IL-36 in hidradenitis suppurativa: Evidence for a distinctive pro-inflammatory role and a key factor in the development of an inflammatory loop

Abstract

Background

A possible regulatory involvement of the interleukin (IL)-36 family in inflammatory diseases has been suggested.

Objectives

To analyze the expression of IL-36α, β, γ, and the antagonistic cytokines IL-36Ra, IL-37, and IL38 in the skin of hidradenitis suppurativa (HS) patients.

Methods

Skin samples from lesional and corresponding perilesional HS skin, and from healthy controls were included in this study and analyzed by quantitative real-time RT-PCR. To evaluate the PCR results of IL-36α, β, and γ, a subset of skin samples was studied by immunohistochemistry.

Results

Expression levels of IL-36α, β, γ, and IL-36Ra were all significantly higher in lesional HS skin compared to healthy controls. IL-37 and IL-38 were significantly higher in perilesional HS skin compared to healthy controls and decreased in lesional HS skin.

Limitations

Descriptive study and small sample size.

Conclusions

Our results showed a possible involvement of IL-36 cytokines in the inflammatory network of HS and a dysbalance between the agonistic and antagonistic cytokines in HS skin.

This article is protected by copyright. All rights reserved.

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Systemic retinoids and psychiatric disorders in patients with skin diseases: a multifactorial relationship

Abstract

Le Moigne and colleagues reviewed case reports to examine a possible causal linkage between systemic retinoids and psychiatric disorders.¹ The authors conclude that systemic retinoids should be prescribed with vigilance for patients with psychiatric disorders. While we agree with a need for vigilance, we caution against prematurely concluding that there is a causal association.

This article is protected by copyright. All rights reserved.

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Assessment of facial harmony among Caucasian Spaniards 18 to 60 years of age and its relationship with the golden ratio

Abstract

Background

Throughout history, the perception and definition of beauty and attractiveness have changed and have been influenced by cultural norms. This article analyzes the concept of "facial normality" (faces that are considered normal by 90% of respondents and, therefore, do not require esthetic surgery) among Spaniards of Caucasian ancestry. We also sought to determine the relationship between faces that are considered "normal" and the golden ratio.

Methods

We surveyed 54 respondents (equal numbers of women and men) between the ages of 18 and 60. The surveys followed the visual analog scale (VAS) protocol, and 13,514 responses were obtained. The respondents were asked to evaluate up to nine photographed faces according to their degree of attractiveness.

Results

According to the data obtained, "facial normality" or facial beauty can be defined by the following characteristics: (a) the sizes of the three facial segments (equal in proportion), (b) the width of the nose (narrow in women and average in men), and (c) the profile (straight or slightly retracted in women and straight or slightly prominent in men). In addition, five specific facial proportions were directly related to the golden ratio. Thus, the concept of "normal" can be applied to 90% of faces whose proportions fall within distinct ranges that encompass the value of the golden ratio.

Conclusions

We conclude that a standard perception of "facial normality" and facial beauty does exist. We also observed a general correlation between specific facial proportions and the golden ratio.

Level of Evidence: Not ratable.

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Impact of a Saharan dust intrusion over southern Spain on DNI estimation with sky cameras

Publication date: Available online 3 October 2017
Source:Atmospheric Environment
Author(s): J. Alonso-Montesinos, J. Barbero, J. Polo, G. López, J. Ballestrín, F.J. Batlles
To operate Central Tower Solar Power (CTSP) plants properly, solar collector systems must be able to work under varied weather conditions. Therefore, knowing the state of the atmosphere, and more specifically the level of incident radiation, is essential operational information to adapt the electricity production system to atmospheric conditions. In this work, we analyze the impact of a strong Saharan dust intrusion on the Direct normal irradiance (DNI) registered at two sites 35 km apart in southeastern Spain: the University of Almería (UAL) and the Plataforma Solar de Almería (PSA). DNI can be inputted into the European Solar Radiation Atlas (ESRA) clear sky procedure to derive Linke turbidity values, which proved to be extremely high at the UAL. By using the Simple Model of the Atmospheric Radiative Transfer of Sunshine (SMARTS) at the PSA site, AERONET data from PSA and assuming dust dominated aerosol, DNI estimations agreed strongly with the measured DNI values. At the UAL site, a SMARTS simulation of the DNI values also seemed to be compatible with dust dominated aerosol.



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A novel method for estimating methane emissions from underground coal mines: The Yanma coal mine, China

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Zhong-Min Ji, Zhi-Jian Chen, Jie-Nan Pan, Qing-He Niu
As the world's largest coal producer and consumer, China accounts for a relatively high proportion of methane emissions from coal mines. Several estimation methods had been established for the coal mine methane (CMM) emission. However, with large regional differences, various reservoir formation types of coalbed methane (CBM) and due to the complicated geological conditions in China, these methods may be deficient or unsuitable for all the mining areas (e.g. Jiaozuo mining area). By combing the CMM emission characteristics and considering the actual situation of methane emissions from underground coal mine, we found that the methane pre-drainage is a crucial reason creating inaccurate evaluating results for most estimation methods. What makes it so essential is the extensive pre-drainage quantity and its irrelevance with annual coal production. Accordingly, the methane releases were divided into two categories: methane pre-drainage and methane release during mining. On this basis, a pioneering method for estimating CMM emissions was proposed. Taking the Yanma coal mine in the Jiaozuo mining area as a study case, the evaluation method of the pre-drainage methane quantity was established after the correlation analysis between the pre-drainage rate and time. Thereafter, the mining activity influence factor (MAIF) was first introduced to reflect the methane release from the coal and rock seams around where affected by mining activity, and the buried depth was adopted as the predictor of the estimation for future methane emissions. It was verified in the six coal mines of Jiaozuo coalfield (2011) that the new estimation method has the minimum errors of 12.11%, 9.23%, 5.77%, −5.20%, −8.75% and 4.92% respectively comparing with other methods. This paper gives a further insight and proposes a more accurate evaluation method for the CMM emissions, especially for the coal seams with low permeability and strong tectonic deformation in methane outburst coal mines.



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The influence of roadside solid and vegetation barriers on near-road air quality

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Masoud Ghasemian, Seyedmorteza Amini, Marko Princevac
The current study evaluates the influence of roadside solid and vegetation barriers on the near-road air quality. Reynolds Averaged Navier-Stokes (RANS) technique coupled with the k−ε realizable turbulence model is utilized to investigate the flow pattern and pollutant concentration. A scalar transport equation is solved for a tracer gas to represent the roadway pollutant emissions. In addition, a broad range of turbulent Schmidt numbers are tested to calibrate the scalar transport equation. Three main scenarios including flat terrain, solid barrier, and vegetative barrier are studied. To validate numerical methodology, predicted pollutant concentration is compared with published wind tunnel data. Results show that the solid barrier induces an updraft motion and lofts the vehicle emission plume. Therefore, the ground-level pollutant concentration decreases compared to the flat terrain. For the vegetation barrier, different sub-scenarios with different vegetation densities ranging from approximately flat terrain to nearly solid barrier are examined. Dense canopies act in a similar manner as a solid barrier and mitigate the pollutant concentration through vertical mixing. On the other hand, the high porosity vegetation barriers reduce the wind speed and lead to a higher pollutant concentration. As the vegetation density increases, i.e. the barrier porosity decreases, the recirculation zone behind the canopy becomes larger and moves toward the canopy. The dense plant canopy with LAD=3.33m−2m3 can improve the near-road air quality by 10% and high porosity canopy with LAD=1m−2m3 deteriorates near-road air quality by 15%. The results of this study can be implemented as green infrastructure design strategies by urban planners and forestry organizations.



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An optimized inverse modelling method for determining the location and strength of a point source releasing airborne material in urban environment

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): George C. Efthimiou, Ivan V. Kovalets, Alexandros Venetsanos, Spyros Andronopoulos, Christos D. Argyropoulos, Konstantinos Kakosimos
An improved inverse modelling method to estimate the location and the emission rate of an unknown point stationary source of passive atmospheric pollutant in a complex urban geometry is incorporated in the Computational Fluid Dynamics code ADREA-HF and presented in this paper. The key improvement in relation to the previous version of the method lies in a two-step segregated approach. At first only the source coordinates are analysed using a correlation function of measured and calculated concentrations. In the second step the source rate is identified by minimizing a quadratic cost function. The validation of the new algorithm is performed by simulating the MUST wind tunnel experiment. A grid-independent flow field solution is firstly attained by applying successive refinements of the computational mesh and the final wind flow is validated against the measurements quantitatively and qualitatively. The old and new versions of the source term estimation method are tested on a coarse and a fine mesh. The new method appeared to be more robust, giving satisfactory estimations of source location and emission rate on both grids. The performance of the old version of the method varied between failure and success and appeared to be sensitive to the selection of model error magnitude that needs to be inserted in its quadratic cost function. The performance of the method depends also on the number and the placement of sensors constituting the measurement network. Of significant interest for the practical application of the method in urban settings is the number of concentration sensors required to obtain a "satisfactory" determination of the source. The probability of obtaining a satisfactory solution – according to specified criteria –by the new method has been assessed as function of the number of sensors that constitute the measurement network.



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The ozone-climate penalty in the Midwestern U.S.

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Ping Jing, Zifeng Lu, Allison L. Steiner
This paper investigates the relationship between ground-level ozone (O3) and temperature in the Midwestern U.S. during the period 1990–2015. From 1990 to 2015, the overall trend of 95th percentile temperature showed an increase of 0.04 K yr⁻¹, while summertime 95th percentile O3 concentrations in the Midwest decreased at an average rate of 0.7 ppb yr⁻¹ largely because NO2 concentrations decreased by more than 50%. The ozone-climate penalty, defined as the slope of O3 change with increasing temperature (ΔO3/ΔT), was by average 0.43 ppb K⁻¹ less in 1999–2007 than in 1990–1998, indicating the early success of NOx emission controls. However, the slope did not continue to decrease in 2008–2015 despite further NOx emission reductions, and it increased more rapidly with increasing temperature (Δ²O3/ΔT²) by 0.03–0.09 ppb K⁻² in most urban areas of the Midwest. This was accompanied by more frequent dry tropical (DT) weather in the Midwest since 2008. We find that O3 in DT weather was 12 ppb and 17 ppb higher than in non-DT weather in rural and urban areas, respectively. Furthermore, the 2008–2015 period experienced 8% more surface air stagnation days than in 1990–1998. This demonstrates that, in addition to the impact of warmer temperatures, the ozone-climate penalty could be aggravated by altered weather conditions under climate change. It will be challenging for Midwestern cities to attain the National Ambient Air Quality Standard for O3 if such conditions persist in the future, and future air quality improvements may require even greater efforts to reduce both NOx and VOC emissions in the Midwest.



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Direct observation of new particle formation during ozonolysis of isoprene and ethene competing against the growth of preexisting particles

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Satoshi Inomata, Kei Sato, Yosuke Sakamoto, Jun Hirokawa
Secondary organic aerosol formation during the ozonolysis of isoprene and ethene in the presence of ammonium nitrate seed particles (surface area concentrations = (0.8–3) × 10⁷ nm² cm⁻³) was investigated using a 1 nm scanning mobility particle sizer. Based on the size distribution of formed particles, particles with a diameter smaller than the minimum diameter of the seed particles (less than ∼6 nm) formed under dry conditions, but the formation of such particles was substantially suppressed during isoprene ozonolysis and was not observed during ethane ozonolysis under humid conditions. We propose that oligomeric hydroperoxides generated by stabilized Criegee intermediates (sCIs), including C1-sCI (CH2OO), contribute to new particle formation while competing to be taken up onto preexisting particles. The OH reaction products of isoprene and ethene seem to not contribute to new particle formation; however, they are taken up onto preexisting particles and contribute to particle growth.

Graphical abstract

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A modified Brownian force for ultrafine particle penetration through building crack modeling

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Chen Chen, Bin Zhao
Combustion processes related to industry, traffic, agriculture, and waste treatment and disposal increase the amount of outdoor ultrafine particles (UFPs), which have adverse effects on human health. Given that people spend the majority of their time indoors, it is critical to understand the penetration of outdoor UFPs through building cracks in order to estimate human exposure to outdoor-originated UFPs. Lagrangian tracking is an efficient approach for modeling particle penetration. However, the Brownian motion for Lagrangian tracking in ANSYS Fluent^®, a widely used software for particle dispersion modeling, is not able to model UFP dispersion accurately. In this study, we modified the Brownian force by rewriting the Brownian diffusion coefficient and particle integration time step with a user-defined function in ANSYS Fluent^® to model particle penetration through building cracks. The results obtained using the modified model agree much better with the experimental results, with the averaged relative error less than 14% for the smooth crack cases and 21% for the rough crack case. We expect the modified Brownian force model proposed herein to be applied for UFP dispersion modeling in more indoor air quality studies.



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Temporal brow lift vs internal browpexy in females undergoing upper blepharoplasty: Effects on lateral brow lifting

Summary

Background

Lateral brow-lifting surgical procedures in conjunction with upper blepharoplasty may prevent secondary descent following upper blepharoplasty.

Objective

To compare the results of internal browpexy (IBP) and temporal brow lift (TBL) in patients with dermatochalasis undergoing simultaneous upper blepharoplasty.

Methods

This study was a single-center, parallel-group randomized controlled trial conducted on 32 female patients suitable for upper blepharoplasty. Patients were divided into two groups: the IBP group and the TBL group. The brow lift was measured using change in the distance between the ala nasi and lateral tail of the eyebrow as nasal ala to lateral brow (NALB) in millimeter (mm), and the vertical line between the lateral tail of eyebrow and horizontal line extending the lateral cantus as lateral brow plump line (LBPL) in mm before and after the surgery. The follow-up time was 6 months.

Results

The mean ± SD age of patients was 55.93 ± 7.1 years and 53.94 ± 7.7 years in the TBL and IBP groups, respectively (P > .05). No significant change in mean LBPL at 6 months compared to baseline was observed in the TBL group (baseline: 15.7 ± 1.6 mm vs 6 month: 15.8 ± 1.3 mm; P = .602). In the IBP group, a significant increase in mean LBPL at 6 months compared to baseline was observed (baseline: 15.09 ± 2.13 mm vs 6 months: 17. 43 ± 2.68 mm; P < .001).

Conclusions

Internal browpexy combined with blepharoplasty could be considered the better procedure in patients with upper eyelid dermatochalasis in terms of long-lasting stability and lateral brow elevation.

http://ift.tt/2xRe5ZC

Characteristics of ambient ozone (O 3 ) pollution and health risks in Zhejiang Province

Abstract

Troposphere ozone, which is from secondary formation processes, has been increasing dramatically during the last decades in China, inducing high health risks. In this study, temporal and spatial distribution of O₃ was studied among 13 sites of three cities during 2014–2016. The objectives were to clarify the characteristics of the ambient pollution of O₃ under the influence from other pollutants and meteorological parameters and the health outcomes from exposure to O₃. The concentrations of O₃ during summer were much higher than those during winter, and the concentrations in downtown areas were higher than in rural or mountain areas. PM_2.5, NO₂, SO₂, and wind speed (WS) were negatively correlated with O₃, and CO, temperature (T), and relative humidity (RH) were positively correlated with O₃. In multivariable analysis, two separate factors—solar radiation and atmospheric diffusion status, affected the O₃ levels. The concentrations of O₃ reached the highest level at 15:00 and the lowest value at about 6:00–8:00, with the similar trend to T and WS, and opposite to RH. According to the dose-response model, relative risks (RRs) and population attributable fractions (PAFs) with confidence intervals (CIs) for chronic obstructive pulmonary disease (COPD) from exposure to O₃ were 1.0612 (CI 1.0607–1.0616) and 5.32% (CI 5.29–5.36%), respectively, attributable to 2000 deaths in Zhejiang Province in 2014.

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Qualitative and quantitative metals liberation assessment for characterization of various waste printed circuit boards for recycling

Abstract

Metals liberation and composition are decisive attributes in characterization of e-waste for metal recycling. Though end-of-life printed circuit board (PCB) is an integral part of e-waste as secondary resource reservoir, yet no standardized procedure exists for metals liberation and dissolution for its characterization. Thus, the paper aims at assessment of metals liberation upon comminution employing scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS) followed by comparative assessment of the existing United States Environmental Protection Agency (USEPA) digestion procedures, viz., USEPA 3050B, USEPA 3051A, and USEPA 3052, in effective dissolution of metals from comminuted particles of waste PCBs of computer, laptop, mobile phone, and television. Effect of comminution and digestion conditions was assessed to have significant role in metal liberation and dissolution from PCBs. The SEM-EDS analysis demonstrated partial release of metals from the silica matrix of PCBs. The USEPA digestion methods showed statistically significant (P < 0.05) difference with greater dissolution of metals complexed to PCB matrix by the USEPA 3052 method owing to use of strong acid like hydrofluoric acid. Base metals like Cu and Zn and toxic metals such as Pb and Cd were present in abundance in PCBs and in general exceeded the total threshold limit concentration (TTLC). The maximum contents of Cu (20.13 ± 0.04 wt.%) and Zn (1.89 ± 0.05 wt.%) in laptop PCBs, Pb (2.26 ± 0.08 wt.%) in TV PCBs, and Cd (0.0812 ± 0.0008 wt.%) in computer PCBs were observed.

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Quantification of health risks in Ecuadorian population due to dietary ingestion of arsenic in rice

Abstract

In Ecuador alone, 500,000 people in rural areas are estimated to have been exposed to high concentrations of As from water and food, but no quantitative evaluation of health risk has yet been made. The present study quantifies exposure and health risk for the Ecuadorian population from the ingestion of arsenic in white rice. Estimated exposure is correlated with published data on tap water quality and biomarkers of exposure for the population of two towns in the metropolitan area of Quito. Estimated daily intake (EDI) of arsenic for infants living in urban areas of Ecuador is around four times that of European infants, being equal for those livings in rural areas. EDI for the population as a whole is almost twice that of Europe, but between a half and a third of that of Brazil, Bangladesh, and India. Estimated excess lifetime risk (ELTR) for adults is 3 per 10,000, while for infants varies between 10 per 10,000 in rural areas and 20 per 10,000 in urban areas. Future research on arsenic impacts on human health in Ecuador should consider in particular poor populations living in regions where environmental arsenic concentrations are highest, including cross-sectional and longitudinal epidemiologic studies.

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Comprehensive analysis of 225 Castleman’s diseases in the oral maxillofacial and neck region: a rare disease revisited

Abstract

Objectives

The aim of the present study was to comprehensively summarize the epidemiological, clinicopathological characteristics, treatments as well as prognosis of Castleman's disease (CD) identified in the oral maxillofacial and neck region.

Materials and methods

Patients with CD in the oral maxillofacial and neck were retrieved from disease registry at our institution from Jan. 1990 to Dec. 2015. Systematic reviews from both English and Chinese literature were performed to collect the detailed information about the oral maxillofacial and neck CD. The epidemiological, clinicopathological data and treatment outcomes were further statistically analyzed.

Results

Four patients with the oral maxillofacial and neck CD were identified and histologically confirmed as hyaline-vascular type. They underwent surgical excision without recurrence during the follow-up. Systematic literature reviews identified 221 cases from 123 eligible articles which satisfied the inclusion criteria. In 225 patients, most patients were diagnosed as unicentric (207) or hyaline-vascular type (205) of CD and identified in the neck, and treated by surgical resection with good prognosis. In contrast, the minority of patients was multicentric or plasma-cell/mixed type and treated by chemotherapy with inferior outcomes. Kaplan-Meir analyses revealed that both clinical and pathological types were significantly associated with patients' overall survival.

Conclusions

Although rare, most cases of the oral maxillofacial neck CD are found in adults and classified as unicentric and hyaline-vascular type of CD. Complete surgical excision is preferred with favorable prognosis for unicentric disease, whereas chemotherapy is usually exploited for multicentric disease with inferior outcomes.

Clinical relevance

These data provide comprehensive information about the epidemiology, clinicopathological features, treatments, and outcomes of the oral maxillofacial and neck CD.

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Structural Insights into SHARPIN-Mediated Activation of HOIP for the Linear Ubiquitin Chain Assembly

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Jianping Liu, Yingli Wang, Yukang Gong, Tao Fu, Shichen Hu, Zixuan Zhou, Lifeng Pan
The linear ubiquitin chain assembly complex (LUBAC) is the sole identified E3 ligase complex that catalyzes the formation of linear ubiquitin chain, and it is composed of HOIP, HOIL-1L, and SHARPIN. The E3 activity of HOIP can be effectively activated by HOIL-1L or SHARPIN, deficiency of which leads to severe immune system disorders. However, the underlying mechanism governing the HOIP-SHARPIN interaction and the SHARPIN-mediated activation of HOIP remains elusive. Here, we biochemically and structurally demonstrate that the UBL domain of SHARPIN specifically binds to the UBA domain of HOIP and thereby associates with and activates HOIP. We further uncover that SHARPIN and HOIL-1L can separately or synergistically bind to distinct sites of HOIP UBA with induced allosteric effects and thereby facilitate the E2 loading of HOIP for its activation. Thus, our findings provide mechanistic insights into the assembly and activation of LUBAC.

Graphical abstract

Teaser

LUBAC mediates the formation of linear ubiquitin chains and plays critical roles in numerous signaling pathways. Liu et al. determine the crystal structure of HOIP in complex with SHARPIN and examine the molecular mechanism governing the interaction between two LUBAC components.


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Desynchronizing Embryonic Cell Division Waves Reveals the Robustness of Xenopus laevis Development

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Graham A. Anderson, Lendert Gelens, Julie C. Baker, James E. Ferrell
The early Xenopus laevis embryo is replete with dynamic spatial waves. One such wave, the cell division wave, emerges from the collective cell division timing of first tens and later hundreds of cells throughout the embryo. Here, we show that cell division waves do not propagate between neighboring cells and do not rely on cell-to-cell coupling to maintain their division timing. Instead, intrinsic variation in division period autonomously and gradually builds these striking patterns of cell division. Disrupting this pattern of division by placing embryos in a temperature gradient resulted in highly asynchronous entry to the midblastula transition and misexpression of the mesodermal marker Xbra. Remarkably, this gene expression defect is corrected during involution, resulting in delayed yet normal Xbra expression and viable embryos. This implies the existence of a previously unknown mechanism for normalizing mesodermal gene expression during involution.

Graphical abstract

Teaser

Anderson et al. apply strong temperature differences across young frog embryos to desynchronize the regular cell division timing. They find that all cells behave as independent oscillators. Moreover, they see that, although mesoderm induction becomes abnormal initially, the embryos are still able to get their development back on track.


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Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Marilyn Scandaglia, Jose P. Lopez-Atalaya, Alejandro Medrano-Fernandez, Maria T. Lopez-Cascales, Beatriz del Blanco, Michal Lipinski, Eva Benito, Roman Olivares, Shigeki Iwase, Yang Shi, Angel Barco
During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons.

Graphical abstract

Teaser

Scandaglia et al. show that Kdm5c plays critical roles constraining transcription during neuronal differentiation and maturation. Although Kdm5c contribution to neuronal transcription regulation later declines, it retains a genome surveillance role precluding spurious transcription in adult neurons. These functions likely contribute to the pathoetiology of Claes-Jensen-type X-linked intellectual disability.


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AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Rebecca C. Rabinovitch, Bozena Samborska, Brandon Faubert, Eric H. Ma, Simon-Pierre Gravel, Sylvia Andrzejewski, Thomas C. Raissi, Arnim Pause, Julie St.-Pierre, Russell G. Jones
Reactive oxygen species (ROS) are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK) by mitochondrial ROS (mROS) that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.

Graphical abstract

Teaser

AMP-activated protein kinase (AMPK) regulates cellular metabolic balance in response to energy stress. This work by Rabinovitch et al. demonstrates that mitochondrial reactive oxygen species (mROS) are a physiological activator of AMPK and that AMPK couples mROS to an antioxidant program that regulates mitochondrial homeostasis and cellular metabolic balance.


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A Wnt/Calcium Signaling Cascade Regulates Neuronal Excitability and Trafficking of NMDARs

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Andrea McQuate, Elena Latorre-Esteves, Andres Barria
Wnt signaling controls multiple biological process, particularly the embryonic development of metazoans. Sustained expression of Wnt signaling components in the mature mammalian CNS and their apparent deregulation in certain neuropathologies suggest that it also plays a part beyond embryonic development to regulate normal brain function. We describe a noncanonical Wnt/Ca²⁺ signaling cascade that regulates the electrophysiological intrinsic properties of rat neurons, resulting in sustained membrane depolarization and the mobilization of Ca²⁺ from internal stores. These effects require tyrosine kinase-like orphan receptor 2 (RoR2), activation of PLC, and voltage-gated Ca²⁺ channels. Activation of this signaling cascade then promotes surface expression of N-methyl-D-aspartate receptors (NMDARs) through a SNARE-dependent mechanism. This neuronal Wnt/Ca²⁺ signaling pathway represents a mechanism for Wnt ligands to regulate normal brain processes in the mature animal and provides a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders where NMDARs are compromised.

Graphical abstract

Teaser

Wnt signaling is a highly conserved signaling mechanism that controls multiple biological processes. McQuate et al. identify a noncanonical Wnt signaling cascade that regulates electrophysiological intrinsic properties of neurons, resulting in sustained membrane depolarization, mobilization of Ca²⁺ from internal stores, and increased surface expression of NMDAR-type glutamate receptors.


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An Essential Role for the Tetraspanin LHFPL4 in the Cell-Type-Specific Targeting and Clustering of Synaptic GABAA Receptors

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Elizabeth C. Davenport, Valentina Pendolino, Georgina Kontou, Thomas P. McGee, David F. Sheehan, Guillermo López-Doménech, Mark Farrant, Josef T. Kittler
Inhibitory synaptic transmission requires the targeting and stabilization of GABAA receptors (GABAARs) at synapses. The mechanisms responsible remain poorly understood, and roles for transmembrane accessory proteins have not been established. Using molecular, imaging, and electrophysiological approaches, we identify the tetraspanin LHFPL4 as a critical regulator of postsynaptic GABAAR clustering in hippocampal pyramidal neurons. LHFPL4 interacts tightly with GABAAR subunits and is selectively enriched at inhibitory synapses. In LHFPL4 knockout mice, there is a dramatic cell-type-specific reduction in GABAAR and gephyrin clusters and an accumulation of large intracellular gephyrin aggregates in vivo. While GABAARs are still trafficked to the neuronal surface in pyramidal neurons, they are no longer localized at synapses, resulting in a profound loss of fast inhibitory postsynaptic currents. Hippocampal interneuron currents remain unaffected. Our results establish LHFPL4 as a synapse-specific tetraspanin essential for inhibitory synapse function and provide fresh insights into the molecular make-up of inhibitory synapses.

Graphical abstract

Teaser

Davenport et al. identify LHFPL4 as a transmembrane protein that interacts with GABAARs and is essential for their synaptic clustering. Deletion of LHFPL4 results in dramatic cell-type-specific deficits in inhibitory synaptic transmission.


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GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Sylvia Pfennig, Franziska Foss, Diane Bissen, Eva Harde, Julia C. Treeck, Marta Segarra, Amparo Acker-Palmer
Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption of the complex, absence of ApoER2 downstream signaling, and impaired activity-induced and ApoER2-mediated AMPA receptor insertion. Using compound genetics, we show the requirement of this complex for long-term potentiation (LTP). Together, our findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.

Graphical abstract

Teaser

Activity-dependent AMPA receptor dynamic changes modulate synaptic plasticity. Pfennig et al. show that insertion of new AMPA receptors at the synapse is mediated by the formation of a macromolecular complex at the membrane that includes ApoER2, ephrinB2, and AMPA receptors bridged by the multi-PDZ adaptor protein GRIP1.


http://ift.tt/2hLjCdE

Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Roman Praschberger, Simon A. Lowe, Nancy T. Malintan, Carlo N.G. Giachello, Nian Patel, Henry Houlden, Dimitri M. Kullmann, Richard A. Baines, Maria M. Usowicz, Shyam S. Krishnakumar, James J.L. Hodge, James E. Rothman, James E.C. Jepson
Mutations in the Golgi SNARE (SNAP [soluble NSF attachment protein] receptor) protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitous and essential protein mediating ER-to-Golgi membrane fusion. Thus, it is unclear how mutations in Membrin result in a disorder restricted to the nervous system. Here, we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in Drosophila models of GOSR2-PME. Furthermore, we show that Membrin mutations cause fragmentation of the presynaptic cytoskeleton coupled with transsynaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME.

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In this study, Praschberger et al. utilize in vitro assays, patient-derived cells, and Drosophila models to unravel how mutations in the essential Golgi SNARE protein Membrin cause progressive myoclonus epilepsy and to demonstrate a selective vulnerability of developing neurons to partial impairment of ER-to-Golgi trafficking.


http://ift.tt/2hMvFHK

Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Alyssa N. Coyne, Ileana Lorenzini, Ching-Chieh Chou, Meaghan Torvund, Robert S. Rogers, Alexander Starr, Benjamin L. Zaepfel, Jennifer Levy, Jeffrey Johannesmeyer, Jacob C. Schwartz, Hiroshi Nishimune, Konrad Zinsmaier, Wilfried Rossoll, Rita Sattler, Daniela C. Zarnescu
Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism.

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Teaser

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by synaptic failure. Coyne et al. show that in multiple models of ALS, ranging from Drosophila to mice to patient-derived motor neurons, deficits in synaptic vesicle cycling can be explained by dysregulation of the Hsc70-4/HSPA8 chaperone.


http://ift.tt/2hLjwmi

M. tuberculosis-Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Murugesan V.S. Rajaram, Eusondia Arnett, Abul K. Azad, Evelyn Guirado, Bin Ni, Abigail D. Gerberick, Li-Zhen He, Tibor Keler, Lawrence J. Thomas, William P. Lafuse, Larry S. Schlesinger
Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides. We found that MR binds FcRγ-chain, which is required for MR plasma membrane localization and M.tb cell association. Additionally, we discovered that MR-mediated M.tb association triggers immediate MR tyrosine residue phosphorylation and Grb2 recruitment, activating the Rac/Pak/Cdc-42 signaling cascade important for M.tb uptake. MR activation subsequently recruits SHP-1 to the M.tb-containing phagosome, where its activity limits PI(3)P generation at the phagosome and M.tb P-L fusion and promotes M.tb growth. In sum, we identify human MR signaling pathways that temporally regulate phagocytosis and P-L fusion during M.tb infection.

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Teaser

The human mannose receptor (MR) mediates macrophage phagocytosis and immune regulation. MR-specific signaling remains a major gap in the field. Rajaram et al. identify the importance of FcRγ-chain and Grb2 during MR-mediated phagocytosis and subsequent MR-dependent recruitment of SHP-1 to the M.tb phagosome, thereby limiting PI(3)P generation and phagosome-lysosome fusion.


http://ift.tt/2hLjuLc

Host MicroRNAs-221 and -222 Inhibit HIV-1 Entry in Macrophages by Targeting the CD4 Viral Receptor

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Robert Lodge, Jérémy A. Ferreira Barbosa, Félix Lombard-Vadnais, Julian C. Gilmore, Alexandre Deshiere, Annie Gosselin, Tomas Raul Wiche Salinas, Mariana G. Bego, Christopher Power, Jean-Pierre Routy, Petronela Ancuta, Michel J. Tremblay, Éric A. Cohen
Macrophages are heterogeneous immune cells with distinct origins, phenotypes, functions, and tissue localization. Their susceptibility to HIV-1 is subject to variations from permissiveness to resistance, owing in part to regulatory microRNAs. Here, we used RNA sequencing (RNA-seq) to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two microRNAs upregulated in bystander macrophages, miR-221 and miR-222, were identified as negative regulators of CD4 expression and CD4-mediated HIV-1 entry. Both microRNAs were enhanced by tumor necrosis factor alpha (TNF-α), an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-α-treated macrophages by enhancing CD4 expression and increased HIV-1 replication and spread in macrophages by countering TNF-α-enhanced miR-221/miR-222 expression in bystander cells. In line with these findings, HIV-1-resistant intestinal myeloid cells express higher levels of miR-221 than peripheral blood monocytes. Thus, miR-221/miR-222 act as effectors of the antiviral host response activated during macrophage infection that restrict HIV-1 entry.

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Using RNA-seq, Lodge et al. compared microRNA profiles of virus producing and bystander macrophages in HIV-1-infected cultures. Among those enhanced in bystanders were microRNAs-221 and -222. These microRNAs are part of an anti-HIV response in bystanders, potentiated by TNF-α activation, which inhibits HIV-1 entry by reducing CD4 expression.


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Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Javier Rodríguez-Ubreva, Francesc Català-Moll, Nataša Obermajer, Damiana Álvarez-Errico, Ricardo N. Ramirez, Carlos Company, Roser Vento-Tormo, Gema Moreno-Bueno, Robert P. Edwards, Ali Mortazavi, Pawel Kalinski, Esteban Ballestar
Myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) arise from common progenitors. Tumor-derived factors redirect differentiation from immune-promoting DCs to tolerogenic MDSCs, an immunological hallmark of cancer. Indeed, in vitro differentiation of DCs from human primary monocytes results in the generation of MDSCs under tumor-associated conditions (PGE2 or tumor cell-conditioned media). Comparison of MDSC and DC DNA methylomes now reveals extensive demethylation with specific gains of DNA methylation and repression of immunogenic-associated genes occurring in MDSCs specifically, concomitant with increased DNA methyltransferase 3A (DNMT3A) levels. DNMT3A downregulation erases MDSC-specific hypermethylation, and it abolishes their immunosuppressive capacity. Primary MDSCs isolated from ovarian cancer patients display a similar hypermethylation signature in connection with PGE2-dependent DNMT3A overexpression. Our study links PGE2- and DNMT3A-dependent hypermethylation with immunosuppressive MDSC functions, providing a promising target for therapeutic intervention.

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Rodríguez-Ubreva et al. find that inflammatory factors, such as prostaglandin E2, that are able to redirect the differentiation of precursor myeloid cells toward tolerogenic myeloid-derived suppressor cells (MDSCs) also impose a DNMT3A-dependent fingerprint in myeloid genes that leads to the acquisition of suppressive properties.


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CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Zicheng Hu, Yu Li, Annemarie Van Nieuwenhuijze, Hilary J. Selden, Angela M. Jarrett, Anna G. Sorace, Thomas E. Yankeelov, Adrian Liston, Lauren I.R. Ehrlich
Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here, we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7^−/− mice have increased Treg cellularity because of a hematopoietic but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DCs) promotes survival of mature Sirpα⁻ DCs. Thus, CCR7 deficiency results in apoptosis of Sirpα⁻ DCs, which is counterbalanced by expansion of immature Sirpα⁺ DCs that efficiently induce Treg generation. CCR7 deficiency results in enhanced intrathymic generation of Tregs at the neonatal stage and in lymphopenic adults, when Treg differentiation is critical for establishing self-tolerance. Together, these results reveal a complex function for CCR7 in thymic tolerance induction, where CCR7 not only promotes negative selection but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.

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CCR7 promotes thymocyte medullary entry and is thus required for negative selection. Hu et al. show that CCR7 also regulates intrathymic generation of regulatory T cells (Tregs) through a non-T cell intrinsic mechanism. CCR7 regulates the composition of the thymic conventional DC compartment, which, in turn, restrains intrathymic Treg generation.


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Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Sonia Agüera-González, Oliver T. Burton, Elena Vázquez-Chávez, Céline Cuche, Floriane Herit, Jérôme Bouchet, Rémi Lasserre, Iratxe del Río-Iñiguez, Vincenzo Di Bartolo, Andrés Alcover
Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.

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Agüera-González et al. investigate the role of the polarity regulator and tumor suppressor Adenomatous polyposis coli (APC) in CD4 T cell activation and effector function. APC controls microtubule reorganization, NFAT transcription factor localization, and cytokine gene expression. In Apc^Min/+ mutant mice, regulatory T cell (Treg) differentiation and anti-inflammatory function were intrinsically affected.


http://ift.tt/2hMw112

Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Byung-Seok Kim, Huiping Lu, Kenji Ichiyama, Xiang Chen, Yi-Bing Zhang, Nipun A. Mistry, Kentaro Tanaka, Young-hee Lee, Roza Nurieva, Li Zhang, Xuexian Yang, Yeonseok Chung, Wei Jin, Seon Hee Chang, Chen Dong
Th17 cells are potent mediators in autoimmune diseases, and RORγt is required for their development. Recent studies have shown that RORγt⁺ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt⁺ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt⁺ Treg cells in their transcriptomes, peripheral RORγt⁺ Treg cells were derived from Foxp3⁺ thymic Treg cells in an antigen-specific manner. Development of these RORγt⁺ Treg cells, coined T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17-cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates that Tr17 cells are effector Treg cells that potentially restrict autoimmunity.

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Kim et al. find that RORγt⁺Foxp3⁺ T regulatory 17 (Tr17) cells are induced in lymph nodes after immunization. Tr17 cells are generated from thymic Treg cells in an antigen-specific manner through Stat3 signaling. Their data suggest that Tr17 cells represent antigen-specific effector Treg cells that can regulate Th17-cell-dependent autoimmunity.


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Precocious Interleukin 21 Expression in Naive Mice Identifies a Natural Helper Cell Population in Autoimmune Disease

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Elisabeth A. Marnik, Xulong Wang, Thomas J. Sproule, Giljun Park, Gregory J. Christianson, Sarah Kate Lane-Reticker, Shweta Jain, Theodore Duffy, Hongsheng Wang, Gregory W. Carter, Herbert C. Morse, Derry C. Roopenian
Interleukin 21 (IL-21) plays key roles in humoral immunity and autoimmune diseases. It is known to function in mature CD4⁺ T follicular B cell helper (TFH) cells, but its potential involvement in early T cell ontogeny is unclear. Here, we find that a significant population of newly activated thymic and peripheral CD4⁺ T cells functionally expresses IL-21 soon after birth. This naturally occurring population, termed natural (n)TH21 cells, exhibits considerable similarity to mature TFH cells. nTH21 cells originating and activated in the thymus are strictly dependent on autoimmune regulator (AIRE) and express high levels of NUR77, consistent with a bias toward self-reactivity. Their activation/expansion in the periphery requires gut microbiota and is held in check by FoxP3⁺ TREG cells. nTH21 cells are the major thymic and peripheral populations of IL-21⁺ cells to expand in an IL-21-dependent humoral autoimmune disease. These studies link IL-21 to T cell ontogeny, self-reactivity, and humoral autoimmunity.

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Marnik et al. identify a population of activated T cells that precociously express the cytokine interleukin 21. These naturally occurring cells develop within the thymus and periphery and are greatly elevated under autoimmune conditions. Thus, they may be critical contributors to the development of humoral autoimmunity.


http://ift.tt/2hMvv36

Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): James E. Voss, Raiees Andrabi, Laura E. McCoy, Natalia de Val, Roberta P. Fuller, Terrence Messmer, Ching-Yao Su, Devin Sok, Salar N. Khan, Fernando Garces, Laura K. Pritchard, Richard T. Wyatt, Andrew B. Ward, Max Crispin, Ian A. Wilson, Dennis R. Burton
Recent efforts toward HIV vaccine development include the design of immunogens that can engage B cell receptors with the potential to affinity mature into broadly neutralizing antibodies (bnAbs). V2-apex bnAbs, which bind a protein-glycan region on HIV envelope glycoprotein (Env) trimer, are among the most broad and potent described. We show here that a rare "glycan hole" at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bnAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, we immunized wild-type rabbits with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response.

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Voss et al. show that select V2-apex-focusing immunogens derived from bnAb precursor neutralization-sensitive HIV isolates can reproducibly elicit autologous neutralizing responses to components of the bnAb epitope, including K169/K171 and N156, in a wild-type animal model.


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Quantitative Measurement and Thermodynamic Modeling of Fused Enhancers Support a Two-Tiered Mechanism for Interpreting Regulatory DNA

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Md. Abul Hassan Samee, Tara Lydiard-Martin, Kelly M. Biette, Ben J. Vincent, Meghan D. Bragdon, Kelly B. Eckenrode, Zeba Wunderlich, Javier Estrada, Saurabh Sinha, Angela H. DePace
Computational models of enhancer function generally assume that transcription factors (TFs) exert their regulatory effects independently, modeling an enhancer as a "bag of sites." These models fail on endogenous loci that harbor multiple enhancers, and a "two-tier" model appears better suited: in each enhancer TFs work independently, and the total expression is a weighted sum of their expression readouts. Here, we test these two opposing views on how cis-regulatory information is integrated. We fused two Drosophila blastoderm enhancers, measured their readouts, and applied the above two models to these data. The two-tier mechanism better fits these readouts, suggesting that these fused enhancers comprise multiple independent modules, despite having sequence characteristics typical of single enhancers. We show that short-range TF-TF interactions are not sufficient to designate such modules, suggesting unknown underlying mechanisms. Our results underscore that mechanisms of how modules are defined and how their outputs are combined remain to be elucidated.

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Samee et al. identify a gap in our current assumptions of how regulatory sequences control gene expression. It is generally assumed that regulatory sequences act as single modules on transcriptional machinery. Quantitative modeling of a set of synthetic regulatory sequences challenges this assumption.


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How linear response shaped models of neural circuits and the quest for alternatives

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Tim Herfurth, Tatjana Tchumatchenko
In the past decades, many mathematical approaches to solve complex nonlinear systems in physics have been successfully applied to neuroscience. One of these tools is the concept of linear response functions. However, phenomena observed in the brain emerge from fundamentally nonlinear interactions and feedback loops rather than from a composition of linear filters. Here, we review the successes achieved by applying the linear response formalism to topics, such as rhythm generation and synchrony and by incorporating it into models that combine linear and nonlinear transformations. We also discuss the challenges encountered in the linear response applications and argue that new theoretical concepts are needed to tackle feedback loops and non-equilibrium dynamics which are experimentally observed in neural networks but are outside of the validity regime of the linear response formalism.



http://ift.tt/2xXp42T

The many worlds hypothesis of dopamine prediction error: implications of a parallel circuit architecture in the basal ganglia

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Brian Lau, Tiago Monteiro, Joseph J Paton
Computational models of reinforcement learning (RL) strive to produce behavior that maximises reward, and thus allow software or robots to behave adaptively [1]. At the core of RL models is a learned mapping between 'states'—situations or contexts that an agent might encounter in the world—and actions. A wealth of physiological and anatomical data suggests that the basal ganglia (BG) is important for learning these mappings [2,3]. However, the computations performed by specific circuits are unclear. In this brief review, we highlight recent work concerning the anatomy and physiology of BG circuits that suggest refinements in our understanding of computations performed by the basal ganglia. We focus on one important component of basal ganglia circuitry, midbrain dopamine neurons, drawing attention to data that has been cast as supporting or departing from the RL framework that has inspired experiments in basal ganglia research over the past two decades. We suggest that the parallel circuit architecture of the BG might be expected to produce variability in the response properties of different dopamine neurons, and that variability in response profile may not reflect variable functions, but rather different arguments that serve as inputs to a common function: the computation of prediction error.



http://ift.tt/2xRtNBF

The Relative Importance of Perceptual and Memory Sampling Processes in Determining the Time Course of Absolute Identification.

Author: Guest, Duncan; Kent, Christopher; Adelman, James S.

DOI: 10.1037/xlm0000438

Publication Date: POST AUTHOR CORRECTIONS, 2 October 2017

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Use of the antimicrobial photodynamic therapy as a conservative clinical management of caries lesions on a permanent tooth

Publication date: Available online 3 October 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Eliziário Vitoriano de Araújo Neto, Rafaela de Albuquerque Dias




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Announcements

Publication date: October 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 10





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Editorial Board

Publication date: October 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 10





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Calender

Publication date: October 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 10





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William Paske 12 June 1948 to 24 December 2016

Publication date: Available online 3 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Peter Bell, Giorgio M. Biasi, Jose Fernandes e Fernandes, Christos Liapis




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Immediate completion lymph node dissection in stage IIIA melanoma does not provide significant additional staging information beyond EORTC SN tumour burden criteria

Publication date: Available online 3 October 2017
Source:European Journal of Cancer
Author(s): Max F. Madu, Viola Franke, Maarten M. Bruin, Danique M.S. Berger, Carolien Bierman, Katarzyna Jóźwiak, Willem M.C. Klop, Michel W.J.M. Wouters, Alexander C.J. van Akkooi, Bart A. Van de Wiel




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Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Andrea Casadei Gardini, Luca Faloppi, Serena De Matteis, Francesco Giuseppe Foschi, Nicola Silvestris, Francesco Tovoli, Vincenzo Palmieri, Giorgia Marisi, Oronzo Brunetti, Umberto Vespasiani-Gentilucci, Giuseppe Perrone, Martina Valgiusti, Anna Maria Granato, Giorgio Ercolani, Giulia Negrini, Emiliano Tamburini, Giuseppe Aprile, Alessandro Passardi, Daniele Santini, Stefano Cascinu, Giovanni Luca Frassineti, Mario Scartozzi
PurposeIn 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance.Patients and methodsWe analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples.ResultsIn HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013).ConclusionsOur findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.



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‘Corrigendum to “Severe hepatitis under combined immunotherapy: Resolution under corticosteroids plus anti-thymocyte immunoglobulins” [Eur J Cancer 81 (August 2017) 203–205]’

Publication date: Available online 3 October 2017
Source:European Journal of Cancer
Author(s): Iris Spänkuch, Maximilian Gassenmaier, Ioanna Tampouri, Seema Noor, Andrea Forschner, Claus Garbe, Teresa Amaral




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The quest for exceptional drug solubilization in diluted surfactant solutions and consideration of residual solid state

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Wiebke Saal, Nicole Wyttenbach, Jochem Alsenz, Martin Kuentz
Solubility screening in different surfactant solutions is an important part of pharmaceutical profiling. A particular interest is in low surfactant concentrations that mimic the dilution of an oral dosage form. Despite of intensive previous research on solubilization in micelles, there is only limited data available at low surfactant concentrations and generally missing is a physical state analysis of the residual solid. The present work therefore studied 13 model drugs in 6 different oral surfactant solutions (0.5%, w/w) by concomitant X-ray diffraction (XRPD) analysis to consider effects on solvent-mediated phase transformations. A particular aspect was potential occurrence of exceptionally high drug solubilization. As a result, general solubilization correlations were observed especially between surfactants that share chemical similarity. Exceptional solubility enhancement of several hundred-fold was evidenced in case of sodium dodecyl sulfate solutions with dipyridamole and progesterone. Furthermore, carbamazepine and testosterone showed surfactant-type dependent hydrate formation. The present results are of practical relevance for an optimization of surfactant screenings in preformulation and early development and provide a basis for mechanistic modeling of surfactant effects on solubilization and solid state modifications.

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Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Eman Gomaa, Amr S. Abu Lila, Azza A. Hasan, Fakhr-eldin S. Ghazy
Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher Cmax (32 times) and AUC0–4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus.

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Evaluation of critical parameters for in vitro skin permeation and penetration studies using animal skin models

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Fabíola Silva Garcia Praça, Wanessa Silva Garcia Medina, Josimar O. Eloy, Raquel Petrilli, Patrícia Mazureki Campos, Andreia Ascenso, Maria Vitória L.B. Bentley
In vitro skin permeation/penetration studies may be affected by many sources of variation. Herein, we aimed to investigate the major critical procedures of in vitro skin delivery studies. These experiments were performed with model drugs according to official guidelines. The influence of skin source on penetration studies was studied as well as the use of a cryopreservation agent on skin freezing evaluated by transepidermal water loss, electrical resistance, permeation/penetration profiles and histological changes of the skin. The best condition for tape stripping procedure was validated through the evaluation of the distribution of corneocytes, mass of stratum corneum (SC) removed and amount of protein removed using finger pressure, a 2kg weight and a roller. The interchangeability of the tape stripping procedures followed by the epidermis and dermis homogenate and the micrometric horizontal cryostat skin sectioning methods were also investigated, besides the effect of different formulations. Noteworthy, different skin sources were able to ensure reliable interchangeability for in vitro permeation studies. Furthermore, an increased penetration was obtained for stored frozen skin compared to fresh skin, even with the addition of a cryoprotectant agent. The best method for tape stripping was the finger pressure followed by the addition of a propylene glycol solvent leading to better SC removal. Finally, no significant difference was found in skin penetration studies performed by different methods suggesting their possible interchangeability.

Graphical abstract

http://ift.tt/2xQWH7q

Nanocapsules improve indole-3-carbinol photostability and prolong its antinociceptive action in acute pain animal models

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Mailine Gehrcke, Marcel Henrique Marcondes Sari, Luana Mota Ferreira, Allanna Valentini Barbieri, Laura Minussi Giuliani, Vinicius Costa Prado, Jessica Mendes Nadal, Paulo Vitor Farago, Cristina Wayne Nogueira, Letícia Cruz
This study aimed the development of nanocapsules (NCs) for oral indole-3-carbinol (I3C) administration and evaluation of antinociceptive potential of this compound in its two forms, free and nanoencapsulated, using acute pain models. NCs showed adequate physicochemical characteristics and protected the I3C against UVC radiation exposure. It was observed no chemical bond between I3C and polymer by FTIR. Besides, X-ray and DSC analysis suggested that I3C was molecularly dispersed in NCs. The dialysis bag technique showed that almost 100% of the compound was released from NCs at 360min. Mathematical modeling demonstrated that this release occurred in two rates, with an initial burst effect followed by a slower release of I3C. Regarding the in vivo analysis, time-response curve showed that both forms of I3C caused an inhibition in inflammatory phase of nociception induced by formalin and increased the latency response in hot plate test. Interestingly, NCs were able to prolong the I3C effect in both tests. Furthermore, in dose-response curve, only I3C in its nanoencapsulated form presented effect on inflammatory phase of the formalin test. In conclusion, NCs to I3C incorporation presented adequate nanometric characteristics and prolonged its antinociceptive action in acute pain models tested.

Graphical abstract

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TERT promoter mutation and its interaction with IDH mutations in glioma: Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups—A meta-analysis of aggregate data

Publication date: Available online 3 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Huy Gia Vuong, Ahmed M.A. Altibi, Uyen N.P. Duong, Hanh T.T. Ngo, Thong Quang Pham, Aden Ka-Yin Chan, Chul-Kee Park, Kar-Ming Fung, Lewis Hassell
The clinical significance of telomerase reverse transcriptase (TERT) promoter mutation in glioma remains unclear. The aim of our meta-analysis is to investigate the prognostic impact TERT promoter mutation in glioma patients and its interaction with other molecular markers, particularly Isocitrate Dehydrogenase (IDH) mutation from aggregate level data. Relevant articles were searched in four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library. Pooled HRs were calculated using random effect model weighted by inverse variance method. From 1010 studies, we finally included 28 studies with 11519 patients for meta-analyses. TERT mutation is significantly associated with compromised overall survival (OS) (HR=1.38; 95% CI=1.15–1.67) and progression-free survival (PFS) (HR=1.31; 95% CI=1.06–1.63) in glioma patients. In studying its reaction with IDH, TERT promoter mutation was associated with reduced OS in both IDH-mutant (IDH-mut) and IDH-wild type (IDH-wt) glioblastomas but shown to have inverse effects on IDH-mut and IDH-wt grade II/III tumors. Our analysis categorized WHO grade II/III glioma patients into four distinct survival subgroups with descending survival as follow: TERT-mut/IDH-mut≫TERT-wt/IDH-mut≫TERT-wt/IDH-wt≫TERT-mut/IDH-wt. Prognostic value of TERT promoter mutations in gliomas is dependent on tumor grade and the IDH mutational status. With the same tumor grade in WHO grade II and III tumors and the same IDH mutation status, TERT-mut is a prognostic factor.



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Asthma disease as cause of admission to hospitals due to exposure to ambient oxidants in Mashhad, Iran

Abstract

Nowadays, asthma is one of the most common chronic respiratory diseases, worldwide. Many reports have emphasized the correlation between the short-term exposure to the ambient air pollutants and acute respiratory diseases, especially among children with asthmatic symptoms. The aim of this study was to evaluate the relationship between the exposure to three atmospheric antioxidants (NO₂, SO₂, and O₃) and hospital admission due to asthmatic disease (HAAD) in the city of Mashhad, Iran. The concentrations of atmospheric antioxidants were obtained from the real-time monitoring stations located in the city. The collected data were employed for developing predictive models in the AirQ software. In order to investigate the association between short-term exposure to air pollutants and HAAD, the study participants were categorized into two age groups: less than 15 and from 15 to 64 years old. The results indicated that in people less than 15 years increase in NO₂ (attributable proportion (AP) = 3.775%, 95% CI 0.897–6.883%), SO₂ (AP = 3.649%, 95% CI 1.295–5.937%), and O₃ (AP = 0.554%,95% CI 0.00–3.321) results in increase in HAAD. While for those aged between 15 and 64 years, the AP was 4.192% (95% CI 0.450–7.662%) for NO₂; 0.0% (95% CI 0.00–1.687%) for SO₂; and 0.236% (95% CI 0.00–1.216%) for O₃. The number of asthmatic cases who were less than 15 years admitted to the hospitals during the study period was higher than that of those within the age groups between 15 and 64 years as a consequence of exposure to NO₂ (101 vs. 75), SO₂ (98 vs. 0), and O₃ (15 vs. 3), respectively. To the best of our knowledge, the AirQ model has not been applied before to estimate the effect of atmospheric antioxidant exposure on hospital admission because of asthma disease. Eventually, this model is proposed to be applicable for other cities around the world.

http://ift.tt/2hLjNG4

Major and trace metals in suspended and bottom sediments of the Mandovi and Zuari estuaries, western India: distribution, source, and pollution

Abstract

Major elements and trace metals in suspended sediments along transect stations of the Mandovi and Zuari estuaries showed three types of distribution: (a) high concentrations of most metals (Al, Fe, Mn, Cr, Pb, Cu, Ni, Zn, Co, Sc, Mo, and U) in the upper estuary and their decreasing concentrations seaward in every season, (b) lower concentrations of some metals (Mg, Cr, Zr, V, Al, Th) in the upper estuary and bay and their increased concentrations in the lower estuary, and (c) higher concentrations of some metals (Cu, Ni, Zn, Pb, and Cr) in the upper estuary and bay and their decreased concentrations in the lower estuary. Mn was the most significant pollutant in both the estuaries. The Zn, Cr, Fe, and Mo in Mandovi during the monsoon and post-monsoon and, Pb, Ni, and Cr in Zuari during the post- and pre-monsoons were in the range "moderately to heavily polluted." The pollution load index of metals was high at upstream stations, with higher values in Mandovi during monsoon and Zuari during the post- and pre-monsoons. Most trace metals were correlated with Fe and Mn indicating their association primarily with Fe-Mn ore material. The principal component analysis indicated natural and anthropogenic inputs and the latter was predominantly related to ore material in both the estuaries. The distribution factor was high for Al, Mg, Zr, Th, and U in < 2-μm fraction and Cr, Cu, Ni, Zn, Co, V, Sc, and Zr in 2–4-μm size fraction sediments suggesting two sources of sediments. More than 60% concentrations of all trace metals were associated with < 2-μm fraction sediments. The distribution of trace metals along transect was affected by the physico-chemical conditions of the estuary, grain size of sediments, and anthropogenic contribution of metals.

http://ift.tt/2fPaO5U

American Thyroid Association Set to Launch 87th Annual Meeting

ATA Meets in Victoria, BC

October 3, 2017—The American Thyroid Association (ATA) is set to launch its 87^th Annual Meeting on October 18‒22, 2017, in Victoria, British Columbia. Key opinion leaders, thyroid specialists, clinical and basic researchers, and young trainees will gather for four exciting and information-filled days of symposia, scientific presentations, and discussions on the latest advances in thyroidology and clinical management of thyroid diseases. Nearly 1200 attendees have already registered for this outstanding educational and networking opportunity.  A record-setting 519 regular and late-breaking abstracts have been accepted.

Three leaders in the thyroid field, Carmelo Nucera, MD, PhD (Harvard Univ.), Gregory Brent, MD (UCLA), and Julie Ann Sosa, MD (Duke Univ.), will present the opening session on Wednesday evening, "A Year in Thyroidology," in which they will discuss the top recent papers in basic, clinical, and surgical thyroidology.

Weiping Teng, MD, PhD, of First Affiliated Hospital, China Medical University, Shenyang, will give one of two plenary lectures. His topic, "Effect of Iodine Intake on Thyroid Disorders: Learning from China," describes the results of the Chinese government's initial implementation of universal salt iodization in 1999, intended to reduce the high iodine deficiency disorders prevalent across the country (except in Shanghai), and its subsequent reduction of the concentration of salt iodine when excessive iodine intake became a serious problem in many provinces. Dr. Teng provides comparisons with CDC results from the US and some from WHO for pregnant women.

On day three of the meeting, the plenary lecture, "Understanding How Breaches in Immune Tolerance Lead to Autoimmune Thyroid Disease (AITD)," will be given by John C. Cambier, PhD, of the Department of Immunology and Microbiology, University of Colorado School of Medicine. Dr. Cambier and his research team are studying the thyroid antigen-reactive B cells in the peripheral blood of both recent-onset and long-standing AITD patients.

The ATA will reveal the recipient of the 2017 Van Meter Award the first morning of the meeting, and the winner, recognized for outstanding contributions to research on the thyroid gland or related subjects, will present the Van Meter Award Lecture. The Paul Starr Award lecturer is Quan-Yang Duh, MD, recognized for his outstanding contributions to clinical thyroidology, and Julie Ann Sosa, MD will deliver the 2017 Lewis E. Braverman Lectureship with a talk entitled "Re-Telling the Story About Thyroid Cancer – Rising Incidence, Mortality, and Maybe an Explanation."  Yuri Nikiforov, MD, PhD is this year's Sidney H. Ingbar Awardee speaking on "Genomic Evolution of Thyroid Nodules and Cancer – New Answers to Old Questions." The ATA will also present the John B. Stanbury Thyroid Pathophysiology Medal to James A. Fagin, MD, and the 2017 Distinguished Service Award to Bryan R. Haugen, MD, both of whom are past presidents of the Society.

The program highlights presentations by the seven recent ATA Research Grant recipients. This year's awardees are investigating research topics that include the genetics of advanced thyroid cancer, mouse modeling of medullary thyroid carcinoma, and the role of the renal sodium/iodide symporter in iodide metabolism and thyroid function. See the ATA website for full details www.thyroid.org.  In addition to the plenary and award lectures at the Annual Meeting, many specialized symposia, panel and small workshop educational formats will be offered.

Dr. John Morris, President of the American Thyroid Association, remarks, "ATA meeting attendees will have the opportunity to network with clinicians and investigators, colleagues and newcomers, making scientific and professional connections that will last throughout their careers. Given that we will be located in one of the most beautiful places in the world, it is a meeting not to be missed."

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 The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 94^th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

• The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs
• Development of guidelines for clinical management of thyroid disease and thyroid cancer

 The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

The post American Thyroid Association Set to Launch 87th Annual Meeting appeared first on American Thyroid Association.

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American Thyroid Association Symposia Highlight Novel Thyroid Research

87^th Annual Meeting of the ATA – Victoria, BC

October 2, 2017—The 87^th Annual Meeting of the American Thyroid Association (ATA), taking place October 18‒22, 2017, in Victoria, British Columbia, will offer informative symposia presented by pioneering investigators and key opinion leaders.

New exciting formats this year include an interactive Grand Rounds symposium, moderated by Mary Samuels, MD, focusing on the diagnosis and management of thyroid dysfunction, plus a session featuring recent publications from VideoEndocrinology, one of the flagship journals of the ATA. Andrew Bauer, MD, will lead a special half-day pediatric endocrinology forum in which several experts will discuss the latest research in pediatric endocrinology and clinical disease management.

Opportunity for lively discussions in clinical symposia will focus on advances in the understanding of thyroid cancer. Bryan Haugen, MD, will chair a session entitled "New Directions in Thyroid Nodules and Thyroid Cancer," featuring discussions on the updated Bethesda classification system for reporting thyroid cytopathology, the 8^th edition of the thyroid cancer staging system written by the American Joint Committee on Cancer (AJCC), and the art of balancing necessary thyroid surgeries while reducing risks in a cost-conscious manner.

John Lazarus, MD, will moderate a symposium covering the engaging topic of thyroid disease and pregnancy. The experts in this session will review the controversies surrounding subclinical hypothyroidism during pregnancy, the potential relationships between pregnancy and thyroid cancer, and the newly published "ATA Guidelines for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum."

Basic research symposia will feature:

• Peter Kopp, MD, moderating a discussion of "Thyroid Hormone Transporters," featuring presentations on the role of thyroid hormone receptors in the brain and novel clinical translational approaches
• Antonio Di Cristofano, PhD, chairing presentations in the session "Modulation of TSH Receptors in Thyroid Disease"
• Electron Kebebew, MD, facilitating the symposium "MicroRNAs in Thyroid Cancer"
• Young Kee Shong, MD, PhD, leading a stimulating session on "Novel Molecular Mechanisms in Thyroid Cancer," with an international presentation team on the topics of nuclear receptor signaling and novel genetic mechanisms in benign and malignant thyroid tumors

The annual meeting will focus on recent advances regarding mechanisms, screening, diagnosis, and management of thyroid disorders with attention to translating the latest research findings and clinical management guidelines into practice to enhance patient care.

###

 The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 94^th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

• The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs
• Development of guidelines for clinical management of thyroid disease and thyroid cancer

The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

The post American Thyroid Association Symposia Highlight Novel Thyroid Research appeared first on American Thyroid Association.

http://ift.tt/2xeG2Gv

“The importance of surgical maneuvers during treatment of frontal migraines (site I): a prospective, randomized cohort study evaluating foraminotomy/fasciotomy, myectomy, and arterectomy”

The current prospective, blinded, randomized cohort study aims to delineate the relative contribution of different surgical treatments for frontal migraines.

http://ift.tt/2g7xIT1

Preoperative fasting in children

1A012A033J03

http://ift.tt/2yHpLuy

Paediatric airway infections

1C022D013D00

http://ift.tt/2xSgLDG

Error and Root Cause Analysis

1I032A063I00

http://ift.tt/2yGpTup

Burnout and resilience in anaesthesia and intensive care medicine

1H022H013J02

http://ift.tt/2xRkHof

Decision Making and Psychological Outcomes in Low-Risk Papillary Thyroid Cancer

Condition:   Thyroid Cancer
Intervention:   Behavioral: Questionnaires
Sponsor:   Memorial Sloan Kettering Cancer Center
Recruiting

http://ift.tt/2xOIFmz

Trail Evaluating Apatinib With IMRT for Inoperable or Iodine Refractory Thyroid Cancer

Condition:   Thyroid Cancer
Interventions:   Drug: Apatinib;   Radiation: Intensity modulated radiation therapy
Sponsor:   Xiayun He, MD
Recruiting

http://ift.tt/2g9kJjL

Genetic damage in Rhinella marina populations in habitats affected by agriculture in the middle region of the Sinú River, Colombia

Abstract

Contamination with pesticide residues affects the environmental health of agroecosystems, especially the amphibian fauna that lives in these environments. The objective of the present study was to determine pesticides concentrations in sediments of agroecosystems and to evaluate genetic damage in Rhinella marina populations living in these zones. A total of 91 individuals were collected, 51 in the group exposed in different areas of the middle region of the Sinú River (Irrigation District of Mocari 16, Irrigation District of Aguas Negras 21, Irrigation District of Cerete 14) and 40 in a control group; at the same time, 36 subsamples of sediments were taken at each sampled station to determine pesticides organochlorine by means of chromatography coupled with ISQ Thermo Scientific mass spectrometer. The micronucleus test was applied in erythrocytes of the individuals collected. Results showed the presence of persistent organochlorine pesticides (POPs) in the sediment samples (p,p′-DDT, p,p′-DDE, and p,p′-DDD) of agricultural soils. Two individuals were registered with abnormalities in their limbs at the Mocari station, representing 12.5% of the morphological malformations to this sector. Micronucleus analysis revealed statistically significant genetic damage in exposed individuals (Mocari 9.87 ± 5.1, Cerete 7.7 ± 1.7, Aguas Negras 5.6 ± 3.6) with respect to the control group (2.4 ± 1.9) (p < 0.05). Spearman correlation analysis revealed a positive association between genetic damage and POP concentrations (p < 0.05). In addition, cellular alterations such as nuclear buds, and pyknosis (cell death), were statistically significant in the exposed group compared to the control group (p < 0.05). This study suggests that there is evidence for morphological and genotoxic effects in R. marina populations inhabiting areas influenced by agriculture, possibly associated with the presence of p,p′-DDT, p,p′-DDD, and p,p′-DDE.

http://ift.tt/2fHxXDT

Large-scale Meta-analysis Suggests Low Regional Modularity in Lateral Frontal Cortex

Abstract

Extensive fMRI study of human lateral frontal cortex (LFC) has yet to yield a consensus mapping between discrete anatomy and psychological states, partly due to the difficulty of inferring mental states from brain activity. Despite this, there have been few large-scale efforts to map the full range of psychological states across the entirety of LFC. Here, we used a data-driven approach to generate a comprehensive functional-anatomical mapping of LFC from 11 406 neuroimaging studies. We identified putatively separable LFC regions on the basis of whole-brain co-activation, revealing 14 clusters organized into 3 whole-brain networks. Next, we generated functional preference profiles by using multivariate classification to identify the psychological states that best predicted activity within each cluster. We observed large functional differences between networks, suggesting brain networks support distinct modes of processing. Within each network, however, we observed relatively low functional specificity, suggesting discrete psychological states are not strongly localized to individual regions; instead, our results are consistent with the view that individual LFC regions work as part of distributed networks to give rise to flexible behavior. Collectively, our results provide a comprehensive synthesis of a diverse neuroimaging literature using relatively unbiased data-driven methods.

http://ift.tt/2hJzAF6

The late effect of Kinesio Taping® on handgrip strength

Publication date: Available online 3 October 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Rodrigo Sousa Nilo de Araújo Aguiar, Silvia Regina Matos da Silva Boschi, Leandro Lazzareschi, Alessandro Pereira da Silva, Terigi Augusto Scardovelli, Eduardo Filoni, Ana Lúcia Manrique, Annie France Frère
The Kinesio Taping^® elastic tape is increasingly used in physiotherapy treatment. However, there is a lack of scientific research regarding the late effects of its use. This study quantified the late effects of applying the Kinesio Taping^® elastic tape by measuring changes in handgrip muscle strength after 24, 48 and 72 h of application. The Kinesio Taping^® elastic tape was applied on the dominant and non-dominant limbs of 36 volunteers randomly assigned to three groups: muscle facilitation, muscle inhibition and control group. The statistical test showed there was a statistically significant difference among all groups of dominant limb and non-dominant limb. However, the analysis on intragroup relationship to periods of application (Initial, 24, 48 and 72 h) and the interaction among repeated measures showed there was no statistically significant difference. This result may contribute to the investigation of the late effects of the Kinesio Taping^® elastic tape on the physical rehabilitation.



http://ift.tt/2xREc06

Transabdominal ultrasound: Can it be used to detect and quantify adhesions/reported pain, following Caesarean section?

Publication date: Available online 3 October 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Katharine Spens, Lance Bird, Philip Bright
BackgroundCaesarean section is common in the UK with post–procedural adhesions causing life-long clinical symptoms and impacting future pregnancies. This study's aim was to explore associations between these surgical adhesions, via transabdominal ultrasound findings, and perceived symptoms.MethodFemales demonstrating 1–3 transverse, lower-segment Caesareans were included. Visceral slide transabdominal ultrasound elicited positive adhesions (<1 cm movement) and negative adhesions (>1 cm movement). Scar tissue quality was assessed by the Patient and Observer Scar Assessment Scale (POSAS) and Numerical rating scales (NRS) described pain symptoms. The relationship between adhesions was explored using Fisher's exact test and multiple regression analysis.ResultsTwenty-two subjects (mean-age 35) were recruited; twenty participants (91%) had undergone 1 Caesarean, one each of the remainder had undergone 2 and 3 Caesareans respectively. Increased Visceral slide (>1 cm) was seen as predictive of increased scar pain (R² = 0.76 (95% CI 0.12–0.28), P < 0.001).ConclusionCaesarean adhesion scans showed significant associations with pain symptomology. Comprehensive adhesion assessment needs to be developed to improve long term outcomes of adhesions. Transabdominal Ultrasound can be considered a useful, quick and non-deleterious alternative diagnostic tool to Laparoscopy, therefore preventing further adhesion formation.



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Leg press exercise can reduce functional hamstring/quadriceps ratio in the elderly

Publication date: Available online 3 October 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Lucas Bet da Rosa Orssatto, Bruno Monteiro de Moura, Raphael Luiz Sakugawa, Regis Radaelli, Fernando Diefenthaeler
The aim of this study was to investigate whether 12 weeks of leg press strength training exercise could affect the conventional and functional hamstring/quadriceps ratios in elderly. Twelve elderly participants were submitted to a 12 week progressive training protocol (two sessions/week) using a 45° leg press exercise. A significant increase in the one repetition maximum was observed after 4, 8, and 12 weeks (p = 0.001, p < 0.001, and p < 0.001, respectively) compared to week 0 and after 8 (p = 0.011) and 12 weeks (p = 0.001) compared to week 4. The concentric knee extensor peak torque was significantly higher at weeks 8 (p = 0.001) and 12 (p = 0.024) compared to week 0. There was no change in the concentric and eccentric knee flexor peak torques (p = 0.629 and 0.274, respectively) and conventional ratio (p > 0.314) after 12 weeks of training. The functional ratio (eccentric knee flexor peak torque:concentric knee extensor peak torque) reduced significantly after 8 (p = 0.034) and 12 (p = 0.036) weeks of strength training. Although the 45° leg press exercise requires knee extensor and flexor, hip extensor, and plantar flexor muscle strength, our findings suggest that the isolated use of the 45° leg press exercise reduces the knee functional ratio after 8 weeks of training. Therefore, 45° leg press exercise alone, without a hamstring exercise, should not be recommended for elderly individuals.



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