Ιατρικά Άρθρα: 02/27/18

Τρίτη 27 Φεβρουαρίου 2018

Geographical origin traceability of tea based on multi-element spatial distribution and the relationship with soil in district scale

Publication date: August 2018
Source:Food Control, Volume 90
Author(s): Lei Li, Bo Wen, Xiaolei Zhang, Yue Zhao, Yu Duan, Xiangfei Song, Shuang Ren, Yuhua Wang, Wanping Fang, Xujun Zhu
In this study, a discriminant model was established by determining mineral element contents in tea leaves and the soil, collected from Lishui, Jiangsu Province, China. The contents of 12 elements (Se, Zn, Ni, Mn, Cr, Pb, Mg, Ca, Cu, Al, Na, and K) were determined in both tea leaves and soil samples. Cluster analysis and principal component analysis (PCA) were employed for regional classification of tea samples. After data conversion and correlation analysis, spatial and quantitative prediction models were established by ordinary Kriging interpolation and multiple linear regressions. The results indicated a corresponding relationship of elements between tea and soil, and the cluster analysis and PCA showed a clear distinction between tea from the north to that from the middle and south of Lishui. Kriging interpolation predicted the levels of 12 elements, and among them, Se, Ca, and Cr showed a related spatial distribution. Three linear regression equations were established using Mn, Al, Ni, and K contents and soil pH, and these equations fitted well between predicted and actual values. The established linear equations can be used to identify the predominant mineral elements in tea plants and soil from Lishui and to identify the geographical origin of the tea product.

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Review of reduction factors by buildings for gamma radiation from radiocaesium deposited on the ground due to fallout

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): Hiroko Yoshida-Ohuchi, Norihiro Matsuda, Kimiaki Saito
In order to estimate residents' external dose due to radionuclide exposure resulting from fallout deposit on the ground, the shielding and dose reduction effects provided by structures such as houses and workplaces are taken into account as most individuals spend a large portion of their time indoors. Many works on both calculation and measurement for European and American settlements have been reported and factors such as, shielding factors, protection factors, reduction factors, and location factors have been determined. However, measurement data for Japanese settlements are lacking. Thus, the Japanese government used reduction factors given in the International Atomic Energy Agency documents from American and European settlements when Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident occurred. The United Nations Scientific Committee on the Effects of Atomic Radiation used location factors from European settlements for the same reason. Soon after the FDNPP accident, several measurements and calculations were performed to obtain specific reduction factors for Japanese settlements due to this lack of data. This research reviews previous studies that determined factors such as, shielding factors, protection factors, reduction factors, and location factors and summarizes specific results for Japan. We discuss the issues in determining these factors and in applying them to estimate indoor dose. The contribution of surface contamination to the indoor ambient dose equivalent rate is also discussed.

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7Be concentration in the near-surface layer of the air in Bialystok (north-eastern Poland) in the years 1992–2010

Publication date: July 2018
Source:Journal of Environmental Radioactivity, Volume 187
Author(s): Jacek Kapała, Maria Karpińska, Stanisław Mnich, Anna Gromotowicz-Popławska, Grzegorz Kulesza
Weekly measurements of air ⁷Be concentrations (n = 769) were performed in the years 1992–2010 in Bialystok (north-eastern Poland) using gamma spectrometry. The arithmetic mean (AM) concentration of ⁷Be was 2.51 mBq m⁻³, and the median (M) was 2.24 mBq m⁻³ (range 0.47–7.81 mBq m⁻³). The observed ⁷Be concentrations were within the range of levels recorded in Europe. Typical seasonal variability was observed. Concentrations of ⁷Be in the warm season (May, June, July) were almost twice as high as those in the cold season (November, December, January).A correlation was found between weekly ⁷Be concentrations and mean weekly values of relative humidity, temperature, and wind speed throughout the observation period. Pearson's correlation coefficients were −0.63, p < 0.001; 0.477, p < 0.001; −0.288, p < 0.001, respectively.The correlation coefficient between sunspot number and mean annual ⁷Be concentrations in the air in the years 1992–2010 was −0.609.

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Identification of a unique insertion in Plant Organellar DNA polymerases responsible for 5'-dRP lyase and strand-displacement activities: Implications for Base Excision Repair

Publication date: Available online 27 February 2018
Source:DNA Repair
Author(s): Carlos H. Trasviña-Arenas, Noe Baruch-Torres, Francisco J. Cordoba-Andrade, Víctor M. Ayala-García, Paola L. García-Medel, Corina Díaz-Quezada, Antolín Peralta-Castro, José Juan Ordaz-Ortiz, Luis G. Brieba
Plant mitochondrial and chloroplast genomes encode essential proteins for oxidative phosphorylation and photosynthesis. For proper cellular function, plant organelles must ensure genome integrity. Although plant organelles repair damaged DNA using the multi-enzyme Base Excision Repair (BER) pathway, the details of this pathway in plant organelles are largely unknown. The initial enzymatic steps in BER produce a 5'-deoxyribose phosphate (5'-dRP) moiety that must be removed to allow DNA ligation and in plant organelles, the enzymes responsible for the removal of a 5'-dRP group are unknown. In metazoans, DNA polymerases (DNAPs) remove the 5'-dRP moiety using their intrinsic lyase and/or strand-displacement activities during short or long-patch BER sub-pathways, respectively. The plant model Arabidopsis thaliana encodes two family-A DNAPs paralogs, AtPolIA and AtPolIB, which are the sole DNAPs in plant organelles identified to date. Herein we demonstrate that both AtPolIs present 5'-dRP lyase activities. AtPolIB performs efficient strand-displacement on a BER-associated 1-nt gap DNA substrate, whereas AtPolIA exhibits only moderate strand-displacement activity. Both lyase and strand-displacement activities are dependent on an amino acid insertion that is exclusively present in plant organellar DNAPs. Within this insertion, we identified that residue AtPollB-Lys593 acts as nucleophile for lyase activity. Our results demonstrate that AtPolIs are functionally equipped to play a role in short-patch BER and suggest a major role of AtPolIB in a predicted long-patch BER sub-pathway. We propose that the acquisition of insertion 1 in the polymerization domain of AtPolIs was a key component in their evolution as BER associated and replicative DNAPs.

Graphical abstract

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Erratum to “DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine”[DNA Repair, 62 (2018) 1–7]

Publication date: Available online 27 February 2018
Source:DNA Repair
Author(s): Marketa Tomkova, Michael McClellan, Skirmantas Kriaucionis, Benjamin Schuster-Boockler

http://ift.tt/2GRf0tI

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.

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Molecular and thyroid hormone binding properties of lamprey transthyretins: The role of an N-terminal histidine-rich segment in hormone binding with high affinity

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Kentaro Kasai, Norihito Nishiyama, Kiyoshi Yamauchi
Transthyretin (TTR) is a plasma thyroid hormone (TH) binder that emerged from an ancient hydroxyisourate hydrolase by gene duplication. To know how an ancient TTR had high affinity for THs, molecular and TH binding properties of lamprey TTRs were investigated. In adult serum, the lipoprotein LAL was a major T3 binder with low affinity. Lamprey TTRs had an N-terminal histidine-rich segment, and had two classes of binding sites for 3,3′,5-triiodo-L-thyronine (T3): a high-affinity and a low-affinity site. Mutant TTRΔ3-11, lacking the N-terminal histidine-rich segment, lost the high-affinity T3 binding site. [¹²⁵I]T3 binding to wild type TTR and mutant TTRΔ3-11, was differentially modulated by Zn²⁺. Zn²⁺ contents of wild type TTR were 7–10/TTR (mol/mol). Our results demonstrate that lamprey TTR is a Zn²⁺-dependent T3 binder. The N-terminal histidine-rich segment may be essential for neo-functionalization (i.e., high-affinity T3 binding activity) of an ancient TTR after gene duplication.

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Editorial Board

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27

http://ift.tt/2F32VS4

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Neighborhood Resolved Fiber Orientation Distributions (NRFOD) in Automatic Labeling of White Matter Fiber Pathways

Publication date: Available online 27 February 2018
Source:Medical Image Analysis
Author(s): Devran Ugurlu, Zeynep Firat, Ugur Ture, Gozde Unal
Accurate digital representation of major white matter bundles in the brain is an important goal in neuroscience image computing since the representations can be used for surgical planning, intra-patient longitudinal analysis and inter-subject population connectivity studies. Reconstructing desired fiber bundles generally involves manual selection of regions of interest by an expert, which is subject to user bias and fatigue, hence an automation is desirable. To that end, we first present a novel anatomical representation based on Neighborhood Resolved Fiber Orientation Distributions (NRFOD) along the fibers. The resolved fiber orientations are obtained by generalized q-sampling imaging (GQI) and a subsequent diffusion decomposition method. A fiber-to-fiber distance measure between the proposed fiber representations is then used in a density-based clustering framework to select the clusters corresponding to the major pathways of interest. In addition, neuroanatomical priors are utilized to constrain the set of candidate fibers before density-based clustering. The proposed fiber clustering approach is exemplified on automation of the reconstruction of the major fiber pathways in the brainstem: corticospinal tract (CST); medial lemniscus (ML); middle cerebellar peduncle (MCP); inferior cerebellar peduncle (ICP); superior cerebellar peduncle (SCP). Experimental results on Human Connectome Project (HCP)'s publicly available "WU-Minn 500 Subjects + MEG2 dataset" and expert evaluations demonstrate the potential of the proposed fiber clustering method in brainstem white matter structure analysis.

Graphical abstract

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Editorial Board

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27

http://ift.tt/2F32VS4

Editorial Board

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27

http://ift.tt/2F32VS4

Editorial Board

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27

http://ift.tt/2F32VS4

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Editorial Board

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27

http://ift.tt/2F32VS4

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

In Vivo Imaging of Microvasculature during Anesthesia with High-Resolution Photoacoustic Microscopy

Publication date: Available online 28 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Xiang Zhang, Xiaoqin Qian, Chao Tao, Xiaojun Liu
Anesthesia monitoring is extremely important in improving the quality of anesthesia and ensuring the safety of patients in operation. Photoacoustic microscopy (PAM) is proposed to in vivo image the skin microvasculature of 10 nude mice undergoing general anesthesia by using the isoflurane gas with a concentration of 3%. Benefiting from strong optical absorption of hemoglobin, PAM has good contrast and high resolution in mapping of microvasculature. A series of high quality images can clearly reveal the subtle changes of capillaries in morphology over time. Two indices, vessel intensity and vessel density, are extracted from these images to measure the microvasculature quantitatively. The imaging results show that the vessel intensity and density are increased over time. After 65 min, the vessel intensity increased 42.7 ± 8.6% and the density increased 28.6 ± 12.2%. These indices extracted from photoacoustic images accurately reflect the greater blood perfusion undergoing general anesthesia. Additionally, abnormal reductions of vessel intensity and density are also observed as overtime anesthesia. This preclinical study suggests that PAM holds potential to monitor anesthesia by imaging the skin microvasculature.

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Generation of Reactive Oxygen Species in Heterogeneously Sonoporated Cells by Microbubbles with Single-Pulse Ultrasound

Publication date: Available online 27 February 2018
Source:Ultrasound in Medicine & Biology
Author(s): Caixia Jia, Lin Xu, Tao Han, Ping Cai, Alfred C.H. Yu, Peng Qin
To develop and realize sonoporation-based macromolecule delivery, it is important to understand the underlying cellular bioeffects involved. It is known that an appropriate level of reactive oxygen species (ROS) is necessary to maintain normal physiologic function, but excessive ROS triggers adverse downstream bioeffects. However, it is still unclear whether a relationship exists between intracellular ROS levels and sonoporation. Using a customized platform for 1.5-MHz ultrasound exposure (13.33 µs duration and 0.70 MPa peak negative pressure) and imaging the dynamics of sonoporation and intracellular ROS at the single-cell level, we quantified the exogenous molecular uptake and the concentration of intracellular ROS indicator to evaluate the extent of sonoporation and ROS change, respectively. Our results revealed that the intracellular ROS level was correlated with the degree of the sonoporation. (i) Within ~120 s of the onset of ultrasound, during which membrane perforation and complete membrane resealing occurred, intracellular ROS rapidly decreased because of extracellular diffusion of dichlorofluorescein through the perforated membrane and positively correlated with the degree of the sonoporation. (ii) In the following 270 s (120–390 s post-exposure), ROS generation in reversibly sonoporated cells gradually increased and was positively correlated with the degree of the sonoporation. (iii) The ROS level in irreversibly sonoporated cells reduced to depletion during this time interval. It is possible that ROS generation in reversibly sonoporated cells can impact their long-term fate. These results thus provide new insight into the biological response to sonoporation.

http://ift.tt/2EYlwm9

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Silymarin ameliorates expression of urotensin II (U-II) and its receptor (UTR) and attenuates toxic oxidative stress in the heart of rats with type 2 diabetes

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Rahimeh Rahimi, Jamshid Karimi, Iraj Khodadadi, Heidar Tayebinia, Nejat Kheiripour, Mohammad Hashemnia, Fatemeh Goli
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Urotensin II ((U-II)) and its receptor (UTR) are involved in the progression of CVD through enhancement in the production of reactive oxygen species (ROS). Since silymarin (SMN) is a natural agent with anti-diabetic effects, this study aimed to investigate the antioxidant potency of SMN on the expression of (U-II)/UTR system and oxidative stress status in the heart of type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into six groups (n = 6). Control and diabetic groups treated with or without SMN (60 and 120 mg/kg/day) for 2 months. Fasting blood sugar (FBS), insulin, lipid profile, creatine kinase-MB ((CK-MB)), lactate dehydrogenase (LDH) and markers of oxidative stress were measured by spectrophotometric methods while (U-II) and UTR gene expression was determined by qPCR method. SMN significantly reduced the FBS level, increased the concentration of insulin and improved HOMA-IR. SMN prevented diabetes-induced weight loss, and attenuated the increased levels of total oxidative status (TOS), malondialdehyde (MDA), and nitric oxide (NO). Diabetes-induced reduction of total thiol molecules content (TTM) was normalized to the normal level in SMN treated rats. SMN significantly modulated serum lipid profile, reduced the expression of (U-II) and UTR in the heart, and improved histopathological changes in the heart tissues. Therefore, the current study indicated that SMN ameliorated unpleasant diabetic characteristics via down-regulation of (U-II) and UTR gene expression and modulation of oxidative stress in the heart tissue of type 2 diabetic rats.

http://ift.tt/2EWOAdM

Effects of ozone repeated short exposures on the airway/lung inflammation, airway hyperresponsiveness and mucus production in a mouse model of ovalbumin-induced asthma

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Wuping Bao, Yingying Zhang, Min Zhang, Aihua Bao, Xia Fei, Xue Zhang, Xin Zhou
ObjectiveThe purpose of this study is to explore the influence of ozone repeated short exposures on airway/lung inflammation, airway hyperresponsiveness (AHR) and airway hypersecretion in ovalbumin (OVA) sensitized/challenged asthmatic mouse model.MethodsOVA sensitization was performing by intraperitoneal injection. Ozone exposures (3ppm for 3hours) were given one hour after aerosolized OVA challenges (once every other day, 4 times totally). Methacholine (MCH) bronchial provocation tests, Liu's staining of BALF cell smears, hematoxylin-eosin (HE) staining and Periodic Acid-Schiff (PAS) staining of lung tissue were performed. Interleukins (ILs; IL-4, IL-13, IL-1β, and IL-18) protein (ELISA) and mRNA expression levels (RT-qPCR) in murine lung, 8-hydroxy-2′-deoxyguanosine (8-OHdG, ELISA), malondialdehyde (MDA, thiobarbituric acid assay), reduced glutathione (GSH, spectrophotometric method) in bronchoalveolar lavage fluid (BALF), and GSH1 mRNA relative expression levels (RT-qPCR) in lung tissue were analyzed.ResultRepeated ozone exposures down-regulated the AHR to MCH in mice undergoing OVA sensitization and challenge, however not all parameters associated with asthma were decreased since obvious mucus hypersecretion was induced and airway inflammation increased slightly, especially around small airways. Following ozone co-exposure, the increase of IL-4 and IL-13 levels in murine lung caused by OVA sensitization/challenge were reversed. Instead, levels of IL-1β in BALF remained, higher than negative control group. Ozone repeated short exposures also induced significant increase of 8-OHdG in BALF in OVA sensitized and challenged mice.ConclusionFor asthmatic mice undergoing ozone exposures, AHR is not an accurate indicator of the severity of asthma. Repeated short ozone exposures increase mucus hypersecretion, possibly via an increase in oxidative stress and immune dysregulation.

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The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Adel Abdel-Moneim, Heba H. Bakery, Gamal Allam
Diabetes mellitus (DM) is a serious medical problem affecting millions of peoples worldwide, and has a great socio-economic impacts. Cytokines possess a pivotal role in modulation of immune reactions and disease pathogenesis. T-helper type 17 (Th17) cells, an important proinflammatory CD4⁺ T cell subset secreting interleukin 17 (IL-17), has been embroiled in development of DM. There are recent evidences supporting a definitive role of Th17 cells in the etiology of type 1 diabetes (T1D). In addition, IL-17 has been shown to play a crucial role in inflammation, insulin resistance, and type 2 diabetes (T2D). Recently, small molecules which have been specified to block Th17 cells differentiation are considered as potential therapeutics for the disease. Anti-IL-17 neutralizing antibodies and/or antibodies targeting Th17 cells have been investigated to protect individuals at risk from disease development. In this review we aimed to shed light on the potential role of IL-17 and Th17 cells in both T1D and T2D pathogenesis and future therapeutic strategies.

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Multilevel linear modelling of the response-contingent learning of young children with significant developmental delays

Publication date: Available online 28 February 2018
Source:Research in Developmental Disabilities
Author(s): Melinda Raab, Carl J. Dunst, Deborah W. Hamby
AimThe purpose of the study was to isolate the sources of variations in the rates of response-contingent learning among young children with multiple disabilities and significant developmental delays randomly assigned to contrasting types of early childhood intervention.MethodMultilevel, hierarchical linear growth curve modelling was used to analyze four different measures of child response-contingent learning where repeated child learning measures were nested within individual children (Level-1), children were nested within practitioners (Level-2), and practitioners were nested within the contrasting types of intervention (Level-3).ResultsFindings showed that sources of variations in rates of child response-contingent learning were associated almost entirely with type of intervention after the variance associated with differences in practitioners nested within groups were accounted for. Rates of child learning were greater among children whose existing behaviour were used as the building blocks for promoting child competence (asset-based practices) compared to children for whom the focus of intervention was promoting child acquisition of missing skills (needs-based practices).ImplicationsThe methods of analysis illustrate a practical approach to clustered data analysis and the presentation of results in ways that highlight sources of variations in the rates of response-contingent learning among young children with multiple developmental disabilities and significant developmental delays.

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The possible role of stress induced hormonal disbalance in the patophysiology of insulin resistane in lean individuals

Publication date: Available online 27 February 2018
Source:Medical Hypotheses
Author(s): K. Blaslov, I. Kruljac, G. Mirošević, Lora S. Kirigin Biloš, M. Vrkljan
Insulin resistance (IR) is a common denominator of metabolic and hemodynamic disorders simultaneously present in one person and responsible for elevated risk of developing type 2 diabetes (T2DM) and cardiovascular incidents. According to the latest research, IR is present in 25-45% of the general population. Therefore, the mechanism of its development is in the center of scientific and professional interest. Established or acquired factors, or combinations thereof, which disturb any step of the physiological insulin action mechanism: its binding to the cellular receptor, through the complex cascade of intracellular signaling pathways might cause IR. Although the adiposity and its underlying risk factors are considered to be the primary cause of IR, it is present in a great porportion in lean individuals as well.There are insights of the possible role of psychological factors: exposure to stress and deprssion to IR development, although the mechanism of this relationship has not been comperhensively studied. Data driven from cell cultures and experimental animal models suggest that there is an elevated level of counter-regulatory insulin hormones: growth hormone, prolactin and cortisol due to acute stress exposure. However, the relationship between these psychological disorders with the hyperreactivity of the axis of the hypothalamic-pituitary-adrenal axis as the underlying mechanism in the patophysiology of IR in lean individuals has not been systematically investigated. Based on the aforementioned, we hypothesise that this mechanism would be responsible for the formation of IR, and consequently, T2DM in lean individuals.The possible effect of the amount of stress in conjunction with the serum concentration of growth hormone, cortisol, prolactin and dehydroepiandrostendone to the abnormal 5-hour oral glucose tollerance test results could contribute to the primary prevention of diabetes and its complications.

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Individual Differences in Semantic Processing: Insights From the Calgary Semantic Decision Project.

Author: Pexman, Penny M.; Yap, Melvin J.

DOI: 10.1037/xlm0000499

Publication Date: POST AUTHOR CORRECTIONS, 26 February 2018

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Does Evaluative Conditioning Depend on Awareness? Evidence From a Continuous Flash Suppression Paradigm.

Author: Hogden, Fabia; Hutter, Mandy; Unkelbach, Christian

DOI: 10.1037/xlm0000533

Publication Date: POST AUTHOR CORRECTIONS, 26 February 2018

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Perspective From Sweden on the Global Impact of the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A "Sprint" Beyond Evidence in the United States.

Author: Brunstrom, Mattias MD; Carlberg, Bo MD, PhD; Lindholm, Lars H. MD, PhD

Page: 886-888

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Global Impact of the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A Perspective From Italy.

Author: Mancia, Giuseppe MD; Corrao, Giovanni PhD

Page: 889-890

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Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices: The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score.

Author: Soliman, Osama I.I. MD, PhD; Akin, Sakir MD; Muslem, Rahatullah BSc; Boersma, Eric PhD; Manintveld, Olivier C. MD, PhD; Krabatsch, Thomas MD, PhD; Gummert, Jan F. MD, PhD; de By, Theo M.M.H. MBA; Bogers, Ad J.J.C. MD, PhD; Zijlstra, Felix MD, PhD; Mohacsi, Paul MD, eMBA; Caliskan, Kadir MD, PhD; On behalf of the EUROMACS Investigators

Page: 891-906

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When VAD Things Happen to Good People.

Author: Samsky, Marc D. MD; Rogers, Joseph G. MD

Page: 907-909

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2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

Author: Hicks, Karen A. MD ,*; Mahaffey, Kenneth W. MD ,*; Mehran, Roxana MD ,*; Nissen, Steven E. MD ,*; Wiviott, Stephen D. MD; Dunn, Billy MD; Solomon, Scott D. MD; Marler, John R. MD; Teerlink, John R. MD; Farb, Andrew MD; Morrow, David A. MD, MPH; Targum, Shari L. MD, MPH; Sila, Cathy A. MD; Hai, Mary T. Thanh MD; Jaff, Michael R. DO; Joffe, Hylton V. MD, MMSC; Cutlip, Donald E. MD; Desai, Akshay S. MD; Lewis, Eldrin F. MD, MPH; Gibson, C. Michael MD, MS; Landray, Martin J. PHD; Lincoff, A. Michael MD; White, Christopher J. MD; Brooks, Steven S. MD, MBA; Rosenfield, Kenneth MD; Domanski, Michael J. MD; Lansky, Alexandra J. MD; McMurray, John J.V. MD; Tcheng, James E. MD; Steinhubl, Steven R. MD; Burton, Paul MD, PHD; Mauri, Laura MD, MSC; O'Connor, Christopher M. MD; Pfeffer, Marc A. MD, PHD; Hung, H.M. James PHD; Stockbridge, Norman L. MD, PHD; Chaitman, Bernard R. MD; Temple, Robert J. MD; on behalf of the Standardized Data Collection for Cardiovascular Trials Initiative (SCTI)

Page: 961-972

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Gene-Editing Technology Accelerates Cardiovascular Research: Clinical Applications Being Explored.

Author: Kuehn, Bridget M. MSJ

Page: 973-974

http://ift.tt/2t2zjCA

Reduced Blood Lipid Levels With In Vivo CRISPR-Cas9 Base Editing of ANGPTL3.

Author: Chadwick, Alexandra C. PhD; Evitt, Niklaus H. BS; Lv, Wenjian PhD; Musunuru, Kiran MD, PhD, MPH

Page: 975-977

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Outcomes of Patients With Hypoplastic Left Heart Syndrome Reaching Adulthood After Fontan Palliation: Multicenter Study.

Author: Wilson, William M. MBBS; Valente, Anne M. MD; Hickey, Edward J. MD; Clift, Paul MBBS, MD; Burchill, Luke MBBS, PhD; Emmanuel, Yaso MBChB, DPhil; Gibson, Patrick BMBCH, MD; Greutmann, Matthias MD; Grewal, Jasmine MD; Grigg, Leeanne E. MBBS; Gurvitz, Michelle MD; Hickey, Kelsey BA; Khairy, Paul MD, PhD; Mayer, John E. Jr MD; Teo, Eliza MBBS; Vonder Muhll, Isabelle MD; Roche, S. Lucy MBChB; Silversides, Candice K. MD; Wald, Rachel M. MD

Page: 978-981

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Letter by Tampaki et al Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)".

Author: Tampaki, Ekaterini Christina MD, PhD, PharmD; Tampakis, Athanasios MD; Pantos, Costas MD, PhD

Page: 982-983

http://ift.tt/2F86Y2C

Letter by Taegtmeyer and Karlstaedt Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)".

Author: Taegtmeyer, Heinrich MD, DPhil; Karlstaedt, Anja MD, PhD

Page: 986-987

http://ift.tt/2CqKwks

Letter by Jin-shan and Xue-bin Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)".

Author: Jin-shan, He MD; Xue-bin, Li MD

Page: 988

http://ift.tt/2t48j5P

A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy‐Naïve Advanced or Metastatic Nonsquamous Non‐Small Cell Lung Cancer

AbstractBackground.In the absence of a targeted oncogenic driver mutation or high programmed death‐ligand 1 expression, systemic therapy with platinum‐based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non‐small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin‐dependent and insulin‐independent mechanisms and to be potentially synergistic with chemotherapy.Materials and Methods.This open‐label single‐center phase II study (NCT01578551) enrolled patients with chemotherapy‐naïve advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab ± metformin continued until disease progression, intolerable toxicity, or study withdrawal. The primary outcome was 1‐year progression free survival (PFS). Secondary outcomes included overall survival, response to therapy, and toxicity.Results.A total of 25 patients were enrolled from August 2012 to April 2015, of whom 24 received at least one cycle of therapy administration. The study was stopped early due to slow accrual and changes in standard first‐line therapy of advanced NSCLC. The 1‐year PFS on Arm A (n = 18) was 47% (95% confidence interval [CI]: 25%–88%), which exceeded the historical control 1‐year PFS of 15%. Median overall survival of patients treated on Arm A was 15.9 months (95% CI: 8.4–not available [NA]) and 13.9 months (95% CI: 12.7–NA) on Arm B. There were no significant differences in toxicity between the study arms.Conclusion.To the authors' knowledge, this is the first study to show a significant benefit in PFS with the use of metformin in this patient population and is a signal of efficacy for metformin in advanced NSCLC.Implications for Practice.The anticancer effects of metformin continue to be elucidated. To the authors' knowledge, this is the first trial in nondiabetic advanced non‐small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first‐line chemotherapy. Well tolerated and widely available, metformin is a drug that should be considered for further study in the lung cancer treatment landscape.

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A Phase II Study of Tumor Ablation in Patients with Metastatic Sarcoma Stable on Chemotherapy

AbstractLessons Learned. Ablation therapy appears to be a reasonably safe and effective approach to obtain a significant treatment‐free interval for a subset of patients with limited sites of metastatic disease for which systemic control can be obtained with six cycles of chemotherapy.Background.Metastatic sarcoma often becomes resistant to treatment by chemotherapy. There is sometimes prolonged stable disease from active chemotherapy that provides a window of opportunity for an intervention to prolong disease‐free survival.Materials and Methods.We performed a phase II study in patients with metastatic sarcoma who had been stable on six cycles of chemotherapy who then received ablation therapy to their residual disease. Histologies captured in this study included leiomyosarcoma, malignant peripheral nerve sheath tumor, pleiomorphic rhabdomyosarcoma, and myxoid liposarcoma. Sites ablated included lung metastases and retroperitoneal metastatic deposits. In this study, up to three lesions were ablated in any given interventional radiology session. After ablation, patients were not treated with any further therapy but were followed by surveillance imaging to determine progression‐free rate (PFR).Results.Although terminated early because of slow accrual, this study demonstrated a 3‐month PFR of 75% for this cohort of eight patients treated with ablation performed after completion of six cycles of chemotherapy with stable disease. Median progression‐free survival (PFS) was 19.74 months, and the median overall survival (OS) was not reached.Conclusion.Our data are the first prospective study to suggest that ablation therapy in selected patients who are stable on chemotherapy can provide a significant progression‐free interval off therapy and warrants further study in a randomized trial.

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Next‐Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma

AbstractBackground.Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood‐derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC.Materials and Methods.We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild‐type allele fraction was calculated.Results.All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1–8]); median mutant allele fraction, 0.29% (range, 0.1%–37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A‐inactivating and a CTNNB1‐activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX‐2/Wnt inhibitor); des‐gamma‐carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN‐inactivating and a MET‐activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0–15 ng/mL]).Conclusion.ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC.Implications for Practice.This study reports that blood‐derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.

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Effect of Concomitant pH‐Elevating Medications with Pazopanib on Progression‐Free Survival and Overall Survival in Patients with Metastatic Renal Cell Carcinoma

AbstractBackground.Pazopanib is an oral tyrosine‐kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown.Materials and Methods.In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH‐elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression‐free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety.Results.The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups.Conclusion.Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid‐reducing therapy.Implications for Practice.Pazopanib is a preferred category‐one first‐line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.

http://ift.tt/2CPVhsk

Emerging Perspectives on mTOR Inhibitor‐Associated Pneumonitis in Breast Cancer

AbstractSubstantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor‐associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor‐associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor‐associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor‐associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class‐related complication of mTOR inhibitor therapy.Implications for Practice.This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus‐related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor‐associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.

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A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone‐ and/or Enzalutamide‐Refractory Metastatic Castration‐Resistant Prostate Cancer

AbstractLessons Learned. In abiraterone‐ and/or enzalutamide‐refractory metastatic castration‐resistant prostate cancer (mCRPC) patients, selinexor led to prostate‐specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice‐a‐week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second‐generation anti‐androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post‐abiraterone and/or post‐enzalutamide mCRPC space.Background.Selinexor is a first‐in‐class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin‐1 (XPO‐1), leading to nuclear accumulation of tumor suppressor proteins.Methods.This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration‐resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.Results.Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow‐up of 4 months, two patients (14%) had ≥50% prostate‐specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment‐related grade 3–4 AEs. The most common drug‐related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.Conclusion.Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second‐line anti‐androgenic agents.

http://ift.tt/2CPUZle

Second‐Line Treatment Landscape for Renal Cell Carcinoma: A Comprehensive Review

AbstractThe management of advanced clear‐cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second‐line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small‐molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small‐molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin. Together, these and previously approved second‐line treatments offer clinicians the ability to better individualize treatment for patients after progression on first‐line VEGFR‐targeted therapies. In this comprehensive review, we discuss the efficacy and safety results from the pivotal trials of these newly approved therapies, including the quality of study design, the level of evidence, subgroup analyses, and how these data can help to guide clinicians to select the most appropriate second‐line therapy for their patients.Implications for Practice.This review article provides the reader with a comprehensive overview of current treatment options for patients with advanced clear‐cell renal cell carcinoma (RCC) whose disease has progressed after their first therapy. As many patients with RCC experience disease progression with initial treatments, effective second‐line therapies are critical. Nivolumab, cabozantinib, and lenvatinib plus everolimus have recently been approved as second‐line treatments. The new agents discussed in this review increase the therapeutic options available and provide physicians with opportunities to individualize treatments for their patients, with a view to improving disease control and survival outcomes.

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Meeting Kristoff

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Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Graphene/Semiconductor Hybrid Heterostructures for Optoelectronic Device Applications

Publication date: Available online 28 February 2018
Source:Nano Today
Author(s): Chao Xie, Yi Wang, Zhi-Xiang Zhang, Di Wang, Lin-Bao Luo
As one of the most appealing two-dimensional materials, graphene (Gr) has attracted tremendous research interest in optoelectronic device applications for its plenty of exceptional electrical and optical properties. The emergence of Gr/semiconductor hybrid heterostructures provides a promising platform for assembling high-performance optoelectronic devices that can overcome intrinsic limitations of Gr. However, although significant achievements have been made, many challenges still exist. Here, we comprehensively review the progress in the development of various optoelectronic devices based on Gr/semiconductor hybrid heterostructures, including /group II-VI nanostructures, /group III-V semiconductors, /group IV semiconductors, /metal oxides and /other semiconductors, in terms of the device design, device performance and physics, processing techniques for performance optimization, etc. In the final section, conclusions of the existing techniques are presented and future challenges in optoelectronic applications of Gr/semiconductor hybrid heterostructures are addressed.

Graphical abstract

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Volitional and Automatic Control of the Hand When Reaching to Grasp Objects.

Author: Chen, Zhongting; Saunders, Jeffrey Allen

DOI: 10.1037/xhp0000492

Publication Date: POST AUTHOR CORRECTIONS, 26 February 2018

http://ift.tt/2FDfPHo

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond

Publication date: Available online 27 February 2018
Source:Trends in Biochemical Sciences
Author(s): Russell A. DeBose-Boyd, Jin Ye
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.

http://ift.tt/2sYT3Hp

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A. Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC.

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Teaser

Resistance to targeted therapies is a major problem. Pawar et al. investigate the potential mechanisms of acquired resistance to BET inhibitors in prostate cancer and identify actionable targets to overcome the resistance. This study highlights the therapeutic limitation of BET inhibitors as a monotherapy and suggests potential combination therapies in treating prostate cancer.

http://ift.tt/2GMIqJO

SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Lucas Matt, Lyndsey M. Kirk, George Chenaux, David J. Speca, Kyle R. Puhger, Michael C. Pride, Mohammad Qneibi, Tomer Haham, Kristopher E. Plambeck, Yael Stern-Bach, Jill L. Silverman, Jacqueline N. Crawley, Johannes W. Hell, Elva Díaz
Altering AMPA receptor (AMPAR) content at synapses is a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 (synapse differentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapse strength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistry and electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation (LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapse development and function underlying higher-order cognitive plasticity.

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Matt et al. show that mice lacking the AMPAR-associated protein SynDIG4/Prrt1 display deficits in synaptic plasticity and cognition. SynDIG4 modifies AMPAR biophysical properties in heterologous cells, but synaptic AMPAR kinetics are unchanged, suggesting that SynDIG4 establishes a pool of extrasynaptic AMPARs necessary for higher-order cognitive plasticity.

http://ift.tt/2HQztk3

A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Christo P. Christov, Kevin S. Dingwell, Mark Skehel, Helen S. Wilkes, Julian E. Sale, James C. Smith, Torsten Krude
DNA replication in the embryo of Xenopus laevis changes dramatically at the mid-blastula transition (MBT), with Y RNA-independent random initiation switching to Y RNA-dependent initiation at specific origins. Here, we identify xNuRD, an MTA2-containing assemblage of the nucleosome remodeling and histone deacetylation complex NuRD, as an essential factor in pre-MBT Xenopus embryos that overcomes a functional requirement for Y RNAs during DNA replication. Human NuRD complexes have a different subunit composition than xNuRD and do not support Y RNA-independent initiation of DNA replication. Blocking or immunodepletion of xNuRD inhibits DNA replication initiation in isolated nuclei in vitro and causes inhibition of DNA synthesis, developmental delay, and embryonic lethality in early embryos. xNuRD activity declines after the MBT, coinciding with dissociation of the complex and emergence of Y RNA-dependent initiation. Our data thus reveal an essential role for a NuRD complex as a DNA replication factor during early Xenopus development.

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Christov et al. show that the chromatin remodeling complex xNuRD is an essential DNA replication factor in the eggs and early embryos of Xenopus laevis. They demonstrate that xNuRD can initiate DNA replication in the absence of non-coding Y RNAs, which only become essential for replication later in development.

http://ift.tt/2GMIpFK

Nap1l1 Controls Embryonic Neural Progenitor Cell Proliferation and Differentiation in the Developing Brain

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Huimin Qiao, Yanxin Li, Chao Feng, Shuguang Duo, Fen Ji, Jianwei Jiao
The precise function and role of nucleosome assembly protein 1-like 1 (Nap1l1) in brain development are unclear. Here, we find that Nap1l1 knockdown decreases neural progenitor cell (NPC) proliferation and induces premature neuronal differentiation during cortical development. A similar deficiency in embryonic neurogenesis was observed in Nap1l1 knockout (KO) mice, which were generated using the CRISPR-Cas9 system. RNA sequencing (RNA-seq) analysis indicates that Ras-associated domain family member 10 (RassF10) may be the downstream target of Nap1l1. Furthermore, we found that Nap1l1 regulates RassF10 expression by promoting SETD1A-mediated H3K4 trimethylation at the RassF10 promoter. Nap1l1 KO defects may be rescued by RassF10 overexpression, suggesting that Nap1l1 controls NPC differentiation through RassF10. Our findings reveal an essential role for the Nap1l1 histone chaperone in cortical neurogenesis during early embryonic brain development.

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Nap1l1 plays essential roles in embryonic neurogenesis, including the proliferation and differentiation of neural progenitors. Qiao et al. find that Nap1l1 regulates RassF10 through SETD1A-mediated H3K4me3 of the RassF10 promoter.

http://ift.tt/2HNwQzg

A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Jonathan D. Finn, Amy Rhoden Smith, Mihir C. Patel, Lucinda Shaw, Madeleine R. Youniss, Jane van Heteren, Tanner Dirstine, Corey Ciullo, Reynald Lescarbeau, Jessica Seitzer, Ruchi R. Shah, Aalok Shah, Dandan Ling, Jacqueline Growe, Melissa Pink, Ellen Rohde, Kristy M. Wood, William E. Salomon, William F. Harrington, Christian Dombrowski, Walter R. Strapps, Yong Chang, David V. Morrissey
The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform.

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Finn et al. describe the development of a transient, biodegradable LNP-based CRISPR/Cas9 delivery system that achieves >97% knockdown of serum TTR levels following a single administration. Editing levels were stable for 12 months, despite the transient nature of the delivery system and the editing components.

http://ift.tt/2HQ8l4x

Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Pei-Ying Wang, Kuei-Ting Chang, Yu-Mei Lin, Ting-Yu Kuo, Guey-Shin Wang
The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain.

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Wang et al. find that MBNL1 ubiquitination is required for cytoplasmic localization and promotion of neurite outgrowth. In myotonic dystrophy, expanded CUG repeat RNA leads to MBNL1 deubiquitination, resulting in nuclear-translocation-associated morphological defects that can be rescued by preventing degradation of lysine 63-linked polyubiquitin chains or enhancing MBNL1 ubiquitination.

http://ift.tt/2GMIoBG

The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Jinjun Chen, Lingyong Li, Shao-Rui Chen, Hong Chen, Jing-Dun Xie, Rita E. Sirrieh, David M. MacLean, Yuhao Zhang, Meng-Hua Zhou, Vasanthi Jayaraman, Hui-Lin Pan
α2δ-1, commonly known as a voltage-activated Ca²⁺ channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how α2δ-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1 knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. α2δ-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The α2δ-1-NMDAR interaction predominantly occurs through the C terminus of α2δ-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an α2δ-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, α2δ-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of α2δ-1-NMDAR complexes.

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Chen et al. show that α2δ-1, through its C terminus, physically interacts with NMDA receptors and promotes synaptic expression of α2δ-1-NMDA receptor complexes in neuropathic pain. Gabapentin reduces neuropathic pain primarily by targeting α2δ-1-bound NMDA receptors.

http://ift.tt/2HQEedb

Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Haowen Liu, Lei Li, Wei Wang, Jihong Gong, Xiaofei Yang, Zhitao Hu
The locomotion of C. elegans is balanced by excitatory and inhibitory neurotransmitter release at neuromuscular junctions. However, the molecular mechanisms that maintain the balance of synaptic transmission remain enigmatic. Here, we investigated the function of voltage-gated Ca²⁺ channels in triggering spontaneous release at cholinergic and GABAergic synapses. Recordings of the miniature excitatory/inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) showed that UNC-2/CaV2 and EGL-19/CaV1 channels are the two major triggers for spontaneous release. Notably, however, Ca²⁺-independent spontaneous release was observed at GABAergic but not cholinergic synapses. Functional screening led to the identification of hypomorphic unc-64/Syntaxin-1A and snb-1/VAMP2 mutants in which mEPSCs are severely impaired, whereas mIPSCs remain unaltered, indicating differential regulation of these currents at cholinergic and GABAergic synapses. Moreover, Ca²⁺-independent spontaneous GABA release was nearly abolished in the hypomorphic unc-64 and snb-1 mutants, suggesting distinct mechanisms for Ca²⁺-dependent and Ca²⁺-independent spontaneous release.

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Liu et al. show that spontaneous release is differentially regulated between cholinergic and GABAergic synapses at the C. elegans NMJ. Ca²⁺-independent spontaneous release is observed in GABAergic synapses and regulated by synaptic proteins such as syntaxin-1A and VAMP2.

http://ift.tt/2HPPo1W

Two Parallel Pathways Assign Opposing Odor Valences during Drosophila Memory Formation

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Daisuke Yamazaki, Makoto Hiroi, Takashi Abe, Kazumichi Shimizu, Maki Minami-Ohtsubo, Yuko Maeyama, Junjiro Horiuchi, Tetsuya Tabata
During olfactory associative learning in Drosophila, odors activate specific subsets of intrinsic mushroom body (MB) neurons. Coincident exposure to either rewards or punishments is thought to activate extrinsic dopaminergic neurons, which modulate synaptic connections between odor-encoding MB neurons and MB output neurons to alter behaviors. However, here we identify two classes of intrinsic MB γ neurons based on cAMP response element (CRE)-dependent expression, γCRE-p and γCRE-n, which encode aversive and appetitive valences. γCRE-p and γCRE-n neurons act antagonistically to maintain neutral valences for neutral odors. Activation or inhibition of either cell type upsets this balance, toggling odor preferences to either positive or negative values. The mushroom body output neurons, MBON-γ5β′2a/β′2mp and MBON-γ2α′1, mediate the actions of γCRE-p and γCRE-n neurons. Our data indicate that MB neurons encode valence information, as well as odor information, and this information is integrated through a process involving MBONs to regulate learning and memory.

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Teaser

Aversive and appetitive olfactory memories in fruit flies are formed in third order olfactory neurons, the mushroom body Kenyon cells (KCs). Yamazaki et al. identify parallel pathways consisting of two subpopulations of KCs and their output neurons that encode aversive and appetitive valences.

http://ift.tt/2GMInO8

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Sumaira Zamurrad, Hayden A.M. Hatch, Coralie Drelon, Helen M. Belalcazar, Julie Secombe
Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5^A512P). Transcriptome analysis of kdm5^A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation. kdm5^A512P flies also showed impaired learning and/or memory. Significantly, the behavioral and transcriptional changes in kdm5^A512P flies were similar to those specifically lacking demethylase activity. These data suggest that the primary defect of the KDM5^A512P mutation is a loss of histone demethylase activity and reveal an unexpected role for this enzymatic function in gene activation. Because translation is critical for neuronal function, we propose that this defect contributes to the cognitive defects of kdm5^A512P flies.

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In humans, mutations in the transcriptional regulator KDM5 result in intellectual disability (ID). Here, Zamurrad et al. generate a Drosophila strain harboring a KDM5 mutation equivalent to an ID-associated allele to reveal a conserved role for KDM5 in cognition and an unexpected role for KDM5's enzymatic activity in gene activation.

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Action Selection and Flexible Switching Controlled by the Intralaminar Thalamic Neurons

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Shigeki Kato, Ryoji Fukabori, Kayo Nishizawa, Kana Okada, Nozomu Yoshioka, Masateru Sugawara, Yuko Maejima, Kenju Shimomura, Masahiro Okamoto, Satoshi Eifuku, Kazuto Kobayashi
Learning processes contributing to appropriate selection and flexible switching of behaviors are mediated through the dorsal striatum, a key structure of the basal ganglia circuit. The major inputs to striatal subdivisions are provided from the intralaminar thalamic nuclei, including the central lateral nucleus (CL) and parafascicular nucleus (PF). Thalamostriatal neurons in the PF modulate the acquisition and performance of stimulus-response learning. Here, we address the roles of the CL thalamostriatal neurons in learning processes by using a selective neural pathway targeting technique. We show that the CL neurons are essential for the performance of stimulus-response learning and for behavioral flexibility, including reversal and attentional set-shifting of learned responses. In addition, chemogenetic suppression of neural activity supports the requirements of these neurons for behavioral flexibility. Our results suggest that the main contribution of the CL thalamostriatal neurons is functional control of the basal ganglia circuit linked to the prefrontal cortex.

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Intralaminar thalamic nuclei provide the major inputs to the cortico-basal ganglia circuit. Kato et al. describe the essential roles of the thalamostriatal neurons in the CL in the performance of stimulus-response learning and in reversal and set-shifting of learned behaviors, forming a pivotal route that affects the frontostriatal circuit functions.

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Oligodendrocytes in the Mouse Corpus Callosum Maintain Axonal Function by Delivery of Glucose

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Niklas Meyer, Nadine Richter, Zoya Fan, Gabrielle Siemonsmeier, Tatyana Pivneva, Philipp Jordan, Christian Steinhäuser, Marcus Semtner, Christiane Nolte, Helmut Kettenmann
In the optic nerve, oligodendrocytes maintain axonal function by supplying lactate as an energy substrate. Here, we report that, in acute brain slices of the mouse corpus callosum, exogenous glucose deprivation (EGD) abolished compound action potentials (CAPs), which neither lactate nor pyruvate could prevent. Loading an oligodendrocyte with 20 mM glucose using a patch pipette prevented EGD-mediated CAP reduction in about 70% of experiments. Loading oligodendrocytes with lactate rescued CAPs less efficiently than glucose. In mice lacking connexin 47, oligodendrocyte filling with glucose did not prevent CAP loss, emphasizing the importance of glial networks for axonal energy supply. Compared with the optic nerve, the astrocyte network in the corpus callosum was less dense, and loading astrocytes with glucose did not prevent CAP loss during EGD. We suggest that callosal oligodendrocyte networks provide energy to sustain axonal function predominantly by glucose delivery, and mechanisms of metabolic support vary across different white matter regions.

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Meyer et al. find that, unlike in the optic nerve, lactate does not substitute for glucose to sustain axonal function in the mouse corpus callosum. Oligodendrocyte networks in the corpus callosum provide energy substrates to axons predominantly by delivery of glucose, indicating different metabolic support mechanisms among white matter regions.

http://ift.tt/2HOSpPU

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Τρίτη 27 Φεβρουαρίου 2018

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