bluuebunny/crossref_metadata_2025 huggingface dataset:
Infants ask for help when they know they don’t know
Authors: Goupil Louise , Romand-Monnier Margaux , Kouider Sid
Published: March 2016

Significance

Although many animals have been shown to monitor their own uncertainty, only humans seem to have the ability to explicitly communicate their uncertainty to others. It remains unknown whether this ability is present early in development, or whether it only emerges later alongside language development. Here, using a nonverbal memory-monitoring paradigm, we show that infants are able to strategically ask for help to avoid making mistakes. These findings reveal that infants are capable of monitoring and communicating their own uncertainty. We propose that explicit metacognition develops earlier than previously thought, enabling infants to communicate their own uncertainty nonverbally to gain knowledge from others.
Overcoming heterologous protein interdependency to optimize P450-mediated Taxol precursor synthesis in
Escherichia coli
Authors: Biggs Bradley Walters , Lim Chin Giaw , Sagliani Kristen , Shankar Smriti , Stephanopoulos Gregory , De Mey Marjan , Ajikumar Parayil Kumaran
Published: March 2016

Significance

Metabolic engineering is an economically feasible and sustainable alternative for the production of natural products, pharmaceuticals, nutraceuticals, flavors, and fragrances. Of the model systems used to demonstrate and develop this approach, the anticancer agent Taxol stands out for its structural complexity and therapeutic value. A major challenge for the biosynthesis of Taxol and many other natural products is the involvement of cytochrome P450-mediated oxygenation. P450 enzymes are intransigent to functional heterologous expression, especially in
Escherichia coli
, leading many laboratories to abandon this organism when engineering P450-containing pathways. Here, through a series of optimizations, we demonstrate
E. coli
as a viable host for P450-mediated oxidative chemistry, advancing Taxol’s biosynthesis through a fivefold increase in oxygenated terpene titers.
Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4
Authors: Oishi Koji , Aramaki Michihiko , Nakajima Kazunori
Published: March 2016

Significance

The mammalian neocortex consists of six histologically distinct layers, called layer 1 (L1) to L6. Each layer contains several subtypes of neurons, which are characterized by specific cell morphology, gene expression profile, and connectivity to other regions of the central nervous system. As these neurons are mostly born from common progenitor cells, it is important to know how progenitor cells acquire a certain cell type during development. Here, we reveal the essential interactions between two types of transcription factors, Brn1/2 and Rorb, for subtype specification. Brn1/2 and Rorb are expressed in L2/3 and L4, respectively, in the mature neocortex. We found that Brn1/2 and Rorb repress each other and that this reciprocal repression is important for L2/3 and L4 specification.
Neuronal profilins in health and disease: Relevance for spine plasticity and Fragile X syndrome
Authors: Michaelsen-Preusse Kristin , Zessin Sabine , Grigoryan Gayane , Scharkowski Franziska , Feuge Jonas , Remus Anita , Korte Martin
Published: March 2016

Significance

Neuronal morphology is tightly linked to the actin cytoskeleton, which provides stability for synapses while retaining the potential for changes during learning and memory processes (synaptic plasticity). Despite biochemical similarity, isoforms of the small actin-binding protein profilin perform astonishingly diverse tasks in neurons, influencing actin dynamics in an opposing manner. Although the ubiquitous isoform profilin1 supports synaptogenesis, the evolutionary more recent and brain-specific isoform profilin2a mediates synapse function and plasticity. Moreover, we show that in
mammalia
, only profilin1 is bound by Fragile X mental retardation protein, and therefore is most likely crucial in the cause of and in the devastating outcome of Fragile X syndrome, one of the most common forms of inherited cognitive impairment.
Integrated bioprocess for conversion of gaseous substrates to liquids
Authors: Hu Peng , Chakraborty Sagar , Kumar Amit , Woolston Benjamin , Liu Hongjuan , Emerson David , Stephanopoulos Gregory
Published: March 2016

Significance

In the quest for inexpensive feedstocks (cost-effective fuel production), here we show a two-stage integrated bioprocess for the conversion of syngas to lipids. We harness the innate capability of acetogens and explore concepts of gas-to-liquid mass transfer to produce an integrated two-stage bioreactor system that can convert gases to liquid fuels at scale. Additionally, as the rate of CO
2
fixation substantially exceeds that of CO
2
generation in the two units of the process, there is significant potential for CO
2
recycling in our integrated system. In a broader sense, implementation of these concepts for fuel production may extend to a number of commercially important biological platforms, depending on the potential sources of synthesis gas or its conversion products, namely, acetate.
Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty
Authors: Zhou Xin , Zhu Dantong , King Samson G. , Lees Cynthia J. , Bennett Allyson J. , Salinas Emilio , Stanford Terrence R. , Constantinidis Christos
Published: March 2016

Significance

The ability to resist impulsive responses matures late in life, after puberty. This longitudinal study of the prefrontal cortex in monkeys shows that behavioral response inhibition improves not because the adult prefrontal cortex is better able to inhibit the effects of a prepotent stimulus but rather because it can more readily form an alternative plan of action. The finding is revealing about the nature of cognitive maturation and the conditions in which it is impaired that have clinical and social implications.
Structure and mechanism of the phage T4 recombination mediator protein UvsY
Authors: Gajewski Stefan , Waddell Michael Brett , Vaithiyalingam Sivaraja , Nourse Amanda , Li Zhenmei , Woetzel Nils , Alexander Nathan , Meiler Jens , White Stephen W.
Published: March 2016

Significance

UvsY is the phage T4 recombination mediator protein, and structural and biophysical studies provide insights into its role in T4 homologous recombination. Homologous recombination mediates the error-free repair of DNA double-strand breaks and is found in all kingdoms of life. It is the mechanism whereby single-stranded DNA invades homologous double-stranded DNA to seek matching base pairs and then promotes strand exchange prior to DNA repair via recombination-dependent replication. Recombination is mediated by a recombinase that initially competes with single-strand DNA-binding proteins for access to the DNA. The role of the mediator proteins is to facilitate this handover. UvsY represents a model for how this exchange occurs in phage T4 that is directly applicable to higher organisms including humans.
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated
MSH2
DNA mismatch repair gene variants
Authors: Houlleberghs Hellen , Dekker Marleen , Lantermans Hildo , Kleinendorst Roos , Dubbink Hendrikus Jan , Hofstra Robert M. W. , Verhoef Senno , te Riele Hein
Published: March 2016

Significance

The advances in whole-genome sequencing have greatly facilitated the identification of mismatch repair (MMR) gene mutations in suspected Lynch syndrome (LS) cases. The bottleneck in diagnosing LS patients now lies in determining whether MMR gene variants are pathogenic or polymorphic. In some cases the mutation is clearly deleterious for gene function. However, many suspected LS patients carry single missense mutations in one of the MMR genes, and the functional implications of these missense mutations are often elusive. To help clinicians diagnose and treat patients, we present a site-specific mutagenesis screen that takes advantage of oligonucleotide-directed gene-modification and is capable of detecting pathogenic mutator S homolog 2 (
MSH2
) variants in three simple steps.
PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments
Authors: Nicholls Russell E. , Sontag Jean-Marie , Zhang Hong , Staniszewski Agnieszka , Yan Shijun , Kim Carla Y. , Yim Michael , Woodruff Caitlin M. , Arning Erland , Wasek Brandi , Yin Deqi , Bottiglieri Teodoro , Sontag Estelle , Kandel Eric R. , Arancio Ottavio
Published: March 2016

Significance

Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to the cognitive impairments associated with Alzheimer’s disease (AD). We found that by genetically targeting the methylation of protein phosphatase 2A (PP2A) in transgenic mice, we could alter the sensitivity of animals to electrophysiological and cognitive impairments caused by Aβ exposure without affecting Aβ production or the electrophysiological response to low concentrations of Aβ. These data support a role for PP2A methylation in contributing to AD risk and identify a potential therapeutic pathway that might be exploited to target the pathological actions of Aβ selectively.
Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli
Authors: Robinson Jonathan L. , Brynildsen Mark P.
Published: March 2016

Significance

Many bacteria use NO· dioxygenase and NO· reductase to defend themselves against immune-generated NO·. The importance and contribution of these systems under microaerobic conditions, which pathogens are likely to encounter within a host, remain poorly understood. We investigated the NO· response ofEscherichia colithroughout the microaerobic regime, and discovered conditions that largely disabled the NO· defenses ofE. coli, and environments where the [NO·] oscillated. Components found to comprise the oscillatory circuit are distributed broadly among bacterial species, suggesting that these dynamics could be a characteristic feature of how bacteria respond to NO· in low O2environments. In support of this hypothesis, analogous oscillations were observed in NO·-stressed cultures ofPseudomonas aeruginosaunder low O2conditions.
ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria
Authors: Corrigan Rebecca M. , Bellows Lauren E. , Wood Alison , Gründling Angelika
Published: March 2016

Significance

When bacteria encounter stresses such as nutrient deprivation, they react by switching on the stringent response, the effects of which are mediated by two nucleotides collectively referred to as (p)ppGpp. These nucleotides function by binding to target proteins, leading to bacterial cells shutting down active growth and entering a state that promotes survival. In
Staphylococcus aureus
, relatively little is known about the target proteins with which these nucleotides interact. In this work, a genome-wide nucleotide–protein interaction screen was used to identify protein targets of (p)ppGpp to fully establish the pathways these nucleotides control in Gram-positive bacteria. In doing so, we identify several previously unknown targets with roles in ribosomal assembly, cell growth, and antimicrobial tolerance.
Morphogenesis of 3D vascular networks is regulated by tensile forces
Authors: Rosenfeld Dekel , Landau Shira , Shandalov Yulia , Raindel Noa , Freiman Alina , Shor Erez , Blinder Yaron , Vandenburgh Herman H. , Mooney David J. , Levenberg Shulamit
Published: March 2016

Significance

Sorely lacking are techniques to engineer tissue grafts bearing a means to receive adequate blood supply during implantation and after integration with host tissue. Efforts to optimize graft tissue vascularization have manipulated multiple factors but have placed little focus on the role of mechanical forces in blood vessel network assembly. The present work assessed the impact of cell-induced and externally applied forces on the morphology of vessel networks within engineered tissue constructs. Network quality, directly correlated with force intensity and vessel orientation, was tunable by application of different patterns of force. Implantation of grafts bearing networks arranged to match those in the implant site is expected to improve graft integration prospects, as well as their long-term viability and strength.
Bacteroides fragilis
type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species
Authors: Chatzidaki-Livanis Maria , Geva-Zatorsky Naama , Comstock Laurie E.
Published: March 2016

Significance

Mechanisms of competition are not well-studied in the mammalian gut microbiota, especially among abundant species of this ecosystem. Theoretical models predict that antagonistic mechanisms should profoundly affect member fitness, yet identification and experimental analyses of such factors are few. Here we show that the abundant gut species
Bacteroides fragilis
produce T6SSs that deploy previously undescribed toxins able to antagonize numerous species of human gut Bacteroidales. We show that these systems are synthesized in the mammalian gut and allow a producing strain to outcompete a sensitive isogenic strain. Our data support that GA3 T6SSs likely allow the producing
B. fragilis
strain to create a protected niche in the human colon.
A mutualistic symbiosis between a parasitic mite and a pathogenic virus undermines honey bee immunity and health
Authors: Di Prisco Gennaro , Annoscia Desiderato , Margiotta Marina , Ferrara Rosalba , Varricchio Paola , Zanni Virginia , Caprio Emilio , Nazzi Francesco , Pennacchio Francesco
Published: March 2016

Significance

The parasitic mite
Varroa destructor
and the deformed wing virus (DWV) are linked in a mutualistic symbiosis. The mite acts as vector of the viral pathogen, whereas the DWV-induced immunosuppression in honey bees favors mite feeding and reproduction. This functional interaction underpins a rapidly escalating immunosuppression, which can be primed and/or aggravated by a wealth of stress factors that co-trigger colony losses. Our experimental results explain the pivotal role proposed for the
Varroa
–DWV association in the induction of honey bee colony losses. Here we provide a functional framework for studying the dynamics of this multifactorial syndrome and defining effective strategies to reduce its negative impact on the beekeeping industry.
Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization
Authors: Tan Kun , An Lei , Miao Kai , Ren Likun , Hou Zhuocheng , Tao Li , Zhang Zhenni , Wang Xiaodong , Xia Wei , Liu Jinghao , Wang Zhuqing , Xi Guangyin , Gao Shuai , Sui Linlin , Zhu De-Sheng , Wang Shumin , Wu Zhonghong , Bach Ingolf , Chen Dong-bao , Tian Jianhui
Published: March 2016

Significance

Sex ratio is an important indicator of reproductive health, and its skewing reflects disturbed embryonic development. This study focused on sex skewing, which has recently identified in human in vitro fertilization (IVF) babies. We reported herein that the skewed sex ratio in mouse IVF offspring was due to the impaired imprinted X chromosome inactivation via suppressing the ring finger protein 12 (
Rnf12
)/X-inactive specific transcript (
Xist
) pathway; the sex skewing can be corrected by overexpressing
Rnf12
or by supplementation of retinoic acid in embryo culture medium. Hence, our study not only identified a major epigenetic error responsible for sex skewing in IVF offspring, but also implicated a potential strategy for preventing sex skewing and IVF-associated complications by targeting erroneous epigenetic modifications induced by IVF.
Dynamic control of strand excision during human DNA mismatch repair
Authors: Jeon Yongmoon , Kim Daehyung , Martín-López Juana V. , Lee Ryanggeun , Oh Jungsic , Hanne Jeungphill , Fishel Richard , Lee Jong-Bong
Published: March 2016

Significance

The ensemble interactions between the human mismatch repair (MMR) components during mismatch-dependent DNA excision repair remain poorly characterized. We have detailed these interactions in real time to reveal new dynamic collaborations between the four evolutionarily conserved components that ultimately result in a complete MMR event. Our observations demonstrate the stochastic nature of an essential genome maintenance system that ultimately results in robust repair events.
Computer vision cracks the leaf code
Authors: Wilf Peter , Zhang Shengping , Chikkerur Sharat , Little Stefan A. , Wing Scott L. , Serre Thomas
Published: March 2016

Significance

The botanical value of angiosperm leaf shape and venation (“leaf architecture”) is well known, but the astounding complexity and variation of leaves have thwarted efforts to access this underused resource. This challenge is central for paleobotany because most angiosperm fossils are isolated, unidentified leaves. We here demonstrate that a computer vision algorithm trained on several thousand images of diverse cleared leaves successfully learns leaf-architectural features, then categorizes novel specimens into natural botanical groups above the species level. The system also produces heat maps to display the locations of numerous novel, informative leaf characters in a visually intuitive way. With assistance from computer vision, the systematic and paleobotanical value of leaves is ready to increase significantly.
Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis
Authors: Wang Guohao , Liu Xudong , Gaertig Marta A. , Li Shihua , Li Xiao-Jiang
Published: March 2016

Significance

Because of the toxicity gain of expanded polyglutamine (polyQ) repeats, many studies have used RNAi and other approaches to inactivate the mutant
HTT
gene in Huntington’s disease. However, Htt is essential for early embryonic development, and normal function of Htt in adult animals remains unknown. Using conditional Htt knockout mice, we found that loss of Htt causes the lethal phenotype only in postnatal mice but not in adult mice, and this early death is due to acute pancreatitis. Htt interacts with serine protease inhibitor Kazal-type 3 (Spink3) to inhibit trypsin activity in pancreatic cells and thus prevents acinar cell degeneration and pancreatitis. This age- and cell type-dependent function indicates the safety in knocking down neuronal HTT in adult brains for treating Huntington’s disease.
Posttranslational regulation of coordinated enzyme activities in the Pup-proteasome system
Authors: Elharar Yifat , Roth Ziv , Hecht Nir , Rotkopf Ron , Khalaila Isam , Gur Eyal
Published: March 2016

Significance

This work describes how a basic regulatory challenge, namely the balancing of two opposing activities of a single enzyme while coordinating these actions with the activity of another enzyme, is addressed in a biological system. In the Pup-proteasome system, the bacterial parallel of the ubiquitin-proteasome system, Pup modification by Dop (deamidase of Pup) is a prerequisite for pupylation by proteasome accessory factor A. Paradoxically, Dop also reverses pupylation through its ability to depupylate substrates. We show that this challenge is resolved posttranslationally by combining substrate discrimination based on molecular weight, and by regulating enzyme levels in response to external stimuli. These findings provide an example of how directionality and coordination of enzyme activities in a single pathway are regulated according to physiological requirements of the cell.
Prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses
Authors: Neher Richard A. , Bedford Trevor , Daniels Rodney S. , Russell Colin A. , Shraiman Boris I.
Published: March 2016

Significance

Humans mount an antibody-mediated immune response against influenza viruses that can be recalled. Nevertheless, individuals can suffer from recurrent influenza infections as viruses can change their antigenic properties by altering their surface glycoproteins. This antigenic evolution requires frequent update of seasonal influenza vaccines. To inform vaccine updates, laboratories that contribute to the World Health Organization Global Influenza Surveillance and Response System assess the antigenic phenotypes of circulating viruses. Based on the relationship of antigenic distance to genetic differences between viruses, we developed a model to interpret measured antigenic data and predict the properties of viruses that have not been characterized antigenically and explore the model’s value in predicting the future composition of influenza virus populations.
The source of high signal cooperativity in bacterial chemosensory arrays
Authors: Piñas Germán E. , Frank Vered , Vaknin Ady , Parkinson John S.
Published: March 2016

Significance

In
Escherichia coli
, chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW form a highly networked chemotaxis signaling array that clusters at the cell poles. Arrayed chemoreceptors control multiple CheA molecules in highly cooperative responses to chemoeffector ligands, but the molecular interactions responsible for this behavior are unknown. We found that lesions affecting the interface 2 interaction between CheW and the P5 domain of CheA caused severe array clustering defects and abolished response cooperativity, demonstrating that along with its critical structural role, interface 2 is the route for transmitting signaling-related conformational changes throughout the array. It should be possible to exploit interface 2 mutants to develop more incisive experimental approaches and theoretical models for investigating the signaling mechanisms of chemosensory arrays.
EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression
Authors: Lee Nara , Yario Therese A. , Gao Jessica S. , Steitz Joan A.
Published: March 2016

Significance

In recent years, next-generation sequencing has facilitated the discovery of thousands of nonprotein-coding RNAs (ncRNAs). Some of these ncRNAs have been shown to interact with transcription regulators and may thus form a new class of ncRNAs that function in controlling gene expression. Identifying proteins that interact with this class of ncRNAs will be instrumental in elucidating their poorly understood molecular mode of action. The ncRNA EBV-encoded RNA 2 (EBER2) expressed by the oncogenic Epstein–Barr virus interacts with the cellular transcription factor paired box protein 5 (PAX5) to impact viral gene expression. In this study, we identified additional functionally important protein components of the EBER2–PAX5 complex. Our findings pave the way for investigating whether other transcription-regulating ncRNAs use the same protein components to exert their function.
Estimating Riverwide Abundance of Juvenile Fish Populations: How Much Sampling is Enough?
Authors: Korman Josh , Schick Jody , Mossop Brent
Published: March 2016

Estimating riverwide abundance of juvenile fish populations is challenging because detection probability is typically low and juveniles can be patchily distributed over large areas. We used a hierarchical Bayesian model to estimate the abundance of juvenile steelhead Oncorhynchus mykiss in two rivers in British Columbia over 3 years based on a multigear, two-phase sampling design. These estimates were used to drive a simulation model to evaluate how the precision of abundance estimates varied with the number of single-pass index and mark–recapture sites that were sampled, the proportion of shoreline sampled, and the mean and variation of detection probability and fish density across sites. The extent of variation in fish densities across index sites was the most important factor influencing the precision of river-wide abundance estimates, and increasing the number of index sites was the best approach to reduce variability in abundance estimates. River size, which controls the proportion of habitat sampled for a given level of sampling effort, had a moderate effect on precision, but only when the extent of site-to-site variation in fish density was high. Factors affecting detection probability, such as the number of mark–recapture sites, the mean detection probability, or the extent of variation in detection probability across sites, had much less influence on precision of abundance estimates unless the proportion of river sampled was high. Hierarchical Bayesian models are no substitute for collecting informative data, but they improve our understanding of variance structure, which is critical for providing realistic estimates of uncertainty and designing informative and efficient sampling programs.

Received July 16, 2015; accepted October 7, 2015 Published online March 8, 2016
Impacts of Northern Pike on Stocked Rainbow Trout in Pactola Reservoir, South Dakota
Authors: Scheibel Natalie C. , Dembkowski Daniel J. , Davis Jacob L. , Chipps Steven R.
Published: March 2016

Establishment of nonnative Northern Pike Esox lucius in Pactola Reservoir, South Dakota, has prompted concern among biologists about the influence of this species on the lake's intensively managed salmonid fisheries. Ancedotal information suggests that catch rates of Rainbow Trout Oncorhynchus mykiss have declined while mean size and abundance of Northern Pike has increased, although quantitative information on diet and growth of the Northern Pike population is lacking. To address potential interactions between Northern Pike and Rainbow Trout, we assessed size-dependent predation by Northern Pike on Rainbow Trout and determined the relative energetic contribution of stocked Rainbow Trout to Northern Pike growth using bioenergetics modeling. Stable isotopes combined with traditional diet analyses revealed that smaller Northern Pike (<600 mm TL) consumed primarily centrarchids and Rainbow Smelt Osmerus mordax, and Rainbow Trout contributed less than 10% to their annual energy consumption. In contrast, larger Northern Pike (≥600 mm TL) consumed primarily Rainbow Trout, which accounted for 56% of their annual energy consumption. Combining estimates of Northern Pike predation with production costs of catchable-size Rainbow Trout revealed that annual economic losses ranged from US$15,259 to $24,801 per year. Over its lifespan, an age-10 Northern Pike was estimated to consume ~117 Rainbow Trout worth approximately $340. Thus, Northern Pike predation substantially influences salmonid management initiatives and is likely a primary factor contributing to reduced Rainbow Trout abundance and return to anglers in Pactola Reservoir. Strategies for reducing Northern Pike predation on Rainbow Trout include increasing the size of stocked fish or altering the timing and spatial distribution of stocking events.

Received June 5, 2015; accepted November 2, 2015 Published online March 8, 2016
Remote ischaemic preconditioning shortens QT intervals during exercise in healthy subjects
Authors: Caru Maxime , Lalonde François , Gravel Hugo , Daigle Chantal , Tournoux François , Jacquemet Vincent , Curnier Daniel
Published: March 2016

The protective action of remote ischaemic preconditioning (RIPC) has been demonstrated in the context of surgical interventions in cardiology. Application of RIPC to sports performance has been proposed, but its effect on the electrocardiogram (ECG) during exercise remains unknown. This exploratory study aims to measure the changes in ventricular repolarization observed during exercise following RIPC in healthy subjects. In an experimental randomized crossover study, 17 subjects underwent two bouts of constant load exercise tests at 75% and 115% of gas exchange threshold (GET). Prior to exercise, they were allocated to either control or RIPC intervention with four cycles of 5 min of ischaemia followed by 5 min of reperfusion. ECG was continuously recorded during the protocol. QT and RR intervals were measured every 30 s (on an average tracing of the preceding 10 s). Although the time course of RR intervals did not differ between the two interventions (p = .56 at 75% GET and p = .74 at 115% GET), a significant shortening of QT intervals (measured from Q onset to T end) was observed during exercise (mean ± standard deviation of RIPC vs. control: −32 ± 19 ms at 75% GET (p < .001) and −34 ± 12 ms at 115% GET (p < .001)) as well as during recovery (−21 ± 8 ms at 75% GET (p < .001) and −16 ± 11 ms at 115% GET (p < .001)). This effect was not present at rest. These RIPC‐related changes were clearly identifiable on the QT–RR loops after hysteresis reduction. RIPC therefore induces heart rate‐independent shortening of QT intervals that is revealed during exercise.
Arl2- and Msps-dependent microtubule growth governs asymmetric division
Authors: Chen Keng , Koe Chwee Tat , Xing Zhanyuan Benny , Tian Xiaolin , Rossi Fabrizio , Wang Cheng , Tang Quan , Zong Wenhui , Hong Wan Jin , Taneja Reshma , Yu Fengwei , Gonzalez Cayetano , Wu Chunlai , Endow Sharyn , Wang Hongyan
Published: March 2016

Asymmetric division of neural stem cells is a fundamental strategy to balance their self-renewal and differentiation. It is long thought that microtubules are not essential for cell polarity in asymmetrically dividing Drosophila melanogaster neuroblasts (NBs; neural stem cells). Here, we show that Drosophila ADP ribosylation factor like-2 (Arl2) and Msps, a known microtubule-binding protein, control cell polarity and spindle orientation of NBs. Upon arl2 RNA intereference, Arl2-GDP expression, or arl2 deletions, microtubule abnormalities and asymmetric division defects were observed. Conversely, overactivation of Arl2 leads to microtubule overgrowth and depletion of NBs. Arl2 regulates microtubule growth and asymmetric division through localizing Msps to the centrosomes in NBs. Moreover, Arl2 regulates dynein function and in turn centrosomal localization of D-TACC and Msps. Arl2 physically associates with tubulin cofactors C, D, and E. Arl2 functions together with tubulin-binding cofactor D to control microtubule growth, Msps localization, and NB self-renewal. Therefore, Arl2- and Msps-dependent microtubule growth is a new paradigm regulating asymmetric division of neural stem cells.
Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression
Authors: Jourdain Alexis A. , Boehm Erik , Maundrell Kinsey , Martinou Jean-Claude
Published: March 2016

In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized “mitochondrial RNA granules,” mitochondrial subdomains with an emerging role in the regulation of gene expression.
β3 integrin–mediated spreading induced by matrix-bound BMP-2 controls Smad signaling in a stiffness-independent manner
Authors: Fourel Laure , Valat Anne , Faurobert Eva , Guillot Raphael , Bourrin-Reynard Ingrid , Ren Kefeng , Lafanechère Laurence , Planus Emmanuelle , Picart Catherine , Albiges-Rizo Corinne
Published: March 2016

Understanding how cells integrate multiple signaling pathways to achieve specific cell differentiation is a challenging question in cell biology. We have explored the physiological presentation of BMP-2 by using a biomaterial that harbors tunable mechanical properties to promote localized BMP-2 signaling. We show that matrix-bound BMP-2 is sufficient to induce β3 integrin–dependent C2C12 cell spreading by overriding the soft signal of the biomaterial and impacting actin organization and adhesion site dynamics. In turn, αvβ3 integrin is required to mediate BMP-2–induced Smad signaling through a Cdc42–Src–FAK–ILK pathway. β3 integrin regulates a multistep process to control first BMP-2 receptor activity and second the inhibitory role of GSK3 on Smad signaling. Overall, our results show that BMP receptors and β3 integrin work together to control Smad signaling and tensional homeostasis, thereby coupling cell adhesion and fate commitment, two fundamental aspects of developmental biology and regenerative medicine.
Strategies to regulate transcription factor–mediated gene positioning and interchromosomal clustering at the nuclear periphery
Authors: Randise-Hinchliff Carlo , Coukos Robert , Sood Varun , Sumner Michael Chas , Zdraljevic Stefan , Meldi Sholl Lauren , Garvey Brickner Donna , Ahmed Sara , Watchmaker Lauren , Brickner Jason H.
Published: March 2016

In budding yeast, targeting of active genes to the nuclear pore complex (NPC) and interchromosomal clustering is mediated by transcription factor (TF) binding sites in the gene promoters. For example, the binding sites for the TFs Put3, Ste12, and Gcn4 are necessary and sufficient to promote positioning at the nuclear periphery and interchromosomal clustering. However, in all three cases, gene positioning and interchromosomal clustering are regulated. Under uninducing conditions, local recruitment of the Rpd3(L) histone deacetylase by transcriptional repressors blocks Put3 DNA binding. This is a general function of yeast repressors: 16 of 21 repressors blocked Put3-mediated subnuclear positioning; 11 of these required Rpd3. In contrast, Ste12-mediated gene positioning is regulated independently of DNA binding by mitogen-activated protein kinase phosphorylation of the Dig2 inhibitor, and Gcn4-dependent targeting is up-regulated by increasing Gcn4 protein levels. These different regulatory strategies provide either qualitative switch-like control or quantitative control of gene positioning over different time scales.
Lipid droplet–mediated ER homeostasis regulates autophagy and cell survival during starvation
Authors: Velázquez Ariadna P. , Tatsuta Takashi , Ghillebert Ruben , Drescher Ingmar , Graef Martin
Published: March 2016

Lipid droplets (LDs) are conserved organelles for intracellular neutral lipid storage. Recent studies suggest that LDs function as direct lipid sources for autophagy, a central catabolic process in homeostasis and stress response. Here, we demonstrate that LDs are dispensable as a membrane source for autophagy, but fulfill critical functions for endoplasmic reticulum (ER) homeostasis linked to autophagy regulation. In the absence of LDs, yeast cells display alterations in their phospholipid composition and fail to buffer de novo fatty acid (FA) synthesis causing chronic stress and morphologic changes in the ER. These defects compromise regulation of autophagy, including formation of multiple aberrant Atg8 puncta and drastically impaired autophagosome biogenesis, leading to severe defects in nutrient stress survival. Importantly, metabolically corrected phospholipid composition and improved FA resistance of LD-deficient cells cure autophagy and cell survival. Together, our findings provide novel insight into the complex interrelation between LD-mediated lipid homeostasis and the regulation of autophagy potentially relevant for neurodegenerative and metabolic diseases.
Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist
Authors: Sugawara Reiko , Lee Eun-Jung , Jang Min Seong , Jeun Eun-Ji , Hong Chun-Pyo , Kim Jung-Hwan , Park Areum , Yun Chang Ho , Hong Sung-Wook , Kim You-Me , Seoh Ju-Young , Jung YunJae , Surh Charles D. , Miyasaka Masayuki , Yang Bo-Gie , Jang Myoung Ho
Published: March 2016

Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down-regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the ΔdblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4+ T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1β. Moreover, small intestinal eosinophils isolated from IL-1Ra−deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra.
Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging
Authors: Tang Duozhuang , Tao Si , Chen Zhiyang , Koliesnik Ievgen Oleksandrovich , Calmes Philip Gerald , Hoerr Verena , Han Bing , Gebert Nadja , Zörnig Martin , Löffler Bettina , Morita Yohei , Rudolph Karl Lenhard
Published: March 2016

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways.
A treatment-planning comparison of three beam arrangement strategies for stereotactic body radiation therapy for centrally located lung tumors using volumetric-modulated arc therapy
Authors: Ishii Kentaro , Okada Wataru , Ogino Ryo , Kubo Kazuki , Kishimoto Shun , Nakahara Ryuta , Kawamorita Ryu , Ishii Yoshie , Tada Takuhito , Nakajima Toshifumi
Published: March 2016

The purpose of this study was to determine appropriate beam arrangement for volumetric-modulated arc therapy (VMAT)-based stereotactic body radiation therapy (SBRT) in the treatment of patients with centrally located lung tumors. Fifteen consecutive patients with centrally located lung tumors treated at our institution were enrolled. For each patient, three VMAT plans were generated using two coplanar partial arcs (CP VMAT), two non-coplanar partial arcs (NCP VMAT), and one coplanar full arc (Full VMAT). All plans were designed to deliver 70 Gy in 10 fractions. Target coverage and sparing of organs at risk (OARs) were compared across techniques. PTV coverage was almost identical for all approaches. The whole lung V 10Gy was significantly lower with CP VMAT plans than with NCP VMAT plans, whereas no significant differences in the mean lung dose, V 5Gy , V 20Gy or V 40Gy were observed. Full VMAT increased mean contralateral lung V 5Gy by 12.57% and 9.15% when compared with NCP VMAT and CP VMAT, respectively. Although NCP VMAT plans best achieved the dose–volume constraints for mediastinal OARs, the absolute differences in dose were small when compared with CP VMAT. These results suggest that partial-arc VMAT may be preferable to minimize unnecessary exposure to the contralateral lung, and use of NCP VMAT should be considered when the dose–volume constraints are not achieved by CP VMAT.
Tobacco Smoking Is Not Associated With Accelerated Liver Disease in Human Immunodeficiency Virus-Hepatitis C Coinfection: A Longitudinal Cohort Analysis
Authors: Costiniuk Cecilia T. , Brunet Laurence , Rollet-Kurhajec Kathleen C. , Cooper Curtis L. , Walmsley Sharon L. , Gill M. John , Martel-Laferriere Valérie , Klein Marina B.
Published: March 2016

Background.  Tobacco smoking has been shown to be an independent risk factor for liver fibrosis in hepatitis C virus (HCV) infection in some cross-sectional studies. No longitudinal study has confirmed this relationship, and the effect of tobacco exposure on liver fibrosis in human immunodeficiency virus (HIV)-HCV coinfected individuals is unknown.

Methods.  The study population consisted of participants from the Canadian Co-infection Cohort study (CTN 222), a multicenter longitudinal study of HIV-HCV coinfected individuals from 2003 to 2014. Data were analyzed for all participants who did not have significant fibrosis or end-stage liver disease (ESLD) at baseline. The association between time-updated tobacco exposure (ever vs nonsmokers and pack-years) and progression to significant liver fibrosis (defined as an aspartate-to-platelet ratio index [APRI] ≥1.5) or ESLD was assessed by pooled logistic regression.

Results.  Of 1072 participants included in the study, 978 (91%) had ever smoked, 817 (76%) were current smokers, and 161 (15%) were previous smokers. Tobacco exposure was not associated with accelerated progression to significant liver fibrosis nor with ESLD when comparing ever vs never smokers (odds ratio [OR] = 1.06, 95% confidence interval [CI], 0.43–1.69 and OR = 1.20, 95% CI, 0.21–2.18, respectively) or increases in pack-years smoked (OR = 1.05, 95% CI, 0.97–1.14 and OR = 0.94, 95% CI, 0.83–1.05, respectively). Both time-updated alcohol use in the previous 6 months and presence of detectable HCV ribonucleic acid were associated with APRI score ≥1.5.

Conclusions.  Tobacco exposure does not appear to be associated with accelerated progression of liver disease in this prospective study of HIV-HCV coinfected individuals.
Cell-Based Therapies for Lumbar Discogenic Low Back Pain
Authors: Wu Tao , Song Hai-xin , Dong Yan , Li Jian-hua
Published: March 2016

Study Design.

A systematic review and single-arm meta-analysis of clinical trials.

Objective.

To assess the efficacy of mesenchymal stem cells or chondrocyte in patients with discogenic low back pain.

Summary of Background Data.

There is no previous review evaluated the efficacy of mesenchymal stem cell or chondrocyte therapy in adults with discogenic low back pain.

Methods.

A comprehensive literature search was conducted on PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO, and Web of Science from database inception through on September 10th, 2015. We included clinical trials that evaluated stem cells or chondrocyte-based therapy in patients with discogenic back pain. The primary outcomes of interest were pain score and Oswestry Disability Index (ODI). We performed random-effects model meta-analyses to assess net changes in the same outcome variables. Heterogeneity between studies was estimated by I
2 statistic.

Results.

The initial search identified 1393 articles, of which 6 studies were eligible for this review. The pooled mean difference in pain score from baseline to follow-up points was 44.2 points decreased (95% CI: −61.8 to −26.5, P < 0.001, I
2 = 99.4%). Meanwhile, the pooled mean difference in ODI from baseline to follow-up points was 32.2 points decreased (95% CI: −41.6 to −22.9, P < 0.001, I
2 = 99.5%). No related adverse effects were reported by the included studies.

Conclusion.

Cell-based therapy is for patients who have discogenic low back pain associated with improved pain relief and ODI. More stringently designed randomized double-blind clinical trials with appropriately determined sample sizes will be needed to confirm its clinical efficacy and safety.

Level of Evidence: 4
Just add water: cannabinoid discrimination in a water T-maze with FAAH(−/−) and FAAH(+/+) mice
Authors: Wiley Jenny L. , Lefever Timothy W. , Pulley Nikita S. , Marusich Julie A. , Cravatt Benjamin F. , Lichtman Aron H.
Published: March 2016

Incomplete overlap in the discriminative stimulus effects of Δ9-tetrahydrocannabinol (THC) and the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol has been reported in food-reinforced tasks. The aim of this study was to examine cannabinoid discriminative stimulus effects in a nonappetitive procedure. Adult male mice lacking the gene for AEA’s major metabolic enzyme, fatty acid amide hydrolase (FAAH), and FAAH(+/+) mice were trained to discriminate THC or AEA in a water T-maze, in which the response was swimming to an escape platform on the injection-appropriate side. JZL184, a monoacylglycerol lipase inhibitor, was also tested. FAAH(−/−) mice showed faster acquisition than FAAH(+/+) mice. THC and AEA fully substituted, with only minor cross-procedure potency variations. Incomplete substitution of JZL184 was observed in THC-trained FAAH(−/−) mice in the water-maze task, as contrasted with full substitution in a food-reinforced nose-poke procedure. Stress-induced changes in AEA and/or 2-arachidonoylglycerol concentrations in the brain may have mediated this attenuation. JZL184 also partially substituted in AEA-trained FAAH(−/−) mice in the water maze, suggesting incomplete overlap in the stimulus effects of AEA and JZL184. Through the use of a novel water-maze procedure, the present study supports the work of previous behavioral pharmacologists in showing the robustness of the discrimination paradigm.
Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy
Authors: Simon James A. , Laliberté François , Duh Mei Sheng , Pilon Dominic , Kahler Kristijan H. , Nyirady Judit , Davis Pamela J. , Lefebvre Patrick
Published: March 2016

Objective:

To evaluate the risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) complications, and assess healthcare costs in menopausal women using an estradiol transdermal system versus oral estrogen therapy (ET).

Methods:

Health insurance claims from 60 self-insured US companies from 1999 to 2011 were analyzed. Women at least 50 years of age, newly initiated on transdermal or oral ET, were included. Cohorts were matched 1:1 based on exact factors and propensity score-matching methods. The incidence rate ratios (IRRs) of CVD complications, as well as VTE and other CVD events separately, were assessed through conditional Poisson models. Cohorts were also compared for healthcare costs using linear regression models to assess per-patient per-month cost differences. Confidence intervals (CIs) and P values were determined using a nonparametric method for cost outcomes.

Results:

From each cohort, 2,551 users were matched to form the study population. A total of 274 transdermal ET users developed CVD complications compared with 316 women in the oral ET cohort (adjusted IRR 0.81; 95% CI, 0.67-0.99). Transdermal ET users also incurred lower adjusted all-cause and VTE/CVD-related healthcare costs relative to oral ET users (all-cause per-patient per-month cost difference [95% CI] = $41 [−34; 137], P = 0.342).

Conclusions:

This large matched-cohort study based on real-world data suggests that women receiving transdermal ET have significantly lower incidences of CVD events compared with those receiving oral ET, and that they also incur lower healthcare costs.
COAGULASE-NEGATIVE STAPHYLOCOCCUS-INDUCED FROSTED BRANCH ANGIITIS AFTER INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION
Authors: Gensure Rebekah H. , Hsu Jason , Federman Jay , Park Carl , Spirn Marc J.
Published: March 2016

Purpose:

To describe a case of frosted branch angiitis after intravitreal ranibizumab injection.

Methods:

Retrospective chart review.

Results:

A patient with a history of neovascular age-related macular degeneration underwent intravitreal ranibizumab injection and subsequently developed coagulase-negative Staphylococcus endophthalmitis with findings of frosted branch angiitis.

Conclusion:

Endophthalmitis presenting as frosted branch angiitis is a rare complication after intravitreal anti–vascular endothelial growth factor injection. Early recognition is critical to optimize outcomes. To our knowledge, this is the second reported case of frosted branch angiitis as a presentation of endophthalmitis with coagulase-negative Staphylococcus.