Journals

An alternative mode of epithelial polarity in the <i>Drosophila</i> midgut

PLOS Biology (new articles) - пт, 2018-10-19 23:00

by Jia Chen, Aram-Christopher Sayadian, Nick Lowe, Holly E. Lovegrove, Daniel St Johnston

Apical–basal polarity is essential for the formation and function of epithelial tissues, whereas loss of polarity is a hallmark of tumours. Studies in Drosophila have identified conserved polarity factors that define the apical (Crumbs, Stardust, Par-6, atypical protein kinase C [aPKC]), junctional (Bazooka [Baz]/Par-3), and basolateral (Scribbled [Scrib], Discs large [Dlg], Lethal [2] giant larvae [Lgl]) domains of epithelial cells. Because these conserved factors mark equivalent domains in diverse types of vertebrate and invertebrate epithelia, it is generally assumed that this system underlies polarity in all epithelia. Here, we show that this is not the case, as none of these canonical factors are required for the polarisation of the endodermal epithelium of the Drosophila adult midgut. Furthermore, like vertebrate epithelia but not other Drosophila epithelia, the midgut epithelium forms occluding junctions above adherens junctions (AJs) and requires the integrin adhesion complex for polarity. Thus, Drosophila contains two types of epithelia that polarise by fundamentally different mechanisms. This diversity of epithelial types may reflect their different developmental origins, junctional arrangement, or whether they polarise in an apical–basal direction or vice versa. Since knock-outs of canonical polarity factors in vertebrates often have little or no effect on epithelial polarity and the Drosophila midgut shares several common features with vertebrate epithelia, this diversity of polarity mechanisms is likely to be conserved in other animals.
Категории: Biology, Journals

EBP1 nuclear accumulation negatively feeds back on FERONIA-mediated RALF1 signaling

PLOS Biology (new articles) - пт, 2018-10-19 23:00

by Chiyu Li, Xuanming Liu, Xiaonan Qiang, Xiaoyan Li, Xiushan Li, Sirui Zhu, Long Wang, Yuan Wang, Hongdong Liao, Sheng Luan, Feng Yu

FERONIA (FER), a plasma membrane receptor-like kinase, is a central regulator of cell growth that integrates environmental and endogenous signals. A peptide ligand rapid alkalinization factor 1 (RALF1) binds to FER and triggers a series of downstream events, including inhibition of Arabidopsis H+-ATPase 2 activity at the cell surface and regulation of gene expression in the nucleus. We report here that, upon RALF1 binding, FER first promotes ErbB3-binding protein 1 (EBP1) mRNA translation and then interacts with and phosphorylates the EBP1 protein, leading to EBP1 accumulation in the nucleus. There, EBP1 associates with the promoters of previously identified RALF1-regulated genes, such as CML38, and regulates gene transcription in response to RALF1 signaling. EBP1 appears to inhibit the RALF1 peptide response, thus forming a transcription–translation feedback loop (TTFL) similar to that found in circadian rhythm control. The plant RALF1-FER-EBP1 axis is reminiscent of animal epidermal growth factor receptor (EGFR) signaling, in which EGF peptide induces EGFR to interact with and phosphorylate EBP1, promoting EBP1 nuclear accumulation to control cell growth. Thus, we suggest that in response to peptide signals, plant FER and animal EGFR use the conserved key regulator EBP1 to control cell growth in the nucleus.
Категории: Biology, Journals

Frontostriatal pathways gate processing of behaviorally relevant reward dimensions

PLOS Biology (new articles) - пт, 2018-10-19 23:00

by Susanna C. Weber, Thorsten Kahnt, Boris B. Quednow, Philippe N. Tobler

The value of rewards arises from multiple hedonic and motivational dimensions. Reward-encoding brain regions such as the ventral striatum (VS) are known to process these dimensions. However, the mechanism whereby distinct reward dimensions are selected for neural processing and guiding behavior remains unclear. Here, we used functional imaging to investigate how human individuals make either hedonic (liking) or motivational (wanting) evaluations of everyday items. We found that the two types of evaluations were differently modulated depending on whether participants won or lost these items. Neural activity in the VS encoded both hedonic and motivational dimensions of reward, whereas ventromedial prefrontal activity encoded primarily motivational evaluations and central orbitofrontal activity encoded predominantly hedonic evaluations. These distinct prefrontal representations arose regardless of which judgment was currently relevant for behavior. Critically, the VS preferentially processed the reward dimension currently being evaluated and showed judgment-specific functional connectivity with the dimension-specific prefrontal areas. Thus, our data are in keeping with a gating mechanism by which prefrontal cortex (PFC)–VS pathways flexibly encode reward dimensions depending on their behavioral relevance. These findings provide a prototype for a generalized information selection mechanism through content-tailored frontostriatal communication.
Категории: Biology, Journals

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

PLOS Biology (new articles) - чт, 2018-10-18 23:00

by Guang-Zhi Jin, Yajuan Zhang, Wen-Ming Cong, Xueyuan Wu, Xiongjun Wang, Siyang Wu, Siyao Wang, Weiping Zhou, Shengxian Yuan, Hong Gao, Guanzhen Yu, Weiwei Yang

Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression.
Категории: Biology, Journals

Running in the wheel: Defining individual severity levels in mice

PLOS Biology (new articles) - чт, 2018-10-18 23:00

by Christine Häger, Lydia M. Keubler, Steven R. Talbot, Svenja Biernot, Nora Weegh, Stephanie Buchheister, Manuela Buettner, Silke Glage, André Bleich

The fine-scale grading of the severity experienced by animals used in research constitutes a key element of the 3Rs (replace, reduce, and refine) principles and a legal requirement in the European Union Directive 2010/63/EU. Particularly, the exact assessment of all signs of pain, suffering, and distress experienced by laboratory animals represents a prerequisite to develop refinement strategies. However, minimal and noninvasive methods for an evidence-based severity assessment are scarce. Therefore, we investigated whether voluntary wheel running (VWR) provides an observer-independent behaviour-centred approach to grade severity experienced by C57BL/6J mice undergoing various treatments. In a mouse model of chemically induced acute colitis, VWR behaviour was directly related to colitis severity, whereas clinical scoring did not sensitively reflect severity but rather indicated marginal signs of compromised welfare. Unsupervised k-means algorithm–based cluster analysis of body weight and VWR data enabled the discrimination of cluster borders and distinct levels of severity. The validity of the cluster analysis was affirmed in a mouse model of acute restraint stress. This method was also applicable to uncover and grade the impact of serial blood sampling on the animal’s welfare, underlined by increased histological scores in the colitis model. To reflect the entirety of severity in a multidimensional model, the presented approach may have to be calibrated and validated in other animal models requiring the integration of further parameters. In this experimental set up, however, the automated assessment of an emotional/motivational driven behaviour and subsequent integration of the data into a mathematical model enabled unbiased individual severity grading in laboratory mice, thereby providing an essential contribution to the 3Rs principles.
Категории: Biology, Journals

Frontal network dynamics reflect neurocomputational mechanisms for reducing maladaptive biases in motivated action

PLOS Biology (new articles) - чт, 2018-10-18 23:00

by Jennifer C. Swart, Michael J. Frank, Jessica I. Määttä, Ole Jensen, Roshan Cools, Hanneke E. M. den Ouden

Motivation exerts control over behavior by eliciting Pavlovian responses, which can either match or conflict with instrumental action. We can overcome maladaptive motivational influences putatively through frontal cognitive control. However, the neurocomputational mechanisms subserving this control are unclear; does control entail up-regulating instrumental systems, down-regulating Pavlovian systems, or both? We combined electroencephalography (EEG) recordings with a motivational Go/NoGo learning task (N = 34), in which multiple Go options enabled us to disentangle selective action learning from nonselective Pavlovian responses. Midfrontal theta-band (4 Hz–8 Hz) activity covaried with the level of Pavlovian conflict and was associated with reduced Pavlovian biases rather than reduced instrumental learning biases. Motor and lateral prefrontal regions synchronized to the midfrontal cortex, and these network dynamics predicted the reduction of Pavlovian biases over and above local, midfrontal theta activity. This work links midfrontal processing to detecting Pavlovian conflict and highlights the importance of network processing in reducing the impact of maladaptive, Pavlovian biases.
Категории: Biology, Journals

Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic

PLOS Biology (new articles) - чт, 2018-10-18 23:00

by Jason Boehme, Natacha Le Moan, Rebecca J. Kameny, Alexandra Loucks, Michael J. Johengen, Amy L. Lesneski, Wenhui Gong, Tina Davis, Kevin Tanaka, Andrew Davis, Youping He, Janel Long-Boyle, Vijay Ivaturi, Jogarao V. S. Gobburu, Jonathan A. Winger, Stephen P. Cary, Sanjeev A. Datar, Jeffrey R. Fineman, Ana Krtolica, Emin Maltepe

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.
Категории: Biology, Journals

Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury

PLOS Biology (new articles) - ср, 2018-10-17 23:00

by Andrew D. Greenhalgh, Juan G. Zarruk, Luke M. Healy, Sam J. Baskar Jesudasan, Priya Jhelum, Christopher K. Salmon, Albert Formanek, Matthew V. Russo, Jack P. Antel, Dorian B. McGavern, Barry W. McColl, Samuel David

Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially modulate each other’s functions. Importantly, microglia-mediated phagocytosis and inflammation are suppressed by infiltrating macrophages. In the context of spinal cord injury (SCI), preventing such communication increases microglial activation and worsens functional recovery. We suggest that macrophages entering the CNS provide a regulatory mechanism that controls acute and long-term microglia-mediated inflammation, which may drive damage in a variety of CNS conditions.
Категории: Biology, Journals

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants

PLOS Biology (new articles) - вт, 2018-10-16 23:00

by Deirdre M. McCarthy, Thomas J. Morgan Jr., Sarah E. Lowe, Matthew J. Williamson, Thomas J. Spencer, Joseph Biederman, Pradeep G. Bhide

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.
Категории: Biology, Journals

Fifteen years in, what next for <i>PLOS Biology</i>?

PLOS Biology (new articles) - пн, 2018-10-15 23:00

by The PLOS Biology Staff Editors

As we celebrate our anniversary, the PLOS Biology editors discuss recent initiatives taken by the journal (meta-research, complementary research policy, preprint posting, short reports, methods and resources, data policy, protocols.io) and look ahead to the next fifteen years.
Категории: Biology, Journals

Training in experimental design and statistics is essential: Response to Jordan

PLOS Biology (new articles) - пн, 2018-10-15 23:00

by Stanley E. Lazic, Charlie J. Clarke-Williams, Marcus R. Munafò

This Formal Comment responds to Jordan et al., and stresses that if scientific findings are to be robust, training in experimental design and statistics is critical to ensure that research questions, design considerations, and analyses are aligned.
Категории: Biology, Journals

Population sampling affects pseudoreplication

PLOS Biology (new articles) - пн, 2018-10-15 23:00

by Crispin Y. Jordan

Категории: Biology, Journals

High-resolution frequency tuning but not temporal coding in the human cochlea

PLOS Biology (new articles) - пн, 2018-10-15 23:00

by Eric Verschooten, Christian Desloovere, Philip X. Joris

Frequency tuning and phase-locking are two fundamental properties generated in the cochlea, enabling but also limiting the coding of sounds by the auditory nerve (AN). In humans, these limits are unknown, but high resolution has been postulated for both properties. Electrophysiological recordings from the AN of normal-hearing volunteers indicate that human frequency tuning, but not phase-locking, exceeds the resolution observed in animal models.
Категории: Biology, Journals

Multimodal sensory information is represented by a combinatorial code in a sensorimotor system

PLOS Biology (new articles) - пн, 2018-10-15 23:00

by Rosangela Follmann, Christopher John Goldsmith, Wolfgang Stein

A ubiquitous feature of the nervous system is the processing of simultaneously arriving sensory inputs from different modalities. Yet, because of the difficulties of monitoring large populations of neurons with the single resolution required to determine their sensory responses, the cellular mechanisms of how populations of neurons encode different sensory modalities often remain enigmatic. We studied multimodal information encoding in a small sensorimotor system of the crustacean stomatogastric nervous system that drives rhythmic motor activity for the processing of food. This system is experimentally advantageous, as it produces a fictive behavioral output in vitro, and distinct sensory modalities can be selectively activated. It has the additional advantage that all sensory information is routed through a hub ganglion, the commissural ganglion, a structure with fewer than 220 neurons. Using optical imaging of a population of commissural neurons to track each individual neuron's response across sensory modalities, we provide evidence that multimodal information is encoded via a combinatorial code of recruited neurons. By selectively stimulating chemosensory and mechanosensory inputs that are functionally important for processing of food, we find that these two modalities were processed in a distributed network comprising the majority of commissural neurons imaged. In a total of 12 commissural ganglia, we show that 98% of all imaged neurons were involved in sensory processing, with the two modalities being processed by a highly overlapping set of neurons. Of these, 80% were multimodal, 18% were unimodal, and only 2% of the neurons did not respond to either modality. Differences between modalities were represented by the identities of the neurons participating in each sensory condition and by differences in response sign (excitation versus inhibition), with 46% changing their responses in the other modality. Consistent with the hypothesis that the commissural network encodes different sensory conditions in the combination of activated neurons, a new combination of excitation and inhibition was found when both pathways were activated simultaneously. The responses to this bimodal condition were distinct from either unimodal condition, and for 30% of the neurons, they were not predictive from the individual unimodal responses. Thus, in a sensorimotor network, different sensory modalities are encoded using a combinatorial code of neurons that are activated or inhibited. This provides motor networks with the ability to differentially respond to categorically different sensory conditions and may serve as a model to understand higher-level processing of multimodal information.
Категории: Biology, Journals

Saving the horseshoe crab: A synthetic alternative to horseshoe crab blood for endotoxin detection

PLOS Biology (new articles) - пт, 2018-10-12 23:00

by Tom Maloney, Ryan Phelan, Naira Simmons

Horseshoe crabs have been integral to the safe production of vaccines and injectable medications for the past 40 years. The bleeding of live horseshoe crabs, a process that leaves thousands dead annually, is an ecologically unsustainable practice for all four species of horseshoe crab and the shorebirds that rely on their eggs as a primary food source during spring migration. Populations of both horseshoe crabs and shorebirds are in decline. This study confirms the efficacy of recombinant Factor C (rFC), a synthetic alternative that eliminates the need for animal products in endotoxin detection. Furthermore, our findings confirm that the biomedical industry can achieve a 90% reduction in the use of reagents derived from horseshoe crabs by using the synthetic alternative for the testing of water and other common materials used in the manufacturing process. This represents an extraordinary opportunity for the biomedical and pharmaceutical industries to significantly contribute to the conservation of horseshoe crabs and the birds that depend on them.
Категории: Biology, Journals

Learning what to approach

PLOS Biology (new articles) - чт, 2018-10-11 23:00

by Neir Eshel, Elizabeth E. Steinberg

Most decisions share a common goal: maximize reward and minimize punishment. Achieving this goal requires learning which choices are likely to lead to favorable outcomes. Dopamine is essential for this process, enabling learning by signaling the difference between what we expect to get and what we actually get. Although all animals appear to use this dopamine prediction error circuit, some do so more than others, and this neural heterogeneity correlates with individual variability in behavior. In this issue of PLOS Biology, Lee and colleagues show that manipulating a simple task parameter can bias the animals’ behavioral strategy and modulate dopamine release, implying that how we learn is just as flexible as what we learn.
Категории: Biology, Journals

Partial homologies between sleep states in lizards, mammals, and birds suggest a complex evolution of sleep states in amniotes

PLOS Biology (new articles) - чт, 2018-10-11 23:00

by Paul-Antoine Libourel, Baptiste Barrillot, Sébastien Arthaud, Bertrand Massot, Anne-Laure Morel, Olivier Beuf, Anthony Herrel, Pierre-Hervé Luppi

It is crucial to determine whether rapid eye movement (REM) sleep and slow-wave sleep (SWS) (or non-REM sleep), identified in most mammals and birds, also exist in lizards, as they share a common ancestor with these groups. Recently, a study in the bearded dragon (P. vitticeps) reported states analogous to REM and SWS alternating in a surprisingly regular 80-s period, suggesting a common origin of the two sleep states across amniotes. We first confirmed these results in the bearded dragon with deep brain recordings and electro-oculogram (EOG) recordings. Then, to confirm a common origin and more finely characterize sleep in lizards, we developed a multiparametric approach in the tegu lizard, a species never recorded to date. We recorded EOG, electromyogram (EMG), heart rate, and local field potentials (LFPs) and included data on arousal thresholds, sleep deprivation, and pharmacological treatments with fluoxetine, a serotonin reuptake blocker that suppresses REM sleep in mammals. As in the bearded dragon, we demonstrate the existence of two sleep states in tegu lizards. However, no clear periodicity is apparent. The first sleep state (S1 sleep) showed high-amplitude isolated sharp waves, and the second sleep state (S2 sleep) displayed 15-Hz oscillations, isolated ocular movements, and a decrease in heart rate variability and muscle tone compared to S1. Fluoxetine treatment induced a significant decrease in S2 quantities and in the number of sharp waves in S1. Because S2 sleep is characterized by the presence of ocular movements and is inhibited by a serotonin reuptake inhibitor, as is REM sleep in birds and mammals, it might be analogous to this state. However, S2 displays a type of oscillation never previously reported and does not display a desynchronized electroencephalogram (EEG) as is observed in the bearded dragons, mammals, and birds. This suggests that the phenotype of sleep states and possibly their role can differ even between closely related species. Finally, our results suggest a common origin of two sleep states in amniotes. Yet, they also highlight a diversity of sleep phenotypes across lizards, demonstrating that the evolution of sleep states is more complex than previously thought.
Категории: Biology, Journals

Confronting climate change in the age of denial

PLOS Biology (new articles) - вт, 2018-10-09 23:00

by Liza Gross

This Editorial introduces a Collection of articles in which the authors explore the challenges and pitfalls of communicating the science of climate change in an atmosphere where evidence doesn't matter.
Категории: Biology, Journals

The placenta goes viral: Retroviruses control gene expression in pregnancy

PLOS Biology (new articles) - вт, 2018-10-09 23:00

by Edward B. Chuong

The co-option of endogenous retroviruses (ERVs) is increasingly recognized as a recurrent theme in placental biology, which has far-reaching implications for our understanding of mammalian evolution and reproductive health. Most research in this area has focused on ERV-derived proteins, which have been repeatedly co-opted to promote cell–cell fusion and immune modulation in the placenta. ERVs also harbor regulatory sequences that can potentially control placental gene expression, but there has been limited evidence to support this role. In a recent study, Dunn-Fletcher and colleagues discover a striking example of an ERV-derived enhancer element that has been co-opted to regulate a gene important for human pregnancy. Using genomic and experimental approaches, they firmly establish that a primate-specific ERV functions as a placenta-specific enhancer for corticotropin-releasing hormone (CRH), a hormone linked to the control of birth timing in humans. Their findings implicate an extensive yet understudied role for retroviruses in shaping the evolution of placental gene regulatory networks.
Категории: Biology, Journals

(Escaping) the paradox of scientific storytelling

PLOS Biology (new articles) - вт, 2018-10-09 23:00

by Michael F. Dahlstrom, Dietram A. Scheufele

Compelling stories about science can motivate people to engage and respond to relevant problems facing society. While science plays a unique role in society, providing the best available evidence for policy choices, understanding the world, and informing citizens’ daily lives, it does not hold any intrinsic advantage in creating captivating stories for mass audiences. Instead, science must compete with other storytellers, many of whom are not bound to scientific evidence. This presents a paradox—how can science preserve its credibility as curator of knowledge while engaging audiences with a communication format that is agnostic to truth?
Категории: Biology, Journals