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Preview: PLoS Biology: New Articles

PLOS Biology: New Articles

A Peer-Reviewed Open-Access Journal

Updated: 2017-12-11T02:23:20Z


(XML) The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity


by Rukeia El-Athman, Nikolai N. Genov, Jeannine Mazuch, Kaiyang Zhang, Yong Yu, Luise Fuhr, Mónica Abreu, Yin Li, Thomas Wallach, Achim Kramer, Clemens A. Schmitt, Angela Relógio

The mammalian circadian clock and the cell cycle are two major biological oscillators whose coupling influences cell fate decisions. In the present study, we use a model-driven experimental approach to investigate the interplay between clock and cell cycle components and the dysregulatory effects of RAS on this coupled system. In particular, we focus on the Ink4a/Arf locus as one of the bridging clock-cell cycle elements. Upon perturbations by the rat sarcoma viral oncogene (RAS), differential effects on the circadian phenotype were observed in wild-type and Ink4a/Arf knock-out mouse embryonic fibroblasts (MEFs), which could be reproduced by our modelling simulations and correlated with opposing cell cycle fate decisions. Interestingly, the observed changes can be attributed to in silico phase shifts in the expression of core-clock elements. A genome-wide analysis revealed a set of differentially expressed genes that form an intricate network with the circadian system with enriched pathways involved in opposing cell cycle phenotypes. In addition, a machine learning approach complemented by cell cycle analysis classified the observed cell cycle fate decisions as dependent on Ink4a/Arf and the oncogene RAS and highlighted a putative fine-tuning role of Bmal1 as an elicitor of such processes, ultimately resulting in increased cell proliferation in the Ink4a/Arf knock-out scenario. This indicates that the dysregulation of the core-clock might work as an enhancer of RAS-mediated regulation of the cell cycle. Our combined in silico and in vitro approach highlights the important role of the circadian clock as an Ink4a/Arf-dependent modulator of oncogene-induced cell fate decisions, reinforcing its function as a tumour-suppressor and the close interplay between the clock and the cell cycle network.(image)

(XML) Slam protein dictates subcellular localization and translation of its own mRNA


by Shuling Yan, Sreemukta Acharya, Stephanie Gröning, Jörg Großhans

Many mRNAs specifically localize within the cytoplasm and are present in RNA-protein complexes. It is generally assumed that localization and complex formation of these RNAs are controlled by trans-acting proteins encoded by genes different than the RNAs themselves. Here, we analyze slow as molasses (slam) mRNA that prominently colocalizes with its encoded protein at the basal cortical compartment during cellularization. The functional implications of this striking colocalization have been unknown. Here, we show that slam mRNA translation is spatiotemporally controlled. We found that translation was largely restricted to the onset of cellularization when Slam protein levels at the basal domain sharply increase. Slam mRNA was translated locally, at least partially, as not yet translated mRNA transiently accumulated at the basal region. Slam RNA accumulated at the basal domain only if Slam protein was present. Furthermore, a slam RNA with impaired localization but full coding capacity was only weakly translated. We detected a biochemical interaction of slam mRNA and protein as demonstrated by specific co-immunoprecipitation from embryonic lysate. The intimate relationship of slam mRNA and protein may constitute a positive feedback loop that facilitates and controls timely and rapid accumulation of Slam protein at the prospective basal region.(image)

(XML) Task relevance modulates the behavioural and neural effects of sensory predictions


by Ryszard Auksztulewicz, Karl J. Friston, Anna C. Nobre

The brain is thought to generate internal predictions to optimize behaviour. However, it is unclear whether predictions signalling is an automatic brain function or depends on task demands. Here, we manipulated the spatial/temporal predictability of visual targets, and the relevance of spatial/temporal information provided by auditory cues. We used magnetoencephalography (MEG) to measure participants’ brain activity during task performance. Task relevance modulated the influence of predictions on behaviour: spatial/temporal predictability improved spatial/temporal discrimination accuracy, but not vice versa. To explain these effects, we used behavioural responses to estimate subjective predictions under an ideal-observer model. Model-based time-series of predictions and prediction errors (PEs) were associated with dissociable neural responses: predictions correlated with cue-induced beta-band activity in auditory regions and alpha-band activity in visual regions, while stimulus-bound PEs correlated with gamma-band activity in posterior regions. Crucially, task relevance modulated these spectral correlates, suggesting that current goals influence PE and prediction signalling.(image)

(XML) Sonic Kayaks: Environmental monitoring and experimental music by citizens


by Amber G. F. Griffiths, Kirsty M. Kemp, Kaffe Matthews, Joanne K. Garrett, David J. Griffiths

The Sonic Kayak is a musical instrument used to investigate nature and developed during open hacklab events. The kayaks are rigged with underwater environmental sensors, which allow paddlers to hear real-time water temperature sonifications and underwater sounds, generating live music from the marine world. Sensor data is also logged every second with location, time and date, which allows for fine-scale mapping of water temperatures and underwater noise that was previously unattainable using standard research equipment. The system can be used as a citizen science data collection device, research equipment for professional scientists, or a sound art installation in its own right.(image)

(XML) Perceptual integration rapidly activates dorsal visual pathway to guide local processing in early visual areas


by Ling Liu, Fan Wang, Ke Zhou, Nai Ding, Huan Luo

Rapidly grouping local elements into an organized object (i.e., perceptual integration) is a fundamental yet challenging task, especially in noisy contexts. Previous studies demonstrate that ventral visual pathway, which is widely known to mediate object recognition, engages in the process by conveying object-level information processed in high-level areas to modulate low-level sensory areas. Meanwhile, recent evidence suggests that the dorsal visual pathway, which is not typically attributable to object recognition, is also involved in the process. However, the underlying whole-brain fine spatiotemporal neuronal dynamics remains unknown. Here we used magnetoencephalography (MEG) recordings in combination with a temporal response function (TRF) approach to dissociate the time-resolved neuronal response that specifically tracks the perceptual grouping course. We demonstrate that perceptual integration initiates robust and rapid responses along the dorsal visual pathway in a reversed hierarchical manner, faster than the ventral pathway. Specifically, the anterior intraparietal sulcus (IPS) responds first (i.e., within 100 ms), followed by activities backpropagating along the dorsal pathway to early visual areas (EVAs). The IPS activity causally modulates the EVA response, even when the global form information is task-irrelevant. The IPS-to-EVA response profile fails to appear when the global form could not be perceived. Our results support the crucial function of the dorsal visual pathway in perceptual integration, by quickly extracting a coarse global template (i.e., an initial object representation) within first 100 ms to guide subsequent local sensory processing so that the ambiguities in the visual inputs can be efficiently resolved.(image)

(XML) Evaluation of RNAi and CRISPR technologies by large-scale gene expression profiling in the Connectivity Map


by Ian Smith, Peyton G. Greenside, Ted Natoli, David L. Lahr, David Wadden, Itay Tirosh, Rajiv Narayan, David E. Root, Todd R. Golub, Aravind Subramanian, John G. Doench

The application of RNA interference (RNAi) to mammalian cells has provided the means to perform phenotypic screens to determine the functions of genes. Although RNAi has revolutionized loss-of-function genetic experiments, it has been difficult to systematically assess the prevalence and consequences of off-target effects. The Connectivity Map (CMAP) represents an unprecedented resource to study the gene expression consequences of expressing short hairpin RNAs (shRNAs). Analysis of signatures for over 13,000 shRNAs applied in 9 cell lines revealed that microRNA (miRNA)-like off-target effects of RNAi are far stronger and more pervasive than generally appreciated. We show that mitigating off-target effects is feasible in these datasets via computational methodologies to produce a consensus gene signature (CGS). In addition, we compared RNAi technology to clustered regularly interspaced short palindromic repeat (CRISPR)-based knockout by analysis of 373 single guide RNAs (sgRNAs) in 6 cells lines and show that the on-target efficacies are comparable, but CRISPR technology is far less susceptible to systematic off-target effects. These results will help guide the proper use and analysis of loss-of-function reagents for the determination of gene function.(image)

(XML) Correction: Approach-Induced Biases in Human Information Sampling


by Laurence T. Hunt, Robb B. Rutledge, W. M. Nishantha Malalasekera, Steven W. Kennerley, Raymond J. Dolan


(XML) Regulation of actions and habits by ventral hippocampal trkB and adolescent corticosteroid exposure


by Elizabeth T. Barfield, Kyle J. Gerber, Kelsey S. Zimmermann, Kerry J. Ressler, Ryan G. Parsons, Shannon L. Gourley

In humans and rodents, stress promotes habit-based behaviors that can interfere with action—outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent—primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB—ERK42/44 tone determines long-term behavioral outcomes.(image)

(XML) Connectivity and systemic resilience of the Great Barrier Reef


by Karlo Hock, Nicholas H. Wolff, Juan C. Ortiz, Scott A. Condie, Kenneth R. N. Anthony, Paul G. Blackwell, Peter J. Mumby

Australia’s iconic Great Barrier Reef (GBR) continues to suffer from repeated impacts of cyclones, coral bleaching, and outbreaks of the coral-eating crown-of-thorns starfish (COTS), losing much of its coral cover in the process. This raises the question of the ecosystem’s systemic resilience and its ability to rebound after large-scale population loss. Here, we reveal that around 100 reefs of the GBR, or around 3%, have the ideal properties to facilitate recovery of disturbed areas, thereby imparting a level of systemic resilience and aiding its continued recovery. These reefs (1) are highly connected by ocean currents to the wider reef network, (2) have a relatively low risk of exposure to disturbances so that they are likely to provide replenishment when other reefs are depleted, and (3) have an ability to promote recovery of desirable species but are unlikely to either experience or spread COTS outbreaks. The great replenishment potential of these ‘robust source reefs’, which may supply 47% of the ecosystem in a single dispersal event, emerges from the interaction between oceanographic conditions and geographic location, a process that is likely to be repeated in other reef systems. Such natural resilience of reef systems will become increasingly important as the frequency of disturbances accelerates under climate change.(image)

(XML) Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus


by Lauren Radlinski, Sarah E. Rowe, Laurel B. Kartchner, Robert Maile, Bruce A. Cairns, Nicholas P. Vitko, Cindy J. Gode, Anne M. Lachiewicz, Matthew C. Wolfgang, Brian P. Conlon

Chronic coinfections of Staphylococcus aureus and Pseudomonas aeruginosa frequently fail to respond to antibiotic treatment, leading to significant patient morbidity and mortality. Currently, the impact of interspecies interaction on S. aureus antibiotic susceptibility remains poorly understood. In this study, we utilize a panel of P. aeruginosa burn wound and cystic fibrosis (CF) lung isolates to demonstrate that P. aeruginosa alters S. aureus susceptibility to bactericidal antibiotics in a variable, strain-dependent manner and further identify 3 independent interactions responsible for antagonizing or potentiating antibiotic activity against S. aureus. We find that P. aeruginosa LasA endopeptidase potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent tobramycin uptake, and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We find that the production of each of these factors varies between clinical isolates and corresponds to the capacity of each isolate to alter S. aureus antibiotic susceptibility. Furthermore, we demonstrate that vancomycin treatment of a S. aureus mouse burn infection is potentiated by the presence of a LasA-producing P. aeruginosa population. These findings demonstrate that antibiotic susceptibility is complex and dependent not only upon the genotype of the pathogen being targeted, but also on interactions with other microorganisms in the infection environment. Consideration of these interactions will improve the treatment of polymicrobial infections.(image)

(XML) Nucleic acid purification from plants, animals and microbes in under 30 seconds


by Yiping Zou, Michael Glenn Mason, Yuling Wang, Eugene Wee, Conny Turni, Patrick J. Blackall, Matt Trau, Jose Ramon Botella

Nucleic acid amplification is a powerful molecular biology tool, although its use outside the modern laboratory environment is limited due to the relatively cumbersome methods required to extract nucleic acids from biological samples. To address this issue, we investigated a variety of materials for their suitability for nucleic acid capture and purification. We report here that untreated cellulose-based paper can rapidly capture nucleic acids within seconds and retain them during a single washing step, while contaminants present in complex biological samples are quickly removed. Building on this knowledge, we have successfully created an equipment-free nucleic acid extraction dipstick methodology that can obtain amplification-ready DNA and RNA from plants, animals, and microbes from difficult biological samples such as blood and leaves from adult trees in less than 30 seconds. The simplicity and speed of this method as well as the low cost and availability of suitable materials (e.g., common paper towelling), means that nucleic acid extraction is now more accessible and affordable for researchers and the broader community. Furthermore, when combined with recent advancements in isothermal amplification and naked eye DNA visualization techniques, the dipstick extraction technology makes performing molecular diagnostic assays achievable in limited resource settings including university and high school classrooms, field-based environments, and developing countries.(image)

(XML) Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents


by Cristin E. Kearns, Dorie Apollonio, Stanton A. Glantz

In 1965, the Sugar Research Foundation (SRF) secretly funded a review in the New England Journal of Medicine that discounted evidence linking sucrose consumption to blood lipid levels and hence coronary heart disease (CHD). SRF subsequently funded animal research to evaluate sucrose’s CHD risks. The objective of this study was to examine the planning, funding, and internal evaluation of an SRF-funded research project titled “Project 259: Dietary Carbohydrate and Blood Lipids in Germ-Free Rats,” led by Dr. W.F.R. Pover at the University of Birmingham, Birmingham, United Kingdom, between 1967 and 1971. A narrative case study method was used to assess SRF Project 259 from 1967 to 1971 based on sugar industry internal documents. Project 259 found a statistically significant decrease in serum triglycerides in germ-free rats fed a high sugar diet compared to conventional rats fed a basic PRM diet (a pelleted diet containing cereal meals, soybean meals, whitefish meal, and dried yeast, fortified with a balanced vitamin supplement and trace element mixture). The results suggested to SRF that gut microbiota have a causal role in carbohydrate-induced hypertriglyceridemia. A study comparing conventional rats fed a high-sugar diet to those fed a high-starch diet suggested that sucrose consumption might be associated with elevated levels of beta-glucuronidase, an enzyme previously associated with bladder cancer in humans. SRF terminated Project 259 without publishing the results. The sugar industry did not disclose evidence of harm from animal studies that would have (1) strengthened the case that the CHD risk of sucrose is greater than starch and (2) caused sucrose to be scrutinized as a potential carcinogen. The influence of the gut microbiota in the differential effects of sucrose and starch on blood lipids, as well as the influence of carbohydrate quality on beta-glucuronidase and cancer activity, deserve further scrutiny.(image)

(XML) Mutualism in museums: A model for engaging undergraduates in biodiversity science


by Anna E. Hiller, Carla Cicero, Monica J. Albe, Theresa L. W. Barclay, Carol L. Spencer, Michelle S. Koo, Rauri C. K. Bowie, Eileen A. Lacey

Museums have an untapped potential to engage students in hands-on learning. Here, we describe the development of a tiered museum-based program at the University of California, Berkeley as a model for engaging undergraduates in biodiversity science. This decade-long effort to increase student participation in collections demonstrates the mutual benefits of undergraduate involvement. Museums benefit from critical help in collections care and an increased intellectual vitality, while students simultaneously gain essential research skills and an unparalleled exposure to biodiversity. Five first steps to creating a program are: dedicate a coordinator, offer credit, diversify participation, create a tiered structure, and build community.(image)

(XML) Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species


by Abigail L. Lind, Jennifer H. Wisecaver, Catarina Lameiras, Philipp Wiemann, Jonathan M. Palmer, Nancy P. Keller, Fernando Rodrigues, Gustavo H. Goldman, Antonis Rokas

Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.(image)

(XML) The prehistory of biology preprints: A forgotten experiment from the 1960s


by Matthew Cobb

In 1961, the National Institutes of Health (NIH) began to circulate biological preprints in a forgotten experiment called the Information Exchange Groups (IEGs). This system eventually attracted over 3,600 participants and saw the production of over 2,500 different documents, but by 1967, it was effectively shut down following the refusal of journals to accept articles that had been circulated as preprints. This article charts the rise and fall of the IEGs and explores the parallels with the 1990s and the biomedical preprint movement of today.(image)

(XML) Conservation demands safe gene drive


by Kevin M. Esvelt, Neil J. Gemmell

Interest in developing gene drive systems to control invasive species is growing, with New Zealand reportedly considering the nascent technology as a way to locally eliminate the mammalian pests that threaten its unique flora and fauna. If gene drives successfully eradicated these invasive populations, many would rejoice, but what are the possible consequences? Here, we explore the risk of accidental spread posed by self-propagating gene drive technologies, highlight new gene drive designs that might achieve better outcomes, and explain why we need open and international discussions concerning a technology that could have global ramifications.(image)

(XML) Correlates of decisional dynamics in the dorsal anterior cingulate cortex


by Habiba Azab, Benjamin Y. Hayden

We hypothesized that during binary economic choice, decision makers use the first option they attend as a default to which they compare the second. To test this idea, we recorded activity of neurons in the dorsal anterior cingulate cortex (dACC) of macaques choosing between gambles presented asynchronously. We find that ensemble encoding of the value of the first offer includes both choice-dependent and choice-independent aspects, as if reflecting a partial decision. That is, its responses are neither entirely pre- nor post-decisional. In contrast, coding of the value of the second offer is entirely decision dependent (i.e., post-decisional). This result holds even when offer-value encodings are compared within the same time period. Additionally, we see no evidence for 2 pools of neurons linked to the 2 offers; instead, all comparison appears to occur within a single functionally homogenous pool of task-selective neurons. These observations suggest that economic choices reflect a context-dependent evaluation of attended options. Moreover, they raise the possibility that value representations reflect, to some extent, a tentative commitment to a choice.(image)

(XML) Pioneer cells established by the [SWI+] prion can promote dispersal and out-crossing in yeast


by Gregory A. Newby, Susan Lindquist

To thrive in an ever-changing environment, microbes must widely distribute their progeny to colonize new territory. Simultaneously, they must evolve and adapt to the stresses of unpredictable surroundings. In both of these regards, diversity is key—if an entire population moved together or responded to the environment in the same way, it could easily go extinct. Here, we show that the epigenetic prion switch [SWI+] establishes a specialized subpopulation with a “pioneer” phenotypic program in Saccharomyces cerevisiae. Cells in the pioneer state readily disperse in water, enabling them to migrate and colonize new territory. Pioneers are also more likely to find and mate with genetically diverse partners, as inhibited mating-type switching causes mother cells to shun their own daughters. In the nonprion [swi] state, cells instead have a “settler” phenotype, forming protective flocs and tending to remain in their current position. Settler cells are better able to withstand harsh conditions like drought and alkaline pH. We propose that these laboratory observations reveal a strategy employed in the wild to rapidly diversify and grant distinct, useful roles to cellular subpopulations that benefit the population as a whole.(image)

(XML) The poverty-related neglected diseases: Why basic research matters


by Peter J. Hotez

Together, malaria and the neglected tropical diseases (NTDs) kill more than 800,000 people annually, while creating long-term disability in millions more. International support for mass drug administration, bed nets, and other preventive measures has resulted in huge public health gains, while support for translational research is leading to the development of some new neglected disease drugs, diagnostics, and vaccines. However, funding for basic science research has not kept up, such that we are missing opportunities to create a more innovative pipeline of control tools for parasitic and related diseases. There is an urgent need to expand basic science approaches for neglected diseases, especially in the areas of systems biology and immunology; ecology, evolution, and mathematical biology; functional and comparative OMICs; gene editing; expanded use of model organisms; and a new single-cell combinatorial indexing RNA sequencing approach. The world’s poor deserve access to innovation for neglected diseases. It should be considered a fundamental human right.(image)

(XML) Capacity of tTreg generation is not impaired in the atrophied thymus


by Jiyoung Oh, Weikan Wang, Rachel Thomas, Dong-Ming Su

Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.(image)

(XML) Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes


by Thai Q. Tran, Mari B. Ishak Gabra, Xazmin H. Lowman, Ying Yang, Michael A. Reid, Min Pan, Timothy R. O’Connor, Mei Kong

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.(image)

(XML) Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number


by Dimitris Katsanos, Sneha L. Koneru, Lamia Mestek Boukhibar, Nicola Gritti, Ritobrata Ghose, Peter J. Appleford, Maria Doitsidou, Alison Woollard, Jeroen S. van Zon, Richard J. Poole, Michalis Barkoulas

Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens.(image)

(XML) Concurrent temporal channels for auditory processing: Oscillatory neural entrainment reveals segregation of function at different scales


by Xiangbin Teng, Xing Tian, Jess Rowland, David Poeppel

Natural sounds convey perceptually relevant information over multiple timescales, and the necessary extraction of multi-timescale information requires the auditory system to work over distinct ranges. The simplest hypothesis suggests that temporal modulations are encoded in an equivalent manner within a reasonable intermediate range. We show that the human auditory system selectively and preferentially tracks acoustic dynamics concurrently at 2 timescales corresponding to the neurophysiological theta band (4–7 Hz) and gamma band ranges (31–45 Hz) but, contrary to expectation, not at the timescale corresponding to alpha (8–12 Hz), which has also been found to be related to auditory perception. Listeners heard synthetic acoustic stimuli with temporally modulated structures at 3 timescales (approximately 190-, approximately 100-, and approximately 30-ms modulation periods) and identified the stimuli while undergoing magnetoencephalography recording. There was strong intertrial phase coherence in the theta band for stimuli of all modulation rates and in the gamma band for stimuli with corresponding modulation rates. The alpha band did not respond in a similar manner. Classification analyses also revealed that oscillatory phase reliably tracked temporal dynamics but not equivalently across rates. Finally, mutual information analyses quantifying the relation between phase and cochlear-scaled correlations also showed preferential processing in 2 distinct regimes, with the alpha range again yielding different patterns. The results support the hypothesis that the human auditory system employs (at least) a 2-timescale processing mode, in which lower and higher perceptual sampling scales are segregated by an intermediate temporal regime in the alpha band that likely reflects different underlying computations.(image)

(XML) Uncovering protein–protein interactions through a team-based undergraduate biochemistry course


by David L. Cookmeyer, Emily S. Winesett, Bashkim Kokona, Adam R. Huff, Sabina Aliev, Noah B. Bloch, Joshua A. Bulos, Irene L. Evans, Christian R. Fagre, Kerilyn N. Godbe, Maryna Khromava, Daniel M. Konstantinovsky, Alexander E. Lafrance, Alexandra J. Lamacki, Robert C. Parry, Jeanne M. Quinn, Alana M. Thurston, Kathleen J. S. Tsai, Aurelio Mollo, Max J. Cryle, Robert Fairman, Louise K. Charkoudian

How can we provide fertile ground for students to simultaneously explore a breadth of foundational knowledge, develop cross-disciplinary problem-solving skills, gain resiliency, and learn to work as a member of a team? One way is to integrate original research in the context of an undergraduate biochemistry course. In this Community Page, we discuss the development and execution of an interdisciplinary and cross-departmental undergraduate biochemistry laboratory course. We present a template for how a similar course can be replicated at other institutions and provide pedagogical and research results from a sample module in which we challenged our students to study the binding interface between 2 important biosynthetic proteins. Finally, we address the community and invite others to join us in making a larger impact on undergraduate education and the field of biochemistry by coordinating efforts to integrate research and teaching across campuses.(image)

(XML) Rate, not selectivity, determines neuronal population coding accuracy in auditory cortex


by Wensheng Sun, Dennis L. Barbour

The notion that neurons with higher selectivity carry more information about external sensory inputs is widely accepted in neuroscience. High-selectivity neurons respond to a narrow range of sensory inputs, and thus would be considered highly informative by rejecting a large proportion of possible inputs. In auditory cortex, neuronal responses are less selective immediately after the onset of a sound and then become highly selective in the following sustained response epoch. These 2 temporal response epochs have thus been interpreted to encode first the presence and then the content of a sound input. Contrary to predictions from that prevailing theory, however, we found that the neural population conveys similar information about sound input across the 2 epochs in spite of the neuronal selectivity differences. The amount of information encoded turns out to be almost completely dependent upon the total number of population spikes in the read-out window for this system. Moreover, inhomogeneous Poisson spiking behavior is sufficient to account for this property. These results imply a novel principle of sensory encoding that is potentially shared widely among multiple sensory systems.(image)

(XML) Correction: What do we talk about when we talk about rhythm?


by Jonas Obleser, Molly J. Henry, Peter Lakatos


(XML) Crowd vocal learning induces vocal dialects in bats: Playback of conspecifics shapes fundamental frequency usage by pups


by Yosef Prat, Lindsay Azoulay, Roi Dor, Yossi Yovel

Vocal learning, the substrate of human language acquisition, has rarely been described in other mammals. Often, group-specific vocal dialects in wild populations provide the main evidence for vocal learning. While social learning is often the most plausible explanation for these intergroup differences, it is usually impossible to exclude other driving factors, such as genetic or ecological backgrounds. Here, we show the formation of dialects through social vocal learning in fruit bats under controlled conditions. We raised 3 groups of pups in conditions mimicking their natural roosts. Namely, pups could hear their mothers' vocalizations but were also exposed to a manipulation playback. The vocalizations in the 3 playbacks mainly differed in their fundamental frequency. From the age of approximately 6 months and onwards, the pups demonstrated distinct dialects, where each group was biased towards its playback. We demonstrate the emergence of dialects through social learning in a mammalian model in a tightly controlled environment. Unlike in the extensively studied case of songbirds where specific tutors are imitated, we demonstrate that bats do not only learn their vocalizations directly from their mothers, but that they are actually influenced by the sounds of the entire crowd. This process, which we term “crowd vocal learning,” might be relevant to many other social animals such as cetaceans and pinnipeds.(image)

(XML) Prediction of drug cocktail effects when the number of measurements is limited


by Anat Zimmer, Avichai Tendler, Itay Katzir, Avi Mayo, Uri Alon

Cocktails of drugs can be more effective than single drugs, because they can potentially work at lower doses and avoid resistance. However, it is impossible to test all drug cocktails drawn from a large set of drugs because of the huge number of combinations. To overcome this combinatorial explosion problem, one can sample a relatively small number of combinations and use a model to predict the rest. Recently, Zimmer and Katzir et al. presented a model that accurately predicted the effects of cocktails at all doses based on measuring pairs of drugs. This model requires measuring each pair at several different doses and uses interpolation to reduce experimental noise. However, often, it is not possible to measure each pair at multiple doses (for example, in scarce patient-derived tumor material or in large screens). Here, we ask whether measurements at only a single dose can also predict high-order drug cocktails. To address this, we present a fully factorial experimental dataset on all drug cocktails built of 6 chemotherapy drugs on 2 cancer cell lines. We develop a formula that uses only pair measurements at a single dose to predict much of the variation up to 6-drug cocktails in the present data, outperforming commonly used Bliss independence and regression approaches. This model, called the pairs model, is an extension of the Bliss independence model to pairs: For M drugs, it equals the product of all pair effects to the power 1/(M−1). The pairs model also shows good agreement with previously published data on antibiotic triplets and quadruplets. The present model can only predict combinations at the same doses in which the pairs were measured and is not able to predict effects at other doses. This study indicates that pair-based approaches might be able to usefully predict and prioritize high-order combinations, even in large screens or when material for testing is limited.(image)

(XML) Imagining the “open” university: Sharing scholarship to improve research and education


by Erin C. McKiernan

Open scholarship, such as the sharing of articles, code, data, and educational resources, has the potential to improve university research and education as well as increase the impact universities can have beyond their own walls. To support this perspective, I present evidence from case studies, published literature, and personal experiences as a practicing open scholar. I describe some of the challenges inherent to practicing open scholarship and some of the tensions created by incompatibilities between institutional policies and personal practice. To address this, I propose several concrete actions universities could take to support open scholarship and outline ways in which such initiatives could benefit the public as well as institutions. Importantly, I do not think most of these actions would require new funding but rather a redistribution of existing funds and a rewriting of internal policies to better align with university missions of knowledge dissemination and societal impact.(image)