bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-specific,pdfr-1-dependent modulation of pheromone avoidance by food abundance enables flexibility inC. elegansforaging behavior
Authors: Luo Jintao , Portman Douglas S.
Published: March 2021

To make adaptive feeding and foraging decisions, animals must integrate diverse sensory streams with multiple dimensions of internal state. InC. elegans, foraging and dispersal behaviors are influenced by food abundance, population density, and biological sex, but the neural and genetic mechanisms that integrate these signals are poorly understood. Here, by systematically varying food abundance, we find that chronic avoidance of the population-density pheromone ascr#3 is modulated by food thickness, such that hermaphrodites avoid ascr#3 only when food is scarce. The integration of food and pheromone signals requires the conserved neuropeptide receptor PDFR-1, aspdfr-1mutant hermaphrodites display strong ascr#3 avoidance even when food is abundant. Conversely, increasing PDFR-1 signaling inhibits ascr#3 aversion when food is sparse, indicating that this signal encodes information about food abundance. In both wild-type andpdfr-1hermaphrodites, chronic ascr#3 avoidance requires the ASI sensory neurons. In contrast, PDFR-1 acts in interneurons, suggesting that it modulates processing of the ascr#3 signal. Although a sex-shared mechanism mediates ascr#3 avoidance, food thickness modulates this behavior only in hermaphrodites, indicating that PDFR-1 signaling has distinct functions in the two sexes. Supporting the idea that this mechanism modulates foraging behavior, ascr#3 promotes ASI-dependent dispersal of hermaphrodites from food, an effect that is markedly enhanced when food is scarce. Together, these findings identify a neurogenetic mechanism that sex-specifically integrates population and food abundance, two important dimensions of environmental quality, to optimize foraging decisions. Further, they suggest that modulation of attention to sensory signals could be an ancient, conserved function ofpdfr-1.
Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Rats
Authors: Nawreen Nawshaba , Baccei Mark L , Herman James P
Published: March 2021

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed one week of recovery following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.

Graphical Abstract

SPS causes a decrease in excitatory synaptic drive and intrinsic excitability of IL pyramidal neurons.
Inducible expression of Oct-3/4 reveals synergy with Klf4 in targeting Cyclin A2 to enhance proliferation during early reprogramming
Authors: Zaveri Lamuk , Dhawan Jyotsna
Published: March 2021

During reprogramming of somatic cells, heightened proliferation is one of the earliest changes observed. While other early events such as mesenchymal-to-epithelial transition have been well studied, the mechanisms by which the cell cycle switches from a slow cycling state to a faster cycling state are still incompletely understood. To investigate the role of Oct-3/4 in this early feature of reprogramming, we created a 4-Hydroxytamoxifen dependent Oct-3/4 Estrogen Receptor fusion (OctER). We show that OctER can substitute for Oct-3/4 to reprogram mouse embryonic fibroblasts to induced pluripotent stem cells. While over-expression of OctER or Klf4 individually did not affect cell proliferation, in combination, these factors hasten the cell cycle, in a tamoxifen dose-dependent manner, supporting a key role for OctER. Oct-3/4 + Klf4 increased proliferation by enhancing expression of Cyclin A2. We verified occupancy of endogenous Oct-3/4 and Klf4 at bioinformatically identified binding sites in the Cyclin A2 promoter in mouse embryonic stem cells (mESC). Using inducible OctER along with Klf4, we show dose-dependent induction of Cyclin A2 promoter-reporter activity and mRNA levels. Taken together, our results provide further evidence of the interdependence of pluripotency and the rapid cell cycle seen in mESC, and identify CyclinA2 as a key early target.
Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways
Authors: Pezzulo Alejandro A. , Thurman Andrew L. , Li Xiaopeng , Villacreses Raul , Yu Wenjie , Mather Steven E. , Romano-Ibarra Guillermo S. , Meyerholz David K. , Stoltz David A. , Welsh Michael J. , Thornell Ian M. , Zabner Joseph
Published: March 2021

The small airways of humans are affected early in several lung diseases. However, because they are relatively inaccessible, little is known about the epithelial cells that line these airways. We performed a single cell RNA-seq census of small and large airways of wild-type pigs and pigs with disrupted cystic fibrosis transmembrane conductance regulator (CFTR) gene. The sequencing data showed that small airway epithelia had similar major cell types as large airways but no ionocytes; moreover, lack ofCFTRexpression had minimal effect on the transcriptome. Small airway epithelial cells expressed a different transcriptome than large airway cells. Quantitative immunohistochemistry showed that small airway basal cells participate in epithelial barrier function. Finally, sequencing data and in vitro electrophysiologic studies suggest that small airway epithelia have a water and ion transport advantage. Our data highlight the archetypal nature of basal, secretory, and ciliated airway cells with location-dependent gene expression and function.
Programming Cell-Free Biosensors with DNA Strand Displacement Circuits
Authors: Jung Jaeyoung K. , Alam Khalid K. , Lucks Julius B.
Published: March 2021

Cell-free biosensors are emerging as powerful platforms for monitoring human and environmental health. Here, we expand the capabilities of biosensors by interfacing their outputs with toehold-mediated strand displacement circuits, a dynamic DNA nanotechnology that enables molecular computation through programmable interactions between nucleic acid strands. We develop design rules for interfacing biosensors with strand displacement circuits, show that these circuits allow fine-tuning of reaction kinetics and faster response times, and demonstrate a circuit that acts like an analog-to-digital converter to create a series of binary outputs that encode the concentration range of the target molecule being detected. We believe this work establishes a pathway to create “smart” diagnostics that use molecular computations to enhance the speed, robustness and utility of biosensors.
Sulfonated rhodamines as impermeable labelling substrates for cell surface protein visualization
Authors: Birke Ramona , Ast Julia , Roosen Dorien A. , Mathes Bettina , Roßmann Kilian , Huhn Christiane , Jones Ben , Lehmann Martin , Haucke Volker , Hodson David J. , Broichhagen Johannes
Published: March 2021

Sulfonated rhodamines that endow xanthene dyes with cellular impermeability are presented. We fuse charged sulfonates to red and far-red dyes to obtain Sulfo549 and Sulfo646, respectively, and further link these to SNAP- and Halo-tag substrates for protein self-labelling. Cellular impermeability is validated in live cell imaging experiments in transfected HEK cells and neurons derived from induced pluripotent stem cells (iPSCs). Lastly, we show that Sulfo646 is amenable to STED nanoscopy by recording membranes of SNAP/Halo-surface-labelled human iPSC-derived neuronal axons. We therefore provide an avenue for rendering dyes impermeable for exclusive extracellular visualization via self-labelling protein tags.
Precise measurements of chromatin diffusion dynamics by modeling using Gaussian processes
Authors: Oliveira Guilherme M. , Oravecz Attila , Kobi Dominique , Maroquenne Manon , Bystricky Kerstin , Sexton Tom , Molina Nacho
Published: March 2021

The spatiotemporal organization of chromatin influences many nuclear processes: from chromo-some segregation to transcriptional regulation. To get a deeper understanding of these processes it is essential to go beyond static viewpoints of chromosome structures, and to accurately characterize chromatin mobility and its diffusion properties. Here, we present GP-FBM: a new computational framework based on Gaussian processes and fractional Brownian motion to analyze and extract diffusion properties from stochastic trajectories of labeled chromatin loci. GP-FBM is able to optimally use the higher-order correlations present in the data and therefore outperforms existing methods. Furthermore, GP-FBM is able to extrapolate trajectories from missing data and account for substrate movement automatically. Using our method we show that diffusive chromatin diffusion properties are surprisingly similar in interphase and mitosis in mouse embryonic stem cells. Moreover, we observe surprising heterogeneity in local chromatin dynamics, which correlates with transcriptional activity. We also present GP-Tool, a user-friendly graphical interface to facilitate the use of GP-FBM by the research community for future studies of nuclear dynamics.
Actin filament alignment causes mechanical hysteresis in cross-linked networks
Authors: Scheff Danielle R. , Redford Steven A. , Lorpaiboon Chatipat , Majumdar Sayantan , Dinner Aaron R. , Gardel Margaret L.
Published: March 2021

Cells dynamically control their material properties through remodeling of the actin cytoskeleton, an assembly of cross-linked networks and bundles formed from the biopolymer actin. We recently found that cross-linked networks of actin filaments reconstituted in vitro can exhibit adaptive behavior and thus serve as a model system to understand the underlying mechanisms of mechanical adaptation of the cytoskeleton. In these networks, training, in the form of applied shear stress, can induce asymmetry in the nonlinear elasticity. Here, we explore control over this mechanical hysteresis by tuning the concentration and mechanical properties of cross-linking proteins in both experimental and simulated networks. We find that this effect depends on two conditions: the initial network must exhibit nonlinear strain stiffening, and filaments in the network must be able to reorient during training. Hysteresis depends strongly and non-monotonically on cross-linker concentration, with a peak at moderate concentrations. In contrast, at low concentrations, where the network does not strain stiffen, or at high concentrations, where filaments are less able to rearrange, there is little response to training. Additionally, we investigate the effect of changing cross-linker properties and find that longer or more flexible cross-linkers enhance hysteresis. Remarkably plotting hysteresis against alignment after training yields a single curve regardless of the physical properties or concentration of the cross-linkers.
DNA Methylation Networks Underlying Mammalian Traits
Authors: Haghani A. , Lu A.T. , Li C.Z. , Robeck T.R. , Belov K. , Breeze C.E. , Brooke R.T. , Clarke S. , Faulkes C.G. , Fei Z. , Ferguson S.H. , Finno C.J. , Gladyshev V.N. , Gorbunova V. , Goya R.G. , Hogan A.N. , Hogg C.J. , Hore T.A. , Kiaris H. , Kordowitzki P. , Banks G. , Koski W.R. , Mozhui K. , Naderi A. , Ostrander E.A. , Parsons K.M. , Plassais J. , Robbins J. , Sears K.E. , Seluanov A. , Steinman K.J. , Szladovits B. , Thompson M.J. , Villar D. , Wang N. , Wilkinson G.S. , Young B.G. , Zhang J. , Zoller J.A. , Ernst J. , Yang X.W. , Raj K. , Horvath S.
Published: March 2021

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to constructphyloepigenetictrees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.
Short communication: Efficacy of two commercial disinfectants onPaenibacillus larvaespores
Authors: Kiriamburi Joseph , Muturi Jamleck , Mugweru Julius , Forsgren Eva , Nilsson Anna
Published: March 2021

SHORT SUMMARY

Paenibacillus larvaeis a spore-forming bacterium causing American foulbrood (AFB) in honey bee larvae. The remains of a diseased larva contains billions of extremely resilientP. larvaespores viable for decades. Burning clinically symptomatic colonies is widely considered the only workable strategy to prevent further spread of the disease, and the management practices used for decontamination requires high concentrations of chemicals or special equipment.

The aim of this study was to test and compare the biocidal effect of two commercially available disinfectants, “ Disinfection for beekeeping” and Virkon S onP. larvae. The two products were applied toP. larvaespores in suspension as well as inoculated on two common beehive materials, wood and styrofoam.

“ Disinfection for beekeeping” had a 100 % biocidal effect onP. larvaespores in suspension compared to 87.0-88.6 % for Virkon S which, however, had a significantly better effect onP. larvaeon styrofoam. The two disinfectants had similar effect on infected wood material.
Sex-specific interactions between procedural and deliberative decision-making systems in a mouse model of Alzheimer’s disease
Authors: Anderson Rachel , Hart Damyan W. , Sweis Brian , Sherman Mathew A. , Thomas Mark J. , Redish A. David , Lesné Sylvain E.
Published: March 2021

A central question in aging and Alzheimer’s disease (AD) is when and how neural substrates underlying decision-making are altered. Here we show that while APP mice, a commonly used mouse model of AD, were able to learn Restaurant Row, a complex neuroeconomic decision-making task, they were significantly impaired in procedural, habit-forming, aspects of cognition and relied heavily on deliberation when making decisions. Surprisingly, these behavioral changes are associated with amyloid-beta (Aβ) pathology and network remodeling in the striatum, a key brain region involved in procedural cognition. Furthermore, APP mice and control mice relied on distinct sex-specific strategies in this neuroeconomic task. These findings provide foundational pillars to examine how aging and age-related neurodegenerative diseases impact decision-making across sexes. They also highlight the need for complex behavioral tasks that allow for the dissociation of competing neurally-distinct decision-making circuits to get an accurate picture of changes in neurodegenerative models of human disease.
Meiotic Cas9 expression mediates genotype conversion in the male and female mouse germline
Authors: Weitzel Alexander J. , Grunwald Hannah A. , Levina Rimma , Gantz Valentino M. , Hedrick Stephen M. , Bier Ethan , Cooper Kimberly L.
Published: March 2021

Highly efficient genotype conversion systems have potential to facilitate the study of complex genetic traits using laboratory mice and to limit loss of biodiversity and disease transmission caused by wild rodent populations. We previously showed that such a system of genotype conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double strand DNA break is feasible in the female mouse germline. In the male germline, however, all double strand breaks were instead repaired by end joining mechanisms to form an ‘insertion/deletion’ (indel) mutation. These observations suggested that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology directed repair (HDR) mechanisms predominate. Here, using a Cas9 knock-in allele at theSpo11locus, we show that meiotic expression of Cas9 does indeed mediate genotype conversion in the male as well as in the female germline. However, the low frequency of both HDR and indel mutation in both male and female germlines suggests that Cas9 may be expressed from theSpo11locus at levels too low for efficient double strand DNA break formation. We suggest that more robust Cas9 expression initiated during early meiosis I may improve the efficiency of genotype conversion and further increase the rate of ‘super-Mendelian’ inheritance from both male and female mice.
GdDO3NI allows imaging of hypoxia after brain injury
Authors: Moghadas Babak , Bharadwaj Vimala N. , Tobey John P. , Tian Yanqing , Stabenfeldt Sarah E. , Kodibagkar Vikram D.
Published: March 2021

Purpose

In this study, we use the hypoxia targeting agent (GdDO3NI, a nitroimidazole-based T1MRI contrast agent) for imaging hypoxia in the injured brain after experimental traumatic brain injury (TBI) using magnetic resonance imaging (MRI), and validate the results with immunohistochemistry (IHC) using pimonidazole.

Methods

TBI induced mice (controlled cortical impact model) were imaged at 7T using a T2weighted fast spin-echo sequence to estimate the extent of the injury. The mice were then were intravenously injected with either conventional T1agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (n=5 for each cohort) along with pimonidazole (60 mg/kg). Mice were imaged pre- and post-contrast using a T1-weighted spin-echo sequence for three hours. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post imaging for immunohistochemical analysis.

Results

GdDO3NI is retained in the injury region for up to 3 hours post-injection (p< 0.05 compared to gadoteridol) while it rapidly clears out of the muscle region. On the other hand, conventional MRI contrast agent gadoteridol clears out of both the injury region and muscle rapidly, although with a relatively more delayed wash out in the injury region. Minimal contrast enhancement was seen for both agents in the contralateral hemisphere. Pimonidazole staining confirms the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort shows good agreement with MRI contrast enhancement.

Conclusion

GdDO3NI was successfully shown to visualize hypoxia in the brain post-TBI using T1-wt MRI.
Identification of anthracnose (Colletotrichum lentis) race 1 resistance loci in lentil by integrating linkage mapping and a genome-wide association study
Authors: Gela Tadesse S. , Ramsay Larissa , Haile Teketel A. , Vandenberg Albert , Bett Kirstin E.
Published: March 2021

Anthracnose, caused byColletotrichum lentis, is a devastating disease of lentil in Western Canada. Growing resistant lentil cultivars is the most cost-effective and environmentally friendly approach to prevent seed yield losses that can exceed 70%. To identify loci conferring resistance to anthracnose race 1 in lentil, biparental quantitative trait loci (QTL) mapping of two recombinant inbred line (RIL) populations was integrated with a genome-wide association study (GWAS) using 200 diverse lentil accessions from a lentil diversity panel (LDP). A major-effect QTL (qAnt1.Lc-3) conferring resistance to race 1 was mapped to lentil chromosome 3 and co-located on the lentil physical map for both RIL populations. Clusters of candidate nucleotide binding-leucine-rich repeats (NB-LRR) and other defense-related genes were uncovered within the QTL region. A GWAS detected 14 significant SNP markers associated with race 1 resistance on chromosomes 3, 4, 5, and 6. The most significant GWAS SNPs on chromosome 3 supportedqAnt1.Lc-3 and delineated a region of 1.6 Mb containing candidate resistance genes. The identified SNP markers can be directly applied in marker-assisted selection to accelerate the introgression of race 1 resistance in lentil breeding.
Characterization of anAgarophyton chilenseoleoresin containing PPARγ natural ligands with insulin-sensitizing effects in a C57BL/6J mouse model of diet-induced obesity and antioxidant activityin Caenorhabditis elegans
Authors: Pinto Claudio , Ibañez María Raquel , Loyola Gloria , León Luisa , Salvatore Yasmin , Gonzalez Carla , Barraza Victor , Castañeda Francisco , Aldunate Rebeca , Contreras-Porcia Loretto , Fuenzalida Karen , Bronfman Francisca C
Published: March 2021

The biomedical potential of the edible red seaweedAgarophyton chilense(formerGracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPARγ nuclear receptor. PPARγ is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. TZDs medical use is limited due to undesired side effects, the fact that it has triggered the search for partial agonists without the TZDs side effects.

We producedA.chilenseoleoresin (Gracilex®) that induces the activation of PPARγ without inducing adipocyte differentiation, similar to PPARγ partial agonists. In a model of high-fat diet-induced obesity in male mice, we showed that treatment withGracilex®improves insulin sensitivity, normalizing altered glucose and insulin parameters.Gracilex®was enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as ß-carotene and tocopherols.Gracilex®possesses antioxidant activity in vitro (CUPRAC) and increased the antioxidant capacityin vivoinCaenorhabditis elegans.These findings support the idea thatGracilex®is an excellent source of healthy lipids targeting PPARγ with antioxidant activity and a high nutraceutical value.
Wheels within wheels, Nested Function-value Traits as a Tool for Modeling Ontogeny
Authors: Hodge John G. , Doust Andrew N.
Published: March 2021

Plant morphologies exhibit a wide array of outcomes that have evolved as a consequence adapting to a wide array of ecological pressures. These disparate morphologies have provided a rich field for comparative morphologists, developmental biologists, and geneticists to explore. Ultimately the array of variation observed in nature across different plant species is built on the same functional unit, the phytomer, which is composed of a leaf, a node, and an internode. Sequentially produced phytomers exhibit heteroblasty, that is, a gradual or abrupt change in shape, either due to size changes or changes due to reproductive phase. The progression of shape change over time is often indirectly measured by sampling several stages of plant growth and comparing allometric relationships between shape variables. However, a more precise method is to use an absolute time scale and measure shape change of sequential organs directly. In this study we use such time-dependent measurements to build a general model of organ growth for several Setaria genotypes, for both leaves and internodes. We term this the second-order function-value trait (2FVT) model, because it generalizes individual function-value trait models generated for each organ. This model reduces phenotypic noise by averaging the general trend of ontogeny and provides a quantitative tool to describe where and when phenotypic shifts occur during the ontogenies of different genotypes. The ability to recognize how ontogenetic variation is distributed within equivalent positions of the body plan at the interspecific level can be used as a tool to explore various questions related to growth and form in plants both for comparative morphology and developmental genetics.
Case study of a rhizosphere microbiome assay on a bamboo rhizome with excessive shoots
Authors: Cui Fuqiang , Yang Yifan , Ye Mengyuan , Wei Wei , Huang Wenqian , Wu Ying , Jiao Xi , Ye Xiaoxue , Zhou Shutong , Hu Zhubing , Gui Renyi , Wu Wenwu , Yrjälä Kim , Overmyer Kirk , Liu Shenkui
Published: March 2021

Young Moso bamboo shoots are a very popular seasonal food. Bamboo is an important source of income for farmers and the value for cultivation has recently been estimated to $30,000 per hectare. A rare and valuable phenomenon has recently appeared where dozens of adjacent buds within a single Moso bamboo rhizome have grown into shoots. Due to its rarity, this phenomenon, which is of practical importance for the production of edible shoots, has not been scientifically studied. We report the occurrence of a rhizome with 18 shoots, of which the microbiome were analyzed, using rhizomes having one or no shoots as controls. The community of prokaryotes, but not fungi, correlated with the shoot numbers.Burkholderiawas the most abundant genus, which negatively correlated with rhizome shoot number, whileClostridiaandKtedonobacteriapositively correlated with many shoots. TwoBurkholderiastrains were isolated and their plant-growth promoting activity was tested. The isolatedBurkholderiastrains attenuated the growth of bamboo seedlings. Analysis of collected events of enhanced shoot production in China showed no evidence that enhanced shoot development was heritable. Overall, our data provides a firsthand study on excessive shoot development of bamboo.
fmr1mutation interacts with sensory experience to alter the early development of behavior and sensory coding in zebrafish
Authors: Zhu Shuyu , McCullough Michael , Pujic Zac , Sibberas Jordan , Sun Biao , Bucknall Bianca , Avitan Lilach , Goodhill Geoffrey J
Published: March 2021

While Autism Spectrum Disorders (ASDs) are developmental in origin little is known about how they affect the early development of behavior and sensory coding, or how this is modulated by the sensory environment. The most common inherited form of autism is Fragile X syndrome, caused by a mutation inFMR1. Here we show that zebrafishfmr1-/-mutant larvae raised in a naturalistic visual environment display early deficits in hunting behavior, tectal map development, tectal network properties and decoding of spatial stimuli. However when given a choice they preferred an environment with reduced visual stimulation, and rearing them in this environment improved these metrics. Olderfmr1-/-fish showed differences in social behavior, spending more time observing a conspecific, but responding more slowly to social cues. Together these results help reveal howfmr1-/-changes the early development of vertebrate brain function, and how manipulating the environment could potentially help reduce these changes.
The Fragile X Mental Retardation Protein protects the lung from xenobiotic stress by facilitating the Integrated Stress Response
Authors: Basu Deblina Sain , Bhavsar Rital , Gulami Imtiyaz , Lingamallu Sai Manoz , Muddashetty Ravi , Veeranna Chandrakanth , Chattarji Sumantra , Thimmulappa Rajesh , Bhattacharya Aditi , Guha Arjun
Published: March 2021

Stress response pathways protect the lung from the damaging effects of environmental toxicants. Here we investigate the role of the Fragile X Mental Retardation Protein (FMRP), a multifunctional protein implicated in stress responses, in the lung. We report that FMRP is expressed in murine and human lungs, in the airways and more broadly. Analysis of airway stress responses in mice and in a murine cell lineex vivo,using the well-established Naphthalene (Nap) injury model, reveals that FMRP-deficient cells exhibit increased expression of markers of oxidative and genotoxic stress and increased cell death. We find that FMRP-deficient cells fail to actuate the Integrated Stress Response Pathway (ISR) and upregulate the transcription factor ATF4. Knockdown of ATF4 expression phenocopies the loss of FMRP. We extend our analysis of the role of FMRP to human bronchial BEAS-2B cells, using a 9, 10-Phenanthrenequinone air pollutant model, to find that FMRP-deficient BEAS-2B also fail to actuate the ISR and exhibit greater susceptibility. Taken together, our data suggest that FMRP has a conserved role in protecting the airways by facilitating the ISR.
Function of theVibrioPomB plug region based on the stator rotation model for bacterial flagellar motor
Authors: Homma Michio , Terashima Hiroyuki , Koiwa Hiroaki , Kojima Seiji
Published: March 2021

Bacterial flagella are the only real rotational motor organs in the biological world. The spiral-shaped flagellar filaments that extend from the cell surface rotate like a screw to create a propulsive force. The base of the flagellar filament has a protein motor consisting of a stator and a rotor embedded in the membrane. The motor part has stators composed of two types of membrane subunits, PomA(MotA) and PomB(MotB), which are energy converters coupled to the ion flow that assemble around the rotor. Recently, structures of the stator, in which two molecules of MotB stuck in the center of the MotA ring made of five molecules, were reported and a model in which the MotA ring rotates with respect to MotB, which is coupled to the influx of ions, was proposed. We focused on theVibrioPomB plug region, which has been reported to control the activation of flagellar motors. We searched for the plug region, which is the interacting region, through site-directed photo-cross-linking and disulfide cross-linking experiments. Our results demonstrated that it interacts with the extracellular short loop region of PomA, which is between transmembrane 3 and 4. Although the motor halted following cross-linking, its function was recovered with a reducing reagent that disrupted the disulfide bond. Our results support the hypothesis, which has been inferred from the stator structure, that the plug region terminates the ion inflow by stopping the rotation of the rotor.

Importance

The flagellar biological motor resembles a mechanical motor, which is composed of stator and rotor and where the rotational force is transmitted by gear-like movements. We hypothesized that the flagellar the rotation of stator that the pentamer of A subunits revolves around the axis of the B subunit dimer with ion flow. The plug region of the B subunit has been shown to regulate the ion flow. Herein, we demonstrated that the ion flow was terminated by the crosslinking between the plug region and the A subunit. These finding support the rotation hypothesis and explain the role of the plug region in terminating the rotation.
Estimating the elevated transmissibility of the B.1.1.7 strain over previously circulating strains in England using GISAID sequence frequencies
Authors: Piantham Chayada , Linton Natalie M. , Nishiura Hiroshi , Ito Kimihito
Published: March 2021

The B.1.1.7 strain, also referred to as Alpha variant, is a variant strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Alpha variant is considered to possess higher transmissibility compared to the strains previously circulating in England. This paper proposes a new method to estimate the selective advantage of a mutant strain over another strain using the time course of strain frequencies and the distribution of the serial interval of infections. This method allows the instantaneous reproduction numbers of infections to vary over calendar time. The proposed method also assumes that the selective advantage of a mutant strain over previously circulating strains is constant. Applying the method to SARS-CoV-2 sequence data from England, the instantaneous reproduction number of the B.1.1.7 strain was estimated to be 26.6–45.9% higher than previously circulating strains in England. This result indicates that control measures should be strengthened by 26.6–45.9% when the B.1.1.7 strain is newly introduced to a country where viruses with similar transmissibility to the preexisting strain in England are predominant.
Machine-Learning Powered Optoacoustic Sensor for Diabetes Progression
Authors: Mohajerani Pouyan , Aguirre Juan , Omar Murad , He Hailong , Karlas Angelos , Fasoula Nikolina-Alexia , Lutz Jessica , Kallmayer Michael , Eckstein Hans-Henning , Ziegler Anette-Gabriele , Füchtenbusch Martin , Ntziachristos Vasilis
Published: March 2021

The assessment of diabetes severity relies primarily on a count of clinical complications to empirically characterize disease. Disease staging based on clinical complications also employs a scoring system that may not be optimally suited for analysis of earlier stages of diabetes development or for monitoring smaller increments of disease progress with high precision. We propose a novel sensor, which goes beyond the abilities of current state-of-the-art approaches and introduces a new concept in the assessment of biomedical markers by means of ultra-broadband optoacoustic detection. Being insensitive to photon scattering, the new sensor can resolve optical biomarkers in fine detail and as a function of depth and relates epidermal and dermal morphological and micro-vascular density features to diabetes state. We demonstrate basic sensor characteristics in phantoms and examine the novel sensing concept presented in a pilot study using data from 86 participants (20 healthy and 66 diabetic) at an ultra-wide optoacoustic bandwidth of 120 MHz. Machine learning based on ensemble trees was developed and trained in a supervised fashion and subsequently used to examine the relation of sensor data to disease severity, in particular as it associates to diabetes without complications vs. diabetic neuropathy or atherosclerotic cardiovascular disease. We also investigated the sensor performance in relation to HbA1C values. The proposed method achieved statistically significant detection in all different patient groups. The effect of technical parameters, in particular sensor area size and the time window of optoacoustic signals used in data training were also examined in measurements from phantoms and humans. We discuss how optoacoustic sensors fundamentally solve limitations present in optical sensing and, empowered by machine learning, open a new chapter in non-invasive portable sensing for biomedical applications.
High risk of patient self-inflicted lung injury in COVID-19 with frequently encountered spontaneous breathing patterns: a computational modelling study
Authors: Weaver Liam , Das Anup , Saffaran Sina , Yehya Nadir , Scott Timothy E. , Chikhani Marc , Laffey John G. , Hardman Jonathan G. , Camporota Luigi , Bates Declan G.
Published: March 2021

Background

There is on-going controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute hypoxaemic respiratory failure. However, direct clinical evidence linking increased inspiratory effort to lung injury is scarce. We adapted a computational simulator of cardiopulmonary pathophysiology to quantify the mechanical forces that could lead to P-SILI at different levels of respiratory effort. In accordance with recent data, the simulator parameters were manually adjusted to generate a population of 10 patients that recapitulate clinical features exhibited by certain COVID-19 patients, i.e. severe hypoxaemia combined with relatively well-preserved lung mechanics, being treated with supplemental oxygen.

Results

Simulations were conducted at tidal volumes (VT) and respiratory rates (RR) of 7 ml/kg and 14 breaths/min (representing normal respiratory effort) and at VT/RR of 7/20, 7/30, 10/14, 10/20 and 10/30 ml/kg / breaths/min. While oxygenation improved with higher respiratory efforts, significant increases in multiple indicators of the potential for lung injury were observed at all higher VT/RR combinations tested. Pleural pressure swing increased from 12.0±0.3 cmH2O at baseline to 33.8±0.4 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 46.2±0.5 cmH2O at 10 ml/kg/30 breaths/min. Transpulmonary pressure swing increased from 4.7±0.1 cmH2O at baseline to 17.9±0.3 cmH2O at VT/RR of 7 ml/kg/30 breaths/min and to 24.2±0.3 cmH2O at 10 ml/kg/30 breaths/min. Total lung strain increased from 0.29±0.006 at baseline to 0.65±0.016 at 10 ml/kg/30 breaths/min. Mechanical power increased from 1.6±0.1 J/min at baseline to 12.9±0.2 J/min at VT/RR of 7 ml/kg/30 breaths/min, and to 24.9±0.3 J/min at 10 ml/kg/30 breaths/min. Driving pressure increased from 7.7±0.2 cmH2O at baseline to 19.6±0.2 at VT/RR of 7 ml/kg/30 breaths/min, and to 26.9±0.3 cmH2O at 10 ml/kg/30 breaths/min.

Conclusions

Our results suggest that the forces generated by increased inspiratory effort commonly seen in COVID-19 acute hypoxaemic respiratory failure are comparable with those that have been associated with ventilator-induced lung injury during mechanical ventilation. Respiratory efforts in these patients should be carefully monitored and controlled to minimise the risk of lung injury.
A feasible and more efficient SARS-Cov-2 vaccine allocation to states and counties in the USA
Authors: Ives Anthony R. , Bozzuto Claudio
Published: March 2021

While discussion of vaccine allocation has centered around who should be prioritized (e.g., health care personnel and the elderly), we argue that vaccines should also be allocated to jurisdictions (e.g., counties within the USA) with the greatest immunization thresholds needed for ending the epidemic. At the current rate of vaccine distribution (March 15, 2021), universal herd immunity in the USA could be reached in roughly 4.5 months. However, distributing vaccines according to where the virus spreads more easily (dense counties with high R0 values), herd immunity would be reached simultaneously in all counties almost two months earlier and would require roughly 40% fewer vaccine doses. Furthermore, under the current distribution strategy densely populated counties would reach herd immunity last, with negative epidemiological and socio-economic consequences. In sum, it would be more fair and efficient to distribute vaccines to jurisdictions that need them most to reach herd immunity.
Neural correlates of metacognition across the adult lifespan
Authors: Overhoff Helen , Ko Yiu Hong , Feuerriegel Daniel , Fink Gereon R. , Stahl Jutta , Weiss Peter H. , Bode Stefan , Niessen Eva
Published: March 2021

Metacognitive accuracy describes the degree of overlap between the subjective perception of one’s decision accuracy (i.e., confidence) and objectively observed performance. With older age, the need for accurate metacognitive evaluation increases; however, error detection rates typically decrease. We investigated the effect of ageing on metacognitive accuracy using event-related potentials (ERPs) reflecting error detection and confidence: the error/correct negativity (Ne/c) and the error/correct positivity (Pe/c). Sixty-five healthy adults (20 to 76 years) completed a complex perceptual task and provided confidence ratings. We found that metacognitive accuracy declined with age beyond the expected decline in task performance, while the adaptive adjustment of behaviour was well preserved. Pe/camplitudes varied by confidence rating, but they did not mirror the reduction in metacognitive accuracy. Ne/camplitudes decreased with age except for high confidence correct responses. The results suggest that age-related difficulties in metacognitive evaluation could be related to an impaired integration of decision accuracy and confidence information processing. Ultimately, training the metacognitive evaluation of fundamental decisions in older adults might constitute a promising endeavour.
Strong genetic structure and limited connectivity among populations of Clark’s Anemonefish (Amphiprion clarkii) in the centre of marine biodiversity
Authors: Ducret Hugo , Timm Janne , Moreno Melina Rodríguez , Huyghe Filip , Kochzius Marc
Published: March 2021

Populations of anemonefish species often show signs of local isolation due limited dispersal potential and oceanographic conditions. Additionally, anthropogenic pressure, such as overharvesting and coral reef exploitation causes reduced population size, eventually leading to local extinction. The understanding of the genetic population structure, as well as the influence of both historical and current connectivity, is required to design effective marine protected area (MPA) networks. In this study, the genetic structure of Clark’s Anemonefish (Amphiprion clarkii) populations of the Indo-Malay Archipelago (IMA) is assessed through mitochondrial control region (mtCR) sequences and nuclear microsatellites. Results provided evidence of a significant genetic structure (mtCR: Φst= 0.42039, Φct= 0.63852; microsatellites: Fst= 0.01449, Fct= 0.05199). Genetic breaks were identified among Western (Padang Karimunjawa), Central (Sulawesi, Borneo, Bali, Komodo, Timor), and Eastern (Biak) IMA populations, which matches with patterns obtained for congeneric and other coral reef taxa. Due to the restricted connectivity among these three regions, it is suggested to consider them as separate management areas in the design of MPA networks.
Dynamic plasticity within the EMT spectrum, rather than static mesenchymal traits, drives tumor heterogeneity and metastatic progression of breast cancers
Authors: Brown Meredith S. , Abdollahi Behnaz , Wilkins Owen M. , Chakraborty Priyanka , Ognjenovic Nevena B. , Muller Kristen E. , Jolly Mohit Kumar , Hassanpour Saeed , Pattabiraman Diwakar R.
Published: March 2021

The Epithelial-to-Mesenchymal Transition (EMT) is a developmental cellular program frequently coopted by cancer cells1and is a key contributor to both heterogeneity in solid tumors2–4and later stage chemo-resistance and metastasis5,6. Rather than being a switch from an epithelial to a mesenchymal state, increasing evidence points to the existence of intermediate EMT states, wherein cells co-express both epithelial and mesenchymal traits7–13. Multiple stable intermediate EMT states possessing unique characteristics exist across the EMT spectrum7,8,14,15, contributing to the complex heterogeneity of tumors to promote metastasis16. While much work has been carried out identifying and characterizing EMT-inducing transcription factors17–20, the transcriptional and epigenetic networks responsible for the stability and maintenance of the midpoints along the EMT spectrum are poorly defined. In addition, there are currently no approaches to identifying and quantifying intermediate EMT subpopulations within patient tumors to evaluate their prognostic significance. Using clonally isolated derivatives of the SUM149PT breast cancer cell line, we systematically interrogate how each EMT state independently contributes to heterogeneity and influences metastatic progression, uncovering the role of RUNX2 in stabilizing certain intermediate states. Using SUM149PT-derived tumors as a training set, we develop an entropy-based model to quantify phenotypic heterogeneity and EMT status. Remarkably, the majority of cell states captured in the SUM149PT model are represented in a selection of patient tumors, laying the foundation for quantification of epithelial-mesenchymal heterogeneity and understanding the role of the intermediate EMT state in tumor progression.
The unphosphorylated form of the PAQosome core subunit RPAP3 binds ribosomal preassembly complexes to modulate ribosome biogenesis
Authors: Pinard Maxime , Cloutier Philippe , Poitras Christian , Gauthier Marie-Soleil , Coulombe Benoit
Published: March 2021

The PAQosome (Particle for Arrangement of Quaternary structure) is a twelve-subunit HSP90 co-chaperone involved in the biogenesis of several human protein complexes. Two mechanisms of client selection have previously been identified, namely the selective recruitment of specific adaptors and the differential use of homologous core subunits. Here, we describe a third client selection mechanism by showing that RPAP3, one of the core PAQosome subunits, is phosphorylated at several Ser residues in HEK293 cells. Affinity purification coupled with mass spectrometry (AP-MS) using expression of tagged RPAP3 with single phospho-null mutations at Ser116, Ser119 or Ser121 reveals binding of the unphosphorylated form to several proteins involved in ribosome biogenesis.In vitrophosphorylation assays indicate that the kinase CK2 phosphorylates these RPAP3 residues. This finding is supported by data showing that pharmacological inhibition of CK2 enhances binding of RPAP3 to ribosome preassembly factors in AP-MS experiments. Moreover, silencing of PAQosome subunits interferes with ribosomal assembly factors’ interactome. Altogether, these results indicate that RPAP3 phosphate group addition/removal at specific residues modulates binding to subunits of preribosomal complexes and allows speculating that PAQosome posttranslational modifications is a mechanism of client selection.
A genomic and morphometric analysis of alpine bumblebees: ongoing reductions in tongue length but no clear genetic component
Authors: Christmas Matthew J. , Jones Julia C. , Olsson Anna , Wallerman Ola , Bunikis Ignas , Kierczak Marcin , Whitley Kaitlyn M. , Sullivan Isabel , Geib Jennifer C. , Miller-Struttmann Nicole E. , Webster Matthew T.
Published: March 2021

Over the last six decades, populations of the bumblebeesBombus sylvicolaandBombus balteatusin Colorado have experienced decreases in tongue length, a trait important for plant-pollinator mutualisms. It has been hypothesized that this observation reflects selection resulting from shifts in floral composition under climate change. Here we used morphometrics and population genomics to determine whether morphological change is ongoing, investigate the genetic basis of morphological variation, and analyze population structure in these populations. We generated a genome assembly ofB. balteatus. We then analyzed whole-genome sequencing data and morphometric measurements of 580 samples of both species from seven high-altitude localities. Out of 281 samples originally identified asB. sylvicola, 67 formed a separate genetic cluster comprising a newly-discovered cryptic species (“incognitus”). However, an absence of genetic structure within species suggests that gene flow is common between mountains. We found a significant decrease in tongue length between bees collected between 2012-2014 and in 2017, indicating that morphological shifts are ongoing. We did not discover any genetic associations with tongue length, but a SNP related to production of a proteolytic digestive enzyme was implicated in body size variation. We identified evidence of covariance between kinship and both tongue length and body size, which is suggestive of a genetic component of these traits, although it is possible that shared environmental effects between colonies are responsible. Our results provide evidence for ongoing modification of a morphological trait important for pollination and indicate that this trait likely has a complex genetic and environmental basis.
Efficacy of Distributed Training Depends on the Dorso-Lateral Striatum
Authors: Mastrorilli Valentina , Centofante Eleonora , Antonelli Federica , Rinaldi Arianna , Mele Andrea
Published: March 2021

Distributed training has long been known to lead to more robust memory formation as compared to massed training. Here we demonstrate that distributed and massed training differentially engage the dorsolateral and dorsomedial striatum and optogenetic priming of dorsolateral striatum can artificially increase the robustness of massed training to the level of distributed training, identifying a novel therapeutic avenue for memory enhancement.