Τετάρτη, 29 Νοεμβρίου 2017

Quantitative Measurements Versus Receiver Operating Characteristics and Visual Grading Regression in CT Images Reconstructed with Iterative Reconstruction

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Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Kristin Jensen, Hilde Kjernlie Andersen, Örjan Smedby, Bjørn Helge Østerås, Anette Aarsnes, Anders Tingberg, Erik Fosse, Anne Catrine Martinsen
Rationale and ObjectivesThis study aimed to evaluate the correlation of quantitative measurements with visual grading regression (VGR) and receiver operating characteristics (ROC) analysis in computed tomography (CT) images reconstructed with iterative reconstruction.Materials and MethodsCT scans on a liver phantom were performed on CT scanners from GE, Philips, and Toshiba at three dose levels. Images were reconstructed with filtered back projection (FBP) and hybrid iterative techniques (ASiR, iDose, and AIDR 3D of different strengths). Images were visually assessed by five readers using a four- and five-grade ordinal scale for liver low contrast lesions and for 10 image quality criteria. The results were analyzed with ROC and VGR. Standard deviation, signal-to-noise ratios, and contrast-to-noise ratios were measured in the images.ResultsAll data were compared to FBP. The results of the quantitative measurements were improved for all algorithms. ROC analysis showed improved lesion detection with ASiR and AIDR and decreased lesion detection with iDose. VGR found improved noise properties for all algorithms, increased sharpness with iDose and AIDR, and decreased artifacts from the spine with AIDR, whereas iDose increased the artifacts from the spine. The contrast in the spine decreased with ASiR and iDose.ConclusionsImproved quantitative measurements in images reconstructed with iterative reconstruction compared to FBP are not equivalent to improved diagnostic image accuracy.



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Prognostic Factors for Survival After Transarterial Chemoembolization Combined with Sorafenib in the Treatment of BCLC Stage B and C Hepatocellular Carcinomas

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Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Jia-yan Ni, Jian Kong, Hong-liang Sun, Yao-ting Chen, Jiang-hong Luo, Wei-dong Wang, Dong Chen, Xiong-ying Jiang, Lin-feng Xu
Rationale and ObjectiveThe objective of this study was to analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stages B and C.Materials and MethodsClinical data of 198 patients with BCLC stage B and C HCCs who underwent TACE combined with sorafenib between June 2012 and January 2017 were retrospectively collected and analyzed. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 11 prognostic factors potentially affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.ResultsBy the end of this study, the median follow-up duration was 43.6 months. The median overall survival (OS) of the patients was 21.0 months (95% confidence interval [CI]: 16.94–25.05), and the 1-, 2-, 3- and 5-year OS rates were 72%, 43%, 28%, and 4%, respectively. Tumor size (χ2 = 33.607, P < 0.0001), tumor number (χ2 = 4.084, P = 0.043), Child-Pugh class (χ2 = 33.187, P < 0.0001), BCLC stage (χ2 = 50.224, P < 0.0001), portal vein tumor thrombus (χ2 = 88.905, P < 0.0001), Eastern Cooperative Oncology Group (ECOG) performance status (χ2 = 98.007, P < 0.0001), extrahepatic spread (χ2 = 34.980, P < 0.0001), TACE times (χ2 = 8.350, P = 0.015), and sorafenib treatment strategy (χ2 = 81.593, P < 0.0001) were found to be significantly associated with OS by univariate analysis. Multivariate analysis showed that BCLC stage (95% CI: 1.133–3.982, P = 0.019), extrahepatic spread (95% CI: 1.136–2.774, P = 0.012), and sorafenib treatment duration (95% CI: 0.352–0.574, P = 0.000) were independent prognostic factors associated with OS. There were no serious treatment-related adverse events.ConclusionsThis study showed that extrahepatic spread was a risk factor, and sorafenib treatment and superior BCLC stage were protective factors. Therefore, the study indicated that TACE combined with sorafenib was an effective and safe treatment for patients with BCLC stage B HCC without extrahepatic spread.



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The Study of Clear Cell Renal Cell Carcinoma with MR Diffusion Kurtosis Tensor Imaging and Its Histopathologic Correlation

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Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Guangyu Wu, Zizhou Zhao, Qiuying Yao, Wen Kong, Jianrong Xu, Jin Zhang, Guiqin Liu, Yongming Dai
Rationale and ObjectivesThe objective of this study was to compare the performance of diffusion kurtosis tensor imaging and diffusion-weighted imaging in the characterization of clear cell renal cell carcinoma (ccRCC) and their correlations with tumor histopathology.Materials and MethodsNinety-one patients diagnosed with ccRCC who underwent diffusion kurtosis tensor imaging were included in this study. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, mean kurtosis (MK), radial kurtosis (Krad), and axial kurtosis (Kax) data were produced. A nuclear grade of 1–4 (G1–4) was assigned for each case based on the Fuhrman grading system, whereas tumor histopathology was characterized by the nuclear-to-cytoplasm ratio, the cell nuclei count, and the cell volume fraction.ResultsAll of the metric values except for Kax and fractional anisotropy could be used to discriminate G1 vs G3, G1 vs G4, G2 vs G3, and G2 vs G4, whereas MK and Kax could be used to discriminate G3 vs G4 (P < 0.05). Moreover, the MK and Krad values exhibited better performance in differentiating G2 from G3 (P < 0.04 compared to the other metrics). The nuclear-to-cytoplasm ratio was positively correlated with the MK, Krad, and Kax values (P < 0.001) and negatively correlated with the mean diffusivity, radial diffusivity, and axial diffusivity values (P < 0.001), whereas the cell volume fraction and the cell nuclei count did not correlate with any metric examined.ConclusionThe kurtosis metrics were superior to the diffusion metrics in grading ccRCC.



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High-risk Plaque and Calcification Detected by Coronary CT Angiography to Predict Future Cardiovascular Events After Percutaneous Coronary Intervention

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Publication date: Available online 29 November 2017
Source:Academic Radiology
Author(s): Nobuo Tomizawa, Kodai Yamamoto, Shinichi Inoh, Takeshi Nojo, Sunao Nakamura
Rationale and ObjectivesThe purpose of this study was to investigate whether high-risk plaque (HRP) and calcium assessed by coronary computed tomography (CT) could predict future cardiovascular events after second-generation drug-eluting stent (DES) placement.Materials and MethodsWe analyzed 317 patients from December 2012 to April 2015 who underwent coronary CT followed by DES placement. HRP was defined as a plaque with positive remodeling and low attenuation or a plaque with a napkin-ring sign. Coronary calcium was assessed by Agatston score (AS). Patients were divided into three groups: low risk, HRP negative and AS <400; intermediate risk, HRP positive and AS ≥400; high risk, HRP positive and AS ≥400. The primary end point was a composite of all-cause mortality, myocardial infarction, fatal arrhythmia, or repeated revascularization. Kaplan-Meier analysis was used to estimate the distribution of time to events.ResultsA total of 74 events (23%) occurred during a median follow-up of 25.8 months. Patients with primary end points had HRP more frequently (70% vs 51%, P = 0.003) and were more calcified (AS, 471 [interquartile range, 143–1614] vs 289 [interquartile range, 63–787]; P = 0.01) than patients without primary end points. The frequency of primary end point increased significantly in the intermediate- and high-risk patients (P = 0.0011). Multivariate analysis showed that the hazard ratio of the intermediate- and high-risk groups was 1.91 (95% confidence interval, 1.04–3.77; P = 0.037) and 2.66 (95% confidence interval, 1.27–5.73; P = 0.009), respectively.ConclusionPlaque and calcification analysis by coronary CT could predict future cardiovascular events after second-generation DES placement.



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Diagnostic accuracy of CTA and MRI/MRA in the evaluation of the cortical venous reflux in the intracranial dural arteriovenous fistula DAVF

Abstract

Purpose

Computed tomography angiography (CTA) and magnetic resonance imaging/angiography (MRI/MRA) are used for the diagnosis of intracranial dural arteriovenous fistulas (DAVFs). The purpose of this study was to compare the diagnostic accuracy of CTA and magnetic resonance imaging/angiography (MRI/MRA) for detection of cortical venous reflux (CVR) in intracranial DAVFs.

Methods

The records of patients with angiography-confirmed intracranial DAVFs who also received CTA and MRI/MRA from January 2008 to July 2016 were reviewed. CTA and MRI/MRA were reviewed for signs of CVR, and the diagnostic accuracy of individual signs was evaluated by receiver operating curve (ROC) analysis.

Results

A total 108 patients were included in this study. CTA signs of CVR included abnormal dilatation, early enhancement, and the presence of a medullary or pial vein. MRI/MRA signs of CVR included abnormal dilatation, early enhancement, flow-related enhancement, flow void, and medullary or pial venous collaterals. The sensitivity of individual CTA signs ranged from 62 to 96%, and specificities from 79 to 94%. The sensitivities of individual MRI/MRA signs ranged from 58 to 83%, and specificities from 77 to 93%. The area under ROC curve (AUC) of CTA and MRI/MRA were 0.91 and 0.87, respectively (P = 0.04 in direct comparison). In subgroup analysis, CTA had better diagnostic accuracy for higher grade disease (P = 0.05) and non-aggressive manifestation (P = 0.04).

Conclusions

Both CTA and MRI/MRA have good diagnostic accuracy for detection of CVR in patients with intracranial DAVFs. There is modest evidence that CTA is better than MRI/MRA.



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Needle use and dosimetric evaluation in cervical cancer brachytherapy using the Utrecht applicator

To analyse the clinical use of needles and examine the feasibility to meet the planning criteria in three fractions of cervical cancer brachytherapy. Furthermore, to investigate whether the needles with the largest discrepancy between application and loading are essential to treatment planning.

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Estimating the number of fractions by tumour site for European countries in 2012 and 2025: An ESTRO-HERO analysis

The optimal number of radiotherapy fractions is a relevant input for planning resource needs. An estimation of the total number of fractions by country and tumour site is assessed for 2012 and 2025.

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Uranium(VI) sorption complexes on silica in the presence of calcium and carbonate

Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Alaaeldine Sh. Saleh, Jun-Yeop Lee, Yongheum Jo, Jong-Il Yun
Uranium sorption on minerals and related solids depends to a large degree on its aqueous speciation. The present work attempts to understand the U(VI) sorption behavior on silica under environmentally relevant conditions, i.e. at neutral to weakly alkaline pH and in the presence of dissolved calcium and carbonate. Under these conditions, Ca(UO2)(CO3)32− and Ca2(UO2)(CO3)3(aq) complexes emerge as the dominant aqueous U(VI) species. The U(VI) sorption affinity was measured as a function of contact time, solution pH, and humic acid. The U(VI) sorption decreased with increase of pH and was not affected by the addition of 50 mg/L humic acid. On the other hand, nitric acid was more effective than EDTA and carbonate at desorbing U(VI). Generally, the U(VI) sorbed on silica at neutral pH was less readily desorbed than that sorbed at higher pH values. Therefore, the U(VI) complex favorably sorbed on silica at the neutral pH is more strongly bound to the silica surface than that sorbed at higher pH values. Time-resolved laser fluorescence spectroscopy confirmed the results of the batch sorption experiments and revealed the presence of two surface U(VI) complexes with fluorescence lifetimes 251 ± 8 μs and 807 ± 24 μs.

Graphical abstract

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Prognostic value of combining a quantitative image feature from positron emission tomography with clinical factors in oligometastatic non-small cell lung cancer

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Publication date: Available online 28 November 2017
Source:Radiotherapy and Oncology
Author(s): Garrett L. Jensen, Christine M. Yost, Dennis S. Mackin, David V. Fried, Shouhao Zhou, Laurence E. Court, Daniel R. Gomez
Background and purposeOligometastatic non-small cell lung cancer (NSCLC) is a heterogeneous condition with few known risk stratification factors. A quantitative imaging feature (QIF) on positron emission tomography (PET), gray-level co-occurrence matrix energy, has been linked with outcome of nonmetastatic NSCLC. We hypothesized that GLCM energy would enhance the ability of models comprising standard clinical prognostic factors (CPFs) to stratify oligometastatic patients based on overall survival (OS).Materials and methodsWe assessed 79 patients with oligometastatic NSCLC (≤3 metastases) diagnosed in 2007–2015. The primary and largest metastases at diagnosis were delineated on pretreatment scans with GLCM energy extracted using imaging biomarker explorer (IBEX) software. Iterative stepwise elimination feature selection based on the Akaike information criterion identified the optimal model comprising CPFs for predicting OS in a multivariate Cox proportional hazards model. GLCM energy was tested for improving prediction accuracy.ResultsEnergy was a significant predictor of OS (P = 0.028) in addition to the selected CPFs. The c-indexes for the CPF-only and CPF + Energy models were 0.720 and 0.739.ConclusionsIncorporating Energy strengthened a CPF model for predicting OS. These findings support further exploration of QIFs, including markers of the primary tumor vs. those of the metastatic sites.



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Analysis of petrous apex meningocele associated with meningioma: is there any relation with chronic intracranial hypertension?

Abstract

Purpose

Petrous apex meningocele (PAM) is an uncommon cystic lesion involving the petrous apex. The underlying cause of PAM may be related to chronic elevated intracranial pressure. The aim of the study was to explore the relationship between PAM and meningioma and between PAM and other intracranial hypertension findings.

Methods

Two hundred seventy-eight consecutive patients with meningiomas were retrospectively studied. Fifty age- and gender-matched controls were also enrolled in this study. The incidence of PAM, empty sella, tortuosity of the optic nerve, and hydrops of optic nerve sheath was evaluated. The maximum width, area, volume of each PAM, or Meckel's cave and volume of meningioma were measured in controls and patients, separately.

Results

One hundred fifty-nine (57.19%) patients were detected with coexistent PAMs. One hundred twenty-five patients had bilateral PAMs, 34 had unilateral lesions, and the remaining 119 did not have PAM. Two subjects (4/50) had unilateral PAMs in normal controls. The maximum width, area, volume of PAM, or Meckel's cave were significantly larger in the patients with bilateral PAM group than those in the unilateral PAM group, in the group without PAM, and those in control group (p = 0.000). The volume of meningioma was positively correlated with the PAM volume (r = 0.48). There was a positive correlation for the incidence between PAM and (1) empty sella (r = 0.901) and (2) tortuosity of the optic nerves and hydrops of the optic sheath (r = 0.825).

Conclusion

Coexistence of PAMs with meningiomas is not rare in incidence, and it suggests a potential role for chronically elevated intracranial pressure and disturbance of CSF circulation in their pathophysiology.



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Output Feedback Stabilization for Stochastic Nonholonomic Systems under Arbitrary Switching

The output feedback controllers of stochastic nonholonomic systems under arbitrary switching are discussed. We adopt an observer which can simplify the design process. The designed control laws cause the calculation of the gain parameter to be very convenient since the denominator of virtual controllers does not contain the gain parameter. Finally, an example is given to show the effectiveness of controllers.

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Purification, Characterization, and Mode of Action of Pentocin JL-1, a Novel Bacteriocin Isolated from Lactobacillus pentosus, against Drug-Resistant Staphylococcus aureus

Staphylococcus aureus and its drug-resistant strains, which threaten public health and food safety, are in need of effective control by biopreservatives. A novel bacteriocin, pentocin JL-1, produced by Lactobacillus pentosus that was isolated from the intestinal tract of Chiloscyllium punctatum, was purified by a four-step chromatographic process. Mass spectrometry based on MALDI-TOF indicated that pentocin JL-1 has a molecular mass of 2987.23 Da. Only six of the twenty-five amino acids could be identified by Edman degradation. This bacteriocin is thermostable and tolerates a pH range of 5–7. Also, it is sensitive to proteinase K, trypsin, pepsin, and alkaline protease. This bacteriocin has a broad inhibitory spectrum against both Gram-positive and Gram-negative strains and in particular is effective against multidrug-resistant S. aureus. Additionally, we showed that the cell membrane is the target of pentocin JL-1 against methicillin-resistant S. aureus (MRSA), causing a loss of proton motive force. Furthermore, pentocin JL-1 has a drastic impact on the structure and integrity of MRSA cells. These results suggest that pentocin JL-1 has potential as a biopreservative in the food industry.

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Resveratrol Inhibits Propagation of Chlamydia trachomatis in McCoy Cells

Resveratrol (RESV), an antifungal compound from grapes and other plants, has a distinct ability to inhibit the Chlamydia (C.) trachomatis developmental cycle in McCoy cells, a classic cell line used for chlamydial research. Inoculation of C. trachomatis with increasing amounts of RESV (from 12.5 to 100 μM) gave a dose-dependent reduction in the number of infected McCoy cells visualized by using monoclonal antibodies against chlamydial lipopolysaccharide. A similar trend has been observed with immunoassay for major outer membrane protein (MOMP). Furthermore, there was a step-wise reduction in the number of C. trachomatis infective progenies caused by the increasing concentrations of RESV. The ability of RESV to arrest C. trachomatis growth in McCoy cells was confirmed by a nucleic acid amplification protocol which revealed dose-dependent changes in mRNAs for different genes of chlamydial developmental cycle (euo, incA, and omcB). Although the precise nature of the antichlamydial activity of RESV is yet to be determined and evaluated in future studies, the observed effect of RESV on C. trachomatis infection was not related to its potential effect on attachment/entry of the pathogen into eukaryotic cells or RESV toxicity to McCoy cells. Similar inhibitory effect was shown for C. pneumoniae and C. muridarum.

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Mechanical Characterisation and Biomechanical and Biological Behaviours of Ti-Zr Binary-Alloy Dental Implants

The objective of the study is to characterise the mechanical properties of Ti-15Zr binary alloy dental implants and to describe their biomechanical behaviour as well as their osseointegration capacity compared with the conventional Ti-6Al-4V (TAV) alloy implants. The mechanical properties of Ti-15Zr binary alloy were characterised using Roxolid© implants (Straumann, Basel, Switzerland) via ultrasound. Their biomechanical behaviour was described via finite element analysis. Their osseointegration capacity was compared via an in vivo study performed on 12 adult rabbits. Young’s modulus of the Roxolid© implant was around 103 GPa, and the Poisson coefficient was around 0.33. There were no significant differences in terms of Von Mises stress values at the implant and bone level between both alloys. Regarding deformation, the highest value was observed for Ti-15Zr implant, and the lowest value was observed for the cortical bone surrounding TAV implant, with no deformation differences at the bone level between both alloys. Histological analysis of the implants inserted in rabbits demonstrated higher BIC percentage for Ti-15Zr implants at 3 and 6 weeks. Ti-15Zr alloy showed elastic properties and biomechanical behaviours similar to TAV alloy, although Ti-15Zr implant had a greater BIC percentage after 3 and 6 weeks of osseointegration.

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Pschyrembel und "Was hab‘ ich?" kooperieren

This press release is only available in German.



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Electromechanical wave imaging and electromechanical wave velocity estimation in a large animal model of myocardial infarction

Echocardiography is often used in the clinic for detection and characterization of myocardial infarction. Electromechanical wave imaging (EWI) is a non-invasive ultrasound-based imaging technique based on time-domain incremental motion and strain estimation that can evaluate changes in contractility in the heart. In this study, electromechanical activation is assessed in infarcted heart to determine whether EWI is capable of detecting and monitoring infarct formation. Additionally, methods for estimating electromechanical wave (EW) velocity are presented, and changes in the EW propagation velocity after infarct formation are studied. Five ( n   =  5) adult mongrels were used in this study. Successful infarct formation was achieved in three animals by ligation of the left anterior descending (LAD) coronary artery. Dogs were survived for a few days after LAD ligation and monitored daily with EWI. At the end of the survival period, dogs were sacrificed and TTC (tetrazol...

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Imbalance of the direct and indirect pathways in focal dystonia: a balanced view

This scientific commentary refers to ‘The direct basal ganglia pathway is hyperfunctional in focal dystonia’ by Simonyan et al. (doi:10.1093/brain/awx263).

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MOG-antibody neuromyelitis optica spectrum disorder: is it a separate disease?

This scientific commentary refers to ‘Clinical presentation and prognosis in MOG-antibody disease: a UK study’, by Jurynczyk et al. (doi:10.1093/brain/awx276).

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Functional brain network architecture may route progression of Alzheimer’s disease pathology

This scientific commentary refers to ‘Distinct influence of specific versus global connectivity on the different Alzheimer’s disease biomarkers’, by Mutlu et al. (doi:10.1093/brain/awx279).

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How far can biomarkers take us in neurodegenerative disorders?

It is difficult to miss. The rise and rise of biomarkers in neurodegenerative disorders is seemingly like a juggernaut, unstoppable in its momentum, sweeping all aside in its path. In Alzheimer’s disease, where the project is at its furthest, it has undoubtedly made significant contributions (Frisoni et al., 2017). Biomarker research has galvanized interest in attempts to detect patients at an earlier, prodromal stage; provided selection criteria for clinical trials to reduce heterogeneity within study populations; and potentially begun to assist clinicians in making a diagnosis.

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A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy

Abstract
See Zhou and Rademakers (doi:10.1093/brain/awx318) for a scientific commentary on this article.Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G>A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant. The protein encoded by TMEM106B is poorly characterized but is reported to have a role in regulation of lysosomal trafficking. Polymorphisms in TMEM106B are thought to modify disease onset in frontotemporal dementia, but its relation to myelination is not understood. Clinical presentation in three of the four patients is remarkably benign compared to other hypomyelinating disorders, with congenital nystagmus and mild motor delay. These findings add TMEM106B to the growing list of genes causing hypomyelinating disorders and emphasize the essential role lysosomes play in myelination.

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Distinct influence of specific versus global connectivity on the different Alzheimer’s disease biomarkers

Abstract
See Franzmeier and Dyrba (doi:10.1093/brain/awx304) for a scientific commentary on this article.Recent findings suggest that the topography and propagation of lesions in Alzheimer’s disease are related to functional connectivity, either showing that regions of high global connectivity are more vulnerable or that lesions propagate neuron-to-neuron from a starting area called the epicentre, thus involving specific connectivity. However, the relative influence of specific and global connectivity and their differential impact on the three main neuroimaging biomarkers of the disease (atrophy, hypometabolism and amyloid-β deposition) have never been investigated to date. Forty-two healthy elderly subjects and 35 amyloid-β positive amnestic mild cognitive impairment and Alzheimer’s disease patients underwent resting-state functional MRI, anatomical T1-weighted MRI, 18F-fluorodeoxyglucose-PET and florbetapir-PET scans. All patients also underwent follow-up T1-weighted MRI, 18F-fluorodeoxyglucose-PET and florbetapir-PET scans 18 months later to assess the lesion propagation. The epicentre was defined per modality as the most altered region at baseline in patients compared to controls. Maps of global and specific functional connectivity were computed from the resting-state functional MRI data of the healthy elderly subjects. Global connectivity corresponds to the connectivity strength of each grey matter area with the rest of the brain (i.e. all other grey matter areas) while specific connectivity refers to the connectivity of a single specific brain region (the epicentre) with the rest of the brain (i.e. all other brain regions). Maps of baseline alterations and propagation were computed for grey matter atrophy, hypometabolism and amyloid-β deposition in patients. Regression analyses were performed across the 239 brain regions to assess the links between global or specific functional connectivity in healthy elderly subjects and Alzheimer’s disease-related baseline disruptions or alteration propagation. Atrophy at baseline was predicted by specific connectivity and inversely correlated with global connectivity, while hypometabolism and amyloid-β deposition were positively influenced by both global and specific connectivity. Regarding longitudinal changes, atrophy spread in regions with high specific connectivity while hypometabolism propagated in areas showing high global connectivity. This is the first study to show that global connectivity has an opposite relationship with atrophy versus hypometabolism and amyloid-β deposition, suggesting that the high level of functional connectivity found in hubs exerts a differential influence on these Alzheimer’s disease lesions. These results sustain the hypotheses of higher vulnerability of hubs to hypometabolism and amyloid-β deposition versus transneuronal propagation of atrophy from the epicentre to connected regions, in Alzheimer’s disease. Global and specific connectivity exert a differential influence on, and provide complementary information to predict, the topography of Alzheimer’s disease lesions and their propagation.

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TMEM106B and myelination: rare leukodystrophy families reveal unexpected connections

This scientific commentary refers to ‘A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy’, by Simons et al. (doi:10.1093/brain/awx314).

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Epigenetic editing of the Dlg4 /PSD95 gene improves cognition in aged and Alzheimer’s disease mice

Abstract
The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer’s disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.

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Synaptic phosphorylated α-synuclein in dementia with Lewy bodies

Abstract
Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

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Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-β 42 in Alzheimer’s disease

Abstract
Accumulation of amyloid-β peptides is a dominant feature in the pathogenesis of Alzheimer’s disease; however, it is not clear how individual amyloid-β species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-β and full-length amyloid-β, depending on disease stage as well as brain area, and determined how these amyloid-β species respectively correlate with clinicopathological features of Alzheimer’s disease. To this end, the amounts of amyloid-β species and other proteins related to amyloid-β metabolism or Alzheimer’s disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer’s disease cases (n = 19), neurologically normal elderly without amyloid-β accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-β accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-β42 and full-length amyloid-β42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-β40 and full-length amyloid-β40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-β42 accumulation was increased in Alzheimer’s disease compared to pathological ageing, whereas cortical full-length amyloid-β42 accumulation was comparable between Alzheimer’s disease and pathological ageing. Moreover, N-terminally truncated amyloid-β42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-β42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-β42 species, represented by pyroglutamylated amyloid-β11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-β42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-β42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-β42 accumulation than those of other amyloid-β species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-β11-x fibrils than full-length amyloid-β fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-β42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-β42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-β42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-β species could play critical roles in the disease by linking other clinicopathological features of Alzheimer’s disease.

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Induced cortical responses require developmental sensory experience

Abstract
Sensory areas of the cerebral cortex integrate the sensory inputs with the ongoing activity. We studied how complete absence of auditory experience affects this process in a higher mammal model of complete sensory deprivation, the congenitally deaf cat. Cortical responses were elicited by intracochlear electric stimulation using cochlear implants in adult hearing controls and deaf cats. Additionally, in hearing controls, acoustic stimuli were used to assess the effect of stimulus mode (electric versus acoustic) on the cortical responses. We evaluated time-frequency representations of local field potential recorded simultaneously in the primary auditory cortex and a higher-order area, the posterior auditory field, known to be differentially involved in cross-modal (visual) reorganization in deaf cats. The results showed the appearance of evoked (phase-locked) responses at early latencies (<100 ms post-stimulus) and more abundant induced (non-phase-locked) responses at later latencies (>150 ms post-stimulus). In deaf cats, substantially reduced induced responses were observed in overall power as well as duration in both investigated fields. Additionally, a reduction of ongoing alpha band activity was found in the posterior auditory field (but not in primary auditory cortex) of deaf cats. The present study demonstrates that induced activity requires developmental experience and suggests that higher-order areas involved in the cross-modal reorganization show more auditory deficits than primary areas.

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Dr W. H. R. Rivers: Siegfried Sassoon and Robert Graves’ ‘fathering friend’

W.H.R. Rivers is best known for treating First World War soldiers for shell-shock, including the war poets Siegfried Sassoon and Robert Graves, whom he met at Craiglockhart Military Hospital. Jean Moorcoft Wilson, biographer of Sassoon and Graves, explores the friendship between these three men and its influence on each man’s work.

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The secret dream laboratory



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Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease

Abstract
Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson’s disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson’s disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson’s disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson’s disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson’s disease susceptibility genes. In our discovery cohort, the majority of Parkinson’s disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson’s disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson’s disease susceptibility.

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Clinical presentation and prognosis in MOG-antibody disease: a UK study

Abstract
See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article.A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

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ABCD1 dysfunction alters white matter microvascular perfusion

Abstract
Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood–brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood–brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

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Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Abstract
Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683–1113] to 641 (IQR 507–694) (−31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

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Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what’s in a name?

Sir,

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Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI

Sir,

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Reply: Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI

Sir,

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Calibration of simulated rainfall characteristics for the study of soil erosion on agricultural land

Rainfall simulation is a widely used method for soil erosion studies on agricultural land. Major problem of this experimental research method is the comparability between different simulators due to differences in simulated rainfall. Therefore the purpose of this study is to characterize the rainfall produced by a rainfall simulator which was widely used during the last decades. Four different calibration methods were used to assess the drop size distribution: 1) Indication Paper, 2) Plaster Micro Plot, 3) Joss-Waldvogel Disdrometer and 4) Laser Distrometer (Thies). Additionally, the latter one was used to measure drop fall velocity in combination with drop diameter. The spatial drop distribution pattern on the plot was measured with 100 rainfallgauges. The spatial rainfall distribution pattern clearly shows a heterogeneity, which is caused by the used nozzle configuration. Considerable differences in drop-size distribution can be observed depending on the used measurement technique. Laser Disdrometer and Plaster Micro Plot cover the whole produced drop size spectrum ranging from < 0.5 mm to > 3.0 mm, whereas Indication Paper as well as the Joss-Waldvogel Disdrometer primarily show drops smaller than 2.0 mm. Characterisation of rainfall is therefore strongly dependent on the used method and if different methods are used, may lead to contradictory results. The volume drop size distribution reflected by the Laser Distrometer is very similar to that one produced by rain with an intensity of 40 mm h -1 . Nevertheless, with maximum velocities above 10 m s -1 small drops are by far too fast and large drops with velocities dominantly below 5 m s -1 are too slow compared to natural rainfall. As an overall result, the simulator can be characterised as suitable for runoff and infiltration measurements, but with constraints due to the low reproducibility of the spatial rain distribution. As a consequence of the produced drop spectrum and fall velocity the erosion quantities may be underestimated systematically. For this, methodological development has to be focussed on homogeneous spatial rainfall distributions and on increasing the amount of large drops with higher fall velocities.

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Space-saving advantage of an inverted retina

Vertebrate eyes are of the simple or camera type with a single optical system that creates an image on the retina in the back of the eye. There, the visual information is encoded as nervous signals by photoreceptors, processed by retinal neurons, and then sent to the brain via the optic nerve. Surprisingly at first sight, the retinal neurons are located between the lens and the light-sensitive parts of the photoreceptors. The tissue scatters some light, which leads to loss of light and image blur. The inverted retina has, therefore, long been regarded as inferior. Here, we provide evidence that the inverted retina actually is a superior space-saving solution, especially in small eyes. The inverted retina has most likely facilitated the evolution of image-forming eyes in vertebrates, and it still benefits especially small and highly visual species.

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Thermodynamics of melittin binding to lipid bilayers. Aggregation and pore formation

Lipid membranes act as catalysts for protein folding. Both alpha-helical and beta-sheet structures can be induced by the interaction of peptides or proteins with lipid surfaces. Melittin, the main component of bee venom, is a particularly well-studied example for the membrane-induced random coil-to-alpha-helix transition. Melittin in water adopts essentially a random coil conformation. The cationic amphipathic molecule has a high affinity for neutral and anionic lipid membranes and exhibits approximately 50-65% alpha-helix conformation in the membrane-bound state. At higher melittin concentrations, the peptide forms aggregates or pores in the membrane. In spite of the long-standing interest in melittin-lipid interactions, no systematic thermodynamic study is available. This is probably caused by the complexity of the binding process. Melittin binding to lipid vesicles is fast and occurs within milliseconds, but the binding process involves at least four steps, namely, (i) the electrostatic attraction of the cationic peptide to an anionic membrane surface, (ii) the hydrophobic insertion into the lipid membrane, (iii) the conformational change from random coil to alpha-helix, and (iv) peptide aggregation in the lipid phase. We have combined microelectrophoresis (measurement of the zeta potential), isothermal titration calorimetry, and circular dichroism spectroscopy to provide a thermodynamic analysis of the individual binding steps. We have compared melittin with a synthetic analogue, [D]-V(5,8),I(17),K(21)-melittin, for which alpha-helix formation is suppressed and replaced by beta-structure formation. The comparison reveals that the thermodynamic parameters for the membrane-induced alpha-helix formation of melittin are identical to those observed earlier for other peptides with an enthalpy h(helix) of -0.7 kcal/mol and a free energy g(helix) of -0.2 kcal/mol per peptide residue. These thermodynamic parameters hence appear to be of general validity for lipid-induced membrane folding. As g(helix) is negative, it further follows that helix formation leads to an enhanced membrane binding for the peptides or proteins involved. In this study, melittin binds by approximately 2 orders of magnitude better to the lipid membrane than [D]-V(5,8),I(17),K(21)-melittin which cannot form an alpha-helix. We also found conditions under which the isothermal titration experiment reports only the aggregation process. Melittin aggregation is an entropy-driven process with an endothermic heat of reaction (DeltaH(agg)) of approximately 2 kcal/mol and an aggregation constant of 20-40 M(-1).

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Emissions of Inorganic and Organic Arsenic Compounds via the Leachate Pathway from Pretreated Municipal Waste Materials: A Landfill Reactor Study

The emission of arsenic (As) with leachate from mechanically biologically pretreated municipal solid waste (MBP-MSW) was quantified over one year using landfill simulation reactors. Arsenic mobilization and transformation processes were studied by simulating different environmental conditions (anoxic conditions with underlying soil or oxic/anoxic conditions). Amounts of mono-, di-, and trimethylated As in MBP-MSW prior to simulation were <48 μg As kg−1 and were magnified to 300−390 μg As kg−1 under anoxic conditions, whereas methylated As was undetectable in the oxic setup. The highest leachate concentrations (up to 84 μg L−1) occurred during the first four weeks of manipulation. The annual Astotal release with leachates averaged 19.6, 7.6, and 4.5 μg kg−1 under an anoxic environment with underlying soil, oxic conditions, and anoxic conditions, respectively, with 15−50% occurring as organic As. The annually released As represented 0.2−0.8% of the Astotal pool, suggesting that As mobilization from waste is a slow process. The anoxia diminished As release rates, whereas anoxic conditions with underlying soil material elevated the As mobilization, probably due to reductive dissolution of soil-derived Fe and Mn (hydr)oxides. The mass balance of methylated As in MBP-MSW and leachates before and after the treatments highlights As methylation under anoxic conditions and demethylation under oxic landfill conditions.

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Experience leaves a lasting structural trace in cortical circuits

Sensory experiences exert a powerful influence on the function and future performance of neuronal circuits in the mammalian neocortex. Restructuring of synaptic connections is believed to be one mechanism by which cortical circuits store information about the sensory world. Excitatory synaptic structures, such as dendritic spines, are dynamic entities that remain sensitive to alteration of sensory input throughout life. It remains unclear, however, whether structural changes at the level of dendritic spines can outlast the original experience and thereby provide a morphological basis for long-term information storage. Here we follow spine dynamics on apical dendrites of pyramidal neurons in functionally defined regions of adult mouse visual cortex during plasticity of eye-specific responses induced by repeated closure of one eye (monocular deprivation). The first monocular deprivation episode doubled the rate of spine formation, thereby increasing spine density. This effect was specific to layer-5 cells located in binocular cortex, where most neurons increase their responsiveness to the non-deprived eye. Restoring binocular vision returned spine dynamics to baseline levels, but absolute spine density remained elevated and many monocular deprivation-induced spines persisted during this period of functional recovery. However, spine addition did not increase again when the same eye was closed for a second time. This absence of structural plasticity stands out against the robust changes of eye-specific responses that occur even faster after repeated deprivation. Thus, spines added during the first monocular deprivation experience may provide a structural basis for subsequent functional shifts. These results provide a strong link between functional plasticity and specific synaptic rearrangements, revealing a mechanism of how prior experiences could be stored in cortical circuits.

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Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA

Ubiquitin-like proteins (UBLs) can change protein function, localization or turnover by covalent attachment to lysine residues. Although UBLs achieve this conjugation through an intricate enzymatic cascade, their bacterial counterparts MoaD and ThiS function as sulphur carrier proteins. Here we show that Urm1p, the most ancient UBL, acts as a sulphur carrier in the process of eukaryotic transfer RNA (tRNA) modification, providing a possible evolutionary link between UBL and sulphur transfer. Moreover, we identify Uba4p, Ncs2p, Ncs6p and Yor251cp as components of this conserved pathway. Using in vitro assays, we show that Ncs6p binds to tRNA, whereas Uba4p first adenylates and then directly transfers sulphur onto Urm1p. Finally, functional analysis reveals that the thiolation function of Urm1p is critical to regulate cellular responses to nutrient starvation and oxidative stress conditions, most likely by increasing translation fidelity.

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The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism

Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore(1). They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system(2). PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements(3). The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT-alpha-haemolysin from Staphylococcus aureus 4. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic alpha-helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains(5-8). ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion(9-11). Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA(12) must undergo large conformational changes to form the transmembrane pore(13,14). Here we report the 3.3 angstrom crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 angstrom, of parts of the monomer, reorganization of the hydrophobic core, and transitions of beta-sheets and loop regions to alpha-helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.

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Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans

Mass-spectrometry-based methods for relative proteome quantification have broadly affected life science research. However, important research directions, particularly those involving mathematical modelling and simulation of biological processes, also critically depend on absolutely quantitative data-that is, knowledge of the concentration of the expressed proteins as a function of cellular state. Until now, absolute protein concentration measurements of a considerable fraction of the proteome (73%) have only been derived from genetically altered Saccharomyces cerevisiae cells, a technique that is not directly portable from yeast to other species. Here we present a mass-spectrometry-based strategy to determine the absolute quantity, that is, the average number of protein copies per cell in a cell population, for a large fraction of the proteome in genetically unperturbed cells. Applying the technology to the human pathogen Leptospira interrogans, a spirochete responsible for leptospirosis, we generated an absolute protein abundance scale for 83% of the mass-spectrometry-detectable proteome, from cells at different states. Taking advantage of the unique cellular dimensions of L. interrogans, we used cryo-electron tomography morphological measurements to verify, at the single-cell level, the average absolute abundance values of selected proteins determined by mass spectrometry on a population of cells. Because the strategy is relatively fast and applicable to any cell type, we expect that it will become a cornerstone of quantitative biology and systems biology.

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Quantitative interaction proteomics using mass spectrometry

We present a mass spectrometry-based strategy for the absolute quantification of protein complex components isolated through affinity purification. We quantified bait proteins via isotope-labeled reference peptides corresponding to an affinity tag sequence and prey proteins by label-free correlational quantification using the precursor ion signal intensities of proteotypic peptides generated in reciprocal purifications. We used this method to quantitatively analyze interaction stoichiometries in the human protein phosphatase 2A network.

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Visual proteomics of the human pathogen Leptospira interrogans

Systems biology conceptualizes biological systems as dynamic networks of interacting elements, whereby functionally important properties are thought to emerge from the structure of such networks. Owing to the ubiquitous role of complexes of interacting proteins in biological systems, their subunit composition and temporal and spatial arrangement within the cell are of particular interest. `Visual proteomics` attempts to localize individual macromolecular complexes inside of intact cells by template matching reference structures into cryo-electron tomograms. Here we combined quantitative mass spectrometry and cryo-electron tomography to detect, count and localize specific protein complexes in the cytoplasm of the human pathogen Leptospira interrogans. We describe a scoring function for visual proteomics and assess its performance and accuracy under realistic conditions. We discuss current and general limitations of the approach, as well as expected improvements in the future.

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Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

Individual behavioral performance during learning is known to be affected by modulatory factors, such as stress and motivation, and by genetic predispositions that influence sensitivity to these factors. Despite numerous studies, no integrative framework is available that could predict how a given animal would perform a certain learning task in a realistic situation. We found that a simple reinforcement learning model can predict mouse behavior in a hole-box conditioning task if model metaparameters are dynamically controlled on the basis of the mouse's genotype and phenotype, stress conditions, recent performance feedback and pharmacological manipulations of adrenergic alpha-2 receptors. We find that stress and motivation affect behavioral performance by altering the exploration-exploitation balance in a genotype-dependent manner. Our results also provide computational insights into how an inverted U-shape relation between stress/arousal/norepinephrine levels and behavioral performance could be explained through changes in task performance accuracy and future reward discounting.

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Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window

To understand the cellular and circuit mechanisms of experience-dependent plasticity, neurons and their synapses need to be studied in the intact brain over extended periods of time. Two-photon excitation laser scanning microscopy (2PLSM), together with expression of fluorescent proteins, enables high-resolution imaging of neuronal structure in vivo. In this protocol we describe a chronic cranial window to obtain optical access to the mouse cerebral cortex for long-term imaging. A small bone flap is replaced with a coverglass, which is permanently sealed in place with dental acrylic, providing a clear imaging window with a large field of view (approximately 0.8-12 mm(2)). The surgical procedure can be completed within approximately 1 h. The preparation allows imaging over time periods of months with arbitrary imaging intervals. The large size of the imaging window facilitates imaging of ongoing structural plasticity of small neuronal structures in mice, with low densities of labeled neurons. The entire dendritic and axonal arbor of individual neurons can be reconstructed.

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Konstruktion und Praxis einer Sakrallandschaft: das Beispiel Tal der Könige

This article describes the ever-changing use of the Valley of the Kings and the cultural connotations associated with the landscape. Whilst cosmological associations shaped the early use of this area, factors such as territoriality and hegemonial traditions gradually took precedence. The economic use characteristic of the 21st Dynasty remained a privilege of the ruling class; memory of the sacrality of the site presumably motivated the burials of the 22nd Dynasty.

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Competition between recombination and epistasis can cause a transition from allele to genotype selection

Biochemical and regulatory interactions central to biological networks are expected to cause extensive genetic interactions or epistasis affecting the heritability of complex traits and the distribution of genotypes in populations. However, the inference of epistasis from the observed phenotype-genotype correlation is impeded by statistical difficulties, while the theoretical understanding of the effects of epistasis remains limited, in turn limiting our ability to interpret data. Of particular interest is the biologically relevant situation of numerous interacting genetic loci with small individual contributions to fitness. Here, we present a computational model of selection dynamics involving many epistatic loci in a recombining population. We demonstrate that a large number of polymorphic interacting loci can, despite frequent recombination, exhibit cooperative behavior that locks alleles into favorable genotypes leading to a population consisting of a set of competing clones. When the recombination rate exceeds a certain critical value that depends on the strength of epistasis, this "genotype selection" regime disappears in an abrupt transition, giving way to "allele selection"--the regime where different loci are only weakly correlated as expected in sexually reproducing populations. We show that large populations attain highest fitness at a recombination rate just below critical. Clustering of interacting sets of genes on a chromosome leads to the emergence of an intermediate regime, where blocks of cooperating alleles lock into genetic modules. These haplotype blocks disappear in a second transition to pure allele selection. Our results demonstrate that the collective effect of many weak epistatic interactions can have dramatic effects on the population structure.

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Type VI secretion apparatus and phage tail-associated protein complexes share a common evolutionary origin

Protein secretion is a common property of pathogenic microbes. Gram-negative bacterial pathogens use at least 6 distinct extracellular protein secretion systems to export proteins through their multilayered cell envelope and in some cases into host cells. Among the most widespread is the newly recognized Type VI secretion system (T6SS) which is composed of 15-20 proteins whose biochemical functions are not well understood. Using crystallographic, biochemical, and bioinformatic analyses, we identified 3 T6SS components, which are homologous to bacteriophage tail proteins. These include the tail tube protein; the membrane-penetrating needle, situated at the distal end of the tube; and another protein associated with the needle and tube. We propose that T6SS is a multicomponent structure whose extracellular part resembles both structurally and functionally a bacteriophage tail, an efficient machine that translocates proteins and DNA across lipid membranes into cells.

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Analysis of cell surface proteome changes via label-free, quantitative mass spectrometry

We present a mass spectrometry-based strategy for the specific detection and quantification of cell surface proteome changes. The method is based on the label-free quantification of peptide patterns acquired by high mass accuracy mass spectrometry using new software tools and the cell surface capturing technology that selectively enriches glycopeptides exposed to the cell exterior. The method was applied to monitor dynamic protein changes in the cell surface glycoproteome of Drosophila melanogaster cells. The results led to the construction of a cell surface glycoprotein atlas consisting of 202 cell surface glycoproteins of D. melanogaster Kc167 cells and indicated relative quantitative changes of cell surface glycoproteins in four different cellular states. Furthermore we specifically investigated cell surface proteome changes upon prolonged insulin stimulation. The data revealed insulin-dependent cell surface glycoprotein dynamics, including insulin receptor internalization, and linked these changes to intracellular signaling networks.

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Protein identification false discovery rates for very large proteomics data sets generated by tandem mass spectrometry

Comprehensive characterization of a proteome is a fundamental goal in proteomics. To achieve saturation coverage of a proteome or specific subproteome via tandem mass spectrometric identification of tryptic protein sample digests, proteomics data sets are growing dramatically in size and heterogeneity. The trend toward very large integrated data sets poses so far unsolved challenges to control the uncertainty of protein identifications going beyond well established confidence measures for peptide-spectrum matches. We present MAYU, a novel strategy that reliably estimates false discovery rates for protein identifications in large scale data sets. We validated and applied MAYU using various large proteomics data sets. The data show that the size of the data set has an important and previously underestimated impact on the reliability of protein identifications. We particularly found that protein false discovery rates are significantly elevated compared with those of peptide-spectrum matches. The function provided by MAYU is critical to control the quality of proteome data repositories and thereby to enhance any study relying on these data sources. The MAYU software is available as standalone software and also integrated into the Trans-Proteomic Pipeline.

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IJMS, Vol. 18, Pages 2562: Bioaccumulation and Toxicity of Carbon Nanoparticles Suspension Injection in Intravenously Exposed Mice

IJMS, Vol. 18, Pages 2562: Bioaccumulation and Toxicity of Carbon Nanoparticles Suspension Injection in Intravenously Exposed Mice

International Journal of Molecular Sciences doi: 10.3390/ijms18122562

Authors: Ping Xie Sheng-Tao Yang Tiantian He Shengnan Yang Xiao-Hai Tang

Carbon nanoparticles suspension injection (CNSI) has been widely used in tumor drainage lymph node mapping, and its new applications in drug delivery, photothermal therapy, and so on have been extensively investigated. To develop new clinical applications, the toxicity of CNSI after intravenous exposure should be thoroughly investigated to ensure its safe use. Herein, we studied the bioaccumulation of CNSI in reticuloendothelial system (RES) organs and the corresponding toxicity to mice. After the intravenous injection of CNSI, no abnormal behavior of mice was observed during the 28-day observation period. The body weight increases were similar among the exposed groups and the control group. The parameters of hematology and serum biochemistry remained nearly unchanged, with very few of them showing significant changes. The low toxicity of CNSI was also reflected by the unchanged histopathological characteristics of these organs. The injection of CNSI did not induce higher apoptosis levels either. The slight oxidative stress was observed in RES organs at high dosages at day 7 post-exposure. The implication to the clinical applications and toxicological evaluations of carbon nanomaterials is discussed.



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IJMS, Vol. 18, Pages 2565: Applications of Alternative Nucleases in the Age of CRISPR/Cas9

IJMS, Vol. 18, Pages 2565: Applications of Alternative Nucleases in the Age of CRISPR/Cas9

International Journal of Molecular Sciences doi: 10.3390/ijms18122565

Authors: Tuhin Guha David Edgell

Breakthroughs in the development of programmable site-specific nucleases, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases (MNs), and most recently, the clustered regularly interspaced short palindromic repeats (CRISPR) associated proteins (including Cas9) have greatly enabled and accelerated genome editing. By targeting double-strand breaks to user-defined locations, the rates of DNA repair events are greatly enhanced relative to un-catalyzed events at the same sites. However, the underlying biology of each genome-editing nuclease influences the targeting potential, the spectrum of off-target cleavages, the ease-of-use, and the types of recombination events at targeted double-strand breaks. No single genome-editing nuclease is optimized for all possible applications. Here, we focus on the diversity of nuclease domains available for genome editing, highlighting biochemical properties and the potential applications that are best suited to each domain.



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Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs. They represent true medical emergencies and an early recognition and appropriate management is decisive for the survival. SJS/TEN manifest with an “influenza-like” prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of < 10%, TEN is defined as skin involvement of > 30%, and SJS/TEN overlap as 10–30% skin involvement. The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology. The mortality rates for SJS and TEN have decreased in the last decades. Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment. Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, non-steroidal anti-inflammatory drugs of the oxicam type, allopurinol, nevirapine, and chlormezanone. Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents. The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens. Our understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified. However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs. In SJS/TEN, the most common complications are ocular, cutaneous, or renal. Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role. However, in the acute phase, septicemia is a leading cause of morbidity and fatality. Pulmonary and hepatic involvement is frequent. The acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.



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What are the position and power of supermarkets in the Australian food system, and the implications for public health? A systematic scoping review

Summary

Supermarkets have been described as having unprecedented and disproportionate power in the food system. This scoping review synthesized the literature that describes the position and power of supermarkets in the Australian food system, and the implications for public health. A systematic search of peer-reviewed and grey literature identified 68 documents that described supermarket power. Implications for public health were also recorded. Data revealed that supermarkets hold a powerful position in the Australian food system, acting as the primary gatekeepers. Supermarkets have obtained instrumental, structural and discursive power from many sources that overlap and reinforce each other. Few positive public health impacts of supermarket power were identified, providing many opportunities for improvement in the domains of food governance, the food system and public health nutrition. There is very little public health research examining the impact of supermarket power in Australia. More research is needed, and examination of supermarket own brands is of particular importance owing to their pivotal role as a source of power and their potential to improve public health outcomes, such as obesity.



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Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study

Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of ...

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Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients

Female breast cancer is frequently diagnosed at a later stage and the leading cause of cancer deaths world-wide. Levels of cell-free circulating microRNAs (miRNAs) can potentially be used as biomarkers to meas...

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Waist circumference and risk of breast cancer in Korean women: A nationwide cohort study

Abstract

Although postmenopausal breast cancer (BC) risk has been linked to adiposity, associations between adiposity and premenopausal BC remain unclear. To address this question, we investigated the association of BC risk with measures of adiposity, including body mass index (BMI) and waist circumference (WC), in a large cohort of Asian women. We used a nationwide cohort of adult Korean women selected from the National Health Insurance Corporation database merged with national health examination data from 2009 to 2015. A total of 11,227,948 women were tracked to retrospectively identify incident cases of BC. Our analysis used Cox proportional hazards models to calculate hazard ratios and assess the association of BC risk with BMI and/or WC in both pre- and postmenopausal women. BMI and WC were robustly associated with increased risk for postmenopausal BC (Ptrend<0.001 for both BMI and WC) but not with premenopausal BC. Association between WC and premenopausal BC was only statistically significant when considering BMI (Ptrend=0.044). In contrast, postmenopausal BC was negatively associated with WC when considering BMI (Ptrend=0.011). In premenopausal women, WC may predict increased BC risk when considering BMI. However, in postmenopausal women, WC is not superior to BMI as an indicator of BC risk. This article is protected by copyright. All rights reserved.



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Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Abstract

Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk-stratification, and present cytogenetically normal AML (CN-AML). In order to develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by sanger sequencing. The top 6 genes were NPM1, FLT3-ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. Additionally, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3-ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event-free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN-AML. This article is protected by copyright. All rights reserved.



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Identification of a novel fusion gene HMGA2-EGFR in glioblastoma

Abstract

Glioblastoma is one of the most malignant forms of cancer, for which no effective targeted therapy has been found. Although the Cancer Genome Atlas (TCGA) has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown. To search for novel fusion genes, we obtained RNA-seq data from TGS-01 human glioma-initiating cells, and identified a novel fusion gene (HMGA2-EGFR), encoding a protein comprising the N-terminal region of the high mobility group AT hook protein 2 (HMGA2) fused to the C-terminal region of epidermal growth factor receptor (EGFR), which retained the transmembrane and kinase domains of the EGFR. This fusion gene product showed transforming potential and a high tumor-forming capacity in cell culture and in vivo. Mechanistically, HMGA2-EGFR constitutively induced a higher level of phosphorylated STAT5B than EGFRvIII, an in-frame exon deletion product of the EGFR gene that is commonly found in primary glioblastoma. Forced expression of HMGA2-EGFR enhanced orthotopic tumor formation of the U87MG human glioma cell line. Furthermore, the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS-01 cells in culture and inhibited tumor formation in vivo. These findings suggest that, in addition to gene amplification and in-frame exon deletion, EGFR signaling can also be activated by gene fusion, suggesting a possible avenue for treatment of glioblastoma. This article is protected by copyright. All rights reserved.



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The effectiveness of prehospital hypertonic saline for hypotensive trauma patients: a systematic review and meta-analysis

The optimal prehospital fluid for the treatment of hypotension is unknown. Hypertonic fluids may increase circulatory volume and mute the pro-inflammatory response of the body to injury and illness. The purpos...

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Shalom, Chicago: Israel shares 90 years of innovation

2017_11_28_21_36_5139_SOSNA_jacob_201711Medical imaging in Israel has a rich heritage and a bright future, and radiologists...


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Volpara highlights 4 studies at RSNA 2017

Breast imaging software developer Volpara Solutions is touting four studies...


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Optellum, Mirada tout lung cancer study at RSNA 2017

Artificial intelligence (AI) software developer Optellum and imaging software...


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Association of urinary concentrations of four chlorophenol pesticides with cardiometabolic risk factors and obesity in children and adolescents

Abstract

This study was undertaken to determine the association of four chlorophenol pesticides with cardiometabolic risk factors and obesity in children and adolescents. This cross-sectional study was conducted in 2016 on 242 children and adolescents, aged 6 to 18 years. The concentrations of 2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol (2,5-DCP), 2,4,5-trichlorophenol (2,4,5-TCP), and 2,4,6-trichlorophenol (2,4,6-TCP) in the urine were examined and their association with indices of obesity and cardiometabolic risk factors was determined. Multivariate linear regression and multinomial logistic regression analyses were applied. Overall, 242 participants with mean (SD) ages of 11.3 (2.5) years completed the survey. After adjustment for confounders, a significant positive association was found between body mass index (BMI) z-score and waist circumference (WC) with 2,5-DCP (0.07 (95% CI 0.04, 0.1)) and 0.79 (95% CI 0.54, 1.03), respectively. A significant association of 2,4,5-TCP was only found with WC (0.23 (95% CI 0.0, 0.46), but the relationship with 2,4-DCP was not significant. 2,5-DCP had a significant relationship only with obesity (1.09 (95% CI 1.1, 1.19)), while 2,4-DCP and 2,4,5-TCP showed no significant correlation with overweight or obesity. 2,4-DCP showed a significant positive relationship with high density lipoprotein-cholesterol (HDL-C). Moreover, 2,5-DCP showed a significant negative relationship only with systolic blood pressure and 2,4,5-TCP had a statistically significant inverse association with total cholesterol and HDL-C (−0.71 (95% CI −0.98, −0.45)). This study suggests potential associations of chlorophenol pesticides with overweight, obesity, lipid profile, and blood pressure in children and adolescents. Longitudinal studies are necessary to assess the clinical impact of these findings.



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Observed differentials in the levels of selected environmental contaminants among Mexican and other Hispanic American children, adolescents, adults, and senior citizens

Abstract

Starting with the 2007–2008 cycle, the National Health and Nutrition Examination Survey (NHANES) also oversampled Hispanics other than Mexicans (OHISP) making it possible to treat OHISP as a separate demographic group along with Mexican Americans (MAs), non-Hispanic whites (NHWs), and non-Hispanic blacks (NHBs). Yet, more often than not, OHISP have been merged with MA to form an all-Hispanic demographic group (HISP) thus limiting comparisons between NHW, NHB, and HISP. Consequently, for the first time, this study was undertaken to evaluate differences in the observed levels of selected environmental contaminants between MA and OHISP from five groups of environmental contaminants, namely, polycyclic aromatic hydrocarbons (PAHs), iodine uptake inhibitors (IUIs), environmental phenols (EPHs), priority pesticides (PPs), and perfluoroalkyl acids (PFAAs). Data for 2007–2010 from NHANES were used to conduct this study. OHISP children born in USA had higher levels of selected PAH metabolites than USA-born MA, and Mexican-born MA adolescents had higher levels of selected PAH metabolites than USA-born MA adolescents. USA-born adolescent MA had higher levels of selected parabens than USA-born adolescent OHISP, and OHISP adults born in another Spanish-speaking country had higher levels of selected parabens than USA-born OHISP adults. USA-born MA adults and seniors had higher levels of selected dichlorophenols than Mexico-born MA adults and seniors, respectively. Females had higher levels of selected PAH metabolites, EPHs, and PPs than males among children, adolescents, adults, and seniors, but the reverse was true for the levels of selected IUIs and PFAAs among adolescents and seniors. Smokers had higher levels of almost all PAH metabolites than non-smokers for adolescents, adults, and seniors. The same was true for urinary thiocynate for adolescents, adults, and seniors. OHISP is a multiracial multiethnic demographic group substantially different from MA with possibly different smoking behavior and with possibly differential levels of exposure to certain environmental contaminants and as such should be treated as a demographic group by itself.



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Oligomerization is involved in pore formation by Bordetella adenylate cyclase toxin

The Bordetella adenylate cyclase-hemolysin (CyaA, ACT, or AC-Hly) is a multifunctional toxin. Simultaneously with promoting calcium ion entry, CyaA delivers into host cells an adenylate cyclase enzyme (AC) and permeabilizes cell membrane by forming small cation-selective pores. Indirect evidence suggested that these two activities were accomplished by different membrane-inserted CyaA conformers, one acting as an AC-delivering monomer and the other as an uncharacterized pore-forming oligomer. We tested this model by directly detecting toxin oligomers in cell membrane and by assessing oligomerization of specific mutants with altered pore-forming properties. CyaA oligomers were revealed in sheep erythrocyte membranes by immunogold labeling and directly demonstrated by pulldown of membrane-inserted CyaA together with biotinylated CyaA-AC(-) toxoid. Membrane oligomers of CyaA could also be resolved by nondenaturing electrophoresis of mild detergent extracts of erythrocytes. Furthermore, CyaA mutants exhibiting enhanced (E581K) or reduced (E570K+E581P) specific hemolytic and pore-forming activity were found to exhibit also a correspondingly enhanced or reduced propensity to form oligomers in erythrocyte membranes. On the other hand, processed CyaA, with the AC domain cleaved off by erythrocyte proteases, was detected only in a monomeric form excluded from the oligomers of unprocessed CyaA. These results provide the first direct evidence that oligomerization is involved in formation of CyaA pores in target membranes and that translocation of the AC domain across cell membrane may be accomplished by monomeric CyaA.

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Remaking and Rewaking of Mental Life Die Kaleidoskopierung des Innenlebens in der Erfahrung des Films (von Hugo Münsterberg bis Harmony Korine)



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Low impact of climate change on subalpine grasslands in the Swiss Northern Alps

While phenological shifts and migration of isolated species under climate change have already been observed on alpine summits, very few studies have focused on community composition changes in subalpine grasslands. Here we use permanent plots monitored since 1954 and precisely located phytosociological censuses from 1970 to study compositional changes of subalpine grasslands in two distinct regions of the Swiss Northern Alps. In both areas, warming trends during the monitoring period were associated with changes in land management (abandonment of goat and sheep pasturing or grazing replaced by mowing). Old and recent inventories were compared with correspondence analyses (CA). Ecological indicator values, community-affinities and biological traits of the species were used to infer the factors responsible for triggering the observed changes. In both regions, subalpine grasslands were stable with smaller changes than have previously been observed in alpine environments. Only a few species appeared or disappeared and changes were generally limited to increasing or decreasing frequency and cover of certain taxa. At one site, grazing abandonment favored fallow species. Some of these species were located at their upper altitudinal distribution limits and may have spread because of rising temperatures. In both areas, declining species were predominantly alpine and low-growing species; their decline was probably due to increased competition (e.g., shadow) with more vigorous subalpine taxa no longer limited by grazing. We conclude that vegetation communities can respond rapidly to warming as long as colonization is facilitated by available space or structural change. In the subalpine grasslands studies, changes were mainly driven by land management. These communities have a dense vegetation cover and newly arriving herbaceous species preferring warmer conditions may take some time to establish themselves. However, climate disturbances, such as exceptional drought, may accelerate community changes by opening gaps for new species.

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