bluuebunny/crossref_metadata_2025_split huggingface dataset:
Convergent evolution of the Hedgehog/Intein fold in protein splicing
Authors: Beyer Hannes M. , Virtanen Salla I. , Aranko A. Sesilja , Mikula Kornelia M. , Lountos George T. , Wlodawer Alexander , Ollila O. H. Samuli , Iwaï Hideo 
Published: March 2020

AbstractThe widely used molecular evolutionary clock assumes the divergent evolution of proteins. Convergent evolution has been proposed only for small protein elements but not for an entire protein fold. We investigated the structural basis of the protein splicing mechanism by class 3 inteins, which is distinct from class 1 and 2 inteins. We gathered structural and mechanistic evidence supporting the notion that the Hedgehog/INTein (HINT) superfamily fold, commonly found in protein splicing and related phenomena, could be an example of convergent evolution of an entire protein fold. We propose that the HINT fold is a structural and biochemical solution fortrans-peptidyl andtrans-esterification reactions.
Transcriptional mediators of treatment resistance in lethal prostate cancer
Authors: He Meng Xiao , Cuoco Michael S. , Crowdis Jett , Bosma-Moody Alice , Zhang Zhenwei , Bi Kevin , Kanodia Abhay , Su Mei-Ju , Rodman Christopher , DelloStritto Laura , Shah Parin , Burke Kelly P. , Izar Benjamin , Bakouny Ziad , Tewari Alok K. , Liu David , Camp Sabrina Y. , Vokes Natalie I. , Park Jihye , Vigneau Sébastien , Fong Lawrence , Rozenblatt-Rosen Orit , Regev Aviv , Rotem Asaf , Taplin Mary-Ellen , Van Allen Eliezer M. 
Published: March 2020

ABSTRACTMetastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity inARsplicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.
Embodied virtual reality for the study of real-world motor learning
Authors: Haar Shlomi , Sundar Guhan , Faisal A. Aldo 
Published: March 2020

AbstractMotor-learning literature focuses on simple laboratory-tasks due to their controlled manner and the ease to apply manipulations to induce learning and adaptation. Recently, we introduced a billiards paradigm and demonstrated the feasibility of real-world-neuroscience using wearables for naturalistic full-body motion-tracking and mobile-brain-imaging. Here we developed an embodied virtual-reality (VR) environment to our real-world billiards paradigm, which allows to control the visual feedback for this complex real-world task, while maintaining sense of embodiment. The setup was validated by comparing real-world ball trajectories with the trajectories of the virtual balls, calculated by the physics engine. We then ran our learning protocol in the embodied VR. Subjects played billiard shots when they held the physical cue and hit a physical ball on the table while seeing it all in VR. We found comparable learning trends in the embodied VR to those we previously reported in the physical real-world task. Embodied VR can be used for learning real-world tasks in a highly controlled environment which enables applying visual manipulations, common in laboratory-tasks and rehabilitation, to a real-world full-body task. Embodied VR enables to manipulate feedback and apply perturbations to isolate and assess interactions between specific motor-learning components, thus enabling addressing the current questions of motor-learning in real-world tasks. Such a setup can be used for rehabilitation, where VR is gaining popularity but the transfer to the real-world is currently limited, presumably, due to the lack of embodiment.
Limits of subjective and objective vection for ultra-high frame rate visual displays
Authors: Weech Séamas , Kenny Sophie , Calderon Claudia Martin , Barnett-Cowan Michael 
Published: March 2020

AbstractLarge-field optic flow generates the illusory percept of self-motion, termed ‘vection’. Smoother visual motion displays generate a more compelling subjective sense of vection and objective postural responses, as well as a greater sense of immersiveness for the user observing the visual display. Research suggests that the function linking frame rate and vection asymptotes at 60 frames per second (FPS), but previous studies have used only moderate frame rates that do not approach the limits of human perception. Here, we measure vection using subjective and objective (mean frequency and path length of postural centre-of-pressure (COP) excursions) responses following the presentation of high-contrast optic flow stimuli at slow and fast speeds and low and ultra-high frame rates. We achieve this using a novel rendering method implemented with a projector capable of sub-millisecond temporal resolution in order to simulate refresh rates ranging from very low (15 FPS) to ultra-high frame rates (480 FPS). The results suggest that subjective vection was experienced most strongly at 60 FPS. Below and above 60 FPS, subjective vection is generally weaker, shorter, and starts later, although this pattern varied slightly according to the speed of stimuli. For objective measures, while the frequency of postural sway was unaffected by frame rate, COP path length was greatest for 480 FPS stimuli. Together, our results support diminishing returns for vection above 60 FPS and provide insight into the use of high frame rate for enhancing the user experience in visual displays.
Anchoring the human olfactory system to a functional gradient
Authors: Waymel Alice , Friedrich Patrick , Bastian Pierre-Antoine , Forkel Stephanie J. , de Schotten Michel Thiebaut 
Published: March 2020

ABSTRACTMargulies et al. (2016) demonstrated the existence of at least five independent functional connectivity gradients in the human brain. However, it is unclear how these functional gradients might link to anatomy. The dual origin theory proposes that differences in cortical cytoarchitecture originate from two trends of progressive differentiation between the different layers of the cortex, referred to as the hippocampocentric and olfactocentric systems. When conceptualising the functional connectivity gradients within the evolutionary framework of the Dual Origin theory, the first gradient likely represents the hippocampocentric system anatomically. Here we expand on this concept and demonstrate that the fifth gradient likely links to the olfactocentric system. We describe the anatomy of the latter as well as the evidence to support this hypothesis. Together, the first and fifth gradients might help to model the Dual Origin theory of the human brain and inform brain models and pathologies.
AMPAR trafficking dependent LTP initiates cortical remapping and adaptive behaviors during sensory experience
Authors: Campelo Tiago , Augusto Elisabete , Chenouard Nicolas , de Miranda Aron , Kouskoff Vladimir , Choquet Daniel , Gambino Frédéric 
Published: March 2020

AbstractCortical plasticity improves behaviors and helps recover lost functions after injury by adapting neuronal computations. However, the underlying synaptic and circuit mechanisms remain unclear. In mice, we found that trimming all but one whisker enhances sensory responses from the spared whisker in the somatosensory barrel cortex and occludes whisker-mediated long-term potentiation (w-LTP)in vivo. In addition, whisking-dependent behaviors that are initially impaired by single whisker experience (SWE) rapidly recover when associated cortical regions remap. Blocking the surface diffusion of AMPA receptors (AMPARs) suppresses the expression of w-LTP in naïve mice with all whiskers intact, demonstrating that physiologically induced LTPin vivorequires AMPARs trafficking. We used this approach to demonstrate that w-LTP is required for SWE-mediated strengthening of synaptic inputs and initiates the recovery of previously learned skills during the early phases of SWE. Taken together, our data reveal that w-LTP mediates cortical remapping and behavioral improvement upon partial sensory deafferentation and demonstrates that restoration of sensory function after peripheral injury can be manipulated.
A preliminary investigation of major bacterial antibiotic resistance genes present in Australian fecal samples using shotgun metagenomics and targeted sequencing
Authors: Guernier-Cambert Vanina , Chamings Anthony , Collier Fiona , Alexandersen Soren 
Published: March 2020

AbstractThe gut microbiota is an immense reservoir of antimicrobial resistance genes (ARGs); however, in Australia the profile of the gut ‘resistome’, or ensemble of ARGs, has not been investigated. This study provides a first preliminary mapping of the major bacterial ARGs present in human, domestic dog and wild duck fecal samples collected from south-eastern Victoria, Australia; and evaluates the use of shotgun metagenomics sequencing (SMS) and targeted amplification of ARGs. We analysed SMS data using an in-house method and web-based bioinformatics tools: ResFinder and KmerResistance. We examined targeted sequences using One Codex or the PanBacterialAnalysis Torrent Suite plugin. All methods detected ARGs in all samples, with resistance to up to 13 classes of antibiotics detected overall. ARGs were more abundant in the human and dog samples than the duck samples. They mostly conferred resistance to three classes of antibiotics that are the most frequently prescribed in Australia: tetracycline, β-lactams and MLSB(macrolide, lincosamide, streptogramin B). Targeted sequencing significantly improved sensitivity for detection of ARGs included in the panel; however, SMS provided quantitative information and allowed tentative identification of the host bacteria. For SMS, web-based and in-house methods gave comparable results, with discrepancies mostly due to different reference databases. The in-house method allowed manually checking results and potential errors, while web-based methods were user-friendlier and less time-consuming. More samples need to be investigated to fully describe the resistome in humans and animals in Australia.
Fast quantitative analysis of timsTOF PASEF data with MSFragger and IonQuant
Authors: Yu Fengchao , Haynes Sarah E. , Teo Guo Ci , Avtonomov Dmitry M. , Polasky Daniel A. , Nesvizhskii Alexey I. 
Published: March 2020

AbstractIon mobility brings an additional dimension of separation to liquid chromatography-mass spectrometry, improving identification of peptides and proteins in complex mixtures. A recently introduced timsTOF mass spectrometer (Bruker) couples trapped ion mobility separation to time-of-flight mass analysis. With the parallel accumulation serial fragmentation (PASEF) method, the timsTOF platform achieves promising results, yet analysis of the data generated on this platform represents a major bottleneck. Currently, MaxQuant and PEAKS are most commonly used to analyze these data. However, due to the high complexity of timsTOF PASEF data, both require substantial time to perform even standard tryptic searches. Advanced searches (e.g. with many variable modifications, semi- or non-enzymatic searches, or open searches for post-translational modification discovery) are practically impossible. We have extended our fast peptide identification tool MSFragger to support timsTOF PASEF data, and developed a label-free quantification tool, IonQuant, for fast and accurate 4-D feature extraction and quantification. Using a HeLa data set published by Meier et al. (2018), we demonstrate that MSFragger identifies significantly (∼30%) more unique peptides than MaxQuant (1.6.10.43), and performs comparably or better than PEAKS X+ (∼10% more peptides). IonQuant outperforms both in terms of number of quantified proteins while maintaining good quantification precision and accuracy. Runtime tests show that MSFragger and IonQuant can fully process a typical two-hour PASEF run in under 70 minutes on a typical desktop (6 CPU cores, 32 GB RAM), significantly faster than other tools. Finally, through semi-enzymatic searching, we significantly increase the number of identified peptides. Within these semi-tryptic identifications, we report evidence of gas-phase fragmentation prior to MS/MS analysis.
Optical trapping of nucleolus reveals viscoelastic properties of nucleoplasm inside mouse germinal vesicle oocytes
Authors: Syrchina Maria S. , Shakhov Aleksander M. , Aybush Arseny V. , Nadtochenko Victor A. 
Published: March 2020

ABSTRACTWe propose a technique of controlled manipulation with mammalian intracellular bodies by means of optical trapping in order to reveal viscoelastic properties of cell interior. Near infrared laser in the spectral range of tissue transparency was applied to study dynamics of the nucleolus-chromatin complex inside the thermodynamically non-equilibrium system of a mouse oocyte. A nucleolus of germinal vesicle (GV) oocyte as spherical probe was displaced from the equilibrium and its relaxation dynamics was observed. We developed software for subdiffraction tracking of a nucleolus position with lateral resolution up to 3 nm and applied it for different GV-oocyte chromatin configurations. We showed differences in viscoelastic properties within nucleoplasm of NSN-oocytes, visualized by Hoechst 33342 staining. Also, we demonstrate that in germ cells basic biophysical properties of nucleoplasm can be obtained by using optical trapping without disruption and modification of cellular interior.
The GspLM inner membrane complex from the bacterial type II secretion system is a dimer of dimers and interacts with the system ATPase with high affinity
Authors: Fulara Aleksandra , Ramou Ioanna , Savvides Savvas N. 
Published: March 2020

ABSTACTThe type II secretion system (T2SS) is a multiprotein machinery spanning the diderm of gram-negative bacteria. T2SS contributes to the virulence of numerous gram-negative pathogens, including the multidrug resistant speciesPseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumoniaandVibrio cholerae. Even though the T2SS has been studied extensively over the past three decades, our understanding of the molecular basis of its biogenesis and of its overall structure still remains unclear. Here we show that the core component of the inner membrane platform, the GspLM membrane protein complex, can be isolated as a dimer of dimers. Importantly, the complex is able to bind the T2SS ATPase, GspE, with high affinity. Finally, we have developed single domain VHH camelid antibodies (nanobodies) against the GspLM complex and have identified a nanobody that effectively prevents the cytoplasmic domain of GspL, GspLcyto, from binding to GspE. Our findings suggest that the T2SS ATPase is permanently associated with the inner membrane platform and that the GspELM complex should be considered as a key subassembly for the biogenesis of the T2SS apparatus.
Neuronal octopamine signaling regulates mating-induced germline stem cell proliferation in femaleDrosophila melanogaster
Authors: Yoshinari Yuto , Ameku Tomotsune , Kondo Shu , Tanimoto Hiromu , Kuraishi Takayuki , Shimada-Niwa Yuko , Niwa Ryusuke 
Published: March 2020

AbstractStem cells fuel the development and maintenance of tissues. Many studies have addressed how local signals from neighboring niche cells regulate stem cell identity and their proliferative potential. However, the regulation of stem cells by tissue-extrinsic signals in response to external cues remains poorly understood. Here we report that efferent octopaminergic neurons projecting to the ovary are essential for germline stem cell (GSC) proliferation in response to mating in femaleDrosophila. The neuronal activity of the octopaminergic neurons is required for mating-induced GSC proliferation as they relay the mating signal from Sex peptide receptor-positive cholinergic neurons. Octopamine and its receptor Oamb are also required for mating-induced GSC proliferation via intracellular Ca2+signaling. Moreover, we identified Matrix metalloproteinase-2 as a downstream component of the octopamine-Ca2+signaling to induce GSC proliferation. Our study provides a mechanism describing how neuronal system couples stem cell behavior to external cues through stem cell niche signaling.
A role for KIF9 in male fertility
Authors: Chen Ken , Cho Sang Yeon , Zhang Yongwei , Beck Amanda , Segall Jeffrey E. 
Published: March 2020

AbstractA mouse was generated containing a floxed exon 3 of the gene for the kinesin family member KIF9. By in situ hybridization, expression of KIF9 mRNA was highest in the testis and was also strong in epithelia containing multi-ciliated cells such as the ependyma, bronchioles and oviduct. Deletion of the exon led to loss of KIF9 expression at the mRNA and protein level with no effect on viability. However, homozygous KIF9 knockout males were sterile. Although KIF9 knockout sperm were motile, they were unable to fertilize oocytes in an in vitro fertilization assay. Closer examination of sperm motility indicated a subtle difference in waveform. Our results suggest that KIF9 plays a role male fertility, possibly through regulation of flagellar waveforms in ciliated cells.
Dmon1andrab7interact to regulate glutamate receptor GluRIIA levels at the larvalDrosophilaneuromuscular junction
Authors: Basargekar Anagha , Yogi Shweta , Mushtaq Zeeshan , Deivasigamani Senthil , Kumar Vimlesh , Ratnaparkhi Girish , Ratnaparkhi Anuradha 
Published: March 2020

AbstractRegulation of post-synaptic receptors plays an important role in determining synaptic strength and plasticity. TheDrosophilalarval neuromuscular junction (nmj) has been used extensively as a model to understand some of these processes. In this context, we are interested in the role ofDrosophilaMonensin sensitive protein 1 (DMon1) in regulating glutamate receptor (GluRIIA) levels at the nmj.Dmon1is an evolutionarily conserved protein which, in complex with CCZ1, regulates the conversion of early endosomes to late endosomes through recruitment of Rab7. C-terminal deletion mutants ofDmon1(Dmon1Δ181) exhibit lethality. The escapers have a short life span and exhibit severe motor defects. At the nmj, these mutants show a defects in synaptic morphology and a strong increase in glutamate receptor GluRIIA levels. The mechanism by whichDmon1regulates GluRIIA is unclear.In this study, we have described the characterization the mutation in an EMS mutant referred to aspog1and demonstrate this mutant to be an allele ofDmon1. Further, we have examined the role ofrab7in regulation the of GluRIIA. We show that similar toDmon1, knock-down ofrab7using RNAi in neurons, and not muscles, leads to an increase in GluRIIA. Loss of one copy each ofDmon1withrab7leads to a synergistic increase in receptor expression. Further, overexpression of an activated Rab7 can rescue the GluRIIA phenotype observed inDmon1Δ181mutants. Together, these results highlight a neuronal role for Rab7 in GluRIIA regulation and underscores the important of the endo-lysosomal pathway in this process.
Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles
Authors: Han Liu , Long Qilai , Li Shenjun , Xu Qixia , Zhang Boyi , Dou Xuefeng , Qian Min , Jiramongkol Yannasittha , Guo Jianming , Cao Liu , Chin Y. Eugene , Lam Eric W-F , Jiang Jing , Sun Yu 
Published: March 2020

ABSTRACTCellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.
Tax structure and economic growth in India: insights from ARDL model
Authors: Neog Yadawananda , Gaur Achal Kumar 
Published: March 2020

PurposeIn the academic debate, the tax–growth relationship is always a controversial one. This paper aims to investigate the relationship between tax structure and economic growth in India for the period 1980-2016. After controlling for total tax revenue share to GDP in the estimation model, the authors examine the long-run and short-run relationship between tax structure and growth in India.Design/methodology/approachAuto-regressive distributed lag (ARDL) model has been used in this study. This bound cointegration model has certain advantages to the traditional cointegration model. This study also applies the threshold cointegration test of Hansen and Seo (2002) for examining non-linearity in tax–growth nexus.FindingsThe analysis shows that income tax share, corporation tax share and excise tax share are harmful to growth in the long-run. While the custom share is enlarging the growth performance. Corporation tax share is also reducing growth in the short-run. Following the Pesaranet al.(2001) approach of ARDL bound testing, the authors find the existence of a long-run relationship between studied variables. However, this study does not find any existence of threshold effect in the tax–growth relationship for India.Practical implicationsBased on the empirical findings, the author suggests that the prime tax change, which has the potential to impact both long-run growth and short-run economic recovery is the reduction of corporate tax rate with sustainable revenue generation. It will definitely enlarge the foreign direct investment, saving and investment in India.Originality/valueThis study will be a contribution to the empirical literature by investigating “tax–growth” relationship in the Indian case. To the knowledge, this will be the first study to examine this relationship for India with a recent data set.