this non-contact device overestimates the apnea-hypopnea index (AHI). We aimed to overcome this limitation by introducing the novel sleep disorder index (SDI) which is sum of the AHI and the period limb movement index (PLMI).

Methods

Between January 2011 and December 2013, we studied a mixed cohort of 57 patients (31 OSA, 19 PLMS). The easy-to-use non-contact device emits a very weak electromagnetic radiation and detects body movement by measuring the Doppler effect. We interpreted the device-generated movement index as the SDI and validated the diagnostic accuracy against simultaneous application of the gold-standard polysomnography (PSG).

Results

We found that the SDI of the non-contact device correlated well with the sum of AHI and PLMI derived from PSG (r = 0.79, p = 0.01). For PSG-derived SDI cutoff ≥ 15/h, we obtained a sensitivity of 92.2% and a specificity of 95.8%. Positive likelihood ratio was 23.3 and negative likelihood ratio 0.03.

Conclusions

The studied non-contact screening device detects accurately the combination of the sleep disorders SDB and/or PLM. However, further testing is required in order to specify the nature of the underlying sleep disorder. At the current stage of algorithm development, the clinical strength is that the studied non-contact device can be used as a rule-out screening device for SDB and PLM.

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Demolition derby plans to honor, raise money for longtime announcer - Daily Herald

Daily Herald

Demolition derby plans to honor, raise money for longtime announcer Daily Herald This winter, doctors found cancer in Jim Louder's tonsils. While they removed them, the cancer spread and Jim Louder was given a choice: remove more of the cancer for a higher survival rate and also lose his voice box, or skip the surgery for ...

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Evidence-based practice: Steps towards a better clinical practice

Publication date: Available online 18 August 2017
Source:Revista de Logopedia, Foniatría y Audiología
Author(s): Jytte Isaksen
Evidence-based practice (EBP) is a common model for clinical decision-making. The model has its origin in medicine, but today also it relates to speech-language therapy. EBP consists of three (sometimes four) parts: external scientific evidence, client values/perspectives, clinical expertise and in some models context. With this model, clinical decision-making is meant to take place after gathering information or evidence from each of the three parts and taking them into consideration. Based on literature, teaching and clinical experience and available online resources this article aims to describe the background of EBP as well as clinical expertise and client values, but primarily focuses on providing practical advice about searching, finding and appraising the external scientific evidence in order to make this decision-making model in speech-language therapy more accessible for the individual speech-language therapist.



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Duration of Adjuvant Trastuzumab in HER2 Positive Breast Cancer: Overall and Disease Free Survival Results from Meta-Analyses of Randomized Controlled Trials

Discovery of trastuzumab has revolutionized the outcome of Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer, a historically aggressive subtype with particularly poor prognosis before the availability of HER2 targeted therapy.[1] Approval of 1 year of trastuzumab by the United States Food and Drug Administration (FDA) for adjuvant treatment of early stage breast cancer in 2006 was paradigm shifting. This decision was supported by results from pivotal Randomized Controlled Trials (RCTs) using trastuzumab for one year for pragmatic reasons rather than due to prior evidence or scientific rationale.

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Effect of Tai Chi on bone mineral density in postmenopausal women: A systematic review and meta-analysis of randomized control trials

This meta-analysis of relative randomized control trials (RCTs) aimed to investigate whether Tai Chi exercise is able to alleviate bone mineral density (BMD) loss in postmenopausal women.

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3D-printed tracheoesophageal puncture and prosthesis placement simulator

A tracheoesophageal prosthesis (TEP) allows for speech after total laryngectomy. However, TEP placement is technically challenging, requiring a coordinated series of steps. Surgical simulators improve technical skills and reduce operative time. We hypothesize that a reusable 3-dimensional (3D)-printed TEP simulator will facilitate comprehension and rehearsal prior to actual procedures.

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Genome-wide identification of sweet orange (Citrus sinensis) metal tolerance proteins and analysis of their expression patterns under zinc, manganese, copper, and cadmium toxicity

Publication date: 20 September 2017
Source:Gene, Volume 629
Author(s): Xing-Zheng Fu, Ya-Hua Tong, Xue Zhou, Li-Li Ling, Chang-Pin Chun, Li Cao, Ming Zeng, Liang-Zhi Peng
Plant metal tolerance proteins (MTPs) play important roles in heavy metal homeostasis; however, related information in citrus plants is limited. Citrus genome sequencing and assembly have enabled us to perform a systematic analysis of the MTP gene family. We identified 12 MTP genes in sweet orange, which we have named as CitMTP1 and CitMTP3 to CitMTP12 based on their sequence similarity to Arabidopsis thaliana MTPs. The CitMTPs were predicted to encode proteins of 864 to 2556 amino acids in length that included 4 to 6 putative transmembrane domains (TMDs). Furthermore, all the CitMTPs contained a highly conserved signature sequence encompassing the TMD-II and the start of the TMD-III. Phylogenetic analysis further classified the CitMTPs into Fe/Zn-MTP, Mn-MTP, and Zn-MTP subgroups, which coincided with the MTPs of A. thaliana and rice. The closely clustered CitMTPs shared a similar gene structure. Expression analysis indicated that most CitMTP transcripts were upregulated to various extents under heavy metal stress. Among these, CitMTP5 in the roots and CitMTP11 in the leaves during Zn stress, CitMTP8 in the roots and CitMTP8.1 in the leaves during Mn stress, CitMTP12 in the roots and CitMTP1 in the leaves during Cu stress, and CitMTP11 in the roots and CitMTP1 in the leaves during Cd stress showed the highest extent of upregulation. These findings are suggestive of their individual roles in heavy metal detoxification.



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The nuclear protein-coding gene ANKRD23 negatively regulates myoblast differentiation

Publication date: 20 September 2017
Source:Gene, Volume 629
Author(s): Xiaojing Wang, Rui Zeng, Haiyang Xu, Zaiyan Xu, Bo Zuo
Muscle fiber formation is a complex process and subject to fine regulation of a variety of protein-coding genes and non-coding RNA. In this study, we identified a nuclear protein-coding gene ANKRD23 which was highly expressed in muscle. Quantitative real-time PCR, western blotting and immunofluorescence were used to detect the expression change of myoblast differentiation marker genes after knockdown and overexpression of ANKRD23. The results showed that the expression of myoblast differentiation marker genes were increased by interference and reduced by ANKRD23 overexpression, indicating that ANKRD23 played a negative role in the myoblast differentiation. Interestingly, we discovered a long non-coding RNA-AK004293 which was overlapped with the 3′UTR of ANKRD23 gene. Then we detected the effect of AK004293 on the expression of ANKRD23 and myoblast differentiation marker genes in C2C12 myoblasts. The results showed that AK004293 had no significant effect on the expression of myoblast differentiation maker genes and ANKRD23. In conclusion, our results established the foundation for further studies about the regulation mechanism of ANKRD23 in muscle development.



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The role of C/EBPβ phosphorylation in modulating membrane phospholipids repairing in LPS-induced human lung/bronchial epithelial cells

Publication date: 20 September 2017
Source:Gene, Volume 629
Author(s): Shiyu Shu, Yan Xu, Ling Xie, Yufang Ouyang
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common critical emergency with high mortality in clinical practice. The key mechanism of ALI/ARDS is that the excessive inflammatory response damages the integrity of alveolar and bronchial cell membrane and thus affects their basic function. Phospholipids are the main component of cell membranes. Phospholipase A2 (PLA2), which catalyzes the cleavage of membrane phospholipids, is the most important inflammatory mediator of ALI. However, clara cell secretory protein 1 (CCSP1), an endogenous PLA2 inhibitor can increase the self-defense of membrane phospholipids. Thus, CCSP1 up-regulation and PLA2 inhibition constitutes an effective method for ensuring the stability of membrane phospholipids and for the treatment of ALI/ARDS. In the present study, we developed an in vitro model of ALI via lipopolysaccharide (LPS) stimulation of a human bronchial epithelial cell line, BEAS-2B, and assessed the mRNA and protein levels of CCSP1 and PLA2 in the model cells. The results demonstrated LPS induction inhibited the transcription and protein expression of CCSP1, but only the protein level of membrane associated PLA2 was increased, suggesting that in the in vitro ALI model, abnormally regulated CCSP1 transcription plays a crucial role in the damage of cell membrane. To find out the reason that CCSP1 expression was decreased in the ALI model, we predicted, by means of bioinformatics, putative transcription factors which would bind to CCSP1 promoter, examined their background and expression, and found that a transcription factor, CCAAT/enhancer binding protein β (C/EBP β), was correlated with the transcription of CCSP1 in the in vitro ALI model, and its phosphorylation in the model was decreased. CHIP-PCR and luciferase reporter assay revealed that C/EBP β bound to CCSP1 promoter and facilitated its transcription. Therefore, we conclude that there is a C/EBP β/CCSP1/PLA2 pathway in the in vitro ALI model. The study of underlying mechanism show that the activity of C/EBP β depends on its phosphorylation:LPS stimulation reduced C/EBP β phosphorylation and suppressed the transcription of CCSP1 in BEAS-2B cells, which resulted in enhanced PLA2 and the consequent membrane damage. And further study shows that overexpression of CDK2(Cyclindependent kinase 2), promoted the phosphorylation of C/EBP β and inhibited PLA2 through the C/EBP β/CCSP1/PLA2 pathway, so as to attenuate membrane damage. The significance of this study lies in that artificial C/EBP β phosphorylation regulation may ease the membrane damage in ALI and improve membrane repair.



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Tolerance of latissimus dorsi in immediate breast reconstruction without implant to radiotherapy

– Immediate breast reconstruction (IBR) improves the quality of life of patients who undergo mastectomy. The latissimus dorsi flap (LDF) method provides particularly good aesthetic results, but its tolerance to subsequent radiotherapy remains unclear. We thus sought to assess tolerance and aesthetic results and satisfaction, as reported by patients who underwent IBR by LDF with or without subsequent radiotherapy.

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Histo-Anatomical Basis of the Gastroepiploic Vascularized Lymph Node Flap – The Overlooked “Micro” Lymph Nodes

Microsurgical treatment of lymphedema in the form of autologous vascularised lymph node (VLN) transfer is increasingly accepted as an effective method, since it reducing limb size and infectious episodes. To date, a multitude of flaps have been described so far, but there is no consensus on specific flap choice. After using the groin and supraclavicular VLN flaps for many years, we investigated alternative sites with potentially less donor site morbidity.1 The gastroepiploic VLN flap was one of the flaps that we explored.

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3D-printed tracheoesophageal puncture and prosthesis placement simulator

A tracheoesophageal prosthesis (TEP) allows for speech after total laryngectomy. However, TEP placement is technically challenging, requiring a coordinated series of steps. Surgical simulators improve technical skills and reduce operative time. We hypothesize that a reusable 3-dimensional (3D)-printed TEP simulator will facilitate comprehension and rehearsal prior to actual procedures.

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Estrogen regulates pathological changes of bones via bone lining cells - Science Daily

Estrogen regulates pathological changes of bones via bone lining cells Science Daily The most important female sex hormone, oestrogen, plays a crucial role in the regulation of bone mass. Oestrogen deficiency is known to be a major cause of postmenopausal osteoporosis, or bone weakness. Skeletal stability and pathological skeletal ... and more »

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Combined immunodeficiency and atopy caused by a dominant negative mutation in CARD11

We show here for the first time that a novel R30W dominant negative mutation in CARD11 can cause a familial autosomal dominant disorder encompassing combined immunodeficiency, severe multi-system atopy and autoimmunity.

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Rescue of T-cell function during persistent pulmonary adenoviral infection by TLR9 activation

Pulmonary persistent adenoviral infections induce an immunosuppressive environment in the lung that renders CD8 T-cells dysfunctional. Innate cell activation during persistent infection re-invigorates effector T cell function leading to viral clearance and immune homeostasis.

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A flow cytometry–based diagnosis of eosinophilic esophagitis

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Advances in Basic and Clinical Immunology 2016

Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T cells and B cells, including cytokines and proteins involved in actin cytoskeleton. The regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohystiocytosis. The role of prenylation in mevalonate kinase deficiency leading to inflammation has been established.

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Everolimus selectively targets vemurafenib resistant BRAF melanoma cells adapted to low pH

Vemurafenib, a BRAF inhibitor, elicits in ∼80 % of BRAFV600E-mutant melanoma patients a transient anti-tumor response which precedes the emergence of resistance. We tested whether an acidic tumor microenvironment may favor a BRAF inhibitor resistance. A375M6 BRAFV600E melanoma cells, either exposed for a short period or chronically adapted to an acidic medium, showed traits compatible with an epithelial-mesenchymal transition, reduced proliferation and high resistance to apoptosis. Both types of acidic cells treated with vemurafenib did not change their proliferation, distribution in cell cycle and level of p-AKT, in contrast to cells grown at standard pH, which showed reduced proliferation, cell cycle arrest and ERK/AKT inhibition.

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PD-1/PD-L1 and immunotherapy for pancreatic cancer

Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.

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Androgen-deprivation therapy with enzalutamide enhances prostate cancer metastasis decreasing the EPHB6 suppressor expression

Early studies suggested that using the recently developed anti-androgen Enzalutamide (Enz, also named as MDV3100) with ADT could extend castration resistant prostate cancer (CRPC) patients' survival extra 4.8 months. Yet the therapy in most patients might eventually fail due to development of Enz-resistance. Here we found Enz might also increase some unwanted side-effects via increasing the CRPC cell invasion that might involve altering the Enz-androgen receptor (AR)/EPHB6 suppressor/JNK signaling.

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Intraoperative implantation of a mesh of directional palladium sources (CivaSheet): Dosimetry verification, clinical commissioning, dose specification, and preliminary experience

Publication date: Available online 18 August 2017
Source:Brachytherapy
Author(s): Gil'ad N. Cohen, Karen Episcopia, Seng-Boh Lim, Thomas J. LoSasso, Mark J. Rivard, Amandeep S. Taggar, Neil K. Taunk, Abraham J. Wu, Antonio L. Damato
PurposeTo present the clinical commissioning of a novel ¹⁰³Pd directional brachytherapy device (CivaSheet) for intraoperative radiation therapy.Methods and MaterialsClinical commissioning for the CivaSheet consisted of establishing: (1) source strength calibration capabilities, (2) experimental verification of TG-43 dosimetry parameters, (3) treatment planning system validation, and (4) departmental practice for dose specification and source ordering. Experimental verification was performed in water with radiochromic film calibrated with a 37 kVp X-ray beam. Percentage difference ([measurements − calculation]/calculation) and distance to agreement (difference between film-to-source distance and distance that minimized the percentage difference) were calculated. Nomogram values (in U/100 Gy) for all configurations (up to 20 × 20 sources) were calculated for source ordering. Clinical commissioning was used on patients enrolled in an ongoing Institutional Review Board-approved protocol.ResultsA source calibration procedure was established, and the treatment planning system was commissioned within standard clinical uncertainties. Percentage dose differences (distances to agreement) between measured and calculated doses were 8.6% (−0.12 mm), 0.6% (−0.01 mm), −6.4% (0.22 mm), and −10.0% (0.44 mm) at depths of 2.3, 5.1, 8.0, and 11.1 mm, respectively. All differences were within the experimental uncertainties. Nomogram values depended on sheet size and spatial extent. A value of 2.4U/100 Gy per CivaDot was found to satisfy most cases, ranging from 2.3 to 3.3U/100 Gy. Nomogram results depended on elongation of the treatment area with a higher variation observed for smaller treatment areas. Postimplantation dose evaluation was feasible.CONCLUSIONSCommissioning and clinical deployment of CivaSheet was feasible using BrachyVision for postoperative dose evaluation. Experimental verification confirmed that the available TG-43 dosimetry parameters are accurate for clinical use.



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Modelling human psychology - Science Daily

Science Daily

Modelling human psychology Science Daily In addition, it includes spatial and temporal dimensions that also play a key role in rationalising the decisions we make and planning our actions. A team of researchers from the Universities of Geneva (UNIGE), Texas, Paris and University College ... and more »

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Errors made by 'DNA spellchecker' revealed as important cause of ... - Science Daily

Errors made by 'DNA spellchecker' revealed as important cause of ... Science Daily Important processes that create mutations that cause cancer have been identified by researchers studying the genomes of more than 1000 tumors. and more »

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Large-scale proteomics combined with transgenic experiments demonstrates an important role of jasmonic acid in potassium deficiency response in wheat and rice [Research]

Potassium (K+) is the most abundant inorganic cation in plants, and molecular dissection of K+ deficiency has received considerable interest in order to minimize K+ fertilizer input and develop high quality K+-efficient crops. However, the molecular mechanism of plant responses to K+ deficiency is still poorly understood. In this study, two-week-old bread wheat seedlings grown hydroponically in Hoagland solution were transferred to K+-free conditions for 8 d, and their root and leaf proteome profiles were assessed using the iTRAQ proteome method. Over 4,000 unique proteins were identified, and 818 K+-responsive protein species showed significant differences in abundance. The differentially expressed protein species were associated with diverse functions and exhibited organ-specific differences. Most of the differentially expressed protein species related to hormone synthesis were involved in jasmonic acid (JA) synthesis and the upregulated abundance of JA synthesis-related enzymes could result in the increased JA concentrations. Abundance of allene oxide synthase (TaAOS), one key JA synthesis-related enzyme, was significantly increased in K+-deficient wheat seedlings, and its overexpression markedly increased concentrations of K+ and JA, altered the transcription levels of some genes encoding K+-responsive protein species, as well as enhanced the tolerance of rice plants to low K+ or K+ deficiency. Moreover, rice AOS mutant (osaos) exhibited more sensitivity to low K+ or K+ deficiency. Our findings could highlight the importance of JA in K+ deficiency, and imply a network of molecular processes underlying plant responses to K+ deficiency.

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High sensitivity quantitative proteomics using automated multidimensional nano-flow chromatography and accumulated ion monitoring on quadrupole-Orbitrap-linear ion trap mass spectrometer [Research]

Quantitative proteomics using high-resolution and accuracy mass spectrometry promises to transform our understanding of biological systems and disease. Recent development of parallel reaction monitoring (PRM) using hybrid instruments substantially improved the specificity of targeted mass spectrometry. Combined with high-efficiency ion trapping, this approach also provided significant improvements in sensitivity. Here, we investigated the effects of ion isolation and accumulation on the sensitivity and quantitative accuracy of targeted proteomics using the recently developed hybrid quadrupole-Orbitrap-linear ion trap mass spectrometer. We leveraged ultra-high efficiency nano-electrospray ionization under optimized conditions to achieve yoctomolar sensitivity with more than seven orders of linear quantitative accuracy. To enable sensitive and specific targeted mass spectrometry, we implemented an automated, two-dimensional (2D) ion exchange-reversed phase nanoscale chromatography system. We found that automated 2D chromatography improved the sensitivity and accuracy of both PRM and an intact precursor scanning mass spectrometry method, termed accumulated ion monitoring (AIM), by more than 100-fold. Combined with automated 2D nano-scale chromatography, AIM achieved sub-attomolar limits of detection of endogenous proteins in complex biological proteomes. This allowed quantitation of absolute abundance of the human transcription factor MEF2C at approximately 100 molecules/cell, and determination of its phosphorylation stoichiometry from as little as 1 μg of extracts isolated from 10,000 human cells. The combination of automated multidimensional nano-scale chromatography and targeted mass spectrometry should enable ultra-sensitive high-accuracy quantitative proteomics of complex biological systems and diseases.

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