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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

The RNA-binding protein AATF coordinates rRNA maturation

AATF is a central regulator of the cellular outcome upon p53 activation, a finding that has primarily been attributed to its function as a transcription factor. Recent data showed that AATF is essential for ribosome biogenesis and plays a role in rRNA maturation. AATF has been implicated to fulfil this role through direct interaction with rRNA and was identified in several RNA-interactome capture experiments. Here, we provide a first comprehensive analysis of the RNA bound by AATF using CLIP-sequencing. Interestingly, this approach shows predominant binding of the 45S pre-ribosomal RNA precursor molecules. Furthermore, AATF binds to mRNAs encoding for ribosome biogenesis factors as well as snoRNAs. These findings are complemented by an in-depth analysis of the protein interactome of AATF containing a large set of proteins known to play a role in rRNA maturation with an emphasis on the protein-RNA-complexes known to be required for the generation of the small ribosomal subunit (SSU). In line with this finding, the binding sites of AATF within the 45S rRNA precursor localize in close proximity to the SSU cleavage sites. Consequently, our multilayer analysis of the protein-RNA interactome of AATF reveals this protein to be an important hub for protein and RNA interactions involved in ribosome biogenesis.

molecular biology↗
bioRxiv2018

Survival cost to relocation does not reduce population self-sustainability in an amphibian

O_LIRelocations are increasingly popular among wildlife managers despite sharp debate and low rate of relocation success in vertebrates. In this context, understanding the influence of extrinsic (e.g., relocation design, habitat characteristics) and intrinsic factors (e.g., age and sex) on demographic parameters such as survival that regulate the dynamics of relocated populations is critical to improve relocation protocols and better predict relocation success.\nC_LIO_LIWe investigated survival in naturally established and relocated populations of yellow-bellied toads (Bombina variegata), an amphibian that was nearly extinct in Belgium by the late 1990s. We quantified survival at three ontogenetic stages (juvenile, subadult, and adult) in the relocated population, the source population, and a control population. In the relocated population, we quantified survival in captive bred individuals and their locally born descendants.\nC_LIO_LIWe showed that survival at juvenile and subadult stages was relatively similar in all populations. In contrast, relocated adult survival was lower than adult survival in the source and control populations. Despite this, offspring of relocated animals (the next generation, regardless of life stage) survived at similar rates to offspring in the source and control populations. Our simulations revealed that the relocated population was self-sustaining under different scenarios and that the fate (e.g., stability or finite rate of increase) of the simulated populations was highly dependent on the fecundity of relocated adults and their offspring.\nC_LIO_LIPolicy implications. Our results indicate that survival in relocated individuals is lower than in non-relocated individuals but that this cost (= reduced survival) disappears in the second generation. A finer understanding of how relocation affects demographic processes is an important step in improving relocation success of amphibians and other animals.\nC_LI

ecology↗
bioRxiv2018

Efficient and reproducible somatic embryogenesis and micro propagation in tomato via novel structures -Rhizoid Tubers.

An improved and highly reproducible system for invitro regeneration via somatic embryogenesis (S.E), applicable to several varieties of tomato (cv. Riogrande, cv. Roma grande, hybrid 17905 and model cv. M82) has been developed. First, we developed a conventional indirect organogenesis for all four varieties used in this study. The cotyledons and hypocotyls of 6-day-old tomato were used as explants (1-2 cm) for callus induction (CI) on different callus induction media (CIM) T0 - T12 (6-Benzylaminopurine BAP, NAA Naphthalene acetic acid, ZEA Zeatin, IAA Indole-3-acetic acid, KIN Kinetin). Maximum CI response was seen on CIMT6 (0.5 mg/L NAA, 1 mg/L BAP) and CIMT7 (2 mg/L IAA, 2 mg/L NAA, 2 mg/L BAP, 4mg/L KIN) in a period of 2 weeks for commercial varieties cvs. Riogrande and Roma. However, cv. M82 responded after 4 weeks to a combination of treatments [CIMT6 (0.5 mg/L NAA + 1 mg/L BAP) and CIMT8 (2 mg/L IAA + 2 mg/L NAA + 2 mg/L BAP + 4 mg/L ZEA)] for the production of calli. The Riogrande, being the most responsive commercial variety, was selected for invitro morphogenesis via S.E. During S.E. young cotyledons and hypocotyls explants were tested on media with different ranges of pH (3 - 7) supplemented with 0.5 and 2 mg/L NAA. Resultantly, numerous rhizoids (~38) were produced from each explant at pH4 in dark conditions. Further incubation of each rhizoid under light conditions led to the formation of a novel structure - rhizoid tubers (RTBs) on MS media supplemented with 5 mg/L TDZ/BAP at pH4. We observed that only lower pH-induced rhizoids and RTBs regenerated into multiple individual shoots on media at normal pH (5.8). The RTBs led to a complete plantlets regeneration in 45 days compared to the conventional invitro morphogenesis (60 days).

plant biology↗
bioRxiv2018

Nitrogen addition has minimal effect in Wyoming big sagebrush (Artemisia tridentata) communities

Nitrogen additions are known to elicit variable responses in semi-arid ecosystems, with responses increasing with precipitation. The response of semi-arid ecosystems to nitrogen are important to understand due to their large spatial extent worldwide and the global trend of increasingly available nitrogen. In this study, we evaluated the impact of a single nitrogen addition pulse on a semi-arid big sagebrush (Artemisia tridentata) ecosystem in western Wyoming. This is important given that sagebrush ecosystems are poorly understood, despite their prevalence in the western US. In addition, large-scale nitrogen additions have begun on sagebrush landscapes in Wyoming in order to mitigate population declines in mule deer (Odocoileus hemionus). The study objectives were (1) to evaluate the effectiveness of a nitrogen fertilization pulse in increasing sagebrush biomass and forage quality, and (2) to assess effects of nitrogen addition on soil biogeochemistry and vegetation community structure. We fertilized 15 plots across 5 locations in western Wyoming using a single pulse of urea (5.5g N m-2). In addition, we immobilized available nitrogen through surface hay treatments (250g hay/m2). Nitrogen additions failed to increase growth of sagebrush, alter nitrogen content of sagebrush leaders, or alter greenhouse gas efflux from soils. The plant community also remained unchanged; total cover, species richness, and community composition were all unaffected by our treatment application. Over the two years of this study, we did not find indications of nitrogen limitation of ecosystem processes, despite a wet growing season in 2014. Thus, we have found a general lack of response to nitrogen in sagebrush ecosystems and no treatment effect of a single pulse of N to sagebrush biomass or forage quality.

ecology↗
bioRxiv2018

The triangle of ageing: a model of how repair, resilience to damage and asymmetric segregation are responses to replicative ageing

Accumulation of damaged proteins is a hallmark of ageing, occurring in organisms ranging from bacteria and yeast to mammalian cells. During cell division in Saccharomyces cerevisiae, damaged proteins are retained within the mother cell, resulting in a new daughter cell with full replicative potential and an ageing mother with a reduced replicative lifespan (RLS). The cell-specific features determining the lifespan remain elusive. It has been suggested that the RLS is dependent on the ability of the cell to repair and retain pre-existing damage. To deepen the understanding of how these factors influence the life span of individual cells, we developed and experimentally validated a dynamic model of damage accumulation accounting for replicative ageing. The model includes five essential properties: cell growth, damage formation, damage repair, cell division and cell death, represented in a theoretical framework describing the conditions allowing for replicative ageing, starvation, immortality or clonal senescence. We introduce the resilience to damage, which can be interpreted as the difference in volume between an old and a young cell. We show that the capacity to retain damage deteriorates with high age, that asymmetric division allows for retention of damage, and that there is a trade-off between retention and the resilience property. Finally, we derive the maximal degree of asymmetry as a function of resilience, proposing that asymmetric cell division is beneficial with respect to replicative ageing as it increases the RLS of a given organism. The proposed model contributes to a deeper understanding of the ageing process in eukaryotic organisms.

systems biology↗
bioRxiv2018

Transcriptional responses of Biomphalaria pfeifferi and Schistosoma mansoni following exposure to niclosamide, with evidence for a synergistic effect on snails following exposure to both stressors

BackgroundSchistosomiasis is one of the worlds most common NTDs. Successful control operations often target snail vectors with the molluscicide niclosamide. Little is known about how niclosamide affects snails, including for Biomphalaria pfeifferi, the most important vector for Schistosoma mansoni in Africa. We used Illumina technology to explore how field-derived B. pfeifferi, either uninfected or harboring cercariae-producing S. mansoni sporocysts, respond to a sublethal exposure of niclosamide. This study afforded the opportunity to determine if snails respond differently to biotic or abiotic stressors, and if they reserve unique responses for when presented with both stressors in combination. We also examined how sporocysts respond when their snail host is exposed to niclosamide.\n\nPrincipal FindingsCercariae-producing sporocysts within snails exposed to niclosamide express ~68% of the genes in the S. mansoni genome, as compared to 66% expressed by intramolluscan stages of S. mansoni in snails not exposed to niclosamide. Niclosamide does not disable sporocysts nor does it seem to provoke from them distinctive responses associated with detoxifying a xenobiotic. For B. pfeifferi, niclosamide treatment alone increases expression of several features not up-regulated in infected snails including particular cytochrome p450s and heat shock proteins, glutathione-S-transferases, antimicrobial factors like LBP/BPI and protease inhibitors, and also provokes strong down regulation of proteases. Exposure of infected snails to niclosamide resulted in numerous up-regulated responses associated with apoptosis along with down-regulated ribosomal and defense functions, indicative of a distinctive, compromised state not achieved with either stimulus alone.\n\nConclusions/SignificanceThis study helps define the transcriptomic responses of an important and under-studied schistosome vector to S. mansoni sporocysts, to niclosamide, and to both in combination. It suggests the response of S. mansoni sporocysts to niclosamide is minimal and not reflective of a distinct repertoire of genes to handle xenobiotics while in the snail host. It also offers new insights for how niclosamide affects snails.\n\nAuthorS SummarySchistosomaisis control programs often employ the use of chemical molluscicides, such as niclosamide, to control the obligatory intermediate snail hosts. Despite its widespread use, we know little about how niclosamide affects snails like Biomphalaria pfeifferi, the most important vector Schistosoma mansoni in Africa. By sequencing the transcriptomes of uninfected and S. mansoni-infected B. pfeifferi exposed to niclosamide, we analyze the snails response to both biotic and abiotic stressors. We can also examine the response of S. mansoni to niclosamide exposure during intramolluscan development. Biomphalaria pfeifferi snails exposed only to niclosamide showed unique up-regulation of stress and defense-related transcripts not seen in snails infected with a biotic, like S. mansoni infection, alone. Schistosoma mansoni-infected B. pfeifferi exposed to niclosamide were clearly unable to regulate normal metabolic and detoxification processes. Cercariae-producing sporocysts within snails exposed to niclosamide are largely unaffected and continue to produce transcripts required for cercariae production.

molecular biology↗
bioRxiv2018

Research challenges in Africa - an exploratory study on the experiences and opinions of African researchers

BackgroundInsufficient research is a major impediment to growth, development and advancement of health in Africa. Africa produces less than 1% of global research output. Meanwhile, African countries face some of the toughest challenges worldwide, most of which can only be tackled through robust and efficient research. Addressing the barriers to conducting research in Africa is a step towards improving research capacity and output. This study aimed to identify the key challenges affecting research practice and output in Africa; and to highlight priority areas for improvement.\n\nMethodsA cross-sectional survey was administered through an online questionnaire, including participants from six countries in Sub-Saharan Africa. Participants included research professionals, research students, research groups and academics.\n\nResultsA total of 424 participants responded to this survey. The ability to conduct and produce high-quality research was seen to be influenced by multiple factors, most of which were related to the research environment in African countries. Priority areas for improvement included providing more training, raising awareness on the importance of research in Africa, encouraging governments to commit to research and increasing collaboration between researchers in Africa.\n\nConclusionThe conditions under which research is done in Africa are severely flawed and do not encourage engagement in research, or continuity of research activity. African governments need to develop initiatives that accelerate and support research and research-based education in Africa, in order to build a solid foundation for research, increase research capacity, and enable institutions to provide valuable training and develop sustainable research opportunities in Africa.

scientific communication and education↗
bioRxiv2018

A small proportion of Talin molecules transmit forces to achieve muscle attachment in vivo

Cells in a developing organism are subjected to particular mechanical forces, which shape tissues and instruct cell fate decisions. How these forces are sensed and transmitted at the molecular level is thus an important question, which has mainly been investigated in cultured cells in vitro. Here, we elucidate how mechanical forces are transmitted in an intact organism. We studied Drosophila muscle attachment sites, which experience high mechanical forces during development and require integrin-mediated adhesion for stable attachment to tendons. Hence, we quantified molecular forces across the essential integrin-binding protein Talin, which links integrin to the actin cytoskeleton. Generating flies expressing three FRET-based Talin tension sensors reporting different force levels between 1 and 11 pN enabled us to quantify physiologically-relevant, molecular forces. By measuring primary Drosophila muscle cells, we demonstrate that Drosophila Talin experiences mechanical forces in cell culture that are similar to those previously reported for Talin in mammalian cell lines. However, in vivo force measurements at developing flight muscle attachment sites revealed that average forces across Talin are comparatively low and decrease even further while attachments mature and tissue-level tension increases. Concomitantly, Talin concentration at attachment sites increases five-fold as quantified by fluorescence correlation spectroscopy, suggesting that only few Talin molecules are mechanically engaged at any given time. We therefore propose that high tissue forces are shared amongst a large excess of adhesion molecules of which less than 15% are experiencing detectable forces at the same time. Our findings define an important new concept of how cells can adapt to changes in tissue mechanics to prevent mechanical failure in vivo.

developmental biology↗
bioRxiv2018

CRISPR-Cas9 Screens Reveal Genes Regulating a G0-like State in Human Neural Progenitors

Single cell RNA-seq has emerged as a powerful tool for resolving cellular states associated with normal and maligned developmental processes. Here, we used scRNA-seq to examine the cell cycle states of expanding human neural stem cells (hNSCs). From this data, we created a cell cycle classifier, which, in addition to traditional cell cycle phases, also identifies a putative quiescent-like state in neuroepithelial-derived cell types during mammalian neurogenesis and in gliomas. This state, Neural G0, is enriched for expression of quiescent NSC genes and other neurodevelopmental markers found in non-dividing neural progenitors. For gliomas, Neural G0 cell populations and gene expression is significantly associated with less aggressive tumors and extended patient survival. Genetic screens to identify modulators of Neural G0 revealed that knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down regulation of quiescence-associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 represents a dynamic quiescent-like state found in neuro-epithelial derived cells and gliomas.

cell biology↗
bioRxiv2018

New Classification of Intrinsic Disorder in the Human Proteome

We propose a new, sequence-only, classification of intrinsically disordered human proteins which is based on two parameters: dr, the percentage of disordered residues, and Ld, the length of the longest disordered segment in the sequence. Depending on dr and Ld, we distinguish five variants: i) ordered proteins (ORDs); ii) not disordered proteins (NDPsj; (iii) proteins with intrinsically disordered regions (PDRs); iv) intrinsically disordered proteins (IDPs) and v) proteins with fragmented disorder (FRAGs). PDRs have been considered in the general category of intrinsically disordered proteins for a long time. We show that PDRs are closer to globular, ordered proteins (ORDs and NDPs) than to disordered ones (IDPs), both in amino acid composition and functionally. Moreover, NDPs and PDRs are uniformly spread over several functional protein classes, whereas IDPs are concentrated only on two, namely nucleic acid binding proteins and transcription factors, which are just a subset of the functions that are commonly associated with protein intrinsic disorder. As a conclusion, PDRs and IDPs should be considered, in future classifications, as distinct variants of disordered proteins, with different physical-chemical properties and functional spectra.

bioinformatics↗
bioRxiv2018

DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

One of the hallmarks of cancer is the existence of a high mutational load in driver genes, which is balanced by upregulation (downregulation) of DNA repair pathways, since almost complete DNA repair is required for mitosis. The prediction of cancer survival with gene expression has been investigated by many groups, however, results of a comprehensive re-evaluation of the original data adjusted by the PCNA metagene indicate that only a small proportion of genes are truly predictive of survival. However, little is known regarding the effect of the PCNA metagene on survival prediction specifically by DNA repair genes. We investigated prediction of overall survival (OS) in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Pathway activation analysis indicates that in the presence of dysfunctional driver genes, the initial damage signaling and minor single-gene repair mechanisms may be abrogated, but with later pathway genes fully activated and intact. Neither PARP1 or PARP2 were significant predictors of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic set of cancers warranting further study are AML, colorectal, and renal papillary, because of their lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer to study is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications, suggesting that DNA repair pathway activation in AML is intact and unaltered genomically. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.\n\nAuthor summaryThe proliferating cell nuclear antigen (PCNA) protein is a homotrimer and activator of polymerase{delta} , which encircles DNA during transcription to recruit other proteins involved in replication and repair. In tumor cells, expression of PCNA is highly upregulated; however, PCNA-related activity is a normal process for DNA transcription in eukaryotes and therefore is not considered to play a central role in the selective genetic pressure associated with tumor development. Since PCNA is widely co-regulated with other genes in normal tissues, we developed workflow involving several functional transforms and regression models to \"remove\" the co-regulatory effect of PCNA on expression of DNA repair genes, and predicted overall cancer survival using DNA repair gene expression with and without removal of the PCNA effect. Other adjustments to survival prediction were employed, such as subject age at diagnosis and tumor stage. Random selection of gene sets was also employed for empirical p-value testing to determine the strength of the PCNA effect on DNA repair and overall survival adjustments. Since TCGA RNA-Seq data were used, we also characterized the frequency of deletions, amplifications, and somatic mutations in the DNA repair genes considered in order to observe which genomic events are the most frequent for the cancers evaluated.

bioinformatics↗
bioRxiv2018

A new universal pore measurement and clustering approach for surgical meshes

The pore structure and pore size is a crucial characteristic of surgical meshes. A huge amount of different approaches for mesh classification based on pore size or materials are available. It is difficult to use these classification methods because of the large variety in knitting structures and pore shapes. No agreement on an established method to measure the pore size is available despite the fact that the surgical community agrees that pore size and geometry are crucial factors for the result of a hernia repair. In this publication a new approach to characterize meshes based on their pore shape and pore size is presented. The pore size is defined by the largest inscribed circle within a mesh pore and the smallest circumscribed circle outside the pore, in addition to hence calculated values. This allows a characterization with regards to tissue ingrowth and bridging behavior. The measurements are made using the scientific image processing software ImageJ and additional customized software plug-in. Since the program ImageJ is public domain and the plug-ins are available, the measurements can be reproduced. Furthermore, the presented pore descriptions can also be used for manual pore size verification.

bioengineering↗
bioRxiv2018

Reverse GWAS: Using Genetics to Identify and Model Phenotypic Subtypes

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automatic statistical approaches to subtype definition particularly valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a bespoke decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show these features can be crucial for power and calibration. We validate RGWAS in practice by recovering known stress subtypes in major depressive disorder. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests genetic heterogeneity may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting potential have potential translational value.\n\nAuthor summaryComplex diseases depend on interactions between many known and unknown genetic and environmental factors. However, most studies aggregate these strata and test for associations on average across samples, though biological factors and medical interventions can have dramatically different effects on different people. Further, more-sophisticated models are often infeasible because relevant sources of heterogeneity are not generally known a priori. We introduce Reverse GWAS to simultaneously split samples into homogeneoues subtypes and to learn differences in genetic or treatment effects between subtypes. Unlike existing approaches to computational subtype identification using high-dimensional trait data, RGWAS accounts for covariates, binary disease traits and, especially, population structure; these features are each invaluable in extensive simulations. We validate RGWAS by recovering known genetic subtypes of major depression. We demonstrate RGWAS is practically useful in a metabolic study, finding three novel subtypes with both SNP- and polygenic-level heterogeneity. Importantly, RGWAS can uncover differential treatment response: for example, we show that statin, a common drug and potential type 2 diabetes risk factor, may have opposing subtype-specific effects on blood glucose.

genetics↗
bioRxiv2018

Murine MPDZ-Linked Hydrocephalus is Caused by Hyperpermeability of the Choroid Plexus

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straight-forward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

neuroscience↗
bioRxiv2018

Functional Morphology of Endurance Swimming Performance and Gait Transition Strategies in Balistoid Fishes

Triggerfishes and filefishes (Balistoidea) use balistiform locomotion to power slow steady swimming with their dorsal and anal fins and transition to a gait dominated by body and caudal fin (BCF) kinematics at high speeds. Fin and body shapes are predicted to be strong determinants of swimming performance and the biomechanics of gait transitions. The goal of this study was to combine morphometrics and critical swimming tests to explore relationships between balistoid fin and body shapes and swimming performance in a phylogenetic context in order to understand the evolution and diversification of the balistiform swimming mode. Among the 13 species of balistoid fishes examined, fishes with high aspect ratio fins tended to achieve higher critical swimming speeds than fishes with low aspect ratio fins. Species with long, large median fins and wide caudal peduncles tended to use the balistiform gait alone for a larger percentage of their total critical swimming speed than fishes with short, small median fins and narrow caudal peduncles. Fishes on both ends of the aspect ratio spectrum achieved higher swimming speeds using the balistiform gait alone than fishes with median fins of intermediate aspect ratios. Each species is specialized for taking advantage of one gait, with balistiform specialists possessing long, large median fins capable of the large power requirements of swimming at high speeds using the median fins alone, while BCF specialists possess short, small median fins, ill-suited for powering high-speed balistiform locomotion, but narrow caudal peduncles capable of efficient caudal fin oscillations to power high-speed locomotion.\n\nSummary StatementGeometric morphometrics reveal that fin and body shapes are good predictors of endurance swimming performance and gait transition strategies of triggerfishes and filefishes.

evolutionary biology↗
bioRxiv2018

Cytoneme-mediated signaling essential for tumorigenesis

Communication between neoplastic cells and cells of their microenvironment is critical to cancer progression. To investigate the role of cytoneme-mediated signaling as a mechanism for distributing growth factor signaling proteins between tumor and tumor-associated cells, we analyzed EGFR and RET Drosophila tumor models. We tested several genetic loss-of-function conditions that impair cytoneme-mediated signaling. diaphanous, Neuroglian, SCAR, capricious are genes that cytonemes require during normal development. Genetic inhibition of cytonemes restored apical basal polarity to tumor cells, reduced tumor growth, and increased organism survival. These findings suggest that cytonemes traffic the signaling proteins that move between tumor and stromal cells, and that cytoneme-mediated signaling is required for tumor growth and malignancy.\n\nSummaryEssential cytonemes for paracrine signaling in Drosophila tumors

cancer biology↗
bioRxiv2018

A new causality measure

Let there are n i.i.d observations, each producing a two tuple of real values (xi, yi), i [isin] {1,......, n} giving rise to random variables X = (x1,..., xn) and Y = (y1,..., yn). What is the statistical significance of the hypothesis that an increase in the independent variable X is causing an increase (or decrease) to the dependent variable Y ?

bioengineering↗
bioRxiv2018

An Analysis of Decision Under Risk in Rats

Prospect Theory is the predominant behavioral economic theory describing decision-making under risk. It accounts for near universal aspects of human choice behavior whose prevalence may reflect fundamental neural mechanisms. We now apply Prospect Theorys framework to rodents, using a task in which rats chose between guaranteed and probabilistic rewards. Like humans, rats distorted probabilities and showed diminishing marginal sensitivity, in which they were less sensitive to differences in larger rewards. They exhibited reference dependence, in which the valence of outcomes (gain or loss) was determined by an internal reference point reflecting reward history. The similarities between rats and humans suggest conserved neural substrates, and enable application of powerful molecular/circuit tools to study mechanisms of psychological phenomena from behavioral economics.

neuroscience↗