bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stratified neural networks in a time-to-event setting
Authors: Kuruc Fabrizio , Binder Harald , Hess Moritz 
Published: February 2021

AbstractDeep neural networks are now frequently employed to predict survival conditional on omics-type biomarkers, e.g. by employing the partial likelihood of Cox proportional hazards model as loss function. Due to the generally limited number of observations in clinical studies, combining different data-sets has been proposed to improve learning of network parameters. However, if baseline hazards differ between the studies, the assumptions of Cox proportional hazards model are violated. Based on high dimensional transcriptome profiles from different tumor entities, we demonstrate how using a stratified partial likelihood as loss function allows for accounting for the different baseline hazards in a deep learning framework. Additionally, we compare the partial likelihood with the ranking loss, which is frequently employed as loss function in machine learning approaches due to its seemingly simplicity. Using RNA-seq data from the Cancer Genome Atlas (TCGA) we show that use of stratified loss functions leads to an overall better discriminatory power and lower prediction error compared to their nonstratified counterparts. We investigate which genes are identified to have the greatest marginal impact on prediction of survival when using different loss functions. We find that while similar genes are identified, in particular known prognostic genes receive higher importance from stratified loss functions. Taken together, pooling data from different sources for improved parameter learning of deep neural networks benefits largely from employing stratified loss functions that consider potentially varying baseline hazards. For easy application, we provide PyTorch code for stratified loss functions and an explanatory Jupyter notebook in a GitHub repository.
Differential dropout analysis captures biological variation in single-cell RNA sequencing data
Authors: Bouland Gerard A. , Mahfouz Ahmed , Reinders Marcel J.T. 
Published: February 2021

AbstractSingle-cell RNA sequencing data is characterized by a large number of zero counts, yet there is growing evidence that these zeros reflect biological variation rather than technical artifacts. We propose differential dropout analysis (DDA) to identify the effects of biological variation in single-cell RNA sequencing data. Using 16 publicly available and simulated datasets, we show that DDA accurately detects biological variation and can assess the relative abundance of transcripts more robustly than methods relying on counts. DDA is available athttps://github.com/gbouland/DDA.
Image denoising for fluorescence microscopy by self-supervised transfer learning
Authors: Wang Yina , Pinkard Henry , Khwaja Emaad , Zhou Shuqin , Waller Laura , Huang Bo 
Published: February 2021

AbstractWhen using fluorescent microscopy to study cellular dynamics, trade-offs typically have to be made between light exposure and quality of recorded image to balance phototoxicity and image signal-to-noise ratio. Image denoising is an important tool for retrieving information from dim live cell images. Recently, deep learning based image denoising is becoming the leading method because of its promising denoising performance, achieved by leveraging available prior knowledge about the noise model and samples at hand. We demonstrate that incorporating temporal information in the model can further improve the results. However, the practical application of this method has seen challenges because of the requirement of large, task-specific training datasets. In this work, addressed this challenge by combining self-supervised learning with transfer learning, which eliminated the demand of task-matched training data while maintaining denoising performance. We demonstrate its application in fluorescent imaging of different subcellular structures.
Regenerating insulin-producing β-cells ectopically from a mesodermal origin in the absence of endothelial specification
Authors: Liu Ka-Cheuk , Villasenor Alethia , Schmitner Nicole , Radros Niki , Rautio Linn , Reischauer Sven , Stainier Didier Y.R. , Andersson Olov 
Published: February 2021

AbstractTo investigate the role of the vasculature in pancreatic β-cell regeneration, we crossed a zebrafish β-cell ablation model into the avascularnpas4lmutant (i.e.cloche). Surprisingly, β-cell regeneration increased markedly innpas4lmutants owing to the ectopic differentiation of β-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic β-cells expressed endocrine markers of pancreatic β-cells, and also reduced glucose levels in the β-cell ablation model. Through lineage tracing, we determined that the vast majority of these ectopic β-cells derived from the mesodermal lineage. Notably, ectopic β-cells were found innpas4lmutants as well as following knockdown of the endothelial determinant Etv2. Together, these data indicate that in the absence of endothelial specification, mesodermal cells possess a remarkable plasticity enabling them to form β-cells, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for β-cell regeneration.
Biosynthesis system of Synechan, a sulfated exopolysaccharide, in the model cyanobacteriumSynechocystissp. PCC 6803
Authors: Maeda Kaisei , Okuda Yukiko , Enomoto Gen , Watanabe Satoru , Ikeuchi Masahiko 
Published: February 2021

AbstractExtracellular polysaccharides of bacteria contribute to biofilm formation, stress tolerance, and infectivity. Cyanobacteria, the oxygenic photoautotrophic bacteria, uniquely and widely have sulfated extracellular polysaccharides and they may utilize the polysaccharides for survival in nature. In addition, sulfated polysaccharides of cyanobacteria and other organisms have been focused as beneficial biomaterial. However, very little is known about their biosynthesis machinery and function in cyanobacteria. Here we found that the model cyanobacterium,Synechocystissp. PCC 6803, formed bloom-like cell aggregates using sulfated extracellular polysaccharides (designated as synechan) and identified whole set of genes responsible for synechan biosynthesis and its transcriptional regulation, thereby suggesting a model for the synechan biosynthesis apparatus. Because similar genes are found in many cyanobacterial genomes with wide variation, our findings may lead elucidation of various sulfated polysaccharides, their functions, and their potential application in biotechnology.
Impact of a human gut microbe onVibrio choleraehost colonization through biofilm enhancement
Authors: Barrasso Kelsey , Chac Denise , Debela Meti D. , Geigel Catherine , Harris Jason B. , LaRocque Regina C. , Midani Firas S. , Qadri Firdausi , Yan Jing , Weil Ana A. , Ng Wai-Leung 
Published: February 2021

AbstractRecent studies indicate that the human intestinal microbiota could impact the outcome of infection byVibrio cholerae, the etiological agent of the diarrheal disease cholera. A commensal bacterium,Paracoccus aminovorans, was previously identified in high abundance in stool collected from individuals infected withV. choleraewhen compared to stool from uninfected persons. However, if and howP. aminovoransinteracts withV. choleraehas not been experimentally determined; moreover, whether any association between this bacterium alters the behaviors ofV. choleraeto affect the disease outcome is unclear. Here we show thatP. aminovoransandV. choleraetogether form dual-species biofilm structures at the air-liquid interface, with previously uncharacterized novel features. Importantly, the presence ofP. aminovoranswithin the murine small intestine enhancesV. choleraecolonization in the same niche that is dependent on theVibrioexopolysaccharide (VPS) and other major components of matureV. choleraebiofilm. These studies illustrate that dual-species biofilm formation is a plausible mechanism used by a gut microbe to increase the virulence of the pathogen, and this interaction may alter outcomes in enteric infections.Significance StatementWhile ample evidence suggests that the outcome of some enteric infections can be affected by the intestinal microbiota, how specific gut microbes change the behaviors of a pathogen is unclear. Here we characterize the interaction betweenVibrio choleraeandParacoccus aminovorans, a gut microbe known to increase in abundance in the intestines during activeV. choleraeinfection in humans. These two bacteria form a dual-species biofilm structure at the air-liquid interface, and the gut microbe increases the host colonization efficiency ofV. cholerae. Importantly, our study identifies a previously unknown mechanism of gut microbe-pathogen interaction that has the potential to alter the disease outcome.
Neuronal control of maternal provisioning in response to social cues
Authors: Wasson Jadiel A. , Harris Gareth , Keppler-Ross Sabine , Brock Trisha J. , Dar Abdul R. , Butcher Rebecca A. , Fischer Sylvia E.J. , Kagias Konstantinos , Clardy Jon , Zhang Yun , Mango Susan 
Published: February 2021

ABSTRACTMothers contribute cytoplasmic components to their progeny in a process called maternal provisioning. Provisioning is influenced by the parental environment, but the molecular pathways that transmit environmental cues from mother to progeny are not well understood. Here we show that in C. elegans, social cues modulate maternal provisioning to regulate gene silencing in offspring. Intergenerational signal transmission depends on a pheromone-sensing neuron and neuronal FMRF (Phe-Met-Arg-Phe)-like peptides. Parental FMRF signaling promotes the deposition of mRNAs for translational components in progeny, which in turn reduces gene silencing. Previous studies had implicated FMRF signaling in short-term responses such as modulated feeding behavior in response to the metabolic state1,2, but our data reveal a broader role, to coordinate energetically expensive processes such as translation and maternal provisioning. This study identifies a new pathway for intergenerational communication, distinct from previously discovered pathways involving small RNAs and chromatin, that links sensory perception to maternal provisioning.
CRISPR targeting of MEIOTIC-TOPOISOMERASE VIB-dCas9 to a recombination hotspot is insufficient to increase crossover frequency in Arabidopsis
Authors: Yelina Nataliya E. , Gonzalez-Jorge Sabrina , Hirsz Dominique , Yang Ziyi , Henderson Ian R. 
Published: February 2021

AbstractDuring meiosis, homologous chromosomes pair and recombine, which can result in reciprocal crossovers that increase genetic diversity. Crossovers are unevenly distributed along eukaryote chromosomes and show repression in heterochromatin and the centromeres. Within the chromosome arms crossovers are often concentrated in hotspots, which are typically in the kilobase range. The uneven distribution of crossovers along chromosomes, together with their low number per meiosis, creates a limitation during crop breeding, where recombination can be beneficial. Therefore, targeting crossovers to specific genome locations has the potential to accelerate crop improvement. In plants, meiotic crossovers are initiated by DNA double strand breaks (DSBs) that are catalysed by SPO11 complexes, which consist of two catalytic (SPO11-1 and SPO11-2) and two non-catalytic subunits (MTOPVIB). We used the model plantArabidopsis thalianato target a dCas9-MTOPVIB fusion protein to the3acrossover hotspot via CRISPR. We observed that this was insufficient to significantly change meiotic crossover frequency or pattern within3a. We discuss the implications of our findings for targeting meiotic recombination within plant genomes.
The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts inC. elegans
Authors: Lang Angelica E. , Lundquist Erik A. 
Published: February 2021

AbstractCell adhesion molecules and their extracellular ligands control morphogenetic events such as directed cell migration. The migration of neuroblasts and neural crest cells establishes the structure of the central and peripheral nervous systems. InC. elegans, the bilateral Q neuroblasts and their descendants undergo long-range migrations with left/right asymmetry. QR and descendants on the right migrate anteriorly, and QL and descendants on the left migrate posteriorly, despite identical patterns of cell division, cell death, and neuronal generation. The initial direction of protrusion of the Q cells relies on the left/right asymmetric function of the transmembrane receptors UNC-40/DCC and PTP-3/LAR in the Q cells. Here we show that Q cell left/right asymmetry of migration is independent of the GPA-16/Gα pathway that regulates other left/right asymmetries including nervous system L/R asymmetry. No extracellular cue has been identified that guides initial Q anterior versus posterior migration. We show that the Collagens DPY-17 and SQT-3 control initial Q direction of protrusion. Genetic interactions with UNC-40/DCC and PTP-3/LAR suggest that DPY-17 and SQT-3 drive posterior migration and might act with both receptors or in a parallel pathway. Analysis of mutants in other Collagens and extracellular matrix components indicated that general perturbation of Collagens and the ECM did not result in directional defects, and that the effect of DPY-17 and SQT-3 on Q direction is specific. DPY-17 and SQT-3 are components of the cuticle, but a role in the basement membrane cannot be excluded. Possibly, DPY-17 and SQT-3 are part of a pattern in the cuticle and/or basement membrane that is oriented to the anterior-posterior axis of the animal and that is deciphered by the Q cells in a left-right asymmetric fashion. Alternatively, DPY-17 and SQT-3 might be involved in the production or stabilization of a guidance cue that directs Q migrations. In any case, these results describe a novel role for the DPY-17 and SQT-3 Collagens in directing posterior Q neuroblast migration.Graphical Abstract
Antennal transcriptome analysis and identification of candidate chemosensory genes of the harlequin ladybird beetle,Harmonia axyridis(Pallas) (Coleoptera: Coccinellidae)
Authors: Rondoni Gabriele , Roman Alessandro , Meslin Camille , Montagné Nicolas , Conti Eric , Jacquin-Joly Emmanuelle 
Published: February 2021

AbstractIn predatory ladybirds (Coleoptera: Coccinellidae), antennae are important for chemosensory reception used during food and mate location, and for finding a suitable oviposition habitat. Based on NextSeq 550 Illumina sequencing, we assembled the antennal transcriptome of matedHarmonia axyridis(Pallas) (Coleoptera: Coccinellidae) males and females and described the first chemosensory gene repertoire expressed in this species. We annotated candidate chemosensory sequences encoding 26 odorant receptors (including the coreceptor, Orco), 17 gustatory receptors, 27 ionotropic receptors, 31 odorant-binding proteins, 12 chemosensory proteins and 4 sensory neuron membrane proteins. Maximum-likelihood phylogenetic analyses allowed to assign candidateH. axyridischemosensory genes to previously described groups in each of these families. Differential expression analysis between males and females revealed low variability between sexes, possibly reflecting the known absence of relevant sexual dimorphism in the structure of the antennae and in the distribution and abundance of the sensilla. However, we revealed significant differences in expression of three chemosensory genes, namely 2 male-biased odorant-binding proteins and 1 male-biased odorant receptor, suggesting their possible involvement in pheromone detection. Our data pave the way for improving the understanding of the molecular basis of chemosensory reception in Coccinellidae.SummaryThe predatory harlequin ladybirdHarmonia axyridis(Pallas) (Coleoptera: Coccinellidae) has been widely released for classical and augmentative biological control programs of insect herbivores and is now distributed worldwide. Because of its invasive behavior and the threat it can pose to local biodiversity, this ladybird has been adopted as a model species for invasive biocontrol predators. A huge existing literature is available on this species. However, little is known about the mechanisms underlyingH. axyridissmell and taste, even though these senses are important in this ladybird for courtship, mating and for locating suitable habitats for feeding and oviposition. Here we describe the first chemosensory gene repertoire that is expressed in the antennae of male and femaleH. axyridis. Our findings would likely represent the basis for future functional studies aiming at increasing the efficacy ofH. axyridisin biological control or at reducing its populations in those areas where the ladybird has become a matter of concern due to its invasiveness.
The ETS Transcription Factor ERF controls the exit from the naïve pluripotent state
Authors: Vega-Sendino M. , Olbrich T. , Tillo D. , Tran A. D. , Domingo C. N. , Franco M. , FitzGerald P. C. , Kruhlak M. J. , Ruiz S. 
Published: February 2021

The naïve epiblast undergoes a transition to a pluripotent primed state during embryo implantation. Despite the relevance of the FGF pathway during this period, little is known about the downstream effectors regulating this signaling. Here, we examined the molecular mechanisms coordinating the naïve to primed transition by using inducible ESC to genetically eliminate all RAS proteins. We show that differentiated RASKOESC remain trapped in an intermediate state of pluripotency with naïve-associated features. Elimination of the transcription factor ERF overcomes the developmental blockage of RAS-deficient cells by naïve enhancer decommissioning. Mechanistically, ERF regulates NANOG expression and ensures naïve pluripotency by strengthening naïve transcription factor binding at ESC enhancers. Moreover, ERF negatively regulates the expression of thede novomethyltransferase DNMT3B, which participates in the extinction of the naïve transcriptional program. Collectively, we demonstrated an essential role for ERF controlling the exit from naïve pluripotency during the progression to primed pluripotency.TeaserERF is the MAPK-dependent switch controlling the transition between naïve and primed pluripotency during embryonic development.
Itaconate and its derivatives repress C2C12 myogenesis
Authors: Oh Tae Seok , Hutchins Damian C. , Mainali Rabina , Goslen Kevin , Quinn Matthew A. 
Published: February 2021

AbstractA Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model ofin vitromyogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere within vitromyogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. More importantly, our findings suggest the therapeutic potential of itaconate and its derivatives could be limited due to deleterious effects on myogenesis.
Isoform-specific functions of Numb in breast cancer progression, metastasis and proteome remodeling
Authors: Zhang Yangjing , Dho Sascha E. , Simpson Craig D. , Othman Kamal , Bondoc Andrew , McGlade C. Jane 
Published: February 2021

ABSTRACTDeregulated alternative splicing of the endocytic adaptorNUMBresulting in high expression of Exon9in (exon 9-containing) isoforms has been reported in several cancer types. However, the role of Numb isoform expression in tumor progression and the underlying mechanisms remain elusive. Here, we report greater exon 9 inclusion in multiple cancer types including all subtypes of breast cancer, and correlation of higher exon 9 inclusion in patients with worse prognosis. Deletion of Exon9in in breast cancer cells leads to reduced cell growth and a significant decrease of lung metastasis in orthotopic xenograft experiments. Quantitative mass spectrometry revealed downregulation of proteins involved in EMT and ECM organization and remodeling of the endocytic protein network in cells lacking the Exon9in Numb isoforms. Exon 9 deletion also results in reduced surface levels of ITGβ5, and downstream signaling to ERK and SRC, consistent with enhance lysosomal targeting mediated by the remaining Exon9sk (exon 9 skipping) Numb isoforms.SIGNIFICANCEExpression ofNUMBExon9in protein isoforms correlate with worse progression free survival, particularly in breast cancer. Our findings also reveal that Exon9in isoforms promote breast cancer progression by relieving Numb mediated down regulation of integrins and implicate Numb alternative splicing as a progression factor in multiple cancer types.
Autonomous Wireless System for Robust and Efficient Inductive Power Transmission to Multi-Node Implants
Authors: Feng Peilong , Constandinou Timothy G. 
Published: February 2021

AbstractA number of recent and current efforts in brain machine interfaces are developing millimetre-sized wireless implants that achieve scalability in the number of recording channels by deploying a distributed ‘swarm’ of devices. This trend poses two key challenges for the wireless power transfer: (1) the system as a whole needs to provide sufficient power to all devices regardless of their position and orientation; (2) each device needs to maintain a stable supply voltage autonomously. This work proposes two novel strategies towards addressing these challenges: a scalable resonator array to enhance inductive networks; and a self-regulated power management circuit for use in each independent mm-scale wireless device. The proposed passive 2-tier resonant array is shown to achieve an 11.9% average power transfer efficiency, with ultra-low variability of 1.77% across the network.The self-regulated power management unit then monitors and autonomously adjusts the supply voltage of each device to lie in the range between 1.7 V-1.9 V, providing both low-voltage and over-voltage protection.