bluuebunny/crossref_metadata_2025 huggingface dataset:
ERO1α promotes hypoxic tumour progression and is associated with poor prognosis in pancreatic cancer
Authors: Gupta Nikhil , Park Jung Eun , Tse Wilford , Low Jee Keem , Kon Oi Lian , McCarthy Neil , Sze Siu Kwan
Published: June 2019

Pancreatic cancer is a leading cause of mortality worldwide due to difficulty detecting early-stage disease and our poor understanding of the mediators that drive the progression of hypoxic solid tumours. We, therefore, used a heavy isotope ‘pulse/trace’ proteomic approach to determine how hypoxia alters pancreatic tumour expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistant (ABCB6), immune suppression (NFIL3,WDR4), angiogenesis (ANGPT4, ERO1α, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1α was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1α substantially reduced growth rates and colony formation in pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1α-deficient tumour cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1α is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.
The bounded rationality of probability distortion
Authors: Zhang Hang , Ren Xiangjuan , Maloney Laurence T.
Published: June 2019

Abstract

In decision-making under risk (DMR) participants’ choices are based on probability values systematically different from those that are objectively correct. Similar systematic distortions are found in tasks involving relative frequency judgments (JRF). These distortions limit performance in a wide variety of tasks and an evident question is, why do we systematically fail in our use of probability and relative frequency information?

We propose a Bounded Log-Odds Model (BLO) of probability and relative frequency distortion based on three assumptions: (1)log-odds: probability and relative frequency are mapped to an internal log-odds scale, (2)boundedness: the range of representations of probability and relative frequency are bounded and the bounds change dynamically with task, and (3)variance compensation: the mapping compensates in part for uncertainty in probability and relative frequency values.

We compared human performance in both DMR and JRF tasks to the predictions of the BLO model as well as eleven alternative models each missing one or more of the underlying BLO assumptions (factorial model comparison). The BLO model and its assumptions proved to be superior to any of the alternatives. In a separate analysis, we found that BLO accounts for individual participants’ data better than any previous model in the DMR literature.

We also found that, subject to the boundedness limitation, participants’ choice of distortion approximately maximized the mutual information between objective task-relevant values and internal values, a form of bounded rationality.

SignificanceStatement

People distort probability in decision under risk and many other tasks. These distortions can be large, leading us to make markedly suboptimal decisions. There is no agreement on why we distort probability. Distortion changes systematically with task, hinting that distortions are dynamic compensations for some intrinsic “bound” on working memory. We first develop a model of the bound and the compensation process and then report an experiment showing that the model accounts for individual human performance in decision under risk and relative frequency judgments. Last, we show that the particular compensation in each experimental condition serve to maximize the mutual information between objective decision variables and their internal representations. We distort probability to compensate for our own working memory limitations.
Pre-existent adult sox10+cardiomyocytes contribute to myocardial regeneration in the zebrafish
Authors: Sande-Melón Marcos , Marques Inês J. , Galardi-Castilla María , Langa Xavier , Pérez-López María , Botos Marius , Guzmán-Martínez Gabriela , Ferreira-Francisco David Miguel , Pavlinic Dinko , Benes Vladimir , Bruggmann Remy , Mercader Nadia
Published: June 2019

During heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from pre-existing ones. It is unclear whether the heart is comprised of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, usingsox10genetic fate mapping, we identified a subset of pre-existent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded massively after cryoinjury. Genetic ablation ofsox10+cardiomyocytes severely impaired cardiac regeneration revealing that they play a crucial role for heart regeneration.
Fine scale population structure linked to neutral divergence in the common sole (Solea solea), a marine fish with high dispersal capacity
Authors: Le Moan Alan , Jiménez-Mena Belén , Bekkevold Dorte , Hemmer-Hansen Jakob
Published: June 2019

The Baltic Sea provides a classical example of how an environmental gradient is associated with the distribution of marine species. Here, numerous genetic studies have revealed clear patterns of population structuring linked to the physical features of the gradient itself. Nevertheless, it remains difficult to distinguish clearly between the different micro-evolutionary processes that shape these structured populationsin situ. The common sole (Solea solea) is a benthic flatfish that rarely occurs within the Baltic Sea, but that exhibits a clear genetic break between populations from the North Sea – Baltic Sea transition zone and the remainder of the Atlantic Ocean. Here, we aim to evaluate the extent to which natural selection is involved in the observed patterns of divergence of sole populations occurring in the transition zone by comparing them with population structures of other flatfish species that have successfully colonized the Baltic Sea. By using several thousand of ddRAD-derived SNPs, we identified a fine-scale pattern of isolation-by-distance (IBD) of sole populations in the region. However, despite strong biological similarities among the flatfishes compared here, the sole IBD was, by far, the lowest detected across the transition zone. While selection was inferred to strongly influence all other flatfishes evolutionary histories, the analytical inference on the sole demographic history suggests that this fine-scale IBD is mainly maintained by neutral processes due to low effective population size of sole in the transition zone and asymmetrical gene flow. Our work contributes to a growing body of evidence suggesting that the strength of the different micro-evolutionary processes is species-specific, even when species occur in the same environment.
Integrating population genetics to define conservation units from the core to the edge ofRhinolophus ferrumequinumwestern range
Authors: Tournayre Orianne , Pons Jean-Baptiste , Leuchtmann Maxime , Leblois Raphael , Piry Sylvain , Filippi-Codaccioni Ondine , Loiseau Anne , Duhayer Jeanne , Garin Inazio , Mathews Fiona , Puechmaille Sébastien , Charbonnel Nathalie , Pontier Dominique
Published: June 2019

The greater horseshoe bat(Rhinolophus ferrumequinum)is among the most widespread bat species in Europe but it has experienced severe declines, especially in Northern Europe. This species is listed Near Threatened in the EuropeanIUCN Red List of Threatened Animalsand it is considered to be highly sensitive to human activities and particularly to habitat fragmentation. Therefore, understanding the population boundaries and demographic history of populations of this species is of primary importance to assess relevant conservation strategies. In this study, we used 17 microsatellite markers to assess the genetic diversity, the genetic structure and the demographic history ofR. ferrumequinumcolonies in the Western European part of its distribution. We found high levels of genetic diversity and large population size on the European mainland and lower estimates in England and Northern France. Analyses of clustering and isolation by distance showed a barrier effect of the Channel and potentially of the Mediterranean Sea onR. ferrumequinumbat dispersal. Conversely, we could not reveal any gene flow disruption from both sides of the Western Pyrenees. These results provide important information to improve the delineation ofR. ferrumequinummanagement units in its western range. We suggest that a large management unit corresponding to the European mainland population must be considered. Particular attention should be given to mating territories as they seem to play a key role in maintaining the high levels of genetic mixing between colonies. Smaller management units corresponding to English and Northern France colonies must also be implemented. These insular or peripheral colonies could be at higher risk of extinction in a near future.
Balancing Model-Based and Memory-Free Action Selection under Competitive Pressure
Authors: Kikumoto Atsushi , Mayr Ulrich
Published: June 2019

In competitive situations, winning depends on selecting actions that surprise the opponent. Such unpredictable action can be generated based on representations of the opponent’s strategy and choice history (model-based counter-prediction) or by choosing actions in a memory-free, stochastic manner. Across five different experiments using a variant of a matching-pennies game with simulated and human opponents we found that people toggle between these two strategies, using model-based selection used when recent wins signal the appropriateness of the current model, but reverting to stochastic selection following losses. Also, after wins, feedback-related, mid-frontal EEG activity reflected information about the opponent’s global and local strategy, and predicted upcoming choices. After losses, this activity was nearly absent—indicating that the internal model is suppressed after negative feedback. We suggest that the mixed-strategy approach allows negotiating two conflicting goals: (1) exploiting the opponent’s deviations from randomness while (2) remaining unpredictable for the opponent.
New mechanism-based inhibitors of aspartate transcarbamoylase for anticancer drug development
Authors: Lei Zhen , Wang Nan , Wang Biying , Lu Zhifang , Tan Hongwei , Zheng Jimin , Jia Zongchao
Published: June 2019

Aspartate transcarbamoylase (ATCase) is a key enzyme which regulates and catalyzes the second step ofde novopyrimidine synthesis in all organisms.E. coliATCase is a prototypic enzyme regulated by both product feedback and substrate cooperativity, whereas human ATCase is a potential anticancer target. Through structural and biochemical analyses, we revealed that R167/130’s loop region in ATCase serves as a gatekeeper for the active site, playing a new and unappreciated role in feedback regulation. Based on virtual compound screening simultaneously targeting the new regulatory region and active site of human ATCase, two compounds were identified to exhibit strong inhibition of ATCase activity, proliferation of multiple cancer cell lines, and growth of xenograft tumors. Our work has not only revealed a previously unknown regulatory region of ATCase that helps explain feedback regulation, but also successfully guided the identification of new ATCase inhibitors for anticancer drug development using a dual-targeting strategy.
Personalized Therapy Design for Liquid Tumors via Optimal Control Theory
Authors: Angaroni Fabrizio , Graudenzi Alex , Rossignolo Marco , Maspero Davide , Calarco Tommaso , Piazza Rocco , Montangero Simone , Antoniotti Marco
Published: June 2019

One of the key challenges in current cancer research is the development of reliable methods for the definition of personalized therapeutic strategies, based on increasingly available experimental data on single patients. To this end, methods from control theory can be effectively employed on patient-specific pharmacokinetic and pharmacodynamic models to generate robust data-driven experimental hypotheses.

Here we introduce the Control Theory for Therapy Design (CT4TD) theoretical framework for the generation of optimized personalized therapeutic strategies in cancer patients, based on optimal control theory and population dynamics modeling. The CT4TD framework can help clinicians in designing patient-specific therapeutic regimens, with the specific goal of optimizing the efficacy of the cure while reducing the costs, especially in terms of toxicity and adverse effects. CT4TD can be used at the time of the diagnosis in order to set optimized personalized therapies to reach selected target drug concentrations. Furthermore, if longitudinal data on patients under treatment are available, our approach introduces the possibility of adjusting the therapy with the explicit goal of minimizing the tumor burden measured in each case.

As a case study, we present the application of CT4TD to Imatinib administration in Chronic Myeloid Leukemia, in which we show that the optimized therapeutic strategies are extremely diversified among patients, and display improvements with respect to the currently employed regimes. Interestingly, we prove that much of the variance in therapeutic response observed among patients is due to the individual differences in pharmacokinetics, rather than in pharmacodynamics.
Numerical cognition based on precise counting with a single spiking neuron
Authors: Rapp Hannes , Nawrot Martin Paul , Stern Merav
Published: June 2019

Insects are able to solve basic numerical cognition tasks. We show that estimation of numerosity can be realized and learned by a single spiking neuron with an appropriate synaptic plasticity rule. This model can be efficiently trained to detect arbitrary spatio-temporal spike patterns on a noisy and dynamic background with high precision and low variance. When put to test in a task that requires counting of visual concepts in a static image it required considerably less training epochs than a convolutional neural network to achieve equal performance. When mimicking a behavioral task in free flying bees that requires numerical cognition the model reaches a similar success rate in making correct decisions. We propose that using action potentials to represent basic numerical concepts with a single spiking neuron is beneficial for organisms with small brains and limited neuronal resources.
Probing apoptosis signaling proteins in single living cells for precision efficacy evaluation of anti-cancer drugs
Authors: Wen Yanrong , Liu Jia , He Hui , Liu Zhen
Published: June 2019

In vitro efficacy evaluation is critical for anti-cancer drug development and precision cancer treatment. Conventional methods, which mainly rely on cell viability and large cell populations, suffer from apparent disadvantages, such as signaling pathway-nonspecific, failing to reflect the real sensitivity of the patient, tedious and time-consuming. Herein, we present a new analytical tool, termed single-cell plasmonic immunosandwich assay (scPISA), for precision efficacy evaluation of anti-cancer drugs. It allows for facilely probing individual signaling proteins as well as protein-protein complexes in single living cells. Based on this approach, two apoptosis signaling proteins, cytochrome C (Cyt C) and caspase-3, were proposed as apoptosis indicators, while three new parameters were proposed as criteria for quantitative efficacy evaluation. Using two typical cytotoxic drugs, actinomycin D (Act D) and staurosporine (STS), as model drugs, the evaluation was found to be consistent among the indicators and parameters. Metformin, a potential anti-cancer drug, was then evaluated using this approach. Interestingly, metformin alone was found to be a less effective anti-cancer drug but its combination with Act D dramatically improved the overall efficacy. The scPISA approach exhibited several unique strengths over conventional assays, including comprehensive and self-consistent evaluation, signaling pathway-specific, simple procedure and high speed. Thus, it holds great promise for personalized drug screening and precision medicine.
Cellular and widefield imaging of sound frequency organization in primary and higher-order fields of the mouse auditory cortex
Authors: Romero Sandra , Hight Ariel E. , Clayton Kameron K. , Resnik Jennifer , Williamson Ross S. , Hancock Kenneth E , Polley Daniel B
Published: June 2019

The mouse auditory cortex (ACtx) contains two core fields – A1 and AAF – arranged in a mirror reversal tonotopic gradient. The best frequency (BF) organization and naming scheme for additional higher-order fields remain a matter of debate, as does the correspondence between smoothly varying global tonotopy and heterogeneity in local cellular tuning. Here, we performed chronic widefield and 2-photon calcium imaging from the ACtx of awake Thy1-GCaMP6s reporter mice. Data-driven parcellation of widefield maps identified five fields, including a previously unidentified area at the ventral posterior extreme of the ACtx (VPAF) and a tonotopically organized suprarhinal auditory field (SRAF) that extended laterally as far as ectorhinal cortex. Widefield maps were stable over time, where single pixel BFs fluctuated by less than 0.5 octaves during a one-month imaging period. After accounting for neuropil signal and frequency tuning strength, BF organization in neighboring layer 2/3 neurons was intermediate to the heterogeneous salt and pepper organization and the highly precise local organization that have each been described in prior studies. Multiscale imaging data suggest there is no ultrasonic field or secondary auditory cortex in the mouse. Instead, VPAF and a dorsoposterior field (DP) emerged as the strongest candidates for higher-order auditory areas.
Arbuscular mycorrhizal fungi, selenium, sulfur, silica-gel and biochar reduce arsenic uptake in plant biomass and improve nutritional quality inPisum sativum
Authors: Alam Mohammad Zahangeer , Hoque Md. Anamul , Ahammed Golam Jalal , Carpenter-Boggs Lynne
Published: June 2019

Arsenic (As) is a carcinogenic substance. It increased in crop grown in field soil from ground water irrigation. Subsequently As transport into the human body through food chains. The reduction of As transport in root, shoot and grain of pea genotypes is significantly important to protect human health. This research is focused on the biomass growth and alleviation of As accumulation in root, shoot and grain of pea genotypes in high As soil (30mgkg−1) amended with arbuscular mycorrhizal fungi (AMF), biochar (BC) of rice husk and saw dust, selenium (Se), silica- gel (Si), and sulfur (S). Shoot length, root, shoot and pod mass were generally higher in pea crops grown in soil amended with AMF, Se, Si- gel and S. Rice husk and saw dust BC less consistently increased some growth parameters, particularly in genotype BARI Motor 2. However, the BC’s more often reduced growth and pod mass. All treatments significantly reduced As concentration in tissues; As in grains was reduced on average 60% by any of the soil amendments. AMF, Se and Si- gel all were found more effective than BC for the reduction of As uptake in pea crops. As in grains was reduced 77% by AMF, 71% by Se and 69% by Si- gel on average. As in root, shoot, and grain was also affected by variety; in control treatments, total As uptake in plants pot−1of BARI Motor 1 and 3 was found 60 to 70% higher than BARI Motor 2. Comparing the variety and treatment with most As in grains (BARI Motor 1 control, 0.35 mg As kg−1) and least As in grains (BARI motor 1, 2 & 3 with AMF with 0.07 mg As kg−1), the choice of variety and soil amendment could reduce human intake of As through pea by 80%. It is recommended that choice of pea variety and soil amendment with AMF and Se have great potential for improving the nutritional quality of pea grown in As contaminated soil, as well as reducing As transfer to human bodies through food chains in pea crops.
Uveal Melanoma OncogeneCYSLTR2Encodes a Constitutively Active GPCR Highly Biased Toward Gq Signaling
Authors: Ceraudo Emilie , Horioka Mizuho , Mattheisen Jordan M. , Hitchman Tyler D. , Moore Amanda R. , Kazmi Manija A. , Chi Ping , Chen Yu , Sakmar Thomas P. , Huber Thomas
Published: June 2019

The G protein-coupled receptor (GPCR) cysteinyl-leukotriene receptor 2 (CysLTR2) with a single amino acid mutation at position 3.43 (Leu replaced with Gln at position 129 in transmembrane helix 3) causes uveal melanoma in humans. The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity. We show that CysLTR2-L129Q is a constitutively active mutant (CAM) that strongly drives Gq/11 signaling pathways in melan-a melanocytes and in HEK293T cells in culture. However, the mutant receptor only very weakly recruits beta-arrestins 1 and 2. The mutant receptor displays profound signaling bias while avoiding arrestin-mediated downregulation. The mechanism of the signaling bias results from the creation of a hydrogen-bond network that stabilizes the active G protein signaling state through novel interactions with the highly-conserved NPxxY motif on helix 7. Furthermore, the mutation destabilizes a putative allosteric sodium-binding site that usually stabilizes the inactive state of GPCRs. Thus, the mutation has a dual role of promoting the active state while destabilizing inactivating allosteric networks. The high degree of constitutive activity renders existing orthosteric antagonist ligands of CysLTR2 ineffective as inverse agonists of the mutant. CysLTR2 is the first example of a GPCR oncogene that encodes a GPCR with constitutive highly biased signaling that can escape cellular downregulation mechanisms.
Specialized NADPH diaphorase membrane-related localizations in the brainstem of the pigeons (Columba livia)
Authors: Jia Yunge , Huo Wei , Li Yinhua , Zhang Tianyi , Wang Xinghang , Wen Xiaoxin , Xu Ximeng , Sun Haoran , Wu Xianhui , Rao Chenxu , Wei Zichun , Zhai Zhenhua , Tan Huibing
Published: June 2019

NADPH diaphorase (N-d) is used to a histochemical identification of subgroup of neuronal cells. Beside regular intracellular N-d positivity, membrane-related positivity revealed as a specialized staining pattern in the pigeon brain stem. In the investigation of the nervous system of homing pigeons (Columba livia) with N-d staining, we found a specialized structure, which temporally was termed as N-d tubular glomerular body/structure or as T-J body related to the last name of authors. This N-d positive specialization constituted by tubular components bilaterally located in the medial to the lemniscus spinalis in the medulla oblongata. The tubular components were moderate staining. T-J body was a longitudinal oriented structure of 2400 μm with N-d staining. N-d positive tubular components were twisted and intermingled together. Beside the young adult pigeons, T-J body s were also consistently detected in the aged pigeons. Membrane-related staining were also detected in the other rostral nuclei in the brain stem. With discussion and review of related scientific literatures, T-J body was considered as a new anatomical structure or a new feature of the existent nucleus. In summary, beside N-d intracellular distribution, there were other three N-d membrane-related localizations: mini-aggregation, patch-aggregation, and arrangement along tubular unit.
The role of multilevel selection in host microbiome evolution
Authors: Vliet Simon van , Doebeli Michael
Published: June 2019

Animals are associated with a microbiome that can affect their reproductive success. It is therefore important to understand how a host and its microbiome coevolve. According to the hologenome concept, hosts and their microbiome form an integrated evolutionary entity, a holobiont, on which selection can potentially act directly. However, this view is controversial and there is an active debate on whether the association between hosts and their microbiomes is strong enough to allow for selection at the holobiont level. Much of this debate is based on verbal arguments, but a quantitative framework is needed to investigate the conditions under which selection can act at the holobiont level. Here we use multilevel selection theory to develop such a framework. We found that selection at the holobiont level can in principle favor a trait that is costly to the microbes but that provides a benefit to the host. However, such scenarios require rather stringent conditions. The degree to which microbiome composition is heritable decays with time, and selection can only act at the holobiont level when this decay is slow enough, which occurs when vertical transmission is stronger than horizontal transmission. Moreover, the host generation time has to be short enough compared to the timescale of the evolutionary dynamics at the microbe level. Our framework thus allows us to quantitatively predict for what kind of systems selection could act at the holobiont level.
EXOSC10 sculpts the transcriptome during the growth-to-maturation transition in mouse oocytes
Authors: Wu Di , Dean Jurrien
Published: June 2019

Growing mammalian oocytes accumulate substantial amounts of RNA, most of which is degraded during subsequent meiotic maturation. The growth-to-maturation transition begins with germinal vesicle or nuclear envelope breakdown (GVBD) and is critical for oocyte quality and early development. The molecular machinery responsible for the oocyte transcriptome transition remains unclear. Here, we report that an exosome-associated RNase, EXOSC10, sculpts the transcriptome to facilitate the growth-to-maturation transition of mouse oocytes. We establish an oocyte-specific conditional knockout ofExosc10in mice using CRISPR/Cas9 which results in female subfertility due to delayed GVBD. By performing multiple single oocyte RNA-seq, we document dysregulation of several types of RNA, and the mRNAs that encode proteins important for endomembrane trafficking and meiotic cell cycle. As expected, EXOSC10-depleted oocytes have impaired endomembrane components including endosomes, lysosomes, endoplasmic reticulum and Golgi. In addition, CDK1 fails to activate, possibly due to persistent WEE1 activity, which blocks lamina phosphorylation and disassembly. Moreover, we identified rRNA processing defects that cause higher percentage of developmentally incompetent oocytes after EXOSC10 depletion. Collectively, we propose that EXOSC10 promotes normal growth-to-maturation transition in mouse oocytes by sculpting the transcriptome to degrade RNAs encoding growth-phase factors and, thus, support the maturation phase of oogenesis.
Interferons drive development of novel interleukin-15-responsive macrophages
Authors: Gordon Scott M. , Nishiguchi Mailyn A. , Chase Julie M. , Mani Sneha , Mainigi Monica A. , Behrens Edward M.
Published: June 2019

Disruption in homeostasis of interleukin-15 (IL-15) is linked to poor maternal and fetal outcomes during pregnancy. The only cells described to respond to IL-15 at the early maternal-fetal interface have been natural killer (NK) cells. We now show a novel population of macrophages, evident in several organs but enriched in the uterus of mice and humans, expressing the β chain of the IL-15 receptor complex (CD122) and responding to IL-15. CD122+ macrophages (CD122+Macs) are morphologic, phenotypic, and transcriptomic macrophages that can derive from bone marrow monocytes. CD122+Macs develop in the uterus and placenta with kinetics that mirror interferon (IFN) activity at the maternal-fetal interface. Macrophage colony-stimulating factor (M-CSF) permits macrophages to express CD122, and IFNs are sufficient to drive expression of CD122 on macrophages. Neither Type-I nor Type-II IFNs are required to generate CD122+Macs, however. In response to IL-15, CD122+Macs activate the ERK signaling cascade and enhance production of proinflammatory cytokines after stimulation with the Toll-like receptor 9 agonist CpG. Finally, we provide evidence of human cells that phenocopy murine CD122+Macs in secretory phase endometrium during the implantation window and in first-trimester uterine decidua. Our data support a model wherein IFNs local to the maternal-fetal interface direct novel IL-15-responsive macrophages with the potential to mediate IL-15 signals critical for optimal outcomes of pregnancy.

The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE132353.
Estimation of immune cell content in tumor using single-cell RNA-seq reference data
Authors: Yu Xiaoqing , Chen Y. Ann , Conejo-Garcia Jose R. , Chung Christine H. , Wang Xuefeng
Published: June 2019

Background

The rapid development of single-cell RNA sequencing (scRNA-seq) provides unprecedented opportunities to study the tumor ecosystem that involves a heterogeneous mixture of cell types. However, the majority of previous and current studies related to translational and molecular oncology have only focused on the bulk tumor and there is a wealth of gene expression data accumulated with matched clinical outcomes.

Results

In this paper, we introduce a scheme for characterizing cell compositions from bulk tumor gene expression by integrating signatures learned from scRNA-seq data. We derived the reference expression matrix to each cell type based on cell subpopulations identified in head and neck cancer dataset. Our results suggest that scRNA-Req-derived reference matrix outperforms the existing gene panel and reference matrix with respect to distinguishing immune cell subtypes.

Conclusions

Findings and resources created from this study enable future and secondary analysis of tumor RNA mixtures in head and neck cancer for a more accurate cellular deconvolution, and can facilitate the profiling of the immune infiltration in other solid tumors due to the expression homogeneity observed in immune cells.
Environmental harshness is associated with lower investment in collective actions
Authors: Lettinga N. , Jacquet P.O. , André J-B. , Baumard N. , Chevallier C.
Published: June 2019

Although humans cooperate universally, there is variability across individuals, times and cultures in the amount of resources people invest in cooperative activities. The origins of such variability are not known but recent work highlights that variations in environmental harshness may play a key role. A growing body of experimental work in evolutionary psychology suggests that humans adapt to their specific environment by calibrating their life-history strategy. In this paper, we apply structural equation models to test the association between current and childhood environmental harshness, life-history strategy and adult cooperation in two large-scale datasets (the World Values Survey and the European Values Study). The present study replicates existing research linking a harsher environment (both in adulthood and in childhood) with a modulated reproduction-maintenance trade-off and extends these findings to the domain of collective actions. Specifically, we find that a harsher environment (both in adulthood and in childhood) is associated with decreased involvement in collective action and that this association is mediated by individuals’ life-history strategy.
Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants
Authors: Popp Bernt , Erber Ramona , Kraus Cornelia , Vasileiou Georgia , Hoyer Juliane , Burghaus Stefanie , Hartmann Arndt , Beckmann Matthias W. , Reis André , Agaimy Abbas
Published: June 2019

Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.

We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found a FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism.

By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7 - 13.9% of females with an FH deficient UL to carry a germline FH variant.

Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
ppGpp Ribosome Dimerization Model for Bacterial Persister Formation and Resuscitation
Authors: Song Sooyeon , Wood Thomas K.
Published: June 2019

Stress is ubiquitous for bacteria and converts a subpopulation of cells into a dormant state known as persistence, in which cells are tolerant to antimicrobials. These cells revive rapidly when the stress is removed and are likely the cause of many recurring infections such as those associated with tuberculosis, cystic fibrosis, and Lyme disease. However, how persister cells are formed is not understood well. Here we propose the ppGpp ribosome dimerization persister (PRDP) model in which the alarmone guanosine pentaphosphate/tetraphosphate (henceforth ppGpp) generates persister cells directly by inactivating ribosomes via the ribosome modulation factor (RMF) and the hibernation promoting factor (Hpf). We demonstrate both RMF and HpF increase persistence and reduce single-cell persister resuscitation and that ppGpp has no effect on single-cell persister resuscitation. Hence, a direct connection between ppGpp and persistence is shown.
An inducible Cre mouse line to sparsely target nervous system cells, including Remak Schwann cells
Authors: Sapkota Darshan , Dougherty Joseph D.
Published: June 2019

Nerves of the peripheral nervous system contain two classes of Schwann cells– myelinating Schwann cells that ensheath large caliber axons in myelin, and Remak Schwann cells that surround smaller axons and do not myelinate. While tools exist for genetic targeting of myelinating Schwann cells, such reagents have been challenging to generate for the Remak population in part because many of the genes that mark this population in maturity are also robustly expressed in progenitors of all Schwann cells. To circumvent this challenge, we utilized BAC transgenesis to generate a mouse line expressing a tamoxifen-inducible Cre under the control of a Remak-expressed gene promoter (Egr1). However, as Egr1 is also an activity dependent gene expressed by some neurons, we flanked this Cre by flippase (Flpe) recognition target sites, and coinjected a BAC expressing Flpe under control of a pan-neuronal Snap25 promoter, to excise the Cre transgene from these neuronal cells. Genotyping and inheritance demonstrate that the two BACs co-integrated into a single locus, facilitating maintenance of the line. Anatomical studies following a cross to a reporter line show sparse tamoxifen-dependent recombination in Remak Schwann cells within the mature sciatic nerve. However, depletion of neuronal Cre activity by Flpe is partial, with some neurons and astrocytes also showing evidence of Cre reporter activity in the central nervous system. Thus, this mouse line will be useful in mosaic loss-of-function studies, lineage tracing studies following injury, and live cell imaging studies or other experiment benefiting from sparse labeling.
NF-κB-c-REL impairment drives human stem cells into the oligodendroglial fate
Authors: Ruiz-Perera Lucia M , Greiner Johannes FW , Kaltschmidt Christian , Kaltschmidt Barbara
Published: June 2019

Molecular mechanisms underlying fate decisions of human neural stem cells (NSCs) between neurogenesis and gliogenesis are critical during neuronal development and progression of neurodegenerative diseases. Despite its crucial role in murine nervous system development, the potential role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in fate shifts of human stem cells is poorly understood.

Facing this challenge, we demonstrate here that NF-κB-c-REL drives glutamatergic differentiation of adult human stem cells, while its impairment results in a shift towards the oligodendroglial fate. We particularly observed an opposing balance switch from NF-κB-RELB/p52 to NF-κB-c-REL during early neuronal differentiation of NSCs originating from neural crest-derived stem cells. Exposure of differentiating human NSCs to the c-REL inhibiting approved drug pentoxifylline (PTXF) resulted in elevated levels of cell death and significantly decreased amounts of NF200+/VGLUT2+ neurons. PTXF-mediated inhibition of c-REL further drove human NSCs into the oligodendrocyte fate, as demonstrated by a complete switch to OLIG2+/O4+ oligodendrocytes, which also showed PDGFRα, NG2 and MBP transcripts.

In summary, we present here a novel human cellular model of neuronal differentiation with an essential role of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis potentially relevant for multiple sclerosis and schizophrenia.
Expression of nitric oxide synthase and nitric oxide levels in peripheral blood cells and oxidized low-density lipoprotein levels in saliva as early markers of severe dengue
Authors: Hapugaswatta Harsha , Wimalasekara Ruwani L. , Perera Suharshi S. , Premaratna Ranjan , Seneviratne Kapila N. , Jayathilaka Nimanthi
Published: June 2019

Background

Severe dengue (SD), experienced by only a fraction of dengue patients can be lethal. Due to lack of early markers that can predict the evolution of SD, all dengue patients have to be monitored under hospital care. We discovered early oxidative stress markers of SD to identify patients who can benefit from early intervention before the symptoms appear.

Methods

Expression of inducible nitric oxide synthase (iNOS) in peripheral blood cells (PBC), nitric oxide (NO) and oxidized low-density lipoprotein (oxLDL) levels in plasma and saliva collected at early stages of dengue infection from 20 non-severe dengue fever (DF) patients and 20 patients who later developed SD were analyzed in a retrospective nested case-control study.

Results

Expression of iNOS is significantly (P<0.05) lower in patients who developed SD than in DF patients at admission within 4 days from fever onset. Median plasma NO concentration within 4 days from fever onset is also significantly (P<0.05) lower in patients who developed SD (17.9±1.6 μM) than DF (23.0±2.1 μM). Median oxLDL levels in plasma within 3 days from fever onset is significantly (P<0.05) lower in patients who developed SD (509.4±224.1 ng/mL) than DF (740.0±300.0 ng/mL). Median salivary oxLDL levels are also significantly (P<0.05) lower in patients who developed SD (0.8±0.5 ng/mL) than DF (3.6±2.6 ng/mL) within 4 days from fever onset.

Conclusions

These findings suggest that the expression of iNOS (73% sensitivity, 86% specificity) and plasma NO (96% sensitivity, 61% specificity at 22.3 μM; P<0.05) may serve as early markers of SD within 3 days from fever onset. Salivary oxLDL levels may serve as early non-invasive markers of SD with a sensitivity and specificity respectively of 57% and 91% at 0.9 ng/mL, 76% and 55% at 2.3 ng/mL and 100% and 50% at 4.6 ng/mL; P<0.05) within 4 days from fever onset.
Sequence-based prediction of olfactory receptor responses
Authors: Chepurwar Shashank , Gupta Abhishek , Haddad Rafi , Gupta Nitin
Published: June 2019

Computational prediction of how strongly an olfactory receptor responds to various odors can help in bridging the widening gap between the large number of receptors that have been sequenced and the small number of experiments measuring their responses. Previous efforts in this area have predicted the responses of a receptor to some odors, using the known responses of the same receptor to other odors. Here we present a method to predict the responses of a receptor without any known responses, by using available data about the responses of other conspecific receptors and their sequences. We applied this method to olfactory receptors in insects Drosophila melanogaster (both adult and larva) and Anopheles gambiae, and to mouse and human olfactory receptors. We found the predictions to be in significant agreement with the experimental measurements. The method also provides clues about the response-determining positions within the receptor sequences.
Intra-individual variability of sleep and nocturnal cardiac autonomic activity in elite female soccer players during an international tournament
Authors: Costa Júlio A. , Figueiredo Pedro , Nakamura Fábio Y. , Rago Vincenzo , Rebelo António , Brito João
Published: June 2019

Purpose

This study provides insights into the individual sleep patterns and nocturnal cardiac autonomic activity responses of elite female soccer players during an international tournament.

Materials and methods

Twenty elite female soccer players (aged 25.2±3.1 years) wore wrist actigraph units and heart rate (HR) monitors during night-sleep throughout 9 consecutive days (6 day-time training sessions [DT], 2 day-time matches [DM], and 1 evening-time match [EM]) of an international tournament. Training and match loads were monitored using the session-rating of perceived exertion (s-RPE) and wearable 18-Hz GPS (total distance covered [TD], training and match exposure time, and high-speed running [HSR]) to characterize training and match loads.

Results

Individually, s-RPE, TD, exposure time, and HSR during training sessions ranged from 20 to 680 arbitrary units (AU), 892 to 5176 m, 20 to 76 min, and 80 to 1140 m, respectively. During matches, s-RPE, TD, exposure time, and HSR ranged from 149 to 876 AU, 2236 to 11210 m, 20 to 98 min, and 629 to 3213 m, respectively. Individually, players slept less than recommended (<7 hours) on several days of the tournament, especially after EM (n=8; TST ranging between 6:00-6:54 h). Total sleep time coefficient of variation (CV) ranged between 3.1 and 18.7%. However, all players presented good sleep quality (i.e., sleep efficiency ≥75%; individual range between: 75-98%) on each day of the tournament. Most of the players presented small fluctuations in nocturnal cardiac autonomic activity (individual nocturnal heart rate variability [HRV] ranged from 3.91-5.37 ms and HRV CV ranged from 2.8-9.0%), while two players presented higher HRV CV (11.5 and 11.7%; respectively).

Conclusion

Overall, elite female soccer players seemed to be highly resilient to training and match schedules and loads during a 9 day international tournament.
Does holistic cognition frame always promote business model design?
Authors: Wu Yong , Zhang Linqian , Wei Zelong , Hou Mingjun
Published: June 2019

Purpose

This paper aims to explore the effects of holistic cognition frame on novelty-centered business model design and efficiency-centered business model design. Moreover, the authors consider how these effects differ in new ventures vs established firms.

Design/methodology/approach

The authors use survey data to testify the hypotheses based on a database of 204 firms in China. Then, regression analysis is used to examine the relationship between holistic cognition frame and business model design. They also explore the contingency effects of new ventures and established firms on the relationships.

Findings

The authors find that the holistic cognition frame has a positive effect on efficiency-centered business model design, whereas it has an inverse U-shaped effect on novelty-centered business model design. Furthermore, they find that the effects of holistic cognition frame on efficiency-centered business model design and novelty-centered business model design are different in established firms and new ventures.

Originality/value

This work offers new insights into the effects of holistic cognition frame on business model design and provides useful suggestions for firms to promote business model design.
Head motion coefficient-based algorithm for distracted driving detection
Authors: Chui Kwok Tai , Alhalabi Wadee , Liu Ryan Wen
Published: June 2019

Purpose

Concentration is the key to safer driving. Ideally, drivers should focus mainly on front views and side mirrors. Typical distractions are eating, drinking, cell phone use, using and searching things in car as well as looking at something outside the car. In this paper, distracted driving detection algorithm is targeting on nine scenarios nodding, head shaking, moving the head 45° to upper left and back to position, moving the head 45° to lower left and back to position, moving the head 45° to upper right and back to position, moving the head 45° to lower right and back to position, moving the head upward and back to position, head dropping down and blinking as fundamental elements for distracted events. The purpose of this paper is preliminary study these scenarios for the ideal distraction detection, the exact type of distraction.

Design/methodology/approach

The system consists of distraction detection module that processes video stream and compute motion coefficient to reinforce identification of distraction conditions of drivers. Motion coefficient of the video frames is computed which follows by the spike detection via statistical filtering.

Findings

The accuracy of head motion analyzer is given as 98.6 percent. With such satisfactory result, it is concluded that the distraction detection using light computation power algorithm is an appropriate direction and further work could be devoted on more scenarios as well as background light intensity and resolution of video frames.

Originality/value

The system aimed at detecting the distraction of the public transport driver. By providing instant response and timely warning, it can lower the road traffic accidents and casualties due to poor physical conditions. A low latency and lightweight head motion detector has been developed for online driver awareness monitoring.