bluuebunny/crossref_metadata_2025_split huggingface dataset:
T606-phosphorylation deprives the function of Kaiso as a transcription and oncogenic factor
Authors: Tian Wei , Yuan Hongfan , Qin Sisi , Liu Wensu , Zhang Baozhen , Gu Liankun , Zhou Jing , Deng Dajun 
Published: March 2020

ABSTRACTIt is well known that Kaiso protein encoded byZBTB33gene is a transcription repressor and that Kaiso–P120ctn interaction increases the shift of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalization are far from clear. Here, we reported that AKT1 could phosphorylate 606-threonine residue (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606-phosphorylated Kaiso (pT606-Kaiso) could directly bind to 14-3-3 family proteins and the depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso–14-3-3 binding. In addition, the Kaiso–P120ctn interaction was essential for the pT606-Kaiso accumulation in the cytoplasm. Notably, enforced14-3-3σ(SFN) overexpression could increase the pT606-Kaiso accumulation in the cytoplasm and de-repress the transcription of Kaiso target geneCDH1. Decreased amounts of both pT606-Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues relative to paired normal controls. The mRNA levels of14-3-3σand Kaiso target geneCDH1were positively and significantly correlated with each other in bioinformatics analyses using publicly available RNA-seq datasets for human normal tissues (n=11688,r=0.60,p<0.001) in the GTEx project and for cancer cell lines (n=1156,r=0.41,p<0.001) in the CCLE project. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cellsin vitroas well as boosted the growth of these cellsin vivo. In conclusion, Kaiso could be phosphorylated by AKT1 at the T606 and the pT606-Kaiso accumulates in the cytoplasm through binding to 14-3-3/P120ctn that de-represses the expression of Kaiso target geneCDH1in normal tissues. Decreased Kaiso phosphorylation may contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer.
Reaching to sounds in virtual reality: A multisensory-motor approach to re-learn sound localisation
Authors: Valzolgher Chiara , Verdelet Grègoire , Salemme Romeo , Lombardi Luigi , Gaveau Valerie , Farné Alessandro , Pavani Francesco 
Published: March 2020

ABSTRACTWhen localising sounds in space the brain relies on internal models that specify the correspondence between the auditory input reaching the ears and initial head-position with coordinates in external space. These models can be updated throughout life, setting the basis for re-learning spatial hearing abilities in adulthood. This is particularly important for individuals who experience long-term auditory alterations (e.g., hearing loss, hearing aids, cochlear implants) as well as individuals who have to adapt to novel auditory cues when listening in virtual auditory environments. Until now, several methodological constraints have limited our understanding of the mechanisms involved in spatial hearing re-learning. In particular, the potential role of active listening and head-movements have remained largely overlooked. Here, we overcome these limitations by using a novel methodology, based on virtual reality and real-time kinematic tracking, to study the role of active multisensory-motor interactions with sounds in the updating of sound-space correspondences. Participants were immersed in a virtual reality scenario showing 17 speakers at ear-level. From each visible speaker a free-field real sound could be generated. Two separate groups of participants localised the sound source either by reaching or naming the perceived sound source, under binaural or monaural listening. Participants were free to move their head during the task and received audio-visual feedback on their performance. Results showed that both groups compensated rapidly for the short-term auditory alteration caused by monaural listening, improving sound localisation performance across trials. Crucially, compared to naming, reaching the sounds induced faster and larger sound localisation improvements. Furthermore, more accurate sound localisation was accompanied by progressively wider head-movements. These two measures were significantly correlated selectively for the Reaching group. In conclusion, reaching to sounds in an immersive visual VR context proved most effective for updating altered spatial hearing. Head movements played an important role in this fast updating, pointing to the importance of active listening when implementing training protocols for improving spatial hearing.HIGHLIGHTS- We studied spatial hearing re-learning using virtual reality and kinematic tracking- Audio-visual feedback combined with active listening improved monaural sound localisation- Reaching to sounds improved performance more than naming sounds- Monaural listening triggered compensatory head-movement behaviour- Head-movement behaviour correlated with re-learning only when reaching to sounds
Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift
Authors: Knight MK , Woolley RE , Kwok A , Parsons S , Jones HBL , Gulácsy CE , Phaal P , Kassaar O , Dawkins K , Rodriguez E , Marques A , Bowsher L , Wells SA , Watts A , van den Elsen JMH , Turner A , O’Hara J , Pudney CR 
Published: March 2020

AbstractAmong the major challenges in the development of biopharmaceuticals are structural heterogeneity and aggregation. The development of a successful therapeutic monoclonal antibody (mAb) requires both a highly active and also stable molecule. Whilst a range of experimental (biophysical) approaches exist to track changes in stability of proteins, routine prediction of stability remains challenging. The fluorescence red edge excitation shift (REES) phenomenon is sensitive to a range of changes in protein structure. Based on recent work, we have found that quantifying the REES effect is extremely sensitive to changes in protein conformational state and dynamics. Given the extreme sensitivity, potentially this tool could provide a ‘fingerprint’ of the structure and stability of a protein. Such a tool would be useful in the discovery and development of biopharamceuticals and so we have explored our hypothesis with a panel of therapeutic mAbs. We demonstrate that the quantified REES data show remarkable sensitivity, being able to discern between structurally identical antibodies and showing sensitivity to unfolding and aggregation. The approach works across a broad concentration range (μg–mg/ml) and is highly consistent. We show that the approach can be applied alongside traditional characterisation testing within the context of a forced degradation study (FDS). Most importantly, we demonstrate the approach is able to predict the stability of mAbs both in the short (hours), medium (days) and long-term (months). The quantified REES data will find immediate use in the biopharmaceutical industry in quality assurance, formulation and development. The approach benefits from low technical complexity, is rapid and uses instrumentation which exists in most biochemistry laboratories without modification.
Regenerated Interneurons Integrate Into Locomotor Circuitry Following Spinal Cord Injury
Authors: Vasudevan Deeptha , Liu Yen-Chyi , Barrios Joshua P. , Wheeler Maya K. , Douglass Adam D. , Dorsky Richard I. 
Published: March 2020

AbstractWhereas humans and other adult mammals lack the ability to regain locomotor function after spinal cord injury, zebrafish are able to recover swimming behavior even after complete spinal cord transection. We have previously shown that zebrafish larvae regenerate lost neurons within 9 days post-injury (dpi), but the functional contribution of these neurons to motor recovery is unknown. Here we show that multiple interneuron subtypes known to play a role in locomotor circuitry are regenerated in injured spinal cord segments during the period of functional recovery. Further, we show that one subtype of newly-generated interneurons receives excitatory input and fires synchronously with motor output by 9 dpi. Taken together, our data show that regenerative neurogenesis in the zebrafish spinal cord produces interneurons with the physiological capacity to participate in the recovery of locomotor function.
Flagellar dynamics reveal fluctuations and kinetic limit in theEscherichia colichemotaxis network
Authors: Bano Roshni , Mears Patrick , Golding Ido , Chemla Yann R. 
Published: March 2020

AbstractTheEscherichia colichemotaxis network, by which bacteria modulate their random run/tumble swimming pattern to navigate their environment, must cope with unavoidable number fluctuations (“noise”) in its molecular constituents like other signaling networks. The probability of clockwise (CW) flagellar rotation, or CW bias, is a measure of the chemotaxis network’s output, and its temporal fluctuations provide a proxy for network noise. Here we quantify fluctuations in the chemotaxis signaling network from the switching statistics of flagella, observed using time-resolved fluorescence microscopy of individual optically trappedE. colicells. This approach allows noise to be quantified across the dynamic range of the network. Large CW bias fluctuations are revealed at steady state, which may play a critical role in driving flagellar switching and cell tumbling. When the network is stimulated chemically to higher activity, fluctuations dramatically decrease. A stochastic theoretical model, inspired by work on gene expression noise, points to CheY activation occurring in bursts, driving CW bias fluctuations. This model also shows that an intrinsic kinetic ceiling on network activity places an upper limit on activated CheY and CW bias, which when encountered suppresses network fluctuations. This limit may also prevent cells from tumbling unproductively in steep gradients.
Organ-specificity of sterol and triterpene accumulation inArabidopsis thaliana
Authors: Lange B. Markus , Poirier Brenton C. , Lange Iris , Schumaker Richard , Rios-Estepa Rigoberto 
Published: March 2020

ABSTRACTSterols serve essential functions as membrane constituents and hormones (brassinosteroids) in plants, while non-sterol triterpenoids have been implicated in defense responses. Surprisingly little is known about the sterol and triterpene profiles in different plant organs. To enhance our understanding of organ-specific sterol and triterpene accumulation, we quantified these metabolite classes in four different organs (root, stem, leaf, seed) ofArabidopsis thaliana(L.). Based on these data sets we developed kinetic mathematical models of sterol biosynthesis to capture flux distribution and pathway regulation in different organs. Simulations indicated that an increased flux through the sterol pathway would not only result in an increase of sterol end products but also a concomitant build-up of certain intermediates. These computational predictions turner out to be consistent with experimental data obtained with transgenic plants ectopically overexpressing 3-hydroxy-3-methylglutary-coenzyme A reductase (HMG1gene). The opportunities and limitations of incorporating mathematical modeling into the design of approaches to engineer sterol biosynthesis are discussed.
Maternal vitamin D deficiency increases the risk of obesity in male mice offspring by affecting the immune response
Authors: Li Pei , Li Ping , Liu Yuanlin , Liu Weijiang , Zha Lanlan , Chen Xiaoyu , Zheng Rongxiu , Qi Kemin , zhang Yi 
Published: March 2020

AbstractRecently, many epidemiological and animal studies have indicated that obesity have their origin in the early stages of life including the inappropriate balance of some nutrients, the objective of this study is to determine the risk of obesity in male mice offspring as a consequence of maternal VD deficiency-mediated disordering of the immune response. Four-week-old C57BL/6J female mice were fed VD-deficient or normal reproductive diets during pregnancy and lactation. Their male offspring were weighted and euthanized after being fed control and high-fat diets (HFD) for 16 weeks starting at the weaning. The serum was collected for biochemical analyses. Epididymal (eWAT) and inguinal (iWAT) white adipose tissues were excised for histological examination, immunohistochemistry, gene expressions of inflammatory factors, and for determining the proportions of immune cells by flow cytometry. Insufficient maternal VD intake exacerbated the development of obesity both in non-obese and obese male offspring as evidenced by larger adipose cells and abnormal glucose and lipid metabolisms. Also, the expression of proinflammatory cytokine genes was increased and that of anti-inflammatory cytokines was decreased in maternal VD-deficient groups in the eWAT and/or iWAT. This was accompanied by higher levels of TNF-α or/and INF-β, and lower levels of IL-4 and IL-10. Insufficient maternal VD intake was also observed to induce a shift in the profiles of immune cells in the eWAT and/or iWAT, resulting in increased percentages of M1 macrophage, ATDCs, and CD4+and CD8+T cells, but caused a significant decrease in the percentage of M2 macrophages, both in non-obese and obese male offspring. All these changes in the immune cell profile were more obvious in the eWAT than in the iWAT. These results indicated that insufficient maternal VD intake promoted the development of obesity in male offspring by modulating the immune cell populations and causing a polarization in the adipose depots.ImportanceEvidence in this study has indicated that insufficient maternal VD intake promotes the development of obesity in the male offspring by modulating the recruitment of immune cell populations and their polarization as well as the expression and secretion of proinflammatory adipokines in the adipose depots in a weight-independent manner, which is more obvious in eWAT than that in the iWAT.
BatchServer: a web server for batch effect evaluation, visualization and correction
Authors: Zhu Tiansheng , Chen Guo-Bo , Yuan Chunhui , Sun Rui , Zhang Fangfei , Yi Xiao , Zhou Shuigen , Guo Tiannan 
Published: March 2020

AbstractBatch effects are unwanted data variations that may obscure biological signals, leading to bias or errors in subsequent data analyses. Effective evaluation and elimination of batch effects are necessary for omics data analysis. In order to facilitate the evaluation and correction of batch effects, here we present BatchSever, an open-source R/Shiny based user-friendly interactive graphical web platform for batch effects analysis. In BatchServer we introduced autoComBat, a modified version of ComBat, which is the most widely adopted tool for batch effect correction. BatchServer uses PVCA (Principal Variance Component Analysis) and UMAP (Manifold Approximation and Projection) for evaluation and visualizion of batch effects. We demonstate its application in multiple proteomics and transcriptomic data sets. BatchServer is provided athttps://lifeinfo.shinyapps.io/batchserver/as a web server. The source codes are freely available athttps://github.com/guomics-lab/batch_server.
The role of UCP3 in brown adipose tissue mitochondrial bioenergetics is complementary to that of UCP1
Authors: Riley Christopher L. , Mills Edward M. 
Published: March 2020

AbstractMitochondrial uncoupling protein 3 (UCP3) plays a complementary role in uncoupling protein 1 (UCP1)-dependent uncoupling in mammalian thermogenesis. Using mouse strains that lack UCP1 or UCP3, plus a UCP1/UCP3 double knockout, we have previously demonstrated that UCP3 is necessary for sustained heat production. However, how and where UCP3 is essential for heat production remains unknown. Here we use brown adipocyte mitochondria from mice lacking UCP1, UCP3, or UCP1 plus UCP3 (double knockout) we found that in the absence of UCP1, UCP3 does not act as a free fatty acid-inducible uncoupling protein; however, UCP3 is necessary for maximal GDP-sensitive respiration. We additionally confirm that the loss of UCP1 is a dominant regulator of mitochondrial respiratory chain activity, assembly, and composition in brown adipose tissue. Our data suggest without UCP1, brown adipose tissue is not a significant source of heat production, and that UCP3-dependent heat generation serves a regulatory function outside of adipose tissues. Together these findings suggest that in brown adipose tissue, UCP3’s thermogenic function is independent of its role as abona fideuncoupling protein.
Ab-Ligity: Identifying sequence-dissimilar antibodies that bind to the same epitope
Authors: Wong Wing Ki , Robinson Sarah A. , Bujotzek Alexander , Georges Guy , Lewis Alan P. , Shi Jiye , Snowden James , Taddese Bruck , Deane Charlotte M. 
Published: March 2020

AbstractSolving the structure of an antibody-antigen complex gives atomic level information of the interactions between an antibody and its antigen, but such structures are expensive and hard to obtain. Alternative experimental sources include epitope mapping and binning experiments which can be used as a surrogate to identify key interacting residues. However, their resolution is usually not sufficient to identify if two antibodies have identical interactions. Computational approaches to this problem have so far been based on the premise that antibodies with similar sequences behave similarly. Such approaches will fail to identify sequence-distant antibodies that target the same epitope.We present Ab-Ligity, a structure-based similarity measure tailored to antibody-antigen interfaces. Using predicted paratopes on model antibody structures, we assessed its ability to identify those antibodies that target highly similar epitopes. Most antibodies adopting similar binding modes can be identified from sequence similarity alone, using methods such as clonotyping. In the challenging subset of antibodies whose sequences differ significantly, Ab-Ligity is still able to predict antibodies that would bind to highly similar epitopes (precision of 0.95 and recall of 0.69). We compared Ab-Ligity’s performance to an existing tool for comparing general protein interfaces, InterComp, and showed improved performance on antibody cases alongside a significant speed-up. These results suggest that Ab-Ligity will allow the identification of diverse (sequence-dissimilar) antibodies that bind to the same epitopes from large datasets such as immune repertoires. The tool is available athttp://opig.stats.ox.ac.uk/resources.
Channel Embedding for Informative Protein Identification from Highly Multiplexed Images
Authors: Magid Salma Abdel , Jang Won-Dong , Schapiro Denis , Wei Donglai , Tompkin James , Sorger Peter K. , Pfister Hanspeter 
Published: March 2020

AbstractInterest is growing rapidly in using deep learning to classify biomedical images, and interpreting these deep-learned models is necessary for life-critical decisions and scientific discovery. Effective interpretation techniques accelerate biomarker discovery and provide new insights into the etiology, diagnosis, and treatment of disease. Most interpretation techniques aim to discover spatially-salient regions within images, but few techniques consider imagery with multiple channels of information. For instance, highly multiplexed tumor and tissue images have 30-100 channels and require interpretation methods that work across many channels to provide deep molecular insights. We propose a novel channel embedding method that extracts features from each channel. We then use these features to train a classifier for prediction. Using this channel embedding, we apply an interpretation method to rank the most discriminative channels. To validate our approach, we conduct an ablation study on a synthetic dataset. Moreover, we demonstrate that our method aligns with biological findings on highly multiplexed images of breast cancer cells while outperforming baseline pipelines.
Autocatalytic–Protection for an Unknown Locus CRISPR–Cas Countermeasure for Undesired Mutagenic Chain Reactions
Authors: Schonfeld Ethan , Schonfeld Elan , Schonfeld Dan 
Published: March 2020

AbstractThe mutagenic chain reaction (MCR) is a genetic tool to use a CRISPR–Cas construct to introduce a homing endonuclease, allowing gene drive to influence whole populations in a minimal number of generations1,2,3. The question arises: if an active genetic terror event is released into a population, could we prevent the total spread of the undesired allele4? Thus far, MCR protection methods require knowledge of the terror locus5. Here we introduce a novel approach, anautocatalytic-Protection for an Unknown Locus(a-PUL), whose aim is to spread through a population and arrest and decrease an active terror event’s spread without any prior knowledge of the terror-modified locus, thus allowing later natural selection and ERACR drives to restore the normal locus6. a-PUL, using a mutagenic chain reaction, includes (i) a segment encoding a non-Cas9 endonuclease capable of homology-directed repair suggested as Type II endonuclease Cpf1 (Cas12a), (ii) a ubiquitously-expressed gene encoding a gRNA (gRNA1) with a U4AU4 3′-overhang specific to Cpf1 and with crRNA specific to some desired genomic sequence of non-coding DNA, (iii) a ubiquitously-expressed gene encoding two gRNAs (gRNA2/gRNA3) both with tracrRNA specific to Cas9 and crRNA specific to two distinct sites of the Cas9 locus, and (iv) homology arms flanking the Cpf1/gRNA1/gRNA2/gRNA3 cassette that are identical to the region surrounding the target cut directed by gRNA17. We demonstrate the proof-of-concept and efficacy of our protection construct through a Graphical Markov model and computer simulation.
SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Authors: Blanco-Melo Daniel , Nilsson-Payant Benjamin E. , Liu Wen-Chun , Møller Rasmus , Panis Maryline , Sachs David , Albrecht Randy A. , tenOever Benjamin R. 
Published: March 2020

ABSTRACTOne of the greatest threats to humanity is the emergence of a pandemic virus. Among those with the greatest potential for such an event include influenza viruses and coronaviruses. In the last century alone, we have observed four major influenza A virus pandemics as well as the emergence of three highly pathogenic coronaviruses including SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. As no effective antiviral treatments or vaccines are presently available against SARS-CoV-2, it is important to understand the host response to this virus as this may guide the efforts in development towards novel therapeutics. Here, we offer the first in-depth characterization of the host transcriptional response to SARS-CoV-2 and other respiratory infections throughin vitro, ex vivo, andin vivomodel systems. Our data demonstrate the each virus elicits both core antiviral components as well as unique transcriptional footprints. Compared to the response to influenza A virus and respiratory syncytial virus, SARS-CoV-2 elicits a muted response that lacks robust induction of a subset of cytokines including the Type I and Type III interferons as well as a numerous chemokines. Taken together, these data suggest that the unique transcriptional signature of this virus may be responsible for the development of COVID-19.