Phase behavior of aqueous polyacrylic acid solutions using atomistic molecular dynamics simulations of model oligomers

Publication date: 7 April 2017
Source:Polymer, Volume 114
Author(s): Ratna S. Katiyar, Prateek K. Jha
We have performed fully atomistic molecular dynamics simulations of aqueous solutions of a weak, pH-responsive polyelectrolyte, polyacrylic acid (PAA). Model oligomers of PAA of different tacticities, molecular weights, degrees of deprotonation, and deprotonation patterns are simulated with water molecules. Deprotonation of PAA chains that occurs with an increase in pH results in an increase in Coulomb repulsion between chain segments on one hand, and a non-monotonic change in the hydrogen bonding between chain segments on the other hand. Consequently, at the single chain level, PAA chains are stretched at higher pH values, where the amount of stretching varies with chain tacticity. For the multiple chains case, PAA forms aggregates at higher concentrations, which are relatively denser and contain lesser water (solid-like) at lower pH than compared to higher pH (liquid-like). Such phase transitions of PAA aggregates with pH has possible implications in the design of pH-responsive polyelectrolytes for applications in drug delivery.

Graphical abstract

http://ift.tt/2nq98lR

Magnetic resonance imaging characteristics of granulomatous mastitis

Publication date: Available online 15 March 2017
Source:Clinical Imaging
Author(s): Amanda N. Chu, Stephen J. Seiler, Jody C. Hayes, Rachel Wooldridge, Jessica H. Porembka, Basak Dogan
Granulomatous mastitis (GM) is a benign chronic inflammatory condition of the breast. This study was performed to determine the utility of magnetic resonance imaging (MRI) in differentiating GM from malignancy. MRI findings in 12 women with clinical or histopathologically-proven GM were retrospectively reviewed. Non-mass enhancement on MRI was present in all 12 patients with clustered ring enhancement being the most common pattern (n=7, 58%). Architectural distortion (n=10, 83%), skin thickening (n=10, 83%) and focal skin enhancement (n=10, 83%) were also very common. MRI features of GM are often identical to features considered suspicious for malignancy on MRI.



http://ift.tt/2nH9Hn6

Absence of the right common carotid artery: a rare case without separate origins of the internal and external carotid arteries

Publication date: Available online 15 March 2017
Source:Clinical Imaging
Author(s): Gretchen Quinones, Ashok Srinivasan
Absence of the common carotid artery (CCA) is a rare anomaly. In the few cases described in the literature, it has been typically associated with separate origins of the internal carotid artery (ICA) and external carotid artery (ECA) Fife (1921), Boyd (1934), Rossiti and Raininko (2001), Cerase et al. (2009), Drazin et al. (2010), Yim et al. (2009), Monaco et al. (2009), Jerius et al. (1995), Dahn et al. (1999), Cakirer et al. (2002), Choi et al. (2015), Bryan et al. (1978), Horowitz et al. (2003), Roberts and Gerald (1978), Rajeshwari (2013), Purkayastha et al. (2006), Maybody et al. (2003), Wood et al. (2011) . To the best of our knowledge, absence of the CCA without separate origins of the ECA and ICA has only been described five times before, one of them in conjunction with a persistent proatlantal intersegmental artery (PIA) Cao et al. (2011) and four with agenesis of the ICA Kobayashi et al. (2013), Kunishio et al. (1987), Chen et al. (2008), Xie et al. (2010) . We present a case of a previously undescribed variation of this rare vascular anomaly.



http://ift.tt/2nq75OF

Comparison of MRI grading for cervical neural foraminal stenosis based on axial and oblique sagittal images: Concordance and reliability study

Publication date: Available online 15 March 2017
Source:Clinical Imaging
Author(s): Wooil Kim, Kyung-Sik Ahn, Chang Ho Kang, Woo Young Kang, Kyung-Sook Yang
The aim of this study was to assess the concordance between magnetic resonance imaging (MRI) grading for cervical neural foraminal stenosis (CNFS) based on axial and oblique sagittal images and evaluate the reliability of each grading plane. CNFS was graded at C2–3 to C7–T1 levels based on axial and oblique sagittal images separately by three radiologists. The concordance between CNFS grading based on axial and oblique sagittal images was strong for all three observers (Kendall's W=0.80, 0.79, and 0.82), despite the tendency of higher grading with oblique sagittal images. Both imaging planes supported strong interobserver reliability.



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Masthead

Publication date: March–April 2017
Source:Brachytherapy, Volume 16, Issue 2





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Table of Contents

Publication date: March–April 2017
Source:Brachytherapy, Volume 16, Issue 2





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Editorial Board

Publication date: March–April 2017
Source:Brachytherapy, Volume 16, Issue 2





http://ift.tt/2nHfVUh

A Study of Trastuzumab Emtansine in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer Who Have Received Prior Anti-HER2 And Chemotherapy-based Treatment

Condition:   Breast Cancer
Intervention:   Drug: Trastuzumab Emtansine
Sponsor:   Hoffmann-La Roche
Recruiting - verified March 2017

http://ift.tt/2npWTpa

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study

Abstract

Purpose

Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.

Methods

We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2–8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2–8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9–14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.

Results

No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:−0.35; p:0.02), Luteinizing Hormone (r:−0.35; p:0.03), FSH (r:−0.37; p:0.02), and (17)estradiol (r: −0.36; p:0.02).

Conclusions

We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small.

In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

http://ift.tt/2ncr17f

American Academy of Dermatology Annual Meeting

http://ift.tt/2nueCZy

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study

Abstract

Purpose

Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.

Methods

We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2–8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2–8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9–14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.

Results

No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:−0.35; p:0.02), Luteinizing Hormone (r:−0.35; p:0.03), FSH (r:−0.37; p:0.02), and (17)estradiol (r: −0.36; p:0.02).

Conclusions

We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small.

In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

http://ift.tt/2ncr17f

Molecular effects of fractional ablative erbium:YAG laser treatment with multiple stacked pulses on standardized human three-dimensional organotypic skin models

Abstract

The molecular changes in gene expression following ablative laser treatment of skin lesions, such as atrophic scars and UV-damaged skin, are not completely understood. A standardized in vitro model of human skin, to study the effects of laser treatment on human skin, has been recently developed. Therefore, the aim of the investigation was to examine morphological and molecular changes caused by fractional ablative erbium:YAG laser treatment on an in vitro full-thickness 3D standardized organotypic model of human skin. A fractional ablative erbium:YAG laser was used to irradiate organotypic human 3D models. Laser treatments were performed at four different settings using a variety of stacked pulses with similar cumulative total energy fluence (60 J/cm²). Specimens were harvested at specified time points and real-time PCR (qRT-PCR) and microarray studies were performed. Frozen sections were examined histologically. Three days after erbium:YAG laser treatment, a significantly increased mRNA expression of matrix metalloproteinases and their inhibitors (MMP1, MMP2, MMP3, TIMP1, and TIMP2), chemokines (CXCL1, CXCL2, CXCL5, and CXCL6), and cytokines such as IL6, IL8, and IL24 could be detected. qRT-PCR studies confirmed the enhanced mRNA expression of IL6, IL8, IL24, CXCLs, and MMPs. In contrast, the mRNA expression of epidermal differentiation markers, such as keratin-associated protein 4, filaggrin, filaggrin 2, and loricrin, and antimicrobial peptides (S100A7A, S100A9, and S100A12) as well as CASP14, DSG2, IL18, and IL36β was reduced. Four different settings with similar cumulative doses have been tested (N10%, C10%, E10%, and W25%). These laser treatments resulted in different morphological changes and effects on gene regulations. Longer pulse durations (1000 μs) especially had the strongest impact on gene expression and resulted in an upregulation of genes, such as collagen-1A2, collagen-5A2, and collagen-6A2, as well as FGF2. Histologically, all treatment settings resulted in a complete regeneration of the epidermis 3 days after irradiation. Fractional ablative erbium:YAG laser treatment with a pulse stacking technique resulted in histological alterations and shifts in the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling depending on the treatment setting applied. A standardized in vitro 3D model of human skin proved to be a useful tool for exploring the effects of various laser settings both on skin morphology and gene expression during wound healing. It provides novel data on the gene expression and microscopic architecture of the exposed skin. This may enhance our understanding of laser treatment at a molecular level.

http://ift.tt/2mvgqAl

A split-face comparison of Q-switched Nd:YAG 1064-nm laser for facial rejuvenation in Nevus of Ota patients

Abstract

We aimed to investigate the efficacy and safety of using the 1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (QSNYL) for skin rejuvenation in patients with Nevus of Ota. A retrospective, randomized, split-faced, clinical study was conducted. Twenty-nine patients with unilateral moderate to severe Nevus of Ota were enrolled. The participants completed 3–13 sessions of QSNYL treatments 3–6 months apart. Two independent physicians compared the treated and untreated sides of the face to evaluate the clearance of Nevus of Ota, the wrinkle severity rating scale (WSRS), the global aesthetic improvement scale (GAIS), and adverse event reporting. Patients' satisfaction levels were also considered. Of the 29 patients, 28 (96.6%) achieved nearly complete pigmentation clearance. After an average of 7.76 ± 2.99 sessions, statistically significant improvement in wrinkles and skin texture were observed, compared with the untreated side. The degree of skin rejuvenation was positively correlated with the number of treatment sessions. No clinically adverse effects were observed. Repeated QSNYL treatments not only remove the pigment in Nevus of Ota effectively and safely but also improve facial rejuvenation.

http://ift.tt/2mQFGUk

RECENT ADVANCES IN GENITOURINARY TUMORS: A REVIEW FOCUSED ON BIOLOGY AND SYSTEMIC TREATMENT

Publication date: Available online 14 March 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Aránzazu González del Alba, José Ángel Arranz, Javier Puente, María José Méndez-Vidal, Enrique Gallardo, Enrique Grande, Begoña Pérez-Valderrama, Enrique González-Billalabeitia, Martín Lázaro-Quintela, Álvaro Pinto, Nuria Lainez, Josep M. Piulats, Emilio Esteban, José Pablo Maroto Rey, Jorge A. García, Cristina Suárez
Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.



http://ift.tt/2m2ryc5

Effects of androgen receptor mutation on testicular histopathology of patient having complete androgen insensitivity

Abstract

Androgens are required for normal male sex differentiation and development of male secondary sexual characteristics. Mutations in AR gene are known to cause defects in male sexual differentiation. In current study, we enrolled a 46,XY phenotypically female patient bearing testes in inguinal canal. DNA sequencing of the AR gene detected a missense mutation C.1715A > G (p. Y572C) in exon 2 which is already known to cause complete androgen insensitivity syndrome (CAIS). We focused on the effects of this mutation on the testicular histopathology of the patient. Surface spreading of testicular tissues showed an absence of spermatocytes while H&E staining showed that seminiferous tubules predominantly have only Sertoli cells. This meiotic failure is likely due to the effect of the AR mutation which ultimately leads to Sertoli cell only syndrome. Tubules were stained with SOX9 and AMH which revealed Sertoli cells maturation arrest. Western blot and realtime PCR data showed that patient had higher levels of AMH, SOX9 and inhibin-B in the testis. Therefore, we suggest that the dysfunctioning of AR by mutation enhances AMH expression which ultimately leads to the failure in maturation of Sertoli cells.

http://ift.tt/2mQwQ9f

Comparison of the effectiveness of soil heating prior or during in situ chemical oxidation (ISCO) of aged PAH-contaminated soils

Abstract

Thermal treatments prior or during chemical oxidation of aged polycyclic aromatic hydrocarbon (PAH)-contaminated soils have already shown their ability to increase oxidation effectiveness. However, they were never compared on the same soil. Furthermore, oxygenated polycyclic aromatic hydrocarbons (O-PACs), by-products of PAH oxidation which may be more toxic and mobile than the parent PAHs, were very little monitored. In this study, two aged PAH-contaminated soils were heated prior (60 or 90 °C under Ar for 1 week) or during oxidation (60 °C for 1 week) with permanganate and persulfate, and 11 O-PACs were monitored in addition to the 16 US Environmental Protection Agency (US EPA) PAHs. Oxidant doses were based on the stoichiometric oxidant demand of the extractable organic fraction of soils by using organic solvents, which is more representative of the actual contamination than only the 16 US EPA PAHs. Higher temperatures actually resulted in more pollutant degradation. Two treatments were about three times more effective than the others: soil heating to 60 °C during persulfate oxidation and soil preheating to 90 °C followed by permanganate oxidation. The results of this study showed that persulfate effectiveness was largely due to its thermal activation, whereas permanganate was more sensitive to PAH availability than persulfate. The technical feasibility of these two treatments will soon be field-tested in the unsaturated zone of one of the studied aged PAH-contaminated soils.

http://ift.tt/2muGOKZ

Biodiversity effects on resource use efficiency and community turnover of plankton in Lake Nansihu, China

Abstract

The relationship between biodiversity and ecosystem functioning is a central issue in ecology, especially in aquatic ecosystems due to the ecophysiological characteristics of plankton. Recently, ecologists have obtained conflicting conclusions while analyzing the influence of species diversity on plankton resource use efficiency (RUE) and community turnover. In this study, both phytoplankton and zooplankton communities were investigated seasonally from 2011 to 2013 in Lake Nansihu, a meso-eutrophic and recovering lake in China. The effects of phytoplankton diversity on RUE of phytoplankton (RUE_PP), zooplankton (RUE_ZP), and community turnover were analyzed. Results showed that both phytoplankton species richness and evenness were positively correlated with RUE_PP. RUE_ZP had a negative relationship with phytoplankton species richness, but a weak unimodal relationship with phytoplankton evenness. Cyanobacteria community had the opposite influence on RUE_PP and RUE_ZP. Thus, cyanobacteria dominance will benefit RUE_PP in eutrophic lakes, but the growth and reproduction of zooplankton are greatly limited. The strong negative relationship between total phosphorus and RUE_ZP confirmed these results. Phytoplankton community turnover tended to decrease with increasing phytoplankton evenness, which was consistent with most previous studies. The correlation coefficient between phytoplankton species richness and community turnover was negative, but not significant (p > 0.05). Therefore, phytoplankton community turnover was more sensitive to the variation of evenness than species richness. These results will be helpful in understanding the effects of species diversity on ecosystem functioning in aquatic ecosystems.

http://ift.tt/2muJGrc

Life cycle analysis of perfluorooctanoic acid (PFOA) and its salts in China

Abstract

China has been the largest producer and emitter of perfluorooctanoic acid and its salts (PFOA/PFO). However, the flows of PFOA/PFO from manufacture and application to the environment are indistinct, especially flows from waste treatment sites to the environment. Here, a life cycle analysis of PFOA/PFO is conducted in which all major flows of PFOA/PFO have been characterized for 2012. Processes related to uses and possible releases of PFOA/PFO include manufacture and use, waste management, and environmental storage. During manufacture and use, emission from application was the most important (117.0 t), regardless of whether it flowed first to waste treatment facilities or was directly released to the environment, followed by manufacture of PFOA/PFO (3.9 t), while flows from the service life and end of life of consumer products were the lowest (1.2 t). Among five waste treatment routes, flows through wastewater treatment plants (WWTPs) were the highest (10.6 t), which resulted in 12.8 t of PFOA/PFO being emitted into the environment. Masses of PFOA/PFO emission were estimated to be 96.3 t to the hydrosphere, 25.6 t to the atmosphere, and 3.2 t to soils. Therefore, control over reduction of PFOA/PFO should focus on application of reliable alternatives and emission reduction from WWTPs using effective treatment techniques.

http://ift.tt/2m1Rjcs

Time-lapse effect of ancient plant coal biochar on some soil agrochemical parameters and soil characteristics

Abstract

Biochar is a solid material obtained from reductive, oxygen-free processes, i.e. the thermo-chemical conversion of biomass in oxygen-limited environment. The obtained products have high carbon sequestration potential and strong nutrient-water absorption capacities because of the enlarged carbon surfaces. It is not yet clear how carbon stimulates agrochemical parameters in soil and how those characteristics are developing as time goes on a long-term basis. Samples of ancient (25, 35, 80 years old) plant coal-affected soils were collected in a temperate deciduous forest site located in the south part of the Bükk Mountains (in North Eastern Hungary). Physical–chemical soil characteristics, such as soil pH, cation exchange capacity (CEC), the organic and inorganic nitrogen (NH₄⁺, NH₃⁻) and the available nutrients (P₂O₅ and K₂O), were estimated beside organic matter (SOM) content, measured by two different methods. Levels of polycyclic aromatic hydrocarbon (PAH) compounds in soil and in various biochar samples were assessed in relation with permissible limit values and potential toxicity. Positive correlation was found between the amount of available nutrients, total organic nitrogen content, cation exchange capacity and the age of plant coal-affected soils. The sample soils were exposed to continuous plant coal biochar effect for 25 years, during which macronutrients absorbed and accumulated in the plant coal surfaces. After this period, the degradation of carbon developed simultaneously with the reduction of the amount of available nutrients, till the end of the studied 80-year-affecting period. Measured CEC level indicated positive correlation with nutrient availability and the age of biochar-affected soils. Our results support the hypothesis that biochar in soil can improve its general agrochemical characteristics in relation with its persistence in a specific soil-plant system. Potential PAH content and toxicity of biochar products are key issues of developing proper application rates in sustainable agricultural practices.

http://ift.tt/2mv1suf

Sorafenib: A Review in Hepatocellular Carcinoma

Abstract

Sorafenib (Nexavar^®) is currently the only systemic agent approved for use in hepatocellular carcinoma (HCC). Its approval was based on the results of the pivotal SHARP and Sorafenib Asia-Pacific (AP) trials in Child-Pugh (CP) class A patients with advanced HCC, which showed significantly longer median overall survival (OS) and time to radiological progression (TTP) with sorafenib 400 mg twice daily than with placebo, with no significant between-group difference in the median time to symptomatic progression (TTSP). Subsequent results from real-world studies such as GIDEON also support the use of sorafenib in HCC, including in carefully selected CP class B patients, although the median OS achieved in these patients appears relatively short. Sorafenib has a well characterized tolerability and safety profile, with strategies available to prevent and manage adverse effects such as hand-foot skin reactions. In conclusion, sorafenib remains an important option for the treatment of HCC.

http://ift.tt/2noMtGj

Erratum to: Acknowledgment to reviewers—2016

http://ift.tt/2nFTbDZ

The role of Kupffer cells in hepatic diseases

Publication date: May 2017
Source:Molecular Immunology, Volume 85
Author(s): Peizhi Li, Kun He, Jinzheng Li, Zuojin Liu, Jianping Gong
Kupffer cells (KCs) constitute 80–90% of the tissue macrophages present in the body. Essential to innate and adaptive immunity, KCs are responsible for the swift containment and clearance of exogenous particulates and immunoreactive materials which are perceived as foreign and harmful to the body. Similar to other macrophages, KCs also sense endogenous molecular signals that may result from perturbed homeostasis of the host. KCs have been implicated in host defense and the pathogenesis of various hepatic diseases, including endotoxin tolerance, liver transplantation, nonalcoholic fatty liver disease, and alcoholic liver disease. In this review, we summarized some novel findings associated with the role of KCs in hepatic diseases, such as the origin and mechanisms KCs polarization, molecular basis for caspase-1 activation called "non-canonical inflammasome pathway" involving the cleavage of Gsdmd by caspase-11, the important role of microRNA in liver transplantation, and so on. A better understanding of KCs biological characteristics and immunologic function in liver homeostasis and pathology may pave the way to investigate new diagnostic and therapeutic approaches for hepatic diseases.



http://ift.tt/2mtNb14

Gene delivery of TIPE2 inhibits breast cancer development and metastasis via CD8+ T and NK cell-mediated antitumor responses

Publication date: May 2017
Source:Molecular Immunology, Volume 85
Author(s): Zhenhua Zhang, Li Liu, Shousong Cao, Yizhun Zhu, Qibing Mei
Breast cancer is the second leading cause of cancer-related deaths in the female patients which was mainly caused by metastasis. Development of target gene therapy for breast cancer to suppress tumor progress and metastasis will improve the therapeutic options and be of great benefit to the patients. Tumor necrosis factor-alpha-induced protein 8-like 2 is a novel molecule for maintaining immune homeostasis and is involved in cancer development. In the present study, we overexpressed TIPE2 in breast cancer cells to investigate the role of TIPE2 in the development of breast cancer. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of 4T1 cells in vitro and in vivo. We constructed a non-viral targeted gene therapeutic system by using the minicircle plasmids expressing TIPE2. We found that the growth and metastasis of breast cancer was significantly inhibited by hydrodynamic gene delivery of TIPE2 plasmids in vivo. Mechanistically, TIPE2 increased T and NK cells, and decreased MDSCs. Gene delivery of TIPE2 up-regulated the production of IFN-γ and TNF-α by CD8⁺ T and NK cells in spleens and tumor microenvironment, and enhanced the cytotoxic activity of CD8⁺ T and NK cells. Taken together, TIPE2 inhibited breast cancer development and metastasis possibly via promoting CD8⁺ T and NK cell-mediated antitumor immune responses. Thus, the results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy.



http://ift.tt/2mPiHJx

Development of PARP inhibitors in gynaecological malignancies

Publication date: Available online 14 March 2017
Source:Current Problems in Cancer
Author(s): Yvonne LE Ang, David SP Tan
PARP inhibitors demonstrate synthetic lethality in tumours with BRCA1/2 mutations and other homologous recombination repair deficiencies by interfering with DNA repair and causing direct toxicity to DNA through PARP trapping. PARP inhibitors have been shown to be beneficial in the treatment of BRCA1/2 mutated ovarian cancers, which has led to a shift in the treatment paradigm of this disease. Further studies to establish the role of PARP inhibitors during earlier stages of treatment are ongoing. The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including use in the neoadjuvant and adjuvant settings. PARP inhibitor combination strategies with chemotherapy, targeted agents, radiotherapy and immunotherapy are also being explored. The role of predictive biomarkers, including molecular signatures and homologous recombination deficiency scores based on loss of heterozygosity and other structural genomic aberrations will be crucial to improved patient stratification in order to enhance the clinical utility of PARP inhibitors. This may also allow the use of PARP inhibitors to be extended beyond tumours with specific homologous recombination DNA repair gene mutations in the future. An improved understanding of the mechanisms underlying PARP inhibitor resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which patients we should be treating with PARP inhibitors and where these agents should come in over the course of treatment.



http://ift.tt/2mtxhCR

Influence of long-term chronic exposure and weather conditions on Scots pine populations

Abstract

Over a period of 8 years (2007–2014), we were evaluating seed quality and morphological abnormalities in Scots pine trees affected as a result of the Chernobyl accident. The calculated dose rates for the trees at the study sites varied from background values at the reference sites to 40 mGy/year at the most contaminated site. We investigated whether radioactive contamination and/or weather factors could decrease the reproductive capacity or increase the frequency of morphological abnormalities of needles in pine trees. Scots pine seeds are characterized by high interannual variability of viability, which is largely determined by weather conditions. No consistent differences in reproductive capacity were detected between the impacted and reference populations. Brachyblasts with three needles were found only in the affected populations; however, their frequency was very low and only at the very border of significance at the p < 0.10 level.

http://ift.tt/2mJPXjN

A comparative analysis of composts and vermicomposts derived from municipal solid waste for the growth and yield of green bean ( Phaseolus vulgaris )

Abstract

This work was conducted to evaluate and compare the responses of Phaseolus vulgaris to three types of composts and vermicomposts derived from municipal solid waste (MSW). Different amendment rates were used and evaluated for their effect on germination, growth, and marketable yield. MSW-derived vermicomposts and composts were substituted into mineral brown-earth soil, applied at rates of 0 (control), 10, 20, 30, 40, 50, and 100% (v/v) in plastic pots of 7.2-L capacity. Green beans which are grown in 40% vermicompost/soil mixtures and compost/soil mixtures yielded 78.3–89.5% higher fruit weights as compared to control. Results showed that MSW vermicomposts consistently outperformed equivalent quantities of composts in terms of fruit yield, shoot, and root dry weights, which can be attributed to the contributions of physicochemical properties and nutrients content (N, P, and K) in the potting experiments. Consequently, it seemed likely that MSW vermicompost provided other biological inputs such as plant growth regulators (PGRs) and plant growth hormones (PGHs), which could have a considerably positive effect on the growth and yields of P. vulgaris as compared to composts. More in-depth scientific investigation is required in order to identify the distinctive effects and the exact mechanisms of these PGRs in MSW vermicomposts which influenced plant growth responses.

http://ift.tt/2m11FJL

PM2.5 emissions from different types of heavy-duty truck: a case study and meta-analysis of the Beijing-Tianjin-Hebei region

Abstract

Beijing-Tianjin-Hebei (BTH) region in China is affected seriously by the hazy weather that has a large impact on human health. PM_2.5 is one of the most important reasons for hazy weather. Understanding the PM_2.5 emission characteristics from different types of heavy-duty trucks (HDTs) is valuable in policies and regulations to improve urban air quality and mitigate vehicle emission in China. The investigation and analysis on HDT population and PM_2.5 emission in BTH region are carried out. The results show that the population and PM_2.5 emission of HDTs in BTH has risen for the last four consecutive years, from 404 thousand and 1795 tons in 2012 to 551 thousand and 2303 tons in 2015. The PM_2.5 emission from HDTs in Hebei is about 10 times more than that of Beijing and 9 times more than that of Tianjin. The proportion of natural gas HDTs is about 5%; however, its PM_2.5 emission only accounts for 0.94% in 2015, which indicates the utilization of HDTs powered by natural gas facilitate PM_2.5 mitigation more than diesel in BTH. The tractor and pickup trucks are the main source of PM_2.5 emission from different types of HDT, while special and dump trucks are relatively clean. This study has provided insights for management method and policy-making of vehicle in terms of environmental demand.

http://ift.tt/2mJXyi7

Plant growth in amended molybdenum mine waste rock

Abstract

This greenhouse study examined the use of organic and inorganic soil amendments in waste rock material from the former Questa Molybdenum Mine in northern New Mexico to promote beneficial soil properties. Waste rock material was amended with 11 soil amendment treatments that included municipal composted biosolids, Biosol®, inorganic fertilizer, and two controls (pure waste rock and sand). Elymus trachycaulus and Robinia neomexicana growth performance and plant chemistry were assessed across all treatments over a period of 99 and 141 days, respectively. Even though waste rock material had more than 200 times the molybdenum concentration of native soils, adverse effects were not observed for either species. The two main limiting factors in this study were soil nutritional status and soil water retention. The biosolid amendment was found to provide the greatest buffer against these limiting factors due to significant increases in both nutrition and soil water retention. As a result, both species responded with the highest levels of biomass production and the least amount of required water demands. Use of organic amendments such as biosolids, even though short lived in the soil, may provide plants the necessary growth stimulus to become more resilient to the harsh conditions found on many mine reclamation sites.

http://ift.tt/2m12thG

Temporal and spatial distributions of PBDEs in atmosphere at Shanghai rural regions, China

Abstract

Atmospheric samples were collected using polyurethane foam (PUF) passive air sampling device for every 3 months from June 2012 to May 2013 in Shanghai rural regions in order to investigate the concentrations, profiles, spatial distributions, and seasonal variations of polybrominated diphenyl ethers (PBDEs). Twelve PBDE congeners (BDE-17, BDE-28, BDE-47, BDE-49, BDE-66, BDE-85, BDE-99, BDE-100, BDE-138, BDE-153, BDE-154, and BDE-183) were measured and analyzed by GC-MS. The results showed that detectable PBDEs were examined in all air samples, which indicated that these pollutants are widespread in the research areas. The ∑₁₂PBDE concentrations in Shanghai rural air ranged from 4.49 to 77.5 pg m⁻³, with mean value up to 26.7 pg m⁻³. The highest concentration was found at Jinshan sampling site in summer (from June to August in 2012). Furthermore, among the PBDE compounds investigated, the most frequently detected and the major congeners were BDE-17, BDE-28, BDE-47, and BDE-99. And the lower brominated diphenyl ethers (accounting for 75.0%) were the majority of the PBDE congeners. Finally, the result of principal component analysis (PCA) revealed that the lower and higher brominated diphenyl ethers in Shanghai rural regions were emitted from different pollutant sources.

http://ift.tt/2mJVO8A

Utility of thermo-alkali-stable γ-CA from polyextremophilic bacterium Aeribacillus pallidus TSHB1 in biomimetic sequestration of CO 2 and as a virtual peroxidase

Abstract

Aeribacillus pallidus TSHB1 polyextremophilic bacterium produces a γ-carbonic anhydrase (ApCA), which is a homotrimeric biocatalyst with a subunit molecular mass of 32 ± 2 kDa. The enzyme is stable in the pH range between 8.0 and 11.0 and thus alkali-stable and moderately thermostable with T_1/2 values of 40 ± 1, 15 ± 1, and 8 ± 0.5 min at 60, 70, and 80 °C, respectively. Activation energy for irreversible inactivation "E _d " of carbonic anhydrase is 67.119 kJ mol⁻¹. The enzyme is stable in the presence of various flue gas contaminants such as SO₃²⁻,SO₄²⁻, and NO₃⁻ and cations Mg²⁺, Mn²⁺, Ca²⁺, and Ba²⁺. Fluorescence studies in the presence of N-bromosuccinimide and fluorescence quenching using KI and acrylamide revealed the importance of tryptophan residues in maintaining the structural integrity of the enzyme. ApCA is more efficient than the commercially available bovine carbonic anhydrase (BCA) in CO₂ sequestration. The enzyme was successfully used in biomineralization of CO₂ from flue gas. Replacement of active site Zn²⁺ with Mn²⁺ enabled ApCA to function as a peroxidase which exhibited alkali-stability and moderate thermostability like ApCA.

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Thawing Human Milk for Hospitalized Infants: Use of a Laboratory Bead Bath May Be an Effective Method for Large Quantities

Publication date: Available online 15 March 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Caroline Steele, Brittnee Gonzalez, Wendi Gornick




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No Fat, No Sugar, No Salt . . . No Problem? Prevalence of “Low-Content” Nutrient Claims and Their Associations with the Nutritional Profile of Food and Beverage Purchases in the United States

Publication date: Available online 15 March 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Lindsey Smith Taillie, Shu Wen Ng, Ya Xue, Emily Busey, Matthew Harding
BackgroundNutrient claims are a commonly used marketing tactic, but the association between claims and nutritional quality of products is unknown. The objective of this study was to examine trends in the proportion of packaged food and beverage purchases with a nutrient claim, whether claims are associated with improved nutritional profile, and whether the proportion of purchases with claims differs by race/ethnicity or socioeconomic status.MethodsThis cross-sectional study examined nutrient claims on more than 80 million food and beverage purchases from a transaction-level database of 40,000 US households from 2008 to 2012. χ² Tests were used to examine whether the proportion of purchases with a low/no-content claim changed over time or differed by race/ethnicity or household socioeconomic status. Pooled transactions were examined using t-tests to compare products' nutritional profiles overall and by food and beverage group.ResultsThirteen percent of food and 35% of beverage purchases had a low-content claim. Prevalence of claims among purchases did not change over time. Low-fat claims were most prevalent for both foods and beverages (10% and 19%, respectively), followed by low-calorie (3% and 9%), low-sugar (2% and 8%), and low-sodium (2% for both) claims. Compared to purchases with no claim, purchases with any low-content claim had lower mean energy, total sugar, total fat, and sodium densities. However, the association between particular claim types and specific nutrient densities varied substantially, and purchases featuring a given low-content claim did not necessarily offer better overall nutritional profiles or better profiles for the claimed nutrient, relative to products without claims. In addition, there was substantial heterogeneity in associations between claims and nutrient densities within food and beverage groups.ConclusionsVariations in nutrient density by claim type and food and beverage group suggests that claims may have differential utility for certain foods or nutrients and, in some cases, may mislead about the overall nutritional quality of the food.



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Racial/Ethnic Differences in Weight-Loss Strategies among US Adults: National Health and Nutrition Examination Survey 2007-2012

Publication date: Available online 15 March 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Becky Marquez, Rosenda Murillo
BackgroundDieting, exercising, and seeking professional help have been associated with intentional weight loss among adults.ObjectiveThis study examined the use of diet (eg, ate less, ate less fat, or switched to low-calorie foods), exercise, diet and exercise, and professional help (eg, weight-loss program or prescribed diet pills) for weight loss among non-Hispanic whites, Mexican Americans, and non-Hispanic blacks.DesignCross-sectional data from the 2007-2012 National Health and Nutrition Examination Survey were used.ParticipantsMales and females (n=9,046) aged 20 to 65 years were included.Main outcome measureThe weight history questionnaire assessed weight-loss attempts and use of weight-loss strategies in the past year.Statistical analyses performedMultivariate logistic regression models were used to estimate associations of race/ethnicity with strategies to lose weight. Models controlled for age, sex, education, and body mass index. In fully adjusted models, interactions of race/ethnicity by sex were tested.ResultsLower proportions of Mexican Americans (35%) and non-Hispanic blacks (35%) than non-Hispanic whites (39%) reported trying to lose weight. Among those who tried to lose weight, non-Hispanic blacks were less likely than non-Hispanic whites to use diet (odds ratio [OR] 0.78, 95% CI 0.67 to 0.90) or exercise (OR 0.83, 95% CI 0.70 to 0.99) for weight loss. Mexican Americans (OR 0.71, 95% CI 0.53 to 0.95) and non-Hispanic blacks (OR 0.71, 95% CI 0.52 to 0.95) were also less likely than non-Hispanic whites to use professional help for weight loss. The relationships between race/ethnicity and weight-loss strategy were stronger for females than males.ConclusionsTargeted efforts are needed to address racial/ethnic disparities in weight-loss attempts and use of recommended strategies especially among females.



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Patient-derived xenografts: A platform for accelerating translational research in prostate cancer

Publication date: Available online 15 March 2017
Source:Molecular and Cellular Endocrinology
Author(s): Alastair H. Davies, Yuzhuo Wang, Amina Zoubeidi
Recently, there has been renewed interest in the development and characterization of patient-derived tumour xenograft (PDX) models. Numerous PDX models have been established for prostate cancer and, importantly, retain the principal molecular, genetic, and histological characteristics of the donor tumour. As such, these models provide significant improvements over standard cell line xenograft models for biological studies, preclinical drug development, and personalized medicine strategies. This review summarizes the current state of the art in this field, illustrating the opportunities and limitations of PDX models in translational prostate cancer research.



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Epigenetic regulation of RET receptor tyrosine kinase and non-coding RNAs in MTC

Publication date: Available online 15 March 2017
Source:Molecular and Cellular Endocrinology
Author(s): Lauren Jin Suk Joo, Jing Ting Zhao, Matti L. Gild, Anthony R. Glover, Stan B. Sidhu
Medullary thyroid carcinoma (MTC) is an aggressive and rare cancer with limited treatment options for metastatic disease. Due to this, there is a need for a better understanding of MTC biology in the hope of improved treatments. One area of improved understanding of cancer biology is epigenetics. Epigenetics is defined as cellular processes which alter gene expression independent of changes in the primary DNA sequence. These processes include modifications such as DNA methylation, microRNA deregulation and post-translational histone modifications, all of which have been implicated in tumorigenesis of MTC. Transcription of the main driver of MTC - the REarranged during Transfection (RET) proto-oncogene can also be modulated by epigenetic alterations. This review will present a review of MTC and its epigenetic links with a particular focus on targeting epigenetic mechanisms as novel therapeutic strategies.



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The risk of cancer in the offspring and parental length of life

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Ruby Del Risco Kollerud, Karl Gerhard Blaasaas, Bjørgulf Claussen, Bente Oftedal, Øyvind Næss
BackgroundWe investigated if cancer onset in offspring is related to having short-lived parents for different cancer types and to see if there was a difference in smoking- and non-smoking related cancers.MethodsOur study included 524,391 individuals born in Norway 1940–1950. All children were followed up for cancer from the age of 20 until they were between 59 and 69 years. Parental longevity was examined by grouping parental age of death into parents dying before 75 years of age and parents dying at 75 years of age or older.ResultsAn increased risk of 1.14 (95%CI=1.10–1.19) among male offspring and 1.08 (95%CI=1.04–1.12) among female offspring was observed for total cancer when both parents died before the age of 75 compared to offspring with two long-lived parents. The highest increase was found for cancer in the lungs and trachea for both male (HR=1.67, 95%CI=1.50–1.86) and female offspring (HR=1.53, 95%CI=1.33–1.76). For other smoking-related cancers, the risk was lower. No increased risk was observed for non-smoking-related cancers.ConclusionOffspring of long-lived parents have lower risk of developing cancer compared with offspring of short-lived parents. Intergenerational transmission of risk factors from parents to offspring may play an important role, especially for tobacco-related cancers. However, genetic factors cannot be ruled out, since consistent evidence has implicated genetic factors in smoking behaviour.



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Water quality of a coastal lagoon (ES, Brazil): abiotic aspects, cytogenetic damage, and phytoplankton dynamics

Abstract

Assessment of water resources requires interdisciplinary studies that include multiple ecosystem aspects. This study evaluated the water quality of Juara Lagoon (ES, Brazil) based on physical and chemical variables, cytogenetic responses in Allium cepa and phytoplankton dynamics. Three sampling sites were defined and water samples were collected during two sampling periods. Analyses such as determination of photic zone, conductivity, and concentrations of nutrients and metals were conducted as well as cytotoxic, mutagenic, and genotoxic potentials using A. cepa test. The main attributes of phytoplankton community, such as total richness, total density, density by class, dominance, and diversity, were also evaluated. Results have revealed that Juara Lagoon has signs of artificial eutrophication at two sampling sites due to high levels of total phosphorus and ammonia nitrogen. Cytotoxic, genotoxic, and mutagenic potentials were detected as well as high concentrations of Fe and Mn. Furthermore, 165 phytoplankton taxa were recorded, with highest richness in Chlorophyceae and Cyanophyceae classes. In addition, Cyanophyceae presented as the highest density class. A. cepa test and phytoplankton community evaluation indicated that the ecological quality of Juara Lagoon is compromised.

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Phytotoxicity of effluents from swine slaughterhouses using lettuce and cucumber seeds as bioindicators

Publication date: 15 August 2017
Source:Science of The Total Environment, Volume 592
Author(s): Michel David Gerber, Thomaz Lucia, Luciara Correa, José Eduardo Pereira Neto, Érico Kunde Correa
This study evaluated the phytotoxic effects of raw and treated effluents from a swine slaughterhouse on cucumber and lettuce seeds and determined correlations among physicochemical characteristics of such effluents and the germination of seeds used as bioindicators. Physicochemical parameters were characterized for both effluents and their phytotoxicity was determined through the germination index (GI), the root length (RL) and the number of germinated seeds (SG) for both plant species. The effluents treatment system was efficient to reduce the concentration of some physicochemical parameters to levels within those recommended by the Brazilian legislation, except for P, ammoniacal N and TKN concentration. Although phytotoxicity of the treated effluent was less in comparison to the raw effluent, the GI for cucumber and lettuce seeds submitted to each of the tested effluents was lower than 80%. Thus, both effluents were phytotoxic for the tested bioindicators (p<0.05). For lettuce seeds, the GI presented negative correlations (p<0.05) with the total Kjeldahl N (−0.93) and the surfactants concentration (−0.83) in the raw effluent. The Zn concentration in the treated effluent showed a negative correlation (p<0.05) with the GI of both lettuce (−0.63) and cucumber seeds (−0.64). Therefore, effluents from swine slaughterhouses may impair the germination of the evaluated plant species if used for agricultural purposes.

Graphical abstract

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Chemistry and petrology of paired feed coal and combustion ash from anthracite-burning stoker boilers

Publication date: 1 July 2017
Source:Fuel, Volume 199
Author(s): James C. Hower, Madison M. Hood, Ross K. Taggart, Heileen Hsu-Kim
The feed coal and corresponding ash from a series of stoker boilers burning Pennsylvania anthracite were investigated for their petrographic and chemical characteristics. The coals have low-S and moderate-ash contents with similar major oxide and minor element compositions. The volatile minor elements, such as Zn and As, decrease in concentration from the feed coal to the stoker ash (comparisons on the ash basis). The light rare earth elements (La through Sm) decrease in concentration relative to the heavy rare earth elements (Eu through Lu) from the coal ash to the stoker ash.



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The role of Zn2+ dopants in the acid-basic catalysis on MgO(001) surface: Ab initio simulations of the dissociative chemisorption of R-O-R′ and R-S-R′ (R, R′=H, CH3, C2H5)

Publication date: July 2017
Source:Surface Science, Volume 661
Author(s): Carla G. Fonseca, Sérgio R. Tavares, Carla V. Soares, Bruno G. daFonseca, Fábio J.F.S. Henrique, Viviane S. Vaiss, Wladmir F. Souza, Sandra S.X. Chiaro, Renata Diniz, Alexandre A. Leitão
Ab initio calculations were performed to study the effect of the Zn²⁺ dopant on the reactivity and the catalytic activity of the MgO(001) surface toward molecular adsorption and dissociation reactions of the H2O, H2S, CH3CH2OH, CH3CH2SH and CH3SCH3 molecules. The electronic analysis showed that Zn²⁺ cation increased the reactivity of the surface locally. All molecules dissociate on both surfaces except for water and ethanol which only dissociate on the MgO:Zn(001) surface, confirming the increased reactivity in this surface. The ΔG° for the dissociation reactions of the CH3CH2SH and CH3SCH3 molecules on pure MgO(001) surface is positive in the entire temperature range. On the other hand, the ΔG° for H2S molecule is negative until 148.7°C. In the case of the MgO:Zn(001) surface, the CH3CH2SH molecule dissociates in the entire temperature range and, for H2S molecule, the dissociation is spontaneous until 349.7°C. The rate constants obtained for the dissociation reactions were very large because the reaction barriers are very low in both surfaces for all the studied molecules, except for CH3SCH3 molecule. The Zn-doped MgO(001) surface, besides being more reactive, presented a better catalytic activity than the MgO(001) surface for the dissociation of this molecule.

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Highlights

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Evaluation of CAAX prenyl protease II of Leishmania donovani as potential drug target: Infectivity and growth of the parasite is significantly lowered after the gene knockout

Publication date: 1 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 102
Author(s): Ruchika Bhardwaj, Mousumi Das, Shalini Singh, Adarsh Kumar Chiranjivi, Sitraraau Vijaya Prabhu, Sanjeev Kumar Singh, Vikash Kumar Dubey
Prenylation pathway is responsible for post translational modification of various signal proteins, including proteins of Ras superfamily. CAAX prenyl proteases are known to be key players in prenylation pathway. In the current study, we have evaluated CAAX prenyl protease II as a possible drug target against Leishmania donovani parasite, the causative agent of visceral leishmaniasis. Gene knockout strategy was employed to target CAAX prenyl protease II and subsequent effects were studied. CAAX prenyl protease II knockout resulted in significant decrease in growth and infectivity.

Graphical abstract

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Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

Conditions:   Solid Tumors;   Lymphoma
Intervention:   Drug: ASTX660
Sponsor:   Astex Pharmaceuticals
Recruiting - verified March 2017

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Nutrient Sensing and the Oxidative Stress Response

Publication date: Available online 15 March 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Hanzhi Luo, Hou-Hsien Chiang, Makensie Louw, Albert Susanto, Danica Chen
The simplicity and effectiveness of calorie restriction (CR) in lifespan and healthspan extension have fascinated generations searching for the Fountain of Youth. CR reduces levels of oxidative stress and damage, which have been postulated in the free radical theory of aging as a major cause of aging and diseases of aging. This reduction has long been viewed as a result of passive slowing of metabolism. Recent advances in nutrient sensing have provided molecular insights into the oxidative stress response and suggest that CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Physiological studies have provided strong support for oxidative stress in the development of aging-associated conditions and diseases but have also revealed the surprising requirement for oxidative stress to support normal physiological functions and, in some contexts, even slow aging and prevent the progression of cancer. Deciphering the molecular mechanisms and physiological implications of the oxidative stress response during CR will increase our understanding of the basic biology of aging and pave the way for the design of CR mimetics to improve healthspan.



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Long-Term Effective Thalamic Deep Brain Stimulation for Neuropathic Tremor in Two Patients with Charcot-Marie-Tooth Disease

Background: It has been described that many Charcot-Marie-Tooth syndrome type 2 patients are affected by a very disabling type of tremor syndrome, the pathophysiology of which remains unclear. Deep brain stimulation (DBS) has been successfully applied to treat most types of tremors by implanting electrodes in the ventral intermediate nucleus of the thalamus (Vim). Methods: We used DBS applied to the Vim in 2 patients with severe axonal inherited polyneuropathies who developed a disabling tremor. Results: Both patients responded positively to stimulation, with a marked reduction of the tremor and with an improvement of their quality of life. Conclusion: We report 2 cases of tremor associated with a hereditary neuropathy with a good response to DBS.
Stereotact Funct Neurosurg 2017;95:102-106

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Comparative analysis of trabecular bone structure and orientation in South African hominin tali

Publication date: May 2017
Source:Journal of Human Evolution, Volume 106
Author(s): Anne Su, Kristian J. Carlson
Tali of several hominin taxa are preserved in the fossil record and studies of the external morphology of these often show a mosaic of human-like and ape-like features. This has contributed to a growing recognition of variability characterizing locomotor kinematics of Australopithecus. In contrast, locomotor kinematics of another Plio-Pleistocene hominin, Paranthropus, are substantially less well-documented, in part, because of the paucity of postcranial fossils securely attributed to the genus. Since the talus transmits locomotor-based loads through the ankle and its internal structure is hypothesized to reflect accommodation to such loads, it is a cornerstone structure for reconstructing locomotor kinematics. Here we quantify and characterize trabecular bone morphology within tali attributed to Australopithecus africanus (StW 102, StW 363, StW 486) and Paranthropus robustus (TM 1517), making quantitative comparisons to modern humans, extant non-human apes, baboons, and a hominin talus attributed to Paranthropus boisei (KNM-ER 1464). Using high-resolution images of fossil tali (25 μm voxels), nine trabecular bone subregions of interest beneath the articular surface of the talar trochlea were segmented to quantify localized patterns in distribution and primary strut orientation. It was found that trabecular strut orientation and shape, in some cases, can discriminate amongst species characterized by different locomotor foot kinematics. Discriminant function analyses using standard trabecular bone structural properties align TM 1517 with Pan and Gorilla, while other hominin tali structurally most resemble those of baboons. In primary strut orientation, Paranthropus tali (KNM-ER 1464 and TM 1517) resemble the human condition in the anterior-medial subregion, where strut orientation appears positioned to distribute compressive loads medially and distally toward the talar head. In A. africanus tali (particularly StW 486), primary strut orientation in this region resembles that of apes. These results suggest that Paranthropus may have had a human-like medial weight shift during the last half of stance phase but Australopithecus did not.



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Single-grain OSL chronologies for the Still Bay and Howieson's Poort industries and the transition between them: Further analyses and statistical modelling

Publication date: June 2017
Source:Journal of Human Evolution, Volume 107
Author(s): Zenobia Jacobs, Richard G. Roberts
The chronology of the Still Bay (SB) and Howieson's Poort (HP) lithic industries remains an issue of keen interest because of the central role of these two phases of technological and behavioural innovation within the Middle Stone Age of southern Africa. Several dating studies have been conducted on SB and HP sites, including a pair published by the present authors and our colleagues in 2008 and 2013. These reported the results of systematically applying single-grain optically stimulated luminescence (OSL) dating procedures to 10 sites in South Africa, Lesotho and Namibia to constrain the timing of the start and end of the SB and HP and reveal the existence of a gap of several millennia between them. Alternative ages for these two industries have since been proposed by others for one of these South African sites (Diepkloof Rockshelter) and some concerns have been raised about the procedures used in our earlier studies to estimate the beta dose rates for a small number of samples. Here, we provide an update on our chronology for the SB and HP and address the issues raised about the methods that we used previously to estimate the beta dose rates and their associated uncertainties. To test the sensitivity of our new SB and HP ages to different underlying assumptions, we have run the same statistical model as that used in our 2008 and 2013 studies under three different scenarios. We show that the ages for the different samples are insensitive to how we analytically process or statistically model our data, and that our earlier conclusions about timing of the start and end of the SB and the HP and the probability of a gap between them remain true for two of the three scenarios. We conclude by bringing our study into the context of additional chronometric, stratigraphic and lithic technology studies that have been conducted in the intervening decade.



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A comprehensive micromechanical modeling of electro-thermo-mechanical behaviors of CNT reinforced smart nanocomposites

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): M.J. Mahmoodi, M. Vakilifard
Electro-thermo-elastic properties of CNT reinforced smart nanocomposites are predicted by a micromechanical method newly developed for piezoelectric and dielectric effects in the present study. The CNT is replaced by an effective rigorous carbon fiber and interphase demonstrating the van der Waals interactions. The CNTs regular and random arrangement within the matrix are taken into account. CNT reinforced PVDF (CNTRPVDF) nanocomposite is considered. Validation of the presented method is carried out by available experimental and theoretical studies. The effects of interphase thickness and Young's modulus, CNT volume fraction (CNTVF), orientation and aspect ratio on the effective properties of CNTRPVDF are examined. Results show that difference between random and square packing are negligible for the thermo-elastic properties while the difference is more pronounced for the piezoelectric properties. It is found that interphase region has a significant influence on the effective properties. Whereas, its influence on longitudinal properties is much greater than transverse properties. The orientation of CNTs plays an important role in the effective properties. An optimum CNT angle for maximum value of any property is reported. The results also state that the short CNTs with aspect ratios more than 100 can be treated as long CNTs for most of the properties.

Graphical abstract

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Towards robust design of thin film transition edge sensors for use in the next-generation superconducting radio frequency cavities

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Alexander Lunt, Zsolt Kovács, Hernán Furci, Torsten Koettig, Floriane Léaux, Giovanna Vandoni
In order to increase the accelerating gradient, the next-generation of Superconducting Radio Frequency (SRF) cavities will be operated with superfluid helium cooling. This upgrade requires the development of a state-of-the-art cryogenic temperature mapping system, which can be used to identify quench initiation in new cavities, and thereby assess their suitability for installation. This paper presents a new mapping system based on an array of Transition Edge Sensors (TESs): electrical devices that exploit the superconducting transition of a thin film to identify temperature changes.The TES array is manufactured using photolithography to deposit a thin film on a 100mm diameter glass wafer. Two different designs of Au-Sn TES have been assessed; Design 1 was composed of a 10nm Cr adhesive layer, followed by 20nm of Au and 100nm of Sn, and Design 2 was identical except that the Cr layer was not applied.Design 1 showed excellent film adherence, however no superconducting transition was observed. In contrast, Design 2 showed poor film bonding but a superconducting transition. These insights are being used to design a new cryogenic temperature mapping device that combines Design 1 for robust electrical contacts and Design 2 for second sound detection.

Graphical abstract

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Effects of SiC interphase on the mechanical and ablation properties of C/C-ZrC-ZrB2-SiC composites prepared by precursor infiltration and pyrolysis

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Mao-yan Zhang, Ke-zhi Li, Xiao-hong Shi, Wen-long Tan
Carbon/Carbon (C/C) composites modified with ZrC-ZrB2-SiC particles were prepared by precursor infiltration and pyrolysis (PIP) process. Effects of SiC interphase on the mechanical and ablation properties of C/C-ZrC-ZrB2-SiC composites were investigated. The SiC interphase was deposited through low pressure chemical vapor infiltration (LPCVI). It was found that as the SiC interphase was introduced into the modified C/C composites, the flexural strength increased by 24% and the failure mode showed brittle fracture. The mechanisms for the strengthening of the modified C/C composites with SiC interphase were identified as (I) the deposition of SiC interphase in short-cut webs that strengthened the bonding between fibers and matrix promoting to stress transfer, and (II) the production of weak bonding between fiber bundles and matrix in non-woven webs improved the utilization of carbon fiber strength. SiC interphase increased adhesion between the ablation products and matrix, it could enhance the ablation resistance of the modified C/C composites in short term under the action of the evaporation. However, the long-time ablation resistance was reduced since the ceramic particles could not be incorporated into the composites during preparation due to the existence of SiC interphase.

Graphical abstract

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Continuous nanobelts of nickel oxide–cobalt oxide hybrid with improved capacitive charge storage properties

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Midhun Harilal, Syam G. Krishnan, Bincy Lathakumary Vijayan, M. Venkatashamy Reddy, Stefan Adams, Andrew R. Barron, Mashitah M. Yusoff, Rajan Jose
This paper reports the synthesis of continuous nanobelts, whose thickness is less than half of its pore diameter, of a material hybrid composing of nanograins of nickel oxide and cobalt oxide by electrospinning technique and their capacitive charge storage properties. While the constituent binary metal oxides (NiO and Co3O4) formed solid cylindrical nanofibers the hybrid and a stoichiometric compound in the Ni-Co-O system, i.e., spinel-type NiCo2O4, formed as thin nanobelts due to the magnetic interaction between nickel and cobalt ions. The nanobelts showed six-fold larger surface area, wider pores, and impressive charge storage capabilities compared to the cylindrical fibres. The hybrid nanobelts showed high specific capacitance (CS~1250Fg⁻¹ at 10Ag⁻¹ in 6M KOH) with high capacity retention, which is appreciably larger than found for the stoichiometric compound (~970Fg⁻¹ at 10Ag⁻¹). It is shown that the hybrid nanobelts have lower internal resistance (1.3Ω), higher diffusion coefficient (4.6×10⁻¹³cm²s⁻¹) and smaller relaxation time (0.03s) than the benchmark materials studied here.

Graphical abstract

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Tung oil based plasticizer and auxiliary stabilizer for poly(vinyl chloride)

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Mei Li, Shouhai Li, Jianling Xia, Chengxiang Ding, Mei Wang, Lina Xu, Xiaohua Yang, Kun Huang
A tung oil derived epoxidized dicarboxylic acid dimethyl ester (epoxidized-C21-DAE), was synthesized through transesterification, a Diels-Alder reaction, and epoxidation. The chemical structure of the epoxidized-C21-DAE was confirmed using Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H NMR) and carbon-13 nuclear magnetic resonance (¹³C NMR). The thermal and migration stabilities and the mechanical properties of PVC samples were investigated using discoloration, tensile, exudation, volatility, and extraction tests as well as thermal gravity analysis (TGA), TGA–FTIR analysis, and dynamic mechanical analysis (DMA). The petroleum-based plasticizer, dioctyl terephthalate (DOTP), and the biobased plasticizer, epoxidized fatty acid methyl ester (EFAME), were chosen as controls and their properties compared with epoxidized-C21-DAE. The application of epoxidized C21-DAE as a biobased, primary plasticizer for poly(vinyl chloride) significantly improved PVC thermal stability over that of DOTP and EFAME. The mechanical properties of this type of PVC were superior to those of DOTP. In addition, the migration and volatility stabilities of epoxidized-C21-DAE were much better than EFAME. Epoxidized-C21-DAE could, therefore, be fully substituted for commercial DOTP or EFAME. Tung oil derived epoxidized-C21-DAE has good potential as a primary PVC plasticizer.

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Effect of incremental equal channel angular pressing (I-ECAP) on the microstructural characteristics and mechanical behaviour of commercially pure titanium

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Muhammad Jawad Qarni, Giribaskar Sivaswamy, Andrzej Rosochowski, Sonia Boczkal
Incremental equal channel angular pressing (I-ECAP) is one of the continuous severe plastic deformation (SPD) processes. This paper presents the processing of commercial purity titanium (CP-Ti) using a double billet variant of I-ECAP process. Ultrafine-grain (UFG) structure was successfully achieved after six passes of I-ECAP at 300°C. Microstructural evolution and texture development were tracked using EBSD. Analysis revealed continuous dynamic recrystallization (CDRX) as one of the grain refinement mechanism during processing. Room temperature tensile tests carried out before and after six passes, shows significant increase in strength with acceptable levels of ductility. The yield strength was increased from 308 to 558MPa and ultimate tensile strength from 549 to 685MPa. Compression tests conducted at different strain rates shows considerable increase in strength and enhanced strain rate sensitivity after processing. A distinct three-stage strain hardening was observed during compression. However the processed material displayed a loss in strain hardening ability during tensile as well as in compression tests. Detailed microhardness measurements show the evolution of hardness after subsequent passes with a reasonable level of homogeneity after the sixth pass. It is demonstrated that I-ECAP is an effective method for grain refinement in CP-Ti and subsequently improving its mechanical properties.

Graphical abstract

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Emergent Awake Intubation

http://orl-agios.blogspot.com/2017/03/emergent-awake-intubation.html

https://youtu.be/MsHTJ_r-Jzo?t=2

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Na-Yiyuan Wu, Hsuan-Shun Huang, Tung Hui Chao, Hsien Ming Chou, Chao Fang, Chong-Zhen Qin, Chueh-Yu Lin, Tang-Yuan Chu, Hong Hao Zhou
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53^−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

Graphical abstract

Teaser

Ovarian high-grade serous carcinomas (HGSOC) originate mainly from the fallopian tube epithelium and exclusively carry early TP53 mutations. Wu et al. find that progesterone, acting via its receptor, induces necroptosis of p53-deficient tubal epithelial cells. Supplementation of progesterone in diestrus further augments this clearance, suggesting that progesterone may be chemopreventive for HGSOC.


http://ift.tt/2mZ2XUL

T Follicular Helper Cells Promote a Beneficial Gut Ecosystem for Host Metabolic Homeostasis by Sensing Microbiota-Derived Extracellular ATP

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Lisa Perruzza, Giorgio Gargari, Michele Proietti, Bruno Fosso, Anna Maria D'Erchia, Caterina Elisa Faliti, Tanja Rezzonico-Jost, Daniela Scribano, Laura Mauri, Diego Colombo, Giovanni Pellegrini, Annalisa Moregola, Catherine Mooser, Graziano Pesole, Mauro Nicoletti, Giuseppe Danilo Norata, Markus B. Geuking, Kathy D. McCoy, Simone Guglielmetti, Fabio Grassi
The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer's patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis. The results of this study indicate that Tfh cells play a role in host-microbiota mutualism beyond protecting the intestinal mucosa by induction of affinity-matured IgA and suggest that extracellular ATP constitutes an inter-kingdom signaling molecule important for selecting a beneficial microbial community for the host via P2X7-mediated regulation of B cell help.

Graphical abstract

Teaser

Gut commensals contribute to host metabolic homeostasis. ATP released by bacteria limits IgA secretion in the small intestine via the P2X7 receptor expressed in T follicular helper cells. Perruzza et al. show that this regulatory mechanism is important for shaping a diverse microbiota that promote host metabolic homeostasis.


http://ift.tt/2mZlf8b

Extracellular Glutamate in the Nucleus Accumbens Is Nanomolar in Both Synaptic and Non-synaptic Compartments

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Delia N. Chiu, Craig E. Jahr
In the CNS, glutamate is both phasically and tonically released into the extracellular space and must be removed by excitatory amino acid transporters (EAATs) to prevent excitotoxic accumulation. There remains uncertainty, however, regarding the functional steady-state concentration, with estimates ranging from tens of nanomolar to tens of micromolar. Efforts to reconcile these disparate values have led to a hypothesis that the extracellular space comprises distinct compartments in which basal glutamate concentrations are maintained independently. We used electrophysiology and two-photon Ca²⁺ imaging to test this hypothesis in the nucleus accumbens (NAc), where it has been proposed that micromolar extracellular glutamate is necessary for normal function. We found that the average concentration of synaptic glutamate is nanomolar, in agreement with previous electrophysiological estimates. Furthermore, this held true when glutamate uptake was inhibited, indicating that extracellular glutamate is not compartmentalized by EAATs.

Graphical abstract

Teaser

Glutamate is present in the extracellular space surrounding neurons, but it is unclear whether the steady-state concentration in synaptic and non-synaptic areas is the same. Chiu and Jahr show that basal extracellular glutamate is nanomolar, both inside and outside the synaptic cleft.


http://ift.tt/2mZ8cE2

Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Dong V. Wang, Thomas Viereckel, Vivien Zell, Åsa Konradsson-Geuken, Carl J. Broker, Aleksandr Talishinsky, Ji Hoon Yoo, Melissa H. Galinato, Emma Arvidsson, Andrew J. Kesner, Thomas S. Hnasko, Åsa Wallén-Mackenzie, Satoshi Ikemoto
Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.

Graphical abstract

Teaser

Wang et al. find that targeted deletion of the gene encoding VGLUT2 in dopamine neurons largely eliminates fast excitatory responses caused by glutamate co-transmission in the ventral striatum in vivo. However, it has little effect on the acquisition of conditioned responses reinforced by the activation of VTA dopamine neurons.


http://ift.tt/2mZa2Vt

Coupling between Protein Stability and Catalytic Activity Determines Pathogenicity of G6PD Variants

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Anna D. Cunningham, Alexandre Colavin, Kerwyn Casey Huang, Daria Mochly-Rosen
G6PD deficiency, an enzymopathy affecting 7% of the world population, is caused by over 160 identified amino acid variants in glucose-6-phosphate dehydrogenase (G6PD). The clinical presentation of G6PD deficiency is diverse, likely due to the broad distribution of variants across the protein and the potential for multidimensional biochemical effects. In this study, we use bioinformatic and biochemical analyses to interpret the relationship between G6PD variants and their clinical phenotype. Using structural information and statistical analyses of known G6PD variants, we predict the molecular phenotype of five uncharacterized variants from a reference population database. Through multidimensional analysis of biochemical data, we demonstrate that the clinical phenotypes of G6PD variants are largely determined by a trade-off between protein stability and catalytic activity. This work expands the current understanding of the biochemical underpinnings of G6PD variant pathogenicity and suggests a promising avenue for correcting G6PD deficiency by targeting essential structural features of G6PD.

Graphical abstract

Teaser

G6PD deficiency is one of the most common human enzymopathies, but the relationship between amino acid variant and clinical phenotype is poorly understood. Cunningham et al. find that clinical severity of a G6PD variant is determined by coupling between catalytic activity and protein stability.


http://ift.tt/2mZ5le5

Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Ioannis Poursaitidis, Xiaomeng Wang, Thomas Crighton, Christiaan Labuschagne, David Mason, Shira L. Cramer, Kendra Triplett, Rajat Roy, Olivier E. Pardo, Michael J. Seckl, Scott W. Rowlinson, Everett Stone, Richard F. Lamb
Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

Graphical abstract

Teaser

Poursaitidis et al. show that EGFR and BRAF mutant cells are sensitive to ferroptosis. Sensitivity was related to activation of MAPK signaling and the generation and release of hydrogen peroxide. To show that this sensitivity can be exploited therapeutically, growth of an EGFR mutant NSCLC xenograft was inhibited by a cyst(e)ine-degrading enzyme.


http://ift.tt/2mZ7dU1

Mitotic Phosphorylation of TREX1 C Terminus Disrupts TREX1 Regulation of the Oligosaccharyltransferase Complex

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Martin Kucej, Charles S. Fermaintt, Kun Yang, Ricardo A. Irizarry-Caro, Nan Yan
TREX1 mutations are associated with several autoimmune and inflammatory diseases. The N-terminal DNase domain of TREX1 is important for preventing self-DNA from activating the interferon response. The C terminus of TREX1 is required for ER localization and regulation of oligosacchariyltransferase (OST) activity. Here, we show that during mitosis TREX1 is predominately phosphorylated at the C-terminal Serine-261 by Cyclin B/CDK1. TREX1 is dephosphorylated quickly at mitotic exit, likely by PP1/PP2-type serine/threonine phosphatase. Mitotic phosphorylation does not affect TREX1 DNase activity. Phosphomimetic mutations of mitotic phosphorylation sites in TREX1 disrupted the interaction with the OST subunit RPN1. RNA-seq analysis of Trex1^−/− mouse embryonic fibroblasts expressing TREX1 wild-type or phosphor-mutants revealed a glycol-gene signature that is elevated when TREX1 mitotic phosphorylation sites are disrupted. Thus, the cell-cycle-dependent post-translation modification of TREX1 regulates its interaction with OST, which may have important implications for immune disease associated with the DNase-independent function of TREX1.

Graphical abstract

Teaser

TREX1 has a DNase-independent function in the C terminus that regulates the ER oligosaccharyltransferase (OST) activity. Kucej et al. found that TREX1 is phosphorylated during mitosis at Serine-261 in the C terminus. Mitotic phosphorylation disrupts TREX1 interaction with the OST complex without affecting its DNase activity.


http://ift.tt/2mZbB5E

Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Kodandaramireddy Nalapareddy, Kalpana J. Nattamai, Rupali S. Kumar, Rebekah Karns, Kathryn A. Wikenheiser-Brokamp, Leesa L. Sampson, Maxime M. Mahe, Nambirajan Sundaram, Mary-Beth Yacyshyn, Bruce Yacyshyn, Michael A. Helmrath, Yi Zheng, Hartmut Geiger
Although intestinal homeostasis is maintained by intestinal stem cells (ISCs), regeneration is impaired upon aging. Here, we first uncover changes in intestinal architecture, cell number, and cell composition upon aging. Second, we identify a decline in the regenerative capacity of ISCs upon aging because of a decline in canonical Wnt signaling in ISCs. Changes in expression of Wnts are found in stem cells themselves and in their niche, including Paneth cells and mesenchyme. Third, reactivating canonical Wnt signaling enhances the function of both murine and human ISCs and, thus, ameliorates aging-associated phenotypes of ISCs in an organoid assay. Our data demonstrate a role for impaired Wnt signaling in physiological aging of ISCs and further identify potential therapeutic avenues to improve ISC regenerative potential upon aging.

Graphical abstract

Teaser

Nalapareddy et al. find that the decline of canonical Wnt signaling in intestinal stem cells (ISCs) leads to decreased ISC regenerative potential upon aging. Addition of exogenous Wnts in vitro improves regeneration of aged ISCs.


http://ift.tt/2mZ68eT

m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Qi Cui, Hailing Shi, Peng Ye, Li Li, Qiuhao Qu, Guoqiang Sun, Guihua Sun, Zhike Lu, Yue Huang, Cai-Guang Yang, Arthur D. Riggs, Chuan He, Yanhong Shi
RNA modifications play critical roles in important biological processes. However, the functions of N⁶-methyladenosine (m⁶A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m⁶A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m⁶A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m⁶A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m⁶A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

Graphical abstract

Teaser

Cui et al. show that m⁶A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs) by regulating mRNA m⁶A enrichment and expression. An FTO inhibitor suppresses glioblastoma progression and prolongs lifespan of GSC-grafted animals, suggesting that targeting the m⁶A mRNA methylation machinery is a promising therapeutic tool for glioblastoma.


http://ift.tt/2mZ4bzq

Mutually Exclusive CBC-Containing Complexes Contribute to RNA Fate

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Simone Giacometti, Nour El Houda Benbahouche, Michal Domanski, Marie-Cécile Robert, Nicola Meola, Michal Lubas, Jakob Bukenborg, Jens S. Andersen, Wiebke M. Schulze, Celine Verheggen, Grzegorz Kudla, Torben Heick Jensen, Edouard Bertrand
The nuclear cap-binding complex (CBC) stimulates processing reactions of capped RNAs, including their splicing, 3′-end formation, degradation, and transport. CBC effects are particular for individual RNA families, but how such selectivity is achieved remains elusive. Here, we analyze three main CBC partners known to impact different RNA species. ARS2 stimulates 3′-end formation/transcription termination of several transcript types, ZC3H18 stimulates degradation of a diverse set of RNAs, and PHAX functions in pre-small nuclear RNA/small nucleolar RNA (pre-snRNA/snoRNA) transport. Surprisingly, these proteins all bind capped RNAs without strong preferences for given transcripts, and their steady-state binding correlates poorly with their function. Despite this, PHAX and ZC3H18 compete for CBC binding and we demonstrate that this competitive binding is functionally relevant. We further show that CBC-containing complexes are short lived in vivo, and we therefore suggest that RNA fate involves the transient formation of mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis.

Graphical abstract

Teaser

The nuclear CBC plays diverse roles in RNA biogenesis and it is not clear how selective effects are achieved for individual RNA families. Giacometti et al. suggest that RNA fate involves the formation of short-lived, mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis.


http://ift.tt/2mZczyS

Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Eiji Obayashi, Rafael E. Luna, Takashi Nagata, Pilar Martin-Marcos, Hiroyuki Hiraishi, Chingakham Ranjit Singh, Jan Peter Erzberger, Fan Zhang, Haribabu Arthanari, Jacob Morris, Riccardo Pellarin, Chelsea Moore, Ian Harmon, Evangelos Papadopoulos, Hisashi Yoshida, Mahmoud L. Nasr, Satoru Unzai, Brytteny Thompson, Eric Aube, Samantha Hustak, Florian Stengel, Eddie Dagraca, Asokan Ananbandam, Philip Gao, Takeshi Urano, Alan G. Hinnebusch, Gerhard Wagner, Katsura Asano
During eukaryotic translation initiation, eIF3 binds the solvent-accessible side of the 40S ribosome and recruits the gate-keeper protein eIF1 and eIF5 to the decoding center. This is largely mediated by the N-terminal domain (NTD) of eIF3c, which can be divided into three parts: 3c0, 3c1, and 3c2. The N-terminal part, 3c0, binds eIF5 strongly but only weakly to the ribosome-binding surface of eIF1, whereas 3c1 and 3c2 form a stoichiometric complex with eIF1. 3c1 contacts eIF1 through Arg-53 and Leu-96, while 3c2 faces 40S protein uS15/S13, to anchor eIF1 to the scanning pre-initiation complex (PIC). We propose that the 3c0:eIF1 interaction diminishes eIF1 binding to the 40S, whereas 3c0:eIF5 interaction stabilizes the scanning PIC by precluding this inhibitory interaction. Upon start codon recognition, interactions involving eIF5, and ultimately 3c0:eIF1 association, facilitate eIF1 release. Our results reveal intricate molecular interactions within the PIC, programmed for rapid scanning-arrest at the start codon.

Graphical abstract

Teaser

During translation initiation, eIF3 binds the solvent-accessible side of the 40S ribosome. Obayashi et al. propose that the N-terminal domain of eIF3c reaches into the decoding center to not only anchor the gate-keeper eIF1 but also facilitate eIF1 release on AUG selection. eIF5 appears to play a role in this regulation.


http://ift.tt/2mZ2amy

LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Longfei Wang, Yunsun Nam, Anna K. Lee, Chunxiao Yu, Kira Roth, Casandra Chen, Elizabeth M. Ransey, Piotr Sliz
LIN28 is an RNA binding protein that plays crucial roles in pluripotency, glucose metabolism, tissue regeneration, and tumorigenesis. LIN28 binds to the let-7 primary and precursor microRNAs through bipartite recognition and induces degradation of let-7 precursors (pre-let-7) by promoting oligouridylation by terminal uridylyltransferases (TUTases). Here, we report that the zinc knuckle domain (ZKD) of mouse LIN28 recruits TUT4 to initiate the oligouridylation of let-7 precursors. Our crystal structure of human LIN28 in complex with a fragment of pre-let-7f-1 determined to 2.0 Å resolution shows that the interaction between ZKD and RNA is constrained to a small cavity with a high druggability score. We demonstrate that the specific interaction between ZKD and pre-let-7 is necessary and sufficient to induce oligouridylation by recruiting the N-terminal fragment of TUT4 (NTUT4) and the formation of a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for the acquired processivity of TUT4.

Graphical abstract

Teaser

LIN28 initiates degradation of let-7 precursors by recruiting terminal uridylyltransferases (TUTases), TUT4 and TUT7, to oligouridylate the let-7 RNA. Wang et al. describe how LIN28, TUT4, and let-7 precursors form a ternary complex and carry out the oligouridylation activity.


http://ift.tt/2mZa8wd

Selective Suppression of Local Circuits during Movement Preparation in the Mouse Motor Cortex

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Masashi Hasegawa, Kei Majima, Takahide Itokazu, Takakuni Maki, Urban-Raphael Albrecht, Nora Castner, Mariko Izumo, Kazuhiro Sohya, Tatsuo K. Sato, Yukiyasu Kamitani, Takashi R. Sato
Prepared movements are more efficient than those that are not prepared for. Although changes in cortical activity have been observed prior to a forthcoming action, the circuits involved in motor preparation remain unclear. Here, we use in vivo two-photon calcium imaging to uncover changes in the motor cortex during variable waiting periods prior to a forepaw reaching task in mice. Consistent with previous reports, we observed a subset of neurons with increased activity during the waiting period; however, these neurons did not account for the degree of preparation as defined by reaction time (RT). Instead, the suppression of activity of distinct neurons in the same cortical area better accounts for RT. This suppression of neural activity resulted in a distinct and reproducible pattern when mice were well prepared. Thus, the selective suppression of network activity in the motor cortex may be a key feature of prepared movements.

Graphical abstract

Teaser

After establishing a delayed reaching task in mice, Hasegawa et al. identify a specific pattern of motor circuit activity during motor preparation. These circuit activity patterns are mediated by the suppression of a majority of neurons in the motor cortex and may be important contributors to motor preparation.


http://ift.tt/2mZ2cuG

Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Kathren L. Fink, Francesc López-Giráldez, In-Jung Kim, Stephen M. Strittmatter, William B.J. Cafferty
Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

Graphical abstract

Teaser

Fink et al. present an original in vivo screen identifying targets that drive spontaneous functional plasticity in intact corticospinal motor neurons after CNS injury. They show that exploitation of one of the targets identified (LPAR1-LPPR1 axis) results in significant anatomical and functional recovery after adult SCI.


http://ift.tt/2mZ4aeQ

γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Michael J. Molumby, Rachel M. Anderson, Dillan J. Newbold, Norah K. Koblesky, Andrew M. Garrett, Dietmar Schreiner, Jason J. Radley, Joshua A. Weiner
The 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules are critical for the elaboration of complex dendritic arbors in the cerebral cortex. Here, we provide evidence that the γ-Pcdhs negatively regulate synapse development by inhibiting the postsynaptic cell adhesion molecule, neuroligin-1 (Nlg1). Mice lacking all γ-Pcdhs in the forebrain exhibit significantly increased dendritic spine density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 γ-Pcdh isoforms. Co-expression of γ-Pcdhs inhibits the ability of Nlg1 to increase spine density and to induce presynaptic differentiation in hippocampal neurons in vitro. The γ-Pcdhs physically interact in cis with Nlg1 both in vitro and in vivo, and we present evidence that this disrupts Nlg1 binding to its presynaptic partner neurexin1β. Together with prior work, these data identify a mechanism through which γ-Pcdhs could coordinate dendrite arbor growth and complexity with spine maturation in the developing brain.

Graphical abstract

Teaser

Using conditional mutant and overexpression mouse lines, Molumby et al. demonstrate that γ-Protocadherins negatively regulate cortical dendritic spine morphogenesis in vivo. The γ-Protocadherins interact physically with neuroligin-1 and inhibit its ability to bind neurexin1β, to promote presynaptic differentiation, and to increase dendritic spine density in hippocampal neurons in vitro.


http://ift.tt/2mYX5e4

Nanoscale Structural Plasticity of the Active Zone Matrix Modulates Presynaptic Function

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Oleg O. Glebov, Rachel E. Jackson, Christian M. Winterflood, Dylan M. Owen, Ellen A. Barker, Patrick Doherty, Helge Ewers, Juan Burrone
The active zone (AZ) matrix of presynaptic terminals coordinates the recruitment of voltage-gated calcium channels (VGCCs) and synaptic vesicles to orchestrate neurotransmitter release. However, the spatial organization of the AZ and how it controls vesicle fusion remain poorly understood. Here, we employ super-resolution microscopy and ratiometric imaging to visualize the AZ structure on the nanoscale, revealing segregation between the AZ matrix, VGCCs, and putative release sites. Long-term blockade of neuronal activity leads to reversible AZ matrix unclustering and presynaptic actin depolymerization, allowing for enrichment of AZ machinery. Conversely, patterned optogenetic stimulation of postsynaptic neurons retrogradely enhanced AZ clustering. In individual synapses, AZ clustering was inversely correlated with local VGCC recruitment and vesicle cycling. Acute actin depolymerization led to rapid (5 min) nanoscale AZ matrix unclustering. We propose a model whereby neuronal activity modulates presynaptic function in a homeostatic manner by altering the clustering state of the AZ matrix.

Graphical abstract

Teaser

Glebov et al. find that the clustered presynaptic matrix restricts the recruitment of presynaptic machinery to the active zone. Neuronal activity bidirectionally controls clustering of the AZ matrix to control presynaptic function. These data suggest that AZ structure may locally control function through molecular crowding.


http://ift.tt/2mZjWGl