bluuebunny/crossref_metadata_2025 huggingface dataset:
The mouse lung early cellular innate immune response is not sufficient to control fungal infection with Cryptococcus neoformans
Authors: Rudman Jacob , Marriott Helen Maria , Carlin Leo M. , Johnston Simon Andrew
Published: June 2019

Cryptococcus neoformanscauses life-threatening infection in the immunocompromised. This and other opportunistic pathogens are an increasing threat as immunosuppression increases globally. To counter antibiotic resistance, there is precedent for developing immune enhancing therapy. However, our understanding of how immunocompetent patients resolve these infections is poor as opportunistic infections typically resolve subclinically. Because this has led to a lack of clinical data, we rely on animal models. Currentin vivoinfection models either lack mammalian immunity or are not compatible with long term high content imaging required to model the complexities of human host-pathogen interactions. Therefore, we have developed anex vivomurine precision cut lung slice (PCLS) model to understand innate immunity in cryptococcosis. C57BL/6 mice were sacrificed 0 or 24 hours post infection withKN99αcryptococci. Lungs were inflated with 37°C agarose, 300μm thick PCLS were prepared on a vibratome and imaged by confocal or wide-field fluorescence microscopy. Using PCLS and immunofluorescence, we demonstrate cryptococcal replication and clearance rates are balanced over the first 24 hours of infection. Cell-mediated immunity is alveolar macrophage centric, although alveolar macrophages demonstrate limited phagocytosis of cryptococci and enable intracellular cryptococcal replication.Cryptococcus neoformansresponded to the lung environment by forming enlarged cells, although these were not large enough to be titan cells. To further understand cryptococcal proliferationin vivo, we also infected animals withplb1mutantCryptococcus neoformansthat has been shown to exhibit proliferation defectsin vivo. We found no difference in fungal burden withplb1infected animals 24 hours post infection, but observed significantly larger fungal cells and no incidences of phagocytosis. Thus, the PCLS model can be used to assess the lung immune response early in cryptococcal infection, demonstrating that resident lung macrophages cannot control cryptococcal infection and offer an intracellular niche forCryptococcus neoformansgrowth.
Phytochemical Constituency Profiling and Antimicrobial Activity Screening of Seaweeds Extracts Collected from the Bay of Bengal Sea Coasts
Authors: Hasan Mahmudul , Imran Md. Abdus Shukur , Bhuiyan Farhana Rumzum , Ahmed Sheikh Rashel , Shanzana Parsha , Moli Mahmuda Akter , Foysal Shakhawat Hossain , Dabi Suma Bala
Published: June 2019

Seaweeds are able to produce a great variety of secondary metabolites that are characterized by a broad spectrum of biological activities. Two seaweeds species, namelyHypnea musciformisandEnteromorpha intestinalis werestudied to evaluate the phytochemical constituency and antimicrobial activities. First of all, crude extracts of both sea weeds were prepared by two different extraction methods (soaking and water bath) using different solvents. Phytochemicals profiling results revealed the presence of bioactive compounds (flavonoids, alkaloids, tannin, saponin and phenols) in both seaweed extracts. Quantification results for ethanolic extracts ofH. musciformis and E. intestinalisestimated 51 mg and 43 mg tannins in per gram of dried samples and flavonoids contents were found 67 mg and 57 mg/g mg QE/g respectively. Total phenolic contents were determined in terms of gallic acid equivalent (GAE).H. musciformisexhibited higher amount of phenolics (59 ± 0.0002 mg GAE/g) thanE. intestinalisextracts (41 ± 0.0002 mg GAE/g). In antimicrobial activity test, ethanol extractsof H. musciformisandE. intestinaliswere found 10 mm of inhibition diameter against all of the bacterial strains. Besides, methanol extracts ofE. intestinaliswere more susceptible toStaphylococcus aureus and Pseudomonaswhich was close to the inhibition diameter (>15 mm) of the mainstream antibiotic; Gentamicin. Moreover,Klebsiella sp. was found more susceptible to ethanol and methanol extracts of Hypnea musciformisas it showed inhibition zone greater than 15 mm. Both Seaweed extracts possessed higher amount of phytochemicals and showed promising antimicrobial activities when compared with the standards.
A phylogenomic analysis ofNepenthes(Nepenthaceae)
Authors: Murphy Bruce , Forest Félix , Barraclough Timothy , Rosindell James , Bellot Sidonie , Cowan Robyn , Golos Michal , Jebb Matthew , Cheek Martin
Published: June 2019

Nepenthaceae is one of the largest carnivorous plant families and features ecological and morphological adaptations indicating an impressive adaptive radiation. However, investigation of evolutionary and taxonomic questions is hindered by poor phylogenetic understanding, with previous molecular studies based on limited loci and taxa. We use high-throughput sequencing with a target-capture methodology based on a 353-loci, probe set to recover sequences for 197 samples, representing 151 described or putativeNepenthesspecies. Phylogenetic analyses were performed using supermatrix and maximum quartet species tree approaches. Our analyses confirm five Western outlier taxa, followed byN. danseri, as successively sister to the remainder of the group. We also find mostly consistent recovery of two major Southeast Asian clades. The first contains common or widespread lowland species plus a Wallacean–New Guinean clade. Within the second clade, sects.InsignesandTentaculataeare well supported, while geographically defined clades representing Sumatra, Indochina, Peninsular Malaysia, Palawan, Mindanao and Borneo are also consistently recovered. However, we find considerable conflicting signal at the site and locus level, and often unstable backbone relationships. A handful of Bornean taxa are inconsistently placed and require further investigation. We make further suggestions for a modified infra-generic classification of genusNepenthes.
Fibronectin receptor integrin α5β1 regulates assembly of PP2A complexes through PDE4D: modulation of vascular inflammation and atherosclerosis
Authors: Yun Sanguk , Hu Rui , Schwaemmle Melanie E. , Scherer Alexander N. , Zhuang Zhenwu , Koleske Anthony J. , Pallas David C. , Schwartz Martin A.
Published: June 2019

Fibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-prone regions of arteries, and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55α complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.
Impact of insertion sequences on convergent evolution ofShigellaspecies
Authors: Hawkey Jane , Monk Jonathan M. , Billman-Jacobe Helen , Palsson Bernhard , Holt Kathryn E.
Published: June 2019

Shigellaspecies are specialised lineages ofEscherichia colithat have converged to become human-adapted and cause dysentery by invading human gut epithelial cells. Most studies ofShigellaevolution have been restricted to comparisons of single representatives of each species; and population genomic studies of individualShigellaspecies have focused on genomic variation caused by single nucleotide variants and ignored the contribution of insertion sequences (IS) which are highly prevalent inShigellagenomes. Here, we investigate the distribution and evolutionary dynamics of IS within populations ofShigella dysenteriaeSd1,Shigella sonneiandShigella flexneri. We find that five IS (IS1, IS2, IS4, IS600and IS911) have undergone expansion in allShigellaspecies, creating substantial strain-to-strain variation within each population and contributing to convergent patterns of functional gene loss within and between species. We find that IS expansion and genome degradation are most advanced inS. dysenteriaeand least advanced inS. sonnei; and using genome-scale models of metabolism we show thatShigellaspecies display convergent loss of coreE. colimetabolic capabilities, withS. sonneiandS. flexnerifollowing a similar trajectory of metabolic streamlining to that ofS. dysenteriae. This study highlights the importance of IS to the evolution ofShigellaand provides a framework for the investigation of IS dynamics and metabolic reduction in other bacterial species.
Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer
Authors: Chen Jian , Fan Guangjian , Xiao Chao , Wang Xiao , Wang Yupeng , Song Guohe , Liu Xueni , Chen Jiayi , Lu Huijun , Guo Weiping , Tang Huamei , Zhuang Guohong , Peng Zhihai
Published: June 2019

Serine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53. In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.
Adaptation to life on land at 21% O2via transition from ferredoxin- to NADH-dependent redox balance
Authors: Gould SB , Garg SG , Handrich M , Nelson-Sathi S , Gruenheit N , Tielens AGM , Martin WF
Published: June 2019

Pyruvate:ferredoxin oxidoreductase (PFO) and iron only hydrogenase ([Fe]-HYD) are common enzymes among eukaryotic microbes that inhabit anaerobic niches. Their function is to maintain redox balance by donating electrons from food oxidation via ferredoxin (Fd) to protons, generating H2as a waste product. Operating in series, they constitute a soluble electron transport chain of one-electron transfers between FeS clusters. They fulfill the same function — redox balance — served by two electron-transfers in the NADH- and O2-dependent respiratory chains of mitochondria. Although they possess O2-sensitive FeS clusters, PFO, Fd and [Fe]-HYD are also present among numerous algae that produce O2. The evolutionary persistence of these enzymes among eukaryotic aerobes is traditionally explained as enabling facultative anaerobic growth. Here we show that algae express enzymes of anaerobic energy metabolism at ambient O2levels (21% v/v),Chlamydomonas reinhardtiiexpresses them with diurnal regulation. High O2environments arose on Earth only some ∼450 million years ago. Gene presence absence and gene expression data indicate that during the transition to high O2environments and terrestrialization, diverse algal lineages retained enzymes of Fd-dependent one-electron based redox balance, while the land plant and land animal lineages underwent irreversible specialization to redox balance involving the O2-insensitive two-electron carrier NADH.

Highlights

- Algae express enzymes of anaerobic metabolism in 21% [v/v] O2atmosphere, independent of anaerobiosis

- Retention of a plastid-encoded NADH dehydrogenase-like (NDH) was likely a prerequisite for the transition to life on land

- Terrestrialization and adaption to high O2is accompanied by a shift to redox balance at higher midpoint potentials

- Eukaryotes adapted to high O2life on land via specialization to two-electron based redox balance
Labelling effect in insects: cue associations influence perceived food value in ants
Authors: Wendt Stephanie , Czaczkes Tomer J.
Published: June 2019

Humans usually assess things not in terms of absolute value, but relative to reference points. The framing of alternatives can strongly affect human decision-making, leading to different choices depending on the context within which options are presented. Similar reference-point effects have been recently reported in ants, in which foragers show a contrast effect: ants overvalue a medium-quality food source if they were expecting a poor one, and vice versa for expectations of good food. However, studies of human consumer psychology have demonstrated that expectations, for example from product labels, can drive value perception in the other direction via assimilation. For example, an expensive bottle of wine is perceived as more enjoyable compared to a cheaper bottle, even if the wine is the same. In this study, we demonstrate a similar labelling-association effect in an insect: ants showed assimilation effects by spending twice as long drinking at a medium quality food source if it was scented with an odour previously associated with high quality than if it was scented with a poor-quality label. The presence of odour cues in the food during consumption and evaluation is critical, as without them, odour-driven expectations of quality result in contrast, not assimilation effects. The addition of a quality label in the food thus reverses contrast effects and causes value to be aligned with expectations, rather than being contrasted against them. As value judgement is a key element in decision-making, relative value perception strongly influences which option is chosen, and ultimately how choices are made.
Estimation of Speciation Times Under the Multispecies Coalescent
Authors: Peng Jing , Swofford David L. , Kubatko Laura
Published: June 2019

Motivation

The multispecies coalescent model is now widely accepted as an effective model for incorporating variation in the evolutionary histories of individual genes into methods for phylogenetic inference from genome-scale data. However, because model-based analysis under the coalescent can be computationally expensive for large data sets, a variety of inferential frameworks and corresponding algorithms have been proposed for estimation of species-level phylogenies and associated parameters, including speciation times and effective population sizes.

Results

We consider the problem of estimating the timing of speciation events along a phylogeny in a coalescent framework. We propose a maximum a posteriori estimator based on composite likelihood (MAPCL) for inferring these speciation times under a model of DNA sequence evolution for which exact site pattern probabilities can be computed under the assumption of a constant θ throughout the species tree. We demonstrate that the MAPCL estimates are statistically consistent and asymptotically normally distributed, and we show how this result can be used to estimate their asymptotic variance. We also provide a more computationally efficient estimator of the asymptotic variance based on the nonparametric bootstrap. We evaluate the performance of our method using simulation and by application to an empirical dataset for gibbons.

Availability and implementation

The method has been implemented in the PAUP* program, freely available at https://paup.phylosolutions.com for Macintosh, Windows, and Linux operating systems.

Contact

peng.650@osu.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
LncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation
Authors: Ninomiya Kensuke , Adachi Shungo , Natsume Tohru , Iwakiri Junichi , Terai Goro , Asai Kiyoshi , Hirose Tetsuro
Published: June 2019

A number of long noncoding RNAs (lncRNAs) are induced in response to specific stresses to construct membrane-less nuclear bodies; however, their function remains poorly understood. Here, we report the role of nuclear stress bodies (nSBs) formed on highly repetitive satellite III (HSATIII) lncRNAs derived from primate-specific satellite III repeats upon thermal stress exposure. A transcriptomic analysis revealed that depletion of HSATIII lncRNAs, resulting in elimination of nSBs, promoted splicing of 533 retained introns during thermal stress recovery. A HSATIII-Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) analysis identified multiple splicing factors in nSBs, including serine and arginine-rich pre-mRNA splicing factors (SRSFs), the phosphorylation states of which affect splicing patterns. SRSFs are rapidly dephosphorylated upon thermal stress exposure. During stress recovery, CDC like kinase 1 (CLK1) was recruited to nSBs and accelerated the re-phosphorylation of SRSF9, thereby promoting target intron retention. Our findings suggest that HSATIII-dependent nSBs serve as a conditional platform for phosphorylation of SRSFs by CLK1 to promote the rapid adaptation of gene expression through intron retention following thermal stress exposure.
Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer
Authors: Sztupinszki Zsofia , Diossy Miklos , Krzystanek Marcin , Borcsok Judit , Pomerantz Mark , Tisza Viktoria , Spisak Sandor , Rusz Orsolya , Csabai István , Freedman Matthew , Szallasi Zoltan
Published: June 2019

Background

Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.

To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.

HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.

Results

Known BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.

Conclusions

These findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).
Maturation of cortical microstructure and cognitive development in childhood and adolescence: a T1w/T2w ratio MRI study
Authors: Norbom Linn B. , Rokicki Jaroslav , Alnæs Dag , Kaufmann Tobias , Doan Nhat Trung , Andreassen Ole A. , Westlye Lars T. , Tamnes Christian K.
Published: June 2019

The restructuring and optimization of the cerebral cortex from early childhood and through adolescence is an essential feature of human brain development, underlying immense cognitive improvements. Beyond established morphometric cortical assessments, the T1w/T2w ratio quantifies partly separate biological processes, and might inform models of typical neurocognitive development and developmental psychopathology. In the present study, we computed vertex-wise T1w/T2w ratio across the cortical surface in 621 youths (3-21 years) sampled from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and tested for associations with individual differences in age, sex, and both general and specific cognitive abilities. The results showed a near global linear age-related increase in T1w/T2w ratio across the brain surface, with a general posterior to anterior increasing gradient in association strength. Moreover, results indicated that boys in late adolescence had regionally higher T1w/T2w ratio as compared to girls. Across individuals, T1w/T2w ratio was negatively associated with general and several specific cognitive abilities mainly within anterior cortical regions. Our study indicates age-related differences in T1w/T2w ratio throughout childhood, adolescence and young adulthood, in line with the known protracted myelination of the cortex. Moreover, the study supports T1w/T2w ratio as a promising surrogate measure of individual differences in intracortical brain structure in neurodevelopment.
The Threshold Elemental Ratio of an ectotherm decreases then increases with rising temperature
Authors: Ruiz Thomas , Koussoroplis Apostolos-Manuel , Danger Michael , Aguer Jean-Pierre , Morel-Desrosiers Nicole , Bec Alexandre
Published: June 2019

Earth is currently facing unprecedented global changes, hurrying scientists to provide predictive tools to explore the futures responses of ecosystems. Among those changes, temperature increase and alterations of nutrient availabilities largely drive consumer performances, yet their interactive effect remains poorly understood. Here we investigate how the dietary C:P ratio that optimizes consumer growth (TERC:P: Threshold Elemental Ratio) changes along temperature gradients by combining a TERC:P model and growth experiments on the model organism Daphnia magna. Both lines of evidence show that the TERC:P responds to temperature in an U-shaped fashion. This shape reconciles previous contradictive observations into a common framework, thereby improving our capacity to forecast the combined effects of nutrient cycle and climatic alterations on ectotherms.
Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation
Authors: Ball Daniel P. , Taabazuing Cornelius Y. , Griswold Andrew R. , Orth Elizabeth L. , Rao Sahana D. , Kotliar Ilana B. , Johnson Darren C. , Bachovchin Daniel A.
Published: June 2019

Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied PRRs oligomerize with the pro-caspase-1-adapter protein ASC to generate a single large structure in the cytosol, which induces the autoproteolysis and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming much smaller “ASC-independent” inflammasomes. It is currently thought that pro-caspase-1 autoproteolysis does not occur during, and is not required for, ASC-independent inflammasome activation. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first PRR that cannot form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is an obligate regulatory step in the activation of human canonical inflammasomes.
Hydrological Extremes and their Association with ENSO Phases in Ethiopia
Authors: Gari Abu Tolcha
Published: June 2019

Ethiopia is a rain fed agriculture country, which is subjected to high climate variability in space and time, leading to hydrological extremes causing loss of life and property more frequently. Droughts are more common and sometime floods are experienced in various parts of the country. Being a tropical country, the inter-annual climate variability in Ethiopia is dominated by ENSO (ElNino and Southern Oscillation).

In this study, an attempt has been made to determine the occurrence of droughts and floods on monthly basis, by calculating the monthly SPI (Standardized Precipitation Index) using the available rainfall data during (1975-2005) at selected 26 stations that spread across the country. Based on the monthly SPI values computed, the droughts and floods of different intensities; extreme, severe and dry have been determined for all stations. The frequencies of the droughts and floods on monthly scale during the two rainy seasons, Belg (Feb-May) and Kiremt (Jun-Sep) seasons have been determined. For instance, during Belg season, there were 11 extreme (SPI < −2.0) droughts at Nazreth, 10 severe (SPI between −1.99 and −1.50) droughts at Diredawa and 14 moderate (SPI between −1.49 and −1.00) droughts at Kulumsa. Total number of droughts of all intensities over the study period is also highest (22) at Kulumsa and lowest (8) at Mekelle. Moreover, at Kulumsa both the numbers of droughts (22) and floods (22) during Belg are more, which shows that the rainfall variability is the highest at this station.

The association of the hydrological extremes during the two rainy seasons, belg and kiremt with the ENSO phases has also been examined, which forms a basis for the prediction of the occurrence of droughts (dry conditions) and floods (wet conditions) at individual stations using ENSO phases.
A novel imaging biomarker for survival prediction in EGFR-mutated NSCLC patients treated with TKI
Authors: Collin Annabelle , Groza Vladimir , Missenard Louise , Chomy François , Colin Thierry , Palussière Jean , Saut Olivier
Published: June 2019

EGFR-mutated non-small cells lung carcinoma are treated with Tyrosine Kinase Inhibitors (TKI). Very often, the disease is only responding for a while before relapsing. TKI efficacy in the long run is therefore challenging to evaluate. Our objective is to derive a new imaging biomarker that could offer better insights on the disease response to treatment. This study includes 17 patients diagnosed as EGFR-mutated non-small cell lung cancer and exposed to an EGFR-targeting TKI. The early response to treatment is evaluated with 3 computed tomography (CT) scans of the primitive tumor (one before the TKI introduction and two after). Using our knowledge of the disease, an imaging biomarker based on the tumor heterogeneity evolution between the first and the third exams is defined and computed using a novel mathematical model calibrated on patient data. Defining the overall survival as the time between the introduction of the TKI treatment and the patient death, we obtain a statistically significant correlation between the overall survival and our imaging marker (p = 0.009). Using the ROC curve, the patients are separated into two populations hence the comparison of the survival curves is statistically significant (p = 0.025). Initial state of the tumor seems to have a role for the prognosis of the response to TKI treatment. More precisely, the imaging marker - defined using only the CT scan before the TKI introduction - allows us to determine a first classification of the population which is refined over time using the imaging marker as more CT scans become available. This exploratory study leads us to think that it is possible to obtain a survival assessment using only few CT scans of the primary tumor.
Antisense oligonucleotide therapy rescues aggresome formation in a novel Spinocerebellar Ataxia type 3 human embryonic stem cell line
Authors: Moore Lauren R. , Keller Laura , Bushart David D. , Delatorre Rodrigo , Li Duojia , McLoughlin Hayley S. , do Carmo Costa Maria , Shakkottai Vikram G. , Smith Gary D. , Paulson Henry L.
Published: June 2019

Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here, we characterize the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred here as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene within the pathogenic repeat range for SCA3. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. Finally, antisense oligonucleotide-mediated reduction of ATXN3 prevented the formation of p62-positive aggresomes in SCA3-hESCs. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of possible SCA3 therapies.

Highlights

Generated first NIH-approved SCA3 human embryonic stem cell line (SCA3-hESC)

SCA3–hESC exhibit robust ATXN3 aggregation pathology and form p62+ aggresomes

Anti-ATXN3 antisense oligonucleotides rescue aggresome formation in SCA3-hESC

Derived SCA3 neurons form aggregates and exhibit impaired protein quality control
Misoprostol Attenuates Cardiomyocyte Proliferation in the Neonatal Heart through Bnip3 and Perinuclear Calcium Signaling
Authors: Martens Matthew D. , Field Jared T. , Seshadri Nivedita , Day Chelsea , Chapman Donald , Keijzer Richard , Doucette Christine R. , Hatch Grant M. , West Adrian R. , Ivanco Tammy L. , Gordon Joseph W.
Published: June 2019

Systemic hypoxia resulting from preterm birth, altered lung development, and cyanotic congenital heart disease is known to impede the regulatory and developmental pathways in the neonatal heart. While the molecular mechanisms are still unknown, hypoxia induces aberrant cardiomyocyte proliferation, which may be initially adaptive, but can ultimately program the heart to fail in early life. Recent evidence suggests that the prostaglandin E1 analogue, misoprostol, is cytoprotective in the hypoxia-exposed neonatal heart by impacting alternative splicing of the Bcl-2 family member Bnip3, resulting in the generation of a variant lacking the third exon (Bnip3ΔExon3 or small Nip; sNip). Using a rodent model of neonatal hypoxia, in combination with rat primary neonatal cardiomyocytes (PVNCs) and H9c2 cells, we sought to determine if misoprostol can prevent cardiomyocyte proliferation and what the key molecular mechanisms might be in this pathway. In PVNCs, exposure to 10% oxygen induced myocyte proliferation concurrent with molecular markers of cell-cycle progression, such as Cyclin-D1, which were prevented by misoprostol treatment. Furthermore, we describe a critical role for sNip in opposing cardiomyocyte proliferation through several mechanisms, including reduced expression of the proliferative MEF2C-myocardin-BMP10 pathway, accumulation of nuclear calcium leading to NFATc3 activation, and increased expression of the cardiac maturation factor BMP2. Intriguingly, misoprostol and sNip inhibited hypoxia-induced glycolytic flux, which directly influenced myocyte proliferation. These observations were further supported by knockdown studies, where hypoxia-induced cardiomyocyte proliferation is restored in misoprostol-treated cells by an siRNA targeting sNip. Finally, in postnatal day (PND)-10 rat pups exposed to hypoxia, we observed histological evidence of increased nuclei number and increased PPH3 staining, which were completely attenuated by misoprostol treatment. Collectively, this data demonstrates how neonatal cardiomyocyte proliferation can be pharmacologically modulated by misoprostol treatment, which may have important implications for both neonatal and regenerative medicine.
Mitochondrial genome of non-photosynthetic mycoheterotrophic plant Hypopitys monotropa,its structure, gene expression and RNA editing
Authors: Shtratnikova Viktoria Y. , Schelkunov Mikhail I. , Penin Aleksey A. , Logacheva Maria D.
Published: June 2019

Heterotrophic plants – the plants that lost the ability to photosynthesis – are characterized by a number of changes at all levels of organization. Heterotrophic plants divide into two large categories – parasitic and mycoheterotrophic. The question of to what extent these changes are similar in these two categories is still open. Plastid genomes of non-photosynthetic plants are well characterized and they demonstrate similar patterns of reduction in both groups. In contrast, little is known about mitochondrial genomes of mycoheterotrophic plants. We report the structure of the mitochondrial genome of Hypopitys monotropa, a mycoheterotrophic member of Ericaceae, and the expression of mitochondrial genes. In contrast to its highly reduced plastid genome, the mitochondrial genome of H. monotropa is larger than that of its photosynthetic relative Vaccinium macrocarpon, its complete size is ~810 Kbp. We found an unusually long repeat-rich structure of the genome that suggests the existence of linear fragments. Despite this unique feature, the gene content of the H. monotropa mitogenome is typical of flowering plants. No acceleration of substitution rates is observed in mitochondrial genes, in contrast to previous observations on parasitic non-photosynthetic plants. Transcriptome sequencing revealed trans-splicing of several genes and RNA editing in 33 genes of 38. Notably, we did not find any traces of horizontal gene transfer from fungi, in contrast to plant parasites which extensively integrate genetic material from their hosts.
Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma
Authors: Corbit Kevin C. , Wilson Camella G. , Lowe Dylan , Tran Jennifer L. , Vera Nicholas B. , Clasquin Michelle , Mattis Aras N. , Weiss Ethan J.
Published: June 2019

Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyteJak2(JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyteJak2(JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here suggests a attention be paid towards inhibition of adipocyte GH signaling as a therapeutic target of metabolic liver disease.
Polyhydroxyalkanoate granule accumulation makes optical density measurement an unreliable method for bacterial growth assessment inBurkholderia thailandensis
Authors: Martinez Sarah , Déziel Eric
Published: June 2019

Optical density (OD) measurement is the standard method used in microbiology for estimating bacterial concentrations in cultures. However, most studies do not compare these measurements with viable cell counts and assume that they reflect the real cell concentration.Burkholderia thailandensiswas recently identified as a polyhydroxyalkanoate (PHA) producer. PHA biosynthesis seems to be coded by an ortholog of theCupriavidus necator phaCgene. When growing cultures of wildtype strain E264 and an isogenicphaC- mutant, we noted a difference in their OD600values, although viable cell counts indicated similar growth. Investigating the cellular morphologies of both strains, we found that under our conditions the wildtype strain was full of PHA granules, deforming the cells, while the mutant contained no granules. These factors apparently affected the light scattering, making the OD600values no longer representative of cell density. We show a direct correlation between OD600values and the accumulation of PHA. We conclude that OD measurement is unreliable for growth evaluation ofB. thailandensisbecause of PHA production. This study also suggests thatB. thailandensiscould represent an excellent candidate for PHA bioproduction. Correlation between OD measurements and viable cell counts should be verified on any study realized inB. thailandensis.
Development and Binocular Matching of Orientation Selectivity in Visual Cortex: A Computational Model
Authors: Xu Xize , Cang Jianhua , Riecke Hermann
Published: June 2019

In mouse visual cortex, right after eye-opening binocular cells have different orientation preferences for input from the two eyes. With normal visual experience during a critical period, these orientation preferences shift and eventually become well matched. To gain insight into the matching process, we developed a computational model of a cortical cell receiving - via plastic synapses - orientation selective inputs that are individually monocular. The model captures the experimentally observed matching of the orientation preferences, the dependence of matching on ocular dominance of the cell, and the relationship between the degree of matching and the resulting monocular orientation selectivity. Moreover, our model puts forward testable predictions: i) the matching speed increases with initial ocular dominance and decreases with initial orientation selectivity; ii) matching proceeds faster than the sharpening of the orientation selectivity, suggesting that orientation selectivity is not a driving force for the matching process; iii) there are two main routes to matching: the preferred orientations either drift towards each other or one of the orientations switches suddenly. The latter occurs for cells with large initial mismatch and can render the cell monocular. We expect that these results provide insight more generally into the development of neuronal systems that integrate inputs from multiple sources, including different sensory modalities.

New & Noteworthy

Animals gather information through multiple modalities (vision, audition, touch, etc). These information streams have to be merged coherently to provide a meaningful representation of the world. Thus, for neurons in visual cortex V1 the orientation selectivities for inputs from the two eyes have to match to enable binocular vision. We analyze the postnatal process underlying this matching using computational modeling. It captures recent experimental results and reveals interdependence between matching, ocular dominance, and orientation selectivity.
Modern methods to monitor end winding vibrations in turbo-generators
Authors: Kreischer Christian
Published: June 2019

Purpose

Problems caused by end winding vibrations in power plant generators have become increasingly evident in recent years and reveal a need for monitoring and diagnostic systems. An increasing number of operational outages are caused by failures of the winding insulation or the conductor itself due to end winding vibrations. Meanwhile, it is clear that the condition of the end winding must be continuously monitored during operation to detect ineffective end winding support in time and to plan the repair.

Design/methodology/approach

In this paper, the complex and nonlinear excitation mechanisms in large machines are presented and modern methods for vibration monitoring are described. Through a consistent use of vibration monitoring in the end winding area as well as the vibration diagnosis done by experts, damage mechanisms can be detected at an early stage, repair measures can be planned and serious damage owing to a weakened main insulation can be avoided.

Findings

By combining modal analysis and trend monitoring in relation to the learned vibration behaviour, the end winding condition can be assessed in a differentiated manner and changes in the end winding structure can be detected early.

Originality/value

Finally, an assessment for a two-pole, air-cooled turbo generator is proposed.
The US dollar and new imperialism under the logic of capital accumulation
Authors: Qiu Haiping , Zhao Min
Published: June 2019

Purpose

The world currency is endowed with two inherent contradictions, namely, the general contradiction of all currencies and the special contradiction between the quality and quantity of the world currency. The paper aims to discuss these issues.

Design/methodology/approach

In the wake of the Second World War, the USA, with its strong economic and military strength, established an international monetary system centered on the US dollar (USD). This gave USD the status of “world currency” and bounded it to the US imperialist hegemony with mutual integration and interaction, making it possible for USD capital to conduct international exploitation and wealth plundering extensively around the world.

Findings

The contradiction between the capital logic and the power logic, which is inherent in capital accumulation models of the new imperialism, also indicates the inevitable decline of USD.

Originality/value

This constitutes an important feature of the new imperialism. However, as a sovereign currency, USD has inextricable and inherent contradictions while exercising its function as the world currency.
Comparing the safety climate of the Indonesian and Australian construction industries
Authors: Loosemore Martin , Sunindijo Riza Yosia , Lestari Fatma , Kusminanti Yuni , Widanarko Baiduri
Published: June 2019

Purpose

The purpose of this paper is to assess, compare and explain safety climate differences between the Indonesian and Australian construction industries.

Design/methodology/approach

The paper reports a comparative safety climate survey of 415 construction personnel working in the Australian and Indonesia construction industries.

Findings

Surprisingly, the results show that the safety climate in Indonesia and Australia are similar and that the differences in safety performance, safety climate must be interpreted within the context of wider health and safety norms, regulations, awareness, knowledge and typical work environments to make any sense.

Research limitations/implications

This research contributes a missing international comparative dimension to the emerging research on construction safety climate. Indonesian studies are notably absent from this literature, despite the size of the country and the poor health and safety record of its construction industry. Similar comparisons between safety climate in other countries need to be made.

Practical implications

This research allows construction managers operating across international boundaries to better understand the cultural and institutional context in which safety climate is developed. This will assist in the development of more culturally sensitive safety management strategies.

Social implications

The construction industry’s poor safety record has serious implications for both individuals working in the industry, their immediate families and the communities in which they live. By improving the safety record of the industry these impacts can be reduced.

Originality/value

This research reveals, for the first time, the cultural and institutional complexities of comparing safety climate across different countries. The results contribute to safety climate research by highlighting the importance of cultural and institutional relativity in making international comparisons of health and safety research.
New integrable Vakhnenko–Parkes (VP) equations with time-dependent coefficients
Authors: Wazwaz Abdul-Majid
Published: June 2019

Purpose

The purpose of this paper is concerned with developing new integrable Vakhnenko–Parkes equations with time-dependent coeﬃcients. The author obtains multiple soliton solutions and multiple complex soliton solutions for the time-dependent equations.

Design/methodology/approach

The developed time-dependent models have been handled by using the Hirota’s direct method. The author also uses Hirota’s complex criteria for deriving multiple complex soliton solutions.

Findings

The developed integrable models exhibit complete integrability for any analytic time-dependent coeﬃcient.

Research limitations/implications

The paper presents an eﬃcient algorithm for handling time-dependent integrable equations with time-dependent coeﬃcients.

Practical implications

The author develops two Vakhnenko–Parkes equations with time-dependent coeﬃcients. These models represent more speciﬁc data than the related equations with constant coeﬃcients. The author showed that integrable equations with time-dependent coeﬃcients give real and complex soliton solutions.

Social implications

The work presents useful techniques for ﬁnding integrable equations with time-dependent coeﬃcients.

Originality/value

The paper gives new integrable Vakhnenko–Parkes equations, which give a variety of multiple real and complex soliton solutions.
Convective heat transfer enhancement: effect of multi-frequency heating
Authors: Manna Nirmal Kumar , Biswas Nirmalendu , Mahapatra Pallab Sinha
Published: June 2019

Purpose

This study aims to enhance natural convection heat transfer for a porous thermal cavity. Multi-frequency sinusoidal heating is applied at the bottom of a porous square cavity, considering top wall adiabatic and cooling through the sidewalls. The different frequencies, amplitudes and phase angles of sinusoidal heating are investigated to understand their major impacts on the heat transfer characteristics.

Design/methodology/approach

The finite volume method is used to solve the governing equations in a two-dimensional cavity, considering incompressible laminar flow, Boussinesq approximation and Brinkman–Forchheimer–Darcy model. The mean-temperature constraint is applied for enhancement analysis.

Findings

The multi-frequency heating can markedly enhance natural convection heat transfer even in the presence of porous medium (enhancement up to ∼74 per cent). Only the positive phase angle offers heat transfer enhancement consistently in all frequencies (studied).

Research limitations/implications

The present research idea can usefully be extended to other multi-physical areas (nanofluids, magneto-hydrodynamics, etc.).

Practical implications

The findings are useful for devices working on natural convection.

Originality/value

The enhancement using multi-frequency heating is estimated under different parametric conditions. The effect of different frequencies of sinusoidal heating, along with the uniform heating, is collectively discussed from the fundamental point of view using the average and local Nusselt number, thermal and hydrodynamic boundary layers and heatlines.