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Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

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

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

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

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

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

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>?

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

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

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

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

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

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

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

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

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

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

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

Tracking arctic marine mammal resilience in an era of rapid ecosystem alteration

вт, 2018-10-09 23:00

by Sue E. Moore, Randall R. Reeves

Global warming is significantly altering arctic marine ecosystems. Specifically, the precipitous loss of sea ice is creating a dichotomy between ice-dependent polar bears and pinnipeds that are losing habitat and some cetaceans that are gaining habitat. While final outcomes are hard to predict for the many and varied marine mammal populations that rely on arctic habitats, we suggest a simplified framework to assess status, based upon ranking a population’s size, range, behavior, and health. This basic approach is proposed as a means to prioritize and expedite conservation and management efforts in an era of rapid ecosystem alteration.
Категории: Biology, Journals

Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth

вт, 2018-10-09 23:00

by Tatiana V. Tkatchenko, David Troilo, Alexandra Benavente-Perez, Andrei V. Tkatchenko

Myopia (nearsightedness) is the most common eye disorder, which is rapidly becoming one of the leading causes of vision loss in several parts of the world because of a recent sharp increase in prevalence. Nearwork, which produces hyperopic optical defocus on the retina, has been implicated as one of the environmental risk factors causing myopia in humans. Experimental studies have shown that hyperopic defocus imposed by negative power lenses placed in front of the eye accelerates eye growth and causes myopia, whereas myopic defocus imposed by positive lenses slows eye growth and produces a compensatory hyperopic shift in refractive state. The balance between these two optical signals is thought to regulate refractive eye development; however, the ability of the retina to recognize the sign of optical defocus and the composition of molecular signaling pathways guiding emmetropization are the subjects of intense investigation and debate. We found that the retina can readily distinguish between imposed myopic and hyperopic defocus, and identified key signaling pathways underlying retinal response to the defocus of different signs. Comparison of retinal transcriptomes in common marmosets exposed to either myopic or hyperopic defocus for 10 days or 5 weeks revealed that the primate retina responds to defocus of different signs by activation or suppression of largely distinct pathways. We also found that 29 genes differentially expressed in the marmoset retina in response to imposed defocus are localized within human myopia quantitative trait loci (QTLs), suggesting functional overlap between genes differentially expressed in the marmoset retina upon exposure to optical defocus and genes causing myopia in humans. These findings identify retinal pathways involved in the development of myopia, as well as potential new strategies for its treatment.
Категории: Biology, Journals

Climate communication for biologists: When a picture can tell a thousand words

вт, 2018-10-09 23:00

by Stephan Lewandowsky, Lorraine Whitmarsh

Pictures often tell a story better than the proverbial 1,000 words. However, in connection with climate change, many pictures can be highly misleading, for example, when a snowball is used to ridicule the notion of global warming or when a picture of a dead crop is supposed to alert people to climate change. We differentiate between such inappropriate pictures and those that can be used legitimately because they capture long-term trends. For example, photos of a glacier’s retreat are legitimate indicators of the long-term mass balance loss that is observed for the vast majority of glaciers around the world.
Категории: Biology, Journals