bluuebunny/crossref_metadata_2025 huggingface dataset:
A Connectome-wide Functional Signature of Trait Anger
Authors: Justin Kim M. , Elliott Maxwell L. , Knodt Annchen R. , Hariri Ahmad R.
Published: October 2020

Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions-of-interest, and poor test-retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide general functional connectivity, which has good test-retest reliability, in a sample of 1,048 young adult volunteers. Multi-dimensional matrix regression analysis showed that individual differences in self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor area (SMA) and the right lateral frontal pole. Follow-up seed-based analysis confirmed that high trait anger is associated with hyperconnectivity between these three regions and the somatomotor network as well as hyperconnectivity and hypoconnectivity between SMA and default mode and visual networks, respectively. Supplementary targeted analyses based on theoretical and empirical grounds further revealed that high trait anger is associated with hyperconnectivity between the amygdala and dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, and striatum. These patterns suggest that the dispositional tendency to more easily experience frustration and anger is associated with variability in the functional connectivity of brain networks supporting somatomotor, affective, self-referential, and visual information processes. The emergence of action-related brain regions from our connectome-wide analysis is consistent with trait anger as reflecting a greater propensity to provoked action.
Development of natural scene representation in primary visual cortex requires early postnatal experience
Authors: Kowalewski Nina , Kauttonen Janne , Stan Patricia L. , Jeon Brian B. , Fuchs Thomas , Chase Steven M. , Lee Tai Sing , Kuhlman Sandra J.
Published: October 2020

The development of the visual system is known to be shaped by early-life experience. To identify response properties that contribute to enhanced natural scene representation, we performed calcium imaging of excitatory neurons in the primary visual cortex (V1) of awake mice raised in three different conditions (standard-reared, dark-reared, and delayed-visual experience) and compared neuronal responses to natural scene features relative to simpler grating stimuli that varied in orientation and spatial frequency. We assessed population selectivity in V1 using decoding methods and found that natural scene discriminability increased by 75% between the ages of 4 to 6 weeks. Both natural scene and grating discriminability were higher in standard-reared animals compared to those raised in the dark. This increase in discriminability was accompanied by a reduction in the number of neurons that responded to low-spatial frequency gratings. At the same time there was an increase in neuronal preference for natural scenes. Light exposure restricted to a 2-4 week window during adulthood did not induce improvements in natural scene nor in grating stimulus discriminability. Our results demonstrate that experience reduces the number of neurons required to effectively encode grating stimuli and that early visual experience enhances natural scene discriminability by directly increasing responsiveness to natural scene features.
Aird: A computation-oriented mass spectrometry data format enables higher compression ratio and less decoding time
Authors: Lu Miaoshan , An Shaowei , Wang Ruimin , Wang Jinyin , Yu Changbin
Published: October 2020

With the precision of mass spectrometer going higher and the emergence of data independence acquisition (DIA), the file size is increasing rapidly. Beyond the widely-used open format mzML (Deutsch 2008), near-lossless or lossless compression algorithms and formats have emerged. The data precision is often related to the instrument and subsequent processing algorithms. Unlike storage-oriented formats, which focusing more on lossless compression and compression rate, computation-oriented formats focus as much on decoding speed and disk read strategy as compression rate. Here we describe “Aird", an opensource and computation-oriented format with controllable precision, flexible indexing strategies and high compression rate. Aird uses JavaScript Object Notation (JSON) for metadata storage, multiple indexing, and reordered storage strategies for higher speed of data randomly reading. Aird also provides a novel compressor called Zlib-Diff-PforDelta (ZDPD) for m/z data compression. Compared with Zlib only, m/z data size is about 65% lower in Aird, and merely takes 33% decoding time.

Availability

Aird SDK is written in Java, which allow scholars to access mass spectrometry data efficiently. It is available athttps://github.com/Propro-Studio/Aird-SDKAirdPro can convert vendor files into Aird files, which is available athttps://github.com/Propro-Studio/AirdPro
Information Decomposition in the Frequency Domain: a New Framework to Study Cardiovascular and Cardiorespiratory Oscillations
Authors: Faes Luca , Pernice Riccardo , Mijatovic Gorana , Antonacci Yuri , Krohova Jana Cernanova , Javorka Michal , Porta Alberto
Published: October 2020

While cross-spectral and information-theoretic approaches are widely used for the multivariate analysis of physiological time series, their combined utilization is far less developed in the literature. This study introduces a framework for the spectral decomposition of multivariate information measures, which provides frequency-specific quantifications of the information shared between a target and two source time series and of its expansion into amounts related to how the sources contribute to the target dynamics with unique, redundant and synergistic information. The framework is illustrated in simulations of linearly interacting stochastic processes, showing how it allows to retrieve amounts of information shared by the processes within specific frequency bands which are otherwise not detectable by time-domain information measures, as well as coupling features which are not detectable by spectral measures. Then, it is applied to the time series of heart period, systolic and diastolic arterial pressure and respiration variability measured in healthy subjects monitored in the resting supine position and during head-up tilt. We show that the spectral measures of unique, redundant and synergistic information shared by these variability series, integrated within specific frequency bands of physiological interest, reflect the mechanisms of short term regulation of cardiovascular and cardiorespiratory oscillations and their alterations induced by the postural stress.
The rate of whole-genome duplication can be accelerated by hybridization
Authors: Marsit S. , Hénault M. , Charron G. , Fijarczyk A. , Landry C. R
Published: October 2020

Hybridization and polyploidization are powerful mechanisms of speciation. Hybrid speciation often coincides with whole-genome duplication (WGD) in eukaryotes. This suggests that WGD allows hybrids to thrive by restoring fertility and/or increasing access to adaptive mutations. Alternatively, it has been suggested that hybridization itself may trigger WGD. Testing these models requires quantifying the rate of WGD in hybrids without the confounding effect of natural selection. By measuring the spontaneous rate of WGD of 1304 yeast crosses evolved under relaxed selection, we show that some genotypes are more prone to WGD and WGD can be triggered by hybridization. We also find that higher WGD rate correlates with higher genomic instability and that WGD increases fertility and genetic variability. These results provide evidence that hybridization itself can promote WGD, which in turn facilitates the evolution of hybrids.
Transfer function for YAP/TAZ nuclear translocation revealed through spatial systems modeling
Authors: Scott Kiersten E. , Fraley Stephanie I. , Rangamani Padmini
Published: October 2020

YAP/TAZ is a master regulator of mechanotransduction whose functions rely on translocation from the cytoplasm to the nucleus in response to diverse physical cues. Substrate stiffness, substrate dimensionality, and cell shape are all input signals for YAP/TAZ, and through this pathway, regulate critical cellular functions and tissue homeostasis. Yet, the relative contributions of each biophysical signal and the mechanisms by which they synergistically regulate YAP/TAZ in realistic tissue microenvironments that provide multiplexed input signals remains unclear. For example, in simple 2D culture, YAP/TAZ nuclear localization correlates strongly with substrate stiffness, while in 3D environments, YAP/TAZ translocation can increase with stiffness, decrease with stiffness, or remain unchanged. Here, we develop a spatial model of YAP/TAZ translocation to enable quantitative analysis of the relationships between substrate stiffness, substrate dimensionality, and cell shape. Our model couples cytosolic stiffness to nuclear mechanics to replicate existing experimental trends, and extends beyond current data to predict that increasing substrate activation area through changes in culture dimensionality, while conserving cell volume, forces distinct shape changes that result in nonlinear effect on YAP/TAZ nuclear localization. Moreover, differences in substrate activation area versus total membrane area can account for counterintuitive trends in YAP/TAZ nuclear localization in 3D culture. Based on this multiscale investigation of the different system features of YAP/TAZ nuclear translocation, we predict that how a cell reads its environment is a complex information transfer function of multiple mechanical and biochemical factors. These predictions reveal design principles of cellular and tissue engineering for YAP/TAZ mechanotransduction.

STATEMENT OF SIGNIFICANCE

In chemical engineering, a transfer function is a mathematical function that models the output of a reactor for all possible inputs, and enables the reliable design and operation of complex reaction systems. Here, we apply this principle to cells to derive the transfer function by which substrate stiffness is converted into YAP/TAZ nuclear localization. This function is defined by a spatial model of the YAP/TAZ mechano-chemical sensing network, wherein key spatial and physical inputs to the system, namely cell and nuclear shape, surface area to volume ratios of cytoplasmic and nuclear compartments, substrate dimensionality, substrate activation area, and substrate stiffness, are all integrated. The resulting model accounts for seemingly contradictory experimental trends and lends new insight into controlling YAP/TAZ signalling.
The Adaptor Protein Complex 1 limits E-cadherin endocytosis during epithelial morphogenesis
Authors: Moreno Miguel Ramírez , Boswell Katy , Bulgakova Natalia A.
Published: October 2020

Intracellular trafficking regulates the distribution of transmembrane proteins including the key determinants of epithelial polarity and adhesion. The Adaptor Protein 1 (AP-1) complex is the key regulator of vesicle sorting, which binds a large number of specific cargos. We examined roles of the AP-1 complex in epithelial morphogenesis, using theDrosophilawing as a paradigm. We found that AP-1 knockdown leads to ectopic folds caused by trafficking defects of integrins. This occurs concurrently with an increase in the apical cell area and induction of cell death due to defects in E-cadherin trafficking. We discovered a distinct pool of AP-1 localizes at the apical Adherens Junctions, where it limits internalization of E-cadherin from the cell surface. Upon AP-1 knockdown, the accompanying hyperinternalization of E-cadherin induces cell death by an uncharacterised mechanism with a potential tumour-suppressive role. Simultaneously, cells increase expression of E-cadherin in a compensatory mechanism to maintain cell-cell adhesion.
Performances of NeuMoDx, a random-access system for HBV-DNA and HCV-RNA quantification
Authors: Besombes Juliette , Pronier Charlotte , Lefevre Charles , Lagathu Gisèle , Maillard Anne , Grolhier Claire , Thibault Vincent
Published: October 2020

Viral loads (VL) monitoring for hepatitis B and C is essential to evaluate disease progression and treatment response. Automated, random-access rapid systems are becoming standard to provide reliable VL to clinicians. The aim of this study was to evaluate the analytical performances of the recently launched NeuMoDx™for HBV-DNA and HCV-RNA quantification. Clinical samples routinely quantified on the Beckman-Veris system were either retrospectively (frozen samples; HBV n=178, HCV n=249), or in parallel (fresh primary tubes; HBV n=103, HCV n=124) tested using NeuMoDx™. Linearity range was assessed on serial dilutions of high tittered plasmas containing different genotypes for HBV (A-E, n=10) and HCV (1a-b, 2-5, n=12). Overall test failure, mostly internal control amplification failure, was 2.3% and was not influenced by matrix types. For HBV-VL, Kappa agreement was 74%, with 27 (12.6%) discrepancies. Correlation between HBV assays on 72 quantified samples by both methods was excellent (r=0.963) with a mean bias (NeuMoDx™-Veris) of 0.21 log IU/mL. For HCV-VL, Kappa agreement reached 94%, with 9 (2.8%) discrepancies. The r-correlation factor between assays on 104 samples was 0.960 with a mean bias of −0.14 log IU/mL (NeuMoDx™-Veris). Serial dilutions confirmed the claimed linear ranges for all HBV and HCV genotypes. The mean turnaround time was 72’ [55-101] for HBV and 96’ [78-133] for HCV. These results obtained on the NeuMoDx™confirmed the overall good functionality of the system with a short turn-around-time, full traceability and easy handling. These results on HBV- and HCV-VL look promising and should be challenged with further comparisons.
Differentialin vitroactivity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starvedMycobacterium abscessus
Authors: Lee Jin , Ammerman Nicole , Agarwal Anusha , Naji Maram , Li Si-Yang , Nuermberger Eric
Published: October 2020

Current treatment options for lung disease caused byMycobacterium abscessuscomplex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed thein vitrobactericidal activity of single drugs against actively multiplying and net non-replicatingM. abscessuspopulations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growingM. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starvedM. abscessus. Overall, thesein vitrodata suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens forM. abscessusinfections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, againstM. abscessusalso highlights several issues affecting interpretation and translation ofin vitrofindings.
The impact of anorexia nervosa and BMI polygenic risk on childhood growth: a 20-year longitudinal population-based study
Authors: Abdulkadir Mohamed , Hübel Christopher , Herle Moritz , Loos Ruth J.F. , Breen Gerome , Bulik Cynthia M. , Micali Nadia
Published: October 2020

Background

Deviating growth from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life.

Methods

AN-PGS and BMI-PGS were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; N=8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD).

Results

Female participants with one SD higher AN-PGS had on average 0.004% slower growth in BMI between the ages 6.5-24 years and a 0.4% slower growth in BMD between the ages 10-24 years. Higher BMI-PGS was associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN-PGS and a low BMI-PGS showed slower growth compared to those with both a low AN-PGS and a low BMI-PGS.

Conclusion

AN-PGS and BMI-PGS have detectable sex-specific effects on growth trajectories. Female participants with high AN-PGS and low BMI-PGS likely constitute a high-risk group for AN as their growth was slower compared to their peers with high PGS on both traits. Further research is needed to better understand how the AN-PGS and the BMI-PGS co-influence growth during childhood and whether high BMI-PGSs can mitigate the effects of a high AN-PGS.
Distinctcis-acting elements govern purine-responsive regulation of theLeishmania donovaninucleoside transporters, LdNT1 and LdNT2
Authors: Licon M. Haley , Goodstein Francesca , Ortiz Diana , Landfear Scott M. , Yates Phillip A.
Published: October 2020

Purine salvage from the host is an obligatory process for all protozoan parasites. InLeishmania donovani, this is accomplished by four membrane nucleoside and nucleobase transporters, or LdNTs. Previously, we demonstrated that purine starvation invokes a robust stress response inLeishmaniaand characterized the proteomic changes involved. However, becauseLeishmaniado not control the transcription of individual genes, the underlying mechanisms responsible for these changes were ill-defined. LdNT1 and LdNT2 are among the most rapidly and significantly upregulated genes in purine-starvedL. donovaniparasites. Thus, to better understand post-transcriptional mechanisms of purine-responsive gene expression, we have examined regulation of these genes in molecular detail. Here we report that LdNT1 and LdNT2 are controlled by distinctcis-acting elements. In the case of LdNT2, mRNA abundance and translational enhancement under purine stress depend on a 76 nt-long polypyrimidine tract encoded in theLdNT2mRNA 3’-UTR. Transcripts containing theLdNT2polypyrimidine tract were found to localize to discrete cytoplasmic foci in purine-replete cells, suggesting that theLdNT2message may be stored in RNA granules at steady-state. In the case of LdNT1, we found that purine-responsiveness is conferred by a 48 nt-long polypyrimidine tract and additional upstream element, termed UE1. Both features are independently required for regulation, with the polypyrimidine tract and UE1 controlling mRNA abundance and translation, respectively. Together, these results highlight a remarkable degree of complexity in the regulation of theLeishmaniapurine stress response and set the stage for future investigations to identify the larger network of RNA-protein and protein-protein interactions involved.
Cystic Fibrosis Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation ofPseudomonas aeruginosa
Authors: Lin Qiao , Pilewski Joseph M. , Di Y. Peter
Published: October 2020

Pseudomonas aeruginosais the most prevalent bacterial species that contributes to cystic fibrosis (CF) respiratory failure. The impaired function of cystic fibrosis transmembrane conductance regulator leads to abnormal epithelial Cl−/ HCO3−transport and acidification of airway surface liquid. However, it remains unclear whyPseudomonas aeruginosapreferentially colonizes in the CF lungs. In this study, we carried out studies to investigate if lower pH helpsPseudomonas aeruginosaadapt and thrive in the CF-like acidic lung environment. Our results reveal thatPseudomonas aeruginosagenerally forms more biofilm and induces antibiotic resistance faster in acidic conditions and that this can be reversed by returning the acidic environment to physiologically neutral conditions.Pseudomonas aeruginosaappears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronicPseudomonas aeruginosainfection and colonization.
Cas9-mediated Genome Editing Reveals a Significant Contribution of Calcium Signaling Pathways to Anhydrobiosis in Pv11
Authors: Miyata Yugo , Fuse Hiroto , Tokumoto Shoko , Hiki Yusuke , Deviatiiarov Ruslan , Yoshida Yuki , Yamada Takahiro G. , Cornette Richard , Gusev Oleg , Shagimardanova Elena , Funahashi Akira , Kikawada Takahiro
Published: October 2020

Pv11 is an insect cell line established from the midgePolypedilum vanderplankithat exhibits an extreme desiccation tolerance known as anhydrobiosis. Pv11 has also an anhydrobiotic ability which is induced by trehalose treatment. Here we report the successful construction of the genome editing system for Pv11 cells and its application for identifying the signaling pathways in the anhydrobiosis. Using the Cas9-mediated gene knock-in system, we established GCaMP3-stably expressing Pv11 cells to monitor intracellular Ca2+mobilization. Intriguingly, trehalose treatment evoked a transient increase of cytosolic Ca2+concentration, and further experiments indicated the contribution of the calmodulin – calcineurin – NFAT pathway to the tolerance for trehalose treatment as well as the desiccation tolerance, while the calmodulin – calmodulin Kinase – CREB pathway conferred only the desiccation tolerance on Pv11 cells. Thus, our results show the critical contribution of the trehalose–induced Ca2+surge to the anhydrobiosis and the temporal different roles of each signaling pathway.
Quantitative Assays Reveal Cell Fusion at Minimal Levels of SARS-CoV-2 Spike Protein and Fusion-from-Without
Authors: Theuerkauf Samuel A. , Michels Alexander , Riechert Vanessa , Maier Thorsten J. , Flory Egbert , Cichutek Klaus , Buchholz Christian J.
Published: October 2020

Cell entry of the pandemic virus SARS-CoV-2 is mediated by its spike protein S. As main antigenic determinant, S protein is in focus of antibody-based prophylactic and therapeutic strategies. Besides particle-cell fusion, S mediates fusion between infected and uninfected cells resulting in syncytia formation. Here we present quantitative assay systems covering not only particle-cell and cell-cell fusion, but also demonstrating fusion-from-without (FFWO), the formation of syncytia induced by S-containing viral particles in absence of newly synthesized S protein. Based on complementation of split β-galactosidase and virus-like-particles (VLPs) displaying S protein, this assay can be performed at BSL-1. All three assays provided readouts with a high dynamic range and signal-to-noise ratios covering several orders of magnitude. The data obtained confirm the enhancing effect of trypsin and overexpression of angiotensin-converting enzyme 2 (ACE2) on membrane fusion. Neutralizing antibodies as well as sera from convalescent patients inhibited particle-cell fusion with high efficiency. Cell-cell fusion, in contrast, was only moderately inhibited despite requiring much lower levels of S protein, which were below the detection limit of flow cytometry and Western blot. The data indicate that syncytia formation as a pathological consequence in tissues of Covid-19 patients can proceed at low levels of S protein and may not be effectively prevented by antibodies.
Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ
Authors: Hayn Manuel , Hirschenberger Maximilian , Koepke Lennart , Straub Jan H , Nchioua Rayhane , Christensen Maria H , Klute Susanne , Bozzo Caterina Prelli , Aftab Wasim , Zech Fabian , Conzelmann Carina , Müller Janis A , Badarinarayan Smitha Srinivasachar , Stürzel Christina M , Forne Ignasi , Stenger Steffen , Conzelmann Karl-Klaus , Münch Jan , Sauter Daniel , Schmidt Florian I , Imhof Axel , Kirchhoff Frank , Sparrer Konstantin MJ
Published: October 2020

The innate immune system constitutes a powerful barrier against viral infections. However, it may fail because successful emerging pathogens, like SARS-CoV-2, evolved strategies to counteract it. Here, we systematically assessed the impact of 29 SARS-CoV-2 proteins on viral sensing, type I, II and III interferon (IFN) signaling, autophagy and inflammasome formation. Mechanistic analyses show that autophagy and type I IFN responses are effectively counteracted at different levels. For example, Nsp14 induces loss of the IFN receptor, whereas ORF3a disturbs autophagy at the Golgi/endosome interface. Comparative analyses revealed that antagonism of type I IFN and autophagy is largely conserved, except that SARS-CoV-1 Nsp15 is more potent in counteracting type I IFN than its SARS-CoV-2 ortholog. Altogether, however, SARS-CoV-2 counteracts type I IFN responses and autophagy much more efficiently than type II and III IFN signaling. Consequently, the virus is relatively resistant against exogenous IFN-α/β and autophagy modulation but remains highly vulnerable towards IFN-γ and -λ treatment. In combination, IFN-γ and -λ act synergistically, and drastically reduce SARS-CoV-2 replication at exceedingly low doses. Our results identify ineffective type I and II antagonism as weakness of SARS-CoV-2 that may allow to devise safe and effective anti-viral therapies based on targeted innate immune activation.
Locomotor compromises maintain group cohesion in baboon troops on the move
Authors: Harel Roi , Loftus J. Carter , Crofoot Margaret C.
Published: October 2020

When members of a group differ in locomotor capacity, coordinating collective movement poses a challenge: some individuals may have to move faster (or slower) than their preferred speed to remain together. Such compromises have energetic repercussions yet research in collective behavior has largely neglected locomotor consensus costs. Here we integrate high-resolution tracking of wild baboon locomotion and movement with simulations to demonstrate that size-based variation in locomotor capacity poses an obstacle to collective movement. While all baboons modulate their gait and move-pause dynamics during collective movement, the costs of maintaining cohesion are disproportionately borne by smaller group members. Although consensus costs are not distributed equally, all group-mates do make locomotor compromises, suggesting a shared decision-making process drives the pace of collective movement in this highly despotic species. These results highlight the importance of considering how social dynamics and locomotor capacity interact to shape the movement ecology of group-living species.
CASB: A concanavalin A-based sample barcoding strategy for single-cell sequencing
Authors: Fang Liang , Li Guipeng , Zhu Qionghua , Cui Huanhuan , Li Yunfei , Sun Zhiyuan , Liang Weizheng , Wei Wencheng , Hu Yuhui , Chen Wei
Published: October 2020

Sample multiplexing facilitates single cell sequencing by reducing costs, revealing subtle difference between similar samples, and identifying artifacts such as cell doublets. However, universal and cost-effective strategies are rather limited. Here, we reported a Concanavalin A-based Sample Barcoding strategy (CASB), which could be followed by both single-cell mRNA and ATAC (assay for transposase accessible chromatin) sequencing techniques. The method involves minimal sample processing, thereby preserving intact transcriptomic or epigenomic patterns. We demonstrated its high labeling efficiency, high accuracy in assigning cells/nuclei to samples regardless of cell type and genetic background, as well as high sensitivity in detecting doublets by two applications: 1) CASB followed by scRNA-seq to track the transcriptomic dynamics of a cancer cell line perturbed by multiple drugs, which revealed compound-specific heterogeneous response; 2) CASB together with both snATAC-seq and scRNA-seq to illustrate the IFN-γ-mediated dynamic changes on epigenome and transcriptome profile, which identified the transcription factor underlying heterogeneous IFN-γ response.
RTP801 REGULATES MOTOR CORTEX SYNAPTIC TRANSMISSION AND LEARNING
Authors: Pérez-Sisqués L , Martín-Flores N , Masana M , Solana J , Llobet A , Romaní-Aumedes J , Canal M , Campoy G , García-García E. , Sánchez-Fernández N , Fernández-García S , Gilbert JP , Rodríguez MJ , Man H-Y , Feinstein E , Williamson D , Soto D , Gasull X , Alberch J , Malagelada C
Published: October 2020

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death inin vitroandin vivomodels of Parkinson’s and Huntington’s diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson’s and Huntington’s disease mouse models, RTP801 knockdown alleviates motor-learning deficits.

Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning.
Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites
Authors: Borschiwer Marina , Bothe Melissa , Kibar Gözde , Fuchs Alisa , Schöne Stefanie , Prekovic Stefan , Peralta Isabel Mayayo , Chung Ho-Ryun , Zwart Wilbert , Helsen Christine , Claessens Frank , Meijsing Sebastiaan H.
Published: October 2020

The glucocorticoid (GR) and androgen (AR) receptors execute unique functionsin vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied AR and GR in an equivalent cellular context. Analysis of chromatin and sequence features suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the results of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in selectively guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared between AR and GR shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, we find that shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.
High-Resolution Single-Molecule FRET via DNA eXchange (FRET X)
Authors: Filius Mike , Kim Sung Hyun , Severins Ivo , Joo Chirlmin
Published: October 2020

Single-molecule FRET is a versatile tool to study nucleic acids and proteins at the nanometer scale. However, currently, only a couple of FRET pairs can be reliably measured on a single object. The limited number of available FRET pair fluorophores and complicated data analysis makes it challenging to apply single-molecule FRET for structural analysis of biomolecules. Currently, only a couple of FRET pairs can be reliably measured on a single object. Here we present an approach that allows for the determination of multiple distances between FRET pairs in a single object. We use programmable, transient binding between short DNA strands to resolve the FRET efficiency of multiple fluorophore pairs. By allowing only a single FRET pair to be formed at a time, we can determine the FRET efficiency and pair distance with sub-nanometer resolution. We determine the distance between other pairs by sequentially exchanging DNA strands. We name this multiplexing approach FRET X for FRET via DNA eXchange. We envision that our FRET X technology will be a tool for the high-resolution structural analysis of biomolecules and other nano-structures.
Preventing neutrophil from oxygen exposure allows their basal state maintenance
Authors: Injarabian Louise , Gianetto Quentin Giai , Witko-Sarsat Véronique , Marteyn Benoit S
Published: October 2020

Neutrophils are the most abundant circulating white blood cells and are central players of the innate immune response. During their lifecycle, neutrophils mainly evolve under low oxygen conditions (0.1 - 4% O2) to which they are well adapted. Neutrophils are atypical cells since they are mainly glycolytic, and highly susceptible to oxygen-exposure, which induces their activation and death, through mechanisms which remain currently elusive. Nevertheless, nearly all studies conducted on neutrophils are carried out under atmospheric oxygen (21%), corresponding to hyperoxic conditions. Here we investigated the impact of hyperoxia during neutrophil purification and culture on neutrophil viability, activation and cytosolic protein content. Neutrophil hyper-activation (CD62L shedding) is induced during culture under hyperoxic conditions (24h), compared to neutrophils cultured under anoxic conditions. In addition, we show that maintaining neutrophils in autologous plasma is the most suitable strategy to maintain their basal state.

Our results show that manipulating neutrophils under hyperoxic conditions leads to the loss of ~100 cytosolic proteins during purification, while it does not lead to an immediate impact on neutrophils activation (CD11bhigh, CD54high, CD62Llow) or viability (DAPI+). We identified two clusters of proteins belonging to the cholesterol metabolism and to the complement and coagulation cascade pathways, which are highly susceptible to neutrophil oxygen-exposure during their purification.

In conclusion, preserving neutrophil from oxygen-exposure during their manipulation – purification and culture- is recommended to avoid their experimental activation and for preserving a large set of cytosolic proteins from alteration.
Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland
Authors: Watts Deepika , Bechmann Nicole , Meneses Ana , Poutakidou Ioanna K. , Kaden Denise , Conrad Catleen , Krüger Anja , Stein Johanna , El-Armouche Ali , Chavakis Triantafyllos , Eisenhofer Graeme , Peitzsch Mirko , Wielockx Ben
Published: October 2020

The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signalling on its function remains scarcely understood. Here, we reveal that deficiency of HIF (Hypoxia Inducible Factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Concomitant loss of PHD2 in renal erythropoietin (EPO) producing cells stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis) and systemic hypoglycaemia. Using mouse lines displaying only EPO-induced erythrocytosis or anaemia, we show that hypo- or hyperglycaemia is necessary and sufficient to respectively enhance or reduce exocytosis of epinephrine from the adrenal gland. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla and beyond regulates both synthesis and release of catecholamines, especially epinephrine. Our findings are also of great significance in view of the small molecule PHD inhibitors being tested in phase III global clinical development trials for use in renal anaemia patients.
Indirect Vibration of the Upper Limbs Alters Transmission Along Spinal but not Corticospinal Pathways
Authors: Barss Trevor S. , Collins David F. , Miller Dylan , Pujari Amit N.
Published: October 2020

The aim of this study was to investigate whether indirect upper limb vibration (ULV) modulates transmission along spinal and corticospinal pathways that control the human forearm. All measures were assessed under CONTROL (no vibration) and ULV (30 Hz; 0.4 mm displacement) conditions while participants maintained a small contraction of the right flexor carpi radialis (FCR) muscle. To assess spinal pathways, Hoffmann reflexes (H-reflexes) elicited by stimulation of the median nerve were recorded from FCR with motor response (M-wave) amplitudes matched between conditions. An H-reflex conditioning paradigm was also used to assess changes in presynaptic inhibition by stimulating the superficial radial (SR) nerve (5 pulses at 300Hz) 37 ms prior to median nerve stimulation. Cutaneous reflexes in FCR elicited by stimulation of the SR nerve at the wrist were also recorded. To assess corticospinal pathways, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation of the contralateral motor cortex were recorded from the right FCR and biceps brachii (BB). ULV significantly reduced H-reflex amplitude by 15.7% for both conditioned and unconditioned reflexes (24.0±15.7 vs 18.4±11.2 % Mmax;p<0.05). Middle latency cutaneous reflexes were also significantly reduced by 20.0% from CONTROL (−1.50 ± 2.1 % Mmax) to ULV (−1.73 ± 2.2 % Mmax;p<0.05). There was no significant effect of ULV on MEP amplitude (p>0.05). Therefore, ULV inhibits cutaneous and H-reflex transmission without influencing corticospinal excitability of the forearm flexors suggesting increased presynaptic inhibition of afferent transmission as a likely mechanism. A general increase in inhibition of spinal pathways with ULV may have important implications for improving rehabilitation for individuals with spasticity (SCI, stroke, MS, etc).
Pesticide-induced Alterations to Phytoplankton Abundance and Community Structure Alter Ecosystem Respiration: Implications for the Carbon Cycle?
Authors: Rumschlag Samantha L. , Casamatta Dale A. , Mahon Michael B. , Hoverman Jason T. , Raffel Thomas R. , Carrick Hunter J. , Hudson Peter J. , Rohr Jason R.
Published: October 2020

Abstract

Current predictions of the effects of synthetic chemicals on freshwater ecosystems are hampered by the sheer number of chemical contaminants entering aquatic systems, the diversity of organisms inhabiting these systems, and uncertainties about how contaminants alter ecosystem metabolism. We conducted a mesocosm experiment that elucidated the responses of ponds composed of phytoplankton and zooplankton to standardized concentrations of 12 pesticides, nested within four pesticide classes and two pesticide types. We show that the effects of the pesticides on algae were consistent within herbicides and insecticides and responses of over 70 phytoplankton species and genera were consistent within broad taxonomic groups. Insecticides generated top-down effects on phytoplankton community composition and abundance, which were associated with persistent increases in ecosystem respiration. Herbicides reduced phytoplankton abundance, which was associated with decreases in primary productivity and ecosystem respiration. These results suggest that widespread pesticide use could have underexplored implications for the global carbon cycle. While these effects on ecosystem respiration were mediated through complex effects on communities, taxonomic groups of organisms responded similarly to pesticide types, suggesting opportunities to simplify ecological risk assessment.
Reservoir host community and vector density predict human tick-borne diseases across the United States
Authors: Mahon Michael B. , Rohr Jason R.
Published: October 2020

In the United States, tick-borne disease cases have tripled since the 1990s and cost upwards of 10 billion USD annually. Tick density and densities and diversity of non-human mammalian reservoir hosts are hypothesized to drive tick-borne disease dynamics and are targets for interventions. Here, we relate human prevalence of four tick-borne diseases (Lyme disease, monocytic ehrlichiosis, granulocytic anaplasmosis, and babesiosis) to tick and reservoir host community data collected by the U.S. National Ecological Observatory Network (NEON) across the contiguous U.S. We show that human disease prevalence is correlated positively with tick and reservoir host densities and negatively with mammalian diversity for Lyme disease and ehrlichiosis, but positively for anaplasmosis and babesiosis. Our results suggest that the efficacy of tick-borne disease interventions depends on tick and host densities and host diversity. Thus, policymakers and disease managers should consider these ecological contexts before implementing preventative measures.

Significance

Tick-borne disease incidence has increased in the United States over the last three decades. Because life-long symptoms can occur if reactive antibiotics are not administered soon after the tick bite, prevention is imperative. Yet, control of tick-borne zoonoses has been largely unsuccessful, at least partly because of a limited understanding of the ecological complexities of these diseases, especially non-Lyme disease tick-borne zoonoses. We use continental-scale data to quantify the relationships among four tick-borne diseases and tick and reservoir host communities, revealing that disease incidence is driven by a combination of tick densities and reservoir host densities and diversity. Thus, the efficacy of tick-borne disease interventions is likely dependent on these ecological contexts.
Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer
Authors: Malier Marie , Court Magali , Gharzeddine Khaldoun , Laverierre Marie-Hélène , Marsili Sabrina , Thomas Fabienne , Decaens Thomas , Roth Gael , Millet Arnaud
Published: October 2020

Colon adenocarcinoma is characterized by an infiltration of tumor-associated macrophages (TAMs). TAMs are associated with a chemoresistance to 5-Fluorouracil (5-FU), but the mechanisms involved are still poorly understood. In the present study, we found that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to a macrophage-induced chemoresistance to 5-FU by inactivation of the drug. Macrophage DPD expression in hypoxia is translationally controlled by the cap-dependent protein synthesis complex eIF4FHypoxic, which includes HIF-2α. We discovered that TAMs constitute the main contributors to DPD activity in human colorectal primary or secondary tumors where cancer cells do not express significant levels of DPD. Together, these findings shed light on the role of TAMs in forming chemoresistance in colorectal cancers and offer the identification of new therapeutic targets. Additionally, we report that, contrary to what is found in humans, macrophages in mice do not express DPD.
The protein domains of vertebrate species in which selection is more effective have greater intrinsic structural disorder
Authors: Weibel Catherine , James Jennifer E , Willis Sara M , Nelson Paul G , Masel Joanna
Published: October 2020

The effectiveness of selection varies among species. It is often estimated by means of an “effective population size” based on neutral polymorphism, but this is confounded in complex ways with demography. The strength of codon bias more directly pertains to how well adaptation at many sites can be maintained in the face of deleterious mutations, but past metrics that compare codon bias across species are confounded by among-species variation in %GC content and/or amino acid composition. Here we propose a new Codon Adaptation Index of Species (CAIS) that corrects for both confounders. Unlike previous metrics, CAIS yields the expected relationship with adult vertebrate body mass. As an example of the use of CAIS, we ask whether protein domains evolve lower intrinsic structural disorder (ISD) when present in more exquisitely adapted species, as expected given that ISD is higher in eukaryotic proteomes than prokaryotic proteomes. Using phylogenetically corrected linear models, we find, contrary to expectations, that the ISD of a given protein domain evolves to be higher when in well-adapted species. This effect is stronger in young protein domains but is also present in ancient domains.
Quantifying the subjective cost of self-control in humans
Authors: Raio Candace M. , Glimcher Paul W.
Published: October 2020

Since Odysseus committed to resisting the Sirens, mechanisms to limit self-control failure have been a central feature of human behavior. Psychologists have long argued that the use of self-control is an effortful process and, more recently, that its failure arises when the cognitive costs of self-control outweigh its perceived benefits. In a similar way, economists have argued that sophisticated choosers can adopt “pre-commitment strategies” that tie the hands of their future selves in order to reduce these costs. Yet, we still lack an empirical tool to quantify and demonstrate the cost of self-control. Here, we develop and validate a novel economic decision-making task toquantify the subjective cost of self-controlby determining the monetary cost a person is willing to incur in order to eliminate the need for self-control. We find that humans will pay to avoid having to exert self-control in a way that scales with increasing levels of temptation and that these costs are modulated both by motivational incentives and stress exposure. Our psychophysical approach allows us to index moment-to-moment self-control costs at the within-subject level, validating important theoretical work across multiple disciplines and opening new avenues of self-control research in healthy and clinical populations.
Gut Fungi Possess a Conserved Toxin Immunity Gene of Bacterial Origin
Authors: Rizvi Syed M. , Zhang Chengxin , Freddolino Peter L. , Zhang Yang
Published: October 2020

Prokaryotes and some unicellular eukaryotes routinely overcome evolutionary pressures with the help of horizontally acquired genes. In contrast, it is unusual for multicellular eukaryotes to adapt through horizontal gene transfer (HGT). Recent studies identified several cases of adaptive acquisition in the gut-dwelling multicellular fungal phylumNeocallimastigomycota. Here, we add to these cases the acquisition of a putative bacterial toxin immunity gene, PoNi, by an ancient common ancestor of four extantNeocallimastigomycotagenera through HGT from an extracellularRuminococcusbacterium. The PoNi homologs in these fungal genera share extraordinarily high (>70%) amino acid sequence identity with their bacterial donor xenolog, providing definitive evidence of HGT as opposed to lineage-specific gene retention. Furthermore, PoNi genes are nested on native sections of chromosomal DNA in multiple fungal genomes and are also found in polyadenylated fungal transcriptomes, confirming that these genes are authentic fungal genomic regions rather than sequencing artifacts from bacterial contamination. The HGT event, which is estimated to have occurred at least 66 (±10) million years ago in the gut of a Cretaceous mammal, gave the fungi a putative toxin immunity protein (PoNi) which likely helps them survive toxin-mediated attacks by bacterial competitors in the mammalian gut microbiome.

Significance

Adaptation via horizontal gene transfer (HGT) is uncommon in multicellular eukaryotes. Here, we report anotherbona fidecase of adaptive evolution involving the horizontal transfer of a bacterial toxin immunity gene from extracellularRuminococcusbacteria to gut-dwelling multicellular fungi. The acquired gene may help the fungi compete against bacterial neighbors in the gut.