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    Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau 

    Brendel, Matthias; Deussing, Maximilian; Blume, Tanja; Kaiser, Lena; Probst, Federico; Overhoff, Felix; Peters, Finn; von Ungern-Sternberg, Barbara; Ryazanov, Sergey; Leonov, Andrei; et al.
    Griesinger, ChristianZwergal, AndreasLevin, JohannesBartenstein, PeterYakushev, IgorCumming, PaulBoening, GuidoZiegler, SibylleHerms, JochenGiese, ArminRominger, Axel
    Alzheimer's Research & Therapy. 2019 Aug 01;11(1):67
    Abstract Background Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer’s disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study. Methods Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings. Results Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex − 53%, p < 0.001; hippocampus − 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001). Conclusion Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.
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    Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study 

    Miebach, Lisa; Wolfsgruber, Steffen; Polcher, Alexandra; Peters, Oliver; Menne, Felix; Luther, Katja; Incesoy, Enise; Priller, Josef; Spruth, Eike; Altenstein, Slawek; et al.
    Buerger, KatharinaCatak, CihanJanowitz, DanielPerneczky, RobertUtecht, JuliaLaske, ChristophBuchmann, MartinaSchneider, AnjaFliessbach, KlausKalbhen, PascalHeneka, Michael TBrosseron, FredericSpottke, AnnikaRoy, NinaTeipel, Stefan JKilimann, IngoWiltfang, JensBartels, ClaudiaDüzel, EmrahDobisch, LauraMetzger, CoralineMeiberth, DixRamirez, AlfredoJessen, FrankWagner, Michael
    Alzheimer's Research & Therapy. 2019 Jul 31;11(1):66
    Abstract Background Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. Methods We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. Results Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. Conclusions Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
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    Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner 

    French, Timothy; Düsedau, Henning P; Steffen, Johannes; Biswas, Aindrila; Ahmed, Norus; Hartmann, Susanne; Schüler, Thomas; Schott, Björn H; Dunay, Ildiko R
    Journal of Neuroinflammation. 2019 Jul 29;16(1):159
    Abstract Background It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes. Methods Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation. Results Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism. Conclusion Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.
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    Aged mice show an increased mortality after anesthesia with a standard dose of ketamine/xylazine 

    Schuetze, Sandra; Manig, Anja; Ribes, Sandra; Nau, Roland
    Laboratory Animal Research. 2019 Jul 24;35(1):8
    Abstract Geriatric animal models are crucial for a better understanding and an improved therapy of age-related diseases. We observed a high mortality of aged mice after anesthesia with a standard dose of ketamine/xylazine, an anesthetic regimen frequently used in laboratory veterinary medicine. C57BL/6-N mice at the age of 2.14 ± 0.23 months (young mice) and 26.31 ± 2.15 months (aged mice) were anesthetized by intraperitoneal injection of 2 mg ketamine and 0.2 mg xylazine. 4 of 26 aged mice (15.4%) but none of 26 young mice died within 15 min after injection of the anesthetics. The weight of aged mice was significantly higher than that of young mice (32.8 ± 5.4 g versus 23.2 ± 3.4 g, p < 0.0001). Thus, aged mice received lower doses of anesthetics in relation to their body weight which are within the lower range of doses recommended in the literature or even beneath. There were no differences between deceased and surviving aged mice concerning their sex, weight and their motor performance prior to anesthesia. Our data clearly show an age-related increase of mortality upon anesthesia with low standard doses of ketamine/xylazine. Assessment of weight and motor performance did not help to predict vulnerability of aged mice to the anesthetics. Caution is necessary when this common anesthetic regimen is applied in aged mice: lower doses or the use of alternative anesthetics should be considered to avoid unexpected mortality. The present data from our geriatric mouse model strongly corroborate an age-adjusted reduction of anesthetic doses to reduce anesthesia-related mortality in aged individuals.
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    Benchmarking of alignment-free sequence comparison methods 

    Zielezinski, Andrzej; Girgis, Hani Z; Bernard, Guillaume; Leimeister, Chris-Andre; Tang, Kujin; Dencker, Thomas; Lau, Anna K; Röhling, Sophie; Choi, Jae J; Waterman, Michael S; et al.
    Comin, MatteoKim, Sung-HouVinga, SusanaAlmeida, Jonas SChan, Cheong XJames, Benjamin TSun, FengzhuMorgenstern, BurkhardKarlowski, Wojciech M
    Genome Biology. 2019 Jul 25;20(1):144
    Abstract Background Alignment-free (AF) sequence comparison is attracting persistent interest driven by data-intensive applications. Hence, many AF procedures have been proposed in recent years, but a lack of a clearly defined benchmarking consensus hampers their performance assessment. Results Here, we present a community resource (http://afproject.org) to establish standards for comparing alignment-free approaches across different areas of sequence-based research. We characterize 74 AF methods available in 24 software tools for five research applications, namely, protein sequence classification, gene tree inference, regulatory element detection, genome-based phylogenetic inference, and reconstruction of species trees under horizontal gene transfer and recombination events. Conclusion The interactive web service allows researchers to explore the performance of alignment-free tools relevant to their data types and analytical goals. It also allows method developers to assess their own algorithms and compare them with current state-of-the-art tools, accelerating the development of new, more accurate AF solutions.
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    Effectiveness of training general practitioners to improve the implementation of brief stop-smoking advice in German primary care: study protocol of a pragmatic, 2-arm cluster randomised controlled trial (the ABCII trial) 

    Kastaun, Sabrina; Leve, Verena; Hildebrandt, Jaqueline; Funke, Christian; Becker, Stephanie; Lubisch, Diana; Viechtbauer, Wolfgang; Reddemann, Olaf; Hempel, Linn; McRobbie, Hayden; et al.
    Raupach, TobiasWest, RobertKotz, Daniel
    BMC Family Practice. 2019 Jul 27;20(1):107
    Abstract Background The German clinical guideline on tobacco addiction recommends that general practitioners (GPs) provide brief stop-smoking advice to their patients according to the “5A” or the much briefer “ABC” method, but its implementation is insufficient. A lack of training is one barrier for GPs to provide such advice. Moreover, the respective effectiveness of a 5A or ABC training regarding subsequent delivery of stop-smoking advice has not been investigated. We developed a training for GPs according to both methods, and conducted a pilot study with process evaluation to optimize the trainings according to the needs of GPs. This study aims at evaluating the effectiveness of both trainings. Methods A pragmatic 2-arm cluster randomised controlled trial with a pre-post data collection will be conducted in 48 GP practices in North Rhine-Westphalia (Germany). GPs will be randomised to receive a 3.5-h-training in delivering either 5A or ABC, including peer coaching and intensive role plays with professional actors. The patient-reported primary outcome (receipt of GP advice to quit: yes/no) and secondary outcomes (recommendation rates of smoking cessation treatments, group comparison (5A versus ABC): receipt of GP advice to quit) will be collected in smoking patients routinely consulting their GP within 4 weeks prior, and 4 weeks following the training. Additional secondary outcomes will be collected at 4, 12 and 26 weeks following the consultation: use of cessation treatments during the last quit attempt (if so) since the GP consultation, and point-prevalence abstinence rates. The primary data analysis will be conducted using a mixed-effects logistic regression model with random effects for the cluster variable. Discussion If the training increases the rates of delivery of stop-smoking advice, it would offer a low-threshold strategy for the guideline implementation in German primary care. Should one method prove superior, a more specific guideline recommendation can be proposed. Trial registration German Clinical Trials Register (DRKS00012786); registered on 22th August 2017, prior to the first patient in.
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    Phasing quality assessment in a brown layer population through family- and population-based software 

    Frioni, N.; Cavero, D.; Simianer, H.; Erbe, M.
    BMC Genetics. 2019 Jul 17;20(1):57
    Abstract Background Haplotype data contains more information than genotype data and provides possibilities such as imputing low frequency variants, inferring points of recombination, detecting recurrent mutations, mapping linkage disequilibrium (LD), studying selection signatures, estimating IBD probabilities, etc. In addition, haplotype structure is used to assess genetic diversity and expected accuracy in genomic selection programs. Nevertheless, the quality and efficiency of phasing has rarely been a subject of thorough study but was assessed mainly as a by-product in imputation quality studies. Moreover, phasing studies based on data of a poultry population are non-existent. The aim of this study was to evaluate the phasing quality of FImpute and Beagle, two of the most used phasing software. Results We simulated ten replicated samples of a layer population comprising 888 individuals from a real SNP dataset of 580 k and a pedigree of 12 generations. Chromosomes analyzed were 1, 7 and 20. We measured the percentage of SNPs that were phased equally between true and phased haplotypes (Eqp), proportion of individuals completely correctly phased, number of incorrectly phased SNPs or Breakpoints (Bkp) and the length of inverted haplotype segments. Results were obtained for three different groups of individuals, with no parents or offspring genotyped in the dataset, with only one parent, and with both parents, respectively. The phasing was performed with Beagle (v3.3 and v4.1) and FImpute v2.2 (with and without pedigree). Eqp values ranged from 88 to 100%, with the best results from haplotypes phased with Beagle v4.1 and FImpute with pedigree information and at least one parent genotyped. FImpute haplotypes showed a higher number of Bkp than Beagle. As a consequence, switched haplotype segments were longer for Beagle than for FImpute. Conclusion We concluded that for the dataset applied in this study Beagle v4.1 or FImpute with pedigree information and at least one parent genotyped in the data set were the best alternatives for obtaining high quality phased haplotypes.
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    Cerebral salt wasting in a patient with myeloproliferative neoplasm 

    Orlik, Lea; Venzin, Reto; Fehr, Thomas; Hohloch, Karin
    BMC Neurology. 2019 Jul 18;19(1):169
    Abstract Background Cerebral salt wasting (CSW) is a rare metabolic disorder with severe hyponatremia and volume depletion usually caused by brain injury like trauma, cerebral lesion, tumor or a cerebral hematoma. The renal function is normal with excretion of very high amounts of sodium in the urine. Diagnosis is made by excluding other reasons for hyponatremia, mainly the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Case presentation A 60-year-old patient was admitted to the emergency room with pain in the upper abdomen and visual disturbance two weeks after knee replacement. The patient was confused with severe hematoma at the site of the knee endoprosthesis. Laboratory values showed massive thrombocytosis, leukocytosis, anemia, severe hyponatremia and no evidence of infection. CT scan of the abdomen was inconspicuous. Head MRI showed no ischemia or bleeding, but a mild microangiopathy. A myeloproliferative neoplasm (MPN) was suspected and confirmed by bone marrow biopsy. Cerebral salt wasting syndrome was identified as the cause of severe hyponatremia most likely provoked by cerebral microcirculatory disturbance. The hematoma at the operation site was interpreted as a result of a secondary von Willebrand syndrome (vWS) due to the myeloproliferative neoplasm with massive thrombocytosis. After starting cytoreductive therapy with hydroxycarbamide, thrombocytosis and blood sodium slowly improved along with normalization of his mental condition. Conclusion To the best of our knowledge this is the first description of a patient with CSW most likely caused by a microcirculatory disturbance due to a massive thrombocytosis in the context of a myeloproliferative neoplasm.
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    Plasma YKL-40 in the spectrum of neurodegenerative dementia 

    Villar-Piqué, Anna; Schmitz, Matthias; Hermann, Peter; Goebel, Stefan; Bunck, Timothy; Varges, Daniela; Ferrer, Isidre; Riggert, Joachim; Llorens, Franc; Zerr, Inga
    Journal of Neuroinflammation. 2019 Jul 12;16(1):145
    Abstract Background Increased plasma YKL-40 has been reported in Alzheimer’s disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. Methods YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. Results Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. Conclusions Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.
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    Interactive effects of nitrogen and potassium on photosynthesis and photosynthetic nitrogen allocation of rice leaves 

    Hou, Wenfeng; Tränkner, Merle; Lu, Jianwei; Yan, Jinyao; Huang, Siyuan; Ren, Tao; Cong, Rihuan; Li, Xiaokun
    BMC Plant Biology. 2019 Jul 10;19(1):302
    Abstract Background Nitrogen (N) and potassium (K) are two important mineral nutrients in regulating leaf photosynthesis. Studying the interactive effects of N and K on regulating N allocation and photosynthesis (Pn) of rice leaves will be of great significance for further increasing leaf Pn, photosynthetic N use efficiency (PNUE) and grain yield. We measured the gas exchange of rice leaves in a field experiment and tested different kinds of leaf N based on N morphology and function, and calculated the interactive effects of N and K on N allocation and the PNUE. Results Compared with N0 (0 kg N ha− 1) and K0 (0 kg K2O ha− 1) treatments, the Pn was increased by 17.1 and 12.2% with the supply of N and K. Compared with N0K0 (0 kg N and 0 kg K2O ha− 1), N0K120 (0 kg N and 120 kg K2O ha− 1) and N0K180 (0 kg N and 180 kg K2O ha− 1), N supply increased the absolute content of photosynthetic N (Npsn) by 15.1, 15.5 and 10.5% on average, and the storage N (Nstore) was increased by 32.7, 64.9 and 72.7% on average. The relative content of Npsn was decreased by 5.6, 12.1 and 14.5%, while that of Nstore was increased by 8.7, 27.8 and 33.8%. Supply of K promoted the transformation of Nstore to Npsn despite the leaf N content (Na) was indeed decreased. Compared with N0K0, N180K0 (180 kg N and 0 kg K2O ha− 1) and N270K0 (270 kg N and 0 kg K2O ha− 1), K supply increased the relative content of Npsn by 17.7, 8.8 and 7.3%, and decreased the relative content of Nstore by 24.2, 11.4 and 8.7% respectively. Conclusions This study indicated the mechanism that K supply decreased the Na but increased the Npsn content and then increased leaf Pn and PNUE from a new viewpoint of leaf N allocation. The supply of K promoted the transformation of Nstore to Npsn and increased the PNUE. The decreased Nstore mainly resulted from the decrease of non-protein N. Combined use of N and K could optimize leaf N allocation and maintain a high leaf Npsn content and PNUE.
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    Pathological changes are associated with shifts in the employment of synonymous codons at the transcriptome level 

    Fornasiero, Eugenio F; Rizzoli, Silvio O
    BMC Genomics. 2019 Jul 09;20(1):566
    Abstract Background The usage of different synonymous codons reflects the genome organization and has been connected to parameters such as mRNA abundance and protein folding. It is also been established that mutations targeting specific synonymous codons can trigger disease. Results We performed a systematic meta-analysis of transcriptome results from 75 datasets representing 40 pathologies. We found that a subset of codons was preferentially employed in abundant transcripts, while other codons were preferentially found in low-abundance transcripts. By comparing control and pathological transcriptomes, we observed a shift in the employment of synonymous codons for every analyzed disease. For example, cancerous tissue employed preferentially A- or U-ending codons, shifting from G- or C-ending codons, which were preferred by control tissues. This analysis was able to discriminate patients and controls with high specificity and sensitivity. Conclusions Here we show that the employment of specific synonymous codons, quantified at the whole transcriptome level, changes profoundly in many diseases. We propose that the changes in codon employment offer a novel perspective for disease studies, and could be used to design new diagnostic tools.
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    Single and simultaneous effects of acrylamide and ethanol on bone microstructure of mice after one remodeling cycle 

    Sarocka, Anna; Kovacova, Veronika; Omelka, Radoslav; Grosskopf, Birgit; Kapusta, Edyta; Goc, Zofia; Formicki, Grzegorz; Martiniakova, Monika
    BMC Pharmacology and Toxicology. 2019 Jul 01;20(1):38
    Abstract Background This study aimed to examine femoral bone microstructure of mice after single and simultaneous administration to acrylamide and ethanol since both substances are often consumed separately and/or together by humans. Interactive effects of these toxins were analysed after one remodeling cycle. Methods Twenty clinically healthy adult mice were randomly divided into four groups following 2 weeks administration of toxins: A group - mice were fed with acrylamide (40 mg/kg bw); E group - mice were ethanol-fed (15% ethanol); AE group - mice were simultaneously fed with both toxins, and a C group – control (without acrylamide and/or ethanol supplementation). Generally, 2D and 3D imaging methods were used to determine cortical and trabecular bone tissues microstructure. Biochemical analyses of plasma parameters were also realized using commercially available ELISA tests and spectrophotometrically. Results Single and simultaneous exposure to acrylamide and ethanol affected only cortical bone microstructure. No significant changes in trabecular bone morphometry were detected among all groups. In mice from the A group, increased endocortical remodeling associated with a higher level of serum calcium and vasoconstriction of primary osteon’s vascular canals (POVC) were identified. On the contrary, increased cortical porosity consistent with a decreased relative bone volume, bone mineral density (BMD) and lower levels of alkaline phosphatase (ALP), glutathione (GSH), calcium in plasma and also with vasodilation of POVC were observed in the E group. In the AE group, the highest density of secondary osteons associated with a lower BMD and decreased levels of ALP, GSH were documented. The parameters of POVC and Haversian canals approximated to the C group. In addition, single and simultaneous exposure to both toxins caused liver disease consistent with a higher values of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in plasma of all experimental groups. Conclusions Single administration to acrylamide and ethanol had negative effects on cortical bone structure of mice after one remodeling cycle. However, we identified possible antagonistic impact of these toxins on the structure of the cortical bone.
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    The E3 ubiquitin ligase RNF40 suppresses apoptosis in colorectal cancer cells 

    Schneider, Deborah; Chua, Robert L; Molitor, Nicole; Hamdan, Feda H; Rettenmeier, Eva M; Prokakis, Evangelos; Mishra, Vivek K; Kari, Vijayalakshmi; Wegwitz, Florian; Johnsen, Steven A; et al.
    Kosinsky, Robyn L
    Clinical Epigenetics. 2019 Jul 02;11(1):98
    Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide, and deciphering underlying molecular mechanism is essential. The loss of monoubiquitinated histone H2B (H2Bub1) was correlated with poor prognosis of CRC patients and, accordingly, H2Bub1 was suggested as a tumor-suppressive mark. Surprisingly, our previous work revealed that the H2B ubiquitin ligase RING finger protein 40 (RNF40) might exert tumor-promoting functions. Here, we investigated the effect of RNF40 loss on tumorigenic features of CRC cells and their survival in vitro. Methods We evaluated the effects of RNF40 depletion in several human CRC cell lines in vitro. To evaluate cell cycle progression, cells were stained with propidium iodide and analyzed by flow cytometry. In addition, to assess apoptosis rates, caspase 3/7 activity was assessed in a Celigo® S-based measurement and, additionally, an Annexin V assay was performed. Genomic occupancy of H2Bub1, H3K79me3, and H3K27ac was determined by chromatin immunoprecipitation. Transcriptome-wide effects of RNF40 loss were evaluated based on mRNA-seq results, qRT-PCR, and Western blot. To rescue apoptosis-related effects, cells were treated with Z-VAD-FMK. Results Human CRC cell lines displayed decreased cell numbers in vitro after RNF40 depletion. While the differences in confluence were not mediated by changes in cell cycle progression, we discovered highly increased apoptosis rates after RNF40 knockdown due to elevated caspase 3/7 activity. This effect can be explained by reduced mRNA levels of anti-apoptotic and upregulation of pro-apoptotic BCL2 family members. Moreover, the direct occupancy of the RNF40-mediated H2B monoubiquitination was observed in the transcribed region of anti-apoptotic genes. Caspase inhibition by Z-VAD-FMK treatment rescued apoptosis in RNF40-depleted cells. However, knockdown cells still displayed decreased tumorigenic features despite the absence of apoptosis. Conclusions Our findings reveal that RNF40 is essential for maintaining tumorigenic features of CRC cells in vitro by controlling the expression of genes encoding central apoptotic regulators.
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    Big data research guided by sociological theory: a triadic dialogue among big data analysis, theory, and predictive models 

    Luo, Jar-Der; Liu, Jifan; Yang, Kunhao; Fu, Xiaoming
    The Journal of Chinese Sociology. 2019 Jul 05;6(1):11
    Abstract Computational social science has integrated social science theories and methodology with big data analysis. It has opened a number of new topics for big data analysis and enabled qualitative and quantitative sociological research to provide the ground truth for testing the results of data mining. At the same time, threads of evidence obtained by data mining can inform the development of theory and thereby guide the construction of predictive models to infer and explain more phenomena. Using the example of the Internet data of China’s venture capital industry, this paper shows the triadic dialogue among data mining, sociological theory, and predictive models and forms a methodology of big data analysis guided by sociological theories.
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    Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer 

    Maisel, Sabrina A; Broka, Derrick; Atwell, Benjamin; Bunch, Thomas; Kupp, Robert; Singh, Shiv K; Mehta, Shwetal; Schroeder, Joyce
    Journal of Translational Medicine. 2019 Jun 18;17(1):201
    Abstract Background The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases is overexpressed and correlates with poor prognosis and decreased survival in many cancers. The receptor family has been therapeutically targeted, yet tyrosine kinase inhibitors (TKIs) do not inhibit kinase-independent functions and antibody-based targeting does not affect internalized receptors. We have previously demonstrated that a peptide mimicking the internal juxtamembrane domain of HER1 (EGFR; EJ1) promotes the formation of non-functional HER dimers that inhibit kinase-dependent and kinase-independent functions of HER1 (ERBB1/EGFR), HER2 (ERBB2) and HER3 (ERBB3). Despite inducing rapid HER-dependent cell death in vitro, EJ1 peptides are rapidly cleared in vivo, limiting their efficacy. Method To stabilize EJ1 activity, hydrocarbon staples (SAH) were added to the active peptide (SAH-EJ1), resulting in a 7.2-fold increase in efficacy and decreased in vivo clearance. Viability assays were performed across HER1 and HER2 expressing cell lines, therapeutic-resistant breast cancer cells, clinically relevant HER1-mutated lung cancer cells, and patient-derived glioblastoma cells, in all cases demonstrating improved efficacy over standard of care pan-HER therapeutics. Tumor burden studies were also performed in lung, glioblastoma, and inflammatory breast cancer mouse models, evaluating tumor growth and overall survival. Results When injected into mouse models of basal-like and inflammatory breast cancers, EGFRvIII-driven glioblastoma, and lung adenocarcinoma with Erlotinib resistance, tumor growth is inhibited and overall survival is extended. Studies evaluating the toxicity of SAH-EJ1 also demonstrate a broad therapeutic window. Conclusions Taken together, these data indicate that SAH-EJ1 may be an effective therapeutic for HER-driven cancers with the potential to eliminate triple negative inflammatory breast cancer.
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    Parental military deployment as risk factor for children’s mental health: a meta-analytical review 

    Cunitz, Katrin; Dölitzsch, Claudia; Kösters, Markus; Willmund, Gerd-Dieter; Zimmermann, Peter; Bühler, Antje H; Fegert, Jörg M; Ziegenhain, Ute; Kölch, Michael
    Child and Adolescent Psychiatry and Mental Health. 2019 Jun 21;13(1):26
    Abstract There is evidence that military service increases the risk of psychosocial burden for not only service members but also their spouses and children. This meta-analysis aimed to systematically assess the association between military deployment of (at least one) parent and impact on children’s mental health. For this meta-analytic review, publications were systematically searched and assessed for eligibility based on predefined inclusion criteria (studies between 2001 until 2017 involving children with at least one parent working in military services). Measurements were determined by total problem scores of the children as well as symptoms of anxiety/depression, hyperactivity/inattention, and aggressive behavior. Meta-analyses aggregated the effect sizes in random-effect models and were calculated separately for the relation between parental deployment and civilian/normative data and for the relation between parental deployment and non-deployment. Age of the children was used as moderator variable to explore any potential source of heterogeneity between studies. Parental military deployment was associated with problems in children and adolescents compared to civilian/normative samples. Significant effect sizes reached from small to moderate values; the largest effect sizes were found for overall problems and specifically for anxious/depressive symptoms and aggressive behavior. Within the military group, children of deployed parents showed more problem behavior than children of non-deployed parents, but effect sizes were small. Age of the children had no moderating effect. The results emphasize that children of military members, especially with a deployed parent, should be assessed for emotional and behavioral problems.
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    Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy 

    Wu, Jia-Zhen; Ardah, Mustafa; Haikal, Caroline; Svanbergsson, Alexander; Diepenbroek, Meike; Vaikath, Nishant N; Li, Wen; Wang, Zhan-You; Outeiro, Tiago F; El-Agnaf, Omar M; et al.
    Li, Jia-Yi
    Translational Neurodegeneration. 2019 Jun 15;8(1):18
    Abstract Background Progressive accumulation of α-synuclein is a key step in the pathological development of Parkinson’s disease. Impaired protein degradation and increased levels of α-synuclein may trigger a pathological aggregation in vitro and in vivo. The chaperone-mediated autophagy (CMA) pathway is involved in the intracellular degradation processes of α-synuclein. Dysfunction of the CMA pathway impairs α-synuclein degradation and causes cytotoxicity. Results In the present study, we investigated the effects on the CMA pathway and α-synuclein aggregation using bioactive ingredients (Dihydromyricetin (DHM) and Salvianolic acid B (Sal B)) extracted from natural medicinal plants. In both cell-free and cellular models of α-synuclein aggregation, after administration of DHM and Sal B, we observed significant inhibition of α-synuclein accumulation and aggregation. Cells were co-transfected with a C-terminal modified α-synuclein (SynT) and synphilin-1, and then treated with DHM (10 μM) and Sal B (50 μM) 16 hours after transfection; levels of α-synuclein aggregation decreased significantly (68% for DHM and 75% for Sal B). Concomitantly, we detected increased levels of LAMP-1 (a marker of lysosomal homeostasis) and LAMP-2A (a key marker of CMA). Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A with α-synuclein inclusions after treatment with DHM and Sal B. We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo, along with decreased levels of α-synuclein. Moreover, DHM and Sal B treatments exhibited anti-inflammatory activities, preventing astroglia- and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice. Conclusions Our data indicate that DHM and Sal B are effective in modulating α-synuclein accumulation and aggregate formation and augmenting activation of CMA, holding potential for the treatment of Parkinson’s disease.
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    Extracorporeal gas exchange: when to start and how to end? 

    Gattinoni, L.; Vassalli, F.; Romitti, F.; Vasques, F.; Pasticci, I.; Duscio, E.; Quintel, M.
    Critical Care. 2019 Jun 14;23(Suppl 1):203
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    Thinking forward: promising but unproven ideas for future intensive care 

    Marini, John J; DeBacker, Daniel; Gattinoni, Luciano; Ince, Can; Martin-Loeches, Ignacio; Singer, Pierre; Singer, Mervyn; Westphal, Martin; Vincent, Jean-Louis
    Critical Care. 2019 Jun 14;23(Suppl 1):197
    Abstract Progress toward determining the true worth of ongoing practices or value of recent innovations can be glacially slow when we insist on following the conventional stepwise scientific pathway. Moreover, a widely accepted but flawed conceptual paradigm often proves difficult to challenge, modify or reject. Yet, most experienced clinicians, educators and clinical scientists privately entertain untested ideas about how care could or should be improved, even if the supporting evidence base is currently thin or non-existent. This symposium encouraged experts to share such intriguing but unproven concepts, each based upon what the speaker considered a logical but unproven rationale. Such free interchange invited dialog that pointed toward new or neglected lines of research needed to improve care of the critically ill. In this summary of those presentations, a brief background outlines the rationale for each novel and deliberately provocative unconfirmed idea endorsed by the presenter.
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    Assessing biological dissimilarities between five forest communities 

    Hao, Minhui; Corral-Rivas, J. J; González-Elizondo, M. S; Ganeshaiah, K. N; Nava-Miranda, M. G; Zhang, Chunyu; Zhao, Xiuhai; von Gadow, Klaus
    Forest Ecosystems. 2019 Jun 06;6(1):30
    Abstract Background Dissimilarity in community composition is one of the most fundamental and conspicuous features by which different forest ecosystems may be distinguished. Traditional estimates of community dissimilarity are based on differences in species incidence or abundance (e.g. the Jaccard, Sørensen, and Bray-Curtis dissimilarity indices). However, community dissimilarity is not only affected by differences in species incidence or abundance, but also by biological heterogeneities among species. Methods The objective of this study is to present a new measure of dissimilarity involving the biological heterogeneity among species. The “discriminating Avalanche” introduced in this study, is based on the taxonomic dissimilarity between tree species. The application is demonstrated using observations from five stem-mapped forest plots in China and Mexico. We compared three traditional community dissimilarity indices (Jaccard, Sørensen, and Bray-Curtis) with the “discriminating Avalanche” index, which incorporates information, not only about species frequencies, but also about their taxonomic hierarchies. Results Different patterns emerged for different measures of community dissimilarity. Compared with the traditional approaches, the discriminating Avalanche values showed a more realistic estimate of community dissimilarities, indicating a greater similarity among communities when species were closely related. Conclusions Traditional approaches for assessing community dissimilarity disregard the taxonomic hierarchy. In the traditional analysis, the dissimilarity between Pinus cooperi and Pinus durangensis would be the same as the dissimilarity between P. cooperi and Arbutus arizonica. The dissimilarity Avalanche dissimilarity between P. cooperi and P. durangensis is considerably lower than the dissimilarity between P. cooperi and A. arizonica, because the taxonomic hierarchies are incorporated. Therefore, the discriminating Avalanche is a more realistic measure of community dissimilarity. This main result of our study may contribute to improved characterization of community dissimilarities.
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