bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological convolutions improve DNN robustness to noise and generalisation
Authors: Evans Benjamin D. , Malhotra Gaurav , Bowers Jeffrey S. 
Published: February 2021

AbstractDeep Convolutional Neural Networks (DNNs) have achieved superhuman accuracy on standard image classification benchmarks. Their success has reignited significant interest in their use as models of the primate visual system, bolstered by claims of their architectural and representational similarities. However, closer scrutiny of these models suggests that they rely on various forms of shortcut learning to achieve their impressive performance, such as using texture rather than shape information. Such superficial solutions to image recognition have been shown to make DNNs brittle in the face of more challenging tests such as noise-perturbed or out-of-domain images, casting doubt on their similarity to their biological counterparts. In the present work, we demonstrate that adding fixed biological filter banks, in particular banks of Gabor filters, helps to constrain the networks to avoid reliance on shortcuts, making them develop more structured internal representations and more tolerant to noise. Importantly, they also gained around 20 35% improved accuracy when generalising to our novel out-of-domain test image sets over standard end-to-end trained architectures. We take these findings to suggest that these properties of the primate visual system should be incorporated into DNNs to make them more able to cope with real-world vision and better capture some of the more impressive aspects of human visual perception such as generalisation.
Characterization and tissue localization of zebrafish homologs of the humanABCB1multidrug transporter
Authors: Robey Robert W. , Robinson Andrea N. , Ali-Rahmani Fatima , Huff Lyn M. , Lusvarghi Sabrina , Vahedi Shahrooz , Hotz Jordan , Warner Andrew C. , Butcher Donna , Matta Jennifer , Edmondson Elijah F. , Lee Tobie D. , Roth Jacob S. , Lee Olivia W. , Shen Min , Tanner Kandice , Hall Matthew D. , Ambudkar Suresh V. , Gottesman Michael M. 
Published: February 2021

ABSTRACTGiven its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by theABCB1gene) and ABCG2 (encoded by theABCG2gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to humanABCB1, zebrafishabcb4andabcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detectabcb4colocalized with staining by the P-gp antibody C219, whileabcb5was not detected. Zebrafishabcb4also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.
Isolation and characterisation of bacteriophages with activity against invasive non-typhoidalSalmonellacausing bloodstream infection in Malawi
Authors: Rodwell Ella V. , Wenner Nicolas , Pulford Caisey V. , Cai Yueyi , Bowers-Barnard Arthur , Beckett Alison , Rigby Jonathan , Picton David M. , Blower Tim R. , Feasey Nicholas A. , Hinton Jay C. D. , Perez-Sepulveda Blanca M. 
Published: February 2021

AbstractIn recent years, novel lineages of invasive non-typhoidalSalmonella(iNTS) serovars Typhimurium and Enteritidis have been identified in patients with bloodstream infection in sub-Saharan Africa. Here, we isolated and characterised 32 phages capable of infectingS. Typhimurium andS. Enteritidis, from water sources in Malawi and the UK. The phages were classified in three major phylogenetic clusters that were geographically distributed. In terms of host range, Cluster 1 phages were able to infect all bacterial hosts tested, whereas Clusters 2 and 3 had a more restricted profile. Cluster 3 contained two sub-clusters, and 3.b contained the most novel isolates. This study represents the first exploration of the potential for phages to target the lineages ofSalmonellathat are responsible for bloodstream infections in sub-Saharan Africa.
TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Authors: Silva Bruno , Arora Rajika , Azzalin Claus M. 
Published: February 2021

ABSTRACTAlternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required for ALT to occur, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have now developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby initiating BIR and supporting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.
CO2supply modulates lipid remodelling, photosynthetic and respiratory activities inChlorellaspecies
Authors: Cecchin Michela , Paloschi Matteo , Busnardo Giovanni , Cazzaniga Stefano , Cuine Stephan , Li-Beisson Yonghua , Wobbe Lutz , Ballottari Matteo 
Published: February 2021

ABSTRACTMicroalgae represent potential solutions to reduce the atmospheric CO2level through photosynthesis. To boost CO2fixation by microalgae it is essential to understand physiologic and metabolic responses at the base of CO2assimilation and carbon flow. In this work twoTrebouxiophyceaespecies,Chlorella sorokinianaandChlorella vulgaris, were investigated for their metabolic responses to high and low CO2(air level) availability. High CO2availability resulted in an increase in biomass accumulation in both species but with a different chloroplast and mitochondrial responses. InC. sorokinianawe observed increased polar lipids and protein amount and a balanced NADPH redox state and a similar total respiration in the two conditions analysed. In contrast, inC. vulgarishigh CO2level caused an increase in TAG accumulation and a higher NADPH consumption suggesting a CO2dependent increase of reducing power consumption in the chloroplast, which in turn influences the redox state of the mitochondria by lowering total dark respiration. Several rearrangements of the photosynthetic machinery were observed in both species, which differ from those described for the model organismChlamydomonas reinhardtii. In the case ofC. reinhardtii, adaptation of the photosynthetic apparatus to different CO2availability relies on the translational repressor NAB1. NAB1 homologous protein could be identified only inC. vulgarisbut lacked the regulation mechanisms previously described inC. reinhardtii. These findings highlight that the acclimation strategies to cope with a fluctuating inorganic carbon supply are diverse among green microalgae and point to new biotechnological strategies to boost CO2fixation.One sentence summaryHigh/low CO2availability induces cell responses as lipids remodelling, adaptations of the photosynthetic apparatus and modulation of mitochondrial respiration not conserved among green algae
Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner inDrosophila melanogaster
Authors: Fagan Rita R. , Kearney Patrick J. , Luethi Dino , Bolden Nicholas C. , Sitte Harald H. , Emery Patrick , Melikian Haley E. 
Published: February 2021

AbstractDopamine (DA) is required for movement, sleep, and reward, and DA signaling is tightly controlled by the presynaptic DA transporter (DAT). Therapeutic and addictive psychostimulants, including methylphenidate (Ritalin; MPH), cocaine, and amphetamine (AMPH), markedly elevate extracellular DA via their actions as competitive DAT inhibitors (MPH, cocaine) and substrates (AMPH). DAT silencing in mice and invertebrates results in hyperactivity, reduced sleep, and blunted psychostimulant responses, highlighting DAT’s essential role in DA-dependent behaviors. DAT surface expression is not static; rather it is dynamically regulated by endocytic trafficking. PKC-stimulated DAT endocytosis requires the neuronal GTPase, Rit2, and Rit2 silencing in mouse DA neurons impacts psychostimulant sensitivity. However, it is unknown whether or not Rit2-mediated changes in psychostimulant sensitivity are DAT-dependent. Here, we leveragedDrosophila melanogasterto test whether theDrosophilaRit2 ortholog, Ric, impacts dDAT function, trafficking, and DA-dependent behaviors. Orthologous to hDAT and Rit2, dDAT and Ric directly interact, and the constitutively active Ric mutant Q117L increased dDAT surface levels and function in cell lines andex vivo Drosophilabrains. Moreover, DAergic RicQ117L expression caused sleep fragmentation in a DAT-dependent manner but had no effect on total sleep and daily locomotor activity. Importantly, we found that Rit2 is required for AMPH-stimulated DAT internalization in mouse striatum, and that DAergic RicQ117L expression significantly increasedDrosophilaAMPH sensitivity in a DAT-dependent manner, suggesting a conserved impact of Ric-dependent DAT trafficking on AMPH sensitivity. These studies support that the DAT/Rit2 interaction impacts both baseline behaviors and AMPH sensitivity, potentially by regulating DAT trafficking.
Stress alters the activity of Leydig cells dependently on the diurnal time
Authors: Medar Marija Lj , Andric Silvana A , Kostic Tatjana S 
Published: February 2021

AbstractBackgroundThe increasing amount of data points to the circadian timing system as an essential part of processes regulating androgen homeostasis. However, the relationship between stress response, timekeeping-, and steroidogenesis-related systems is unexplored.ObjectiveThe purpose of the study was to analyze the stress-response of the testosterone-producing Leydig cells depending on the stressful event’s time.Materials and methodsThe study was designed to follow the effects of 3-hour immobilization (IMO) applied at different periods during the day. The IMO performed once (1xIMO) or repeated in 10 consecutive days (10xIMO). Principal-component-analysis (PCA) followed the expression study of the clock and steroidogenic-related genes in Leydig cells.ResultsBoth types of IMO in all investigated periods increased corticosterone and decreased testosterone blood level. Transcriptional analysis revealed different sensitivity to IMO events depending on the circadian time. The majority of steroidogenesis-related genes (Lhcgr, Cyp11a1, Cyp17a1, Hsd3b1/2) were down-regulated in the inactive but unchanged or even up-regulated in the active phase of the day. Both types of IMO potentiated the expression of clock elementsBmal1/BMAL1,Per1/PER1 regardless of the day’s stage and reducedReverbain the inactive phase. The PCA confirmed a major shift, for both IMO-types, in the transcription of steroidogenesis and clock genes across the inactive/active phase. Further, the diurnal pattern of the glucocorticoid receptor (Nr3c1/GR) expression in Leydig cells was increased in the inactive phase due to 10xIMO. The observed time-dependent IMO-response of the Leydig cells correlated with different GR engagements.DiscussionStress- and the circadian-system coordinatively shape Leydig cell’s physiology, assuming diverse GR engagement as a possible factor in mediating the diurnal effect of stress.ConclusionThe Leydig cell’s stress-response depends on the time of the stressful situation, emphasizing the importance of circadian activity in supporting androgen homeostasis and male fertility.
The Wild Worm Codon Adapter: a web tool for automated codon adaptation of transgenes for expression in non-Caenorhabditis nematodes
Authors: Bryant Astra S. , Hallem Elissa A. 
Published: February 2021

ABSTRACTAdvances in genomics techniques are expanding the range of nematode species that are amenable to transgenesis. Due to divergent codon usage biases across species, codon optimization is often a critical step for the successful expression of exogenous transgenes in nematodes. Platforms for generating DNA sequences codon optimized for the free-living model nematode Caenorhabditis elegans are broadly available. However, until now such tools did not exist for non-Caenorhabditis nematodes. We therefore developed the Wild Worm Codon Adapter, a tool for rapid transgene codon optimization for expression in non-Caenorhabditis nematodes. The app includes built-in optimization for parasitic nematodes in the Strongyloides, Nippostrongylus and Brugia genera as well as the predatory nematode Pristionchus pacificus. The app also supports custom optimization for any species using user-provided optimization rules. In addition, the app supports automated insertion of synthetic or native introns, as well as the analysis of codon bias in transgene and native sequences. Here, we describe this web-based tool and demonstrate how it may be used to analyze genome-wide codon bias in Strongyloides species.
Natural variation in fertility is correlated with species-wide levels of divergence inCaenorhabditis elegans
Authors: Zhang Gaotian , Mostad Jake D. , Andersen Erik C. 
Published: February 2021

ABSTRACTLife history traits underlie the fitness of organisms and are under strong natural selection in the face of environmental challenges. A new mutation that positively impacts a life history trait will likely increase in frequency and become fixed in a population (e.g.selective sweep). The identification of the beneficial alleles that underlie selective sweeps provides insights into the mechanisms that occurred during the evolution of species. In the global population ofCaenorhabditis elegans,we previously identified selective sweeps that have drastically reduced chromosomal-scale genetic diversity in the species. Here, we measured the fertility (viable offspring) of a collection of wildC. elegansstrains, including many recently isolated divergent strains from the Hawaiian islands and found that strains with larger swept genomic regions on multiple chromosomes have significantly higher fertility than strains that do not have evidence of the recent selective sweeps. We used genome-wide association (GWA) mapping to identify three quantitative trait loci (QTL) underlying the fertility variation. Additionally, we mapped previous fertility data of wildC. elegansstrains andC. elegansrecombinant inbred advanced intercross lines (RIAILs) that were grown in various conditions and detected eight QTL across the genome using GWA and linkage mappings. These QTL show the genetic complexity of life history traits such as fertility across this species. Moreover, the haplotype structure in each GWA QTL region revealed correlations with recent selective sweeps in theC. eleganspopulation. North American and European strains had significantly higher fertility than most strains from Hawaii, a hypothesized origin of theC. elegansspecies, suggesting that beneficial alleles that cause increased fertility could underlie the selective sweeps during the worldwide expansion ofC. elegans.
Hippocampal sharp wave-ripples and the associated sequence replay emerge from structured synaptic interactions in a network model of area CA3
Authors: Ecker András , Bagi Bence , Vértes Eszter , Steinbach-Németh Orsolya , Karlócai Mária R. , Papp Orsolya I. , Miklós István , Hájos Norbert , Freund Tamás F. , Gulyás Attila I. , Káli Szabolcs 
Published: February 2021

AbstractHippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated (“replayed”), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and maintenance of long-term memory. In order to identify the cellular and network mechanisms of SWRs and replay, we constructed and simulated a data-driven model of area CA3 of the hippocampus. Our results show that the chain-like structure of recurrent excitatory interactions established during learning not only determines the content of replay, but is essential for the generation of the SWRs as well. We find that bidirectional replay requires the interplay of the experimentally confirmed, temporally symmetric plasticity rule, and cellular adaptation. Our model provides a unifying framework for diverse phenomena involving hippocampal plasticity, representations, and dynamics, and suggests that the structured neural codes induced by learning may have greater influence over cortical network states than previously appreciated.
Probing cortical excitability under GABAergic modulation
Authors: Lepeu Grégory , Maren Ellen Van , Slabeva Kristina , Fuchs Markus , Anso Juan , Z’Graggen Werner J. , Pollo Claudio , Schindler Kaspar A. , Adamantidis Antoine , Baud Maxime O. 
Published: February 2021

AbstractCortical excitability, the variable response to a given cortical input, is widely studied in neuroscience, from slice experiments and in silico modeling work to human clinical settings. However, a unifying definition and a translational approach to the phenomenon are currently lacking. For example, at the onset of epileptic seizures, cortical excitability may impair resilience to perturbations (external or endogenous). In this study, we testedin vivowhether changes in cortical excitability quantified as evoked response to small perturbation corresponded to changes in resilience to larger perturbations. To do so, we used both cell-type circuit specific optogenetic stimulation in mice and direct intracranial stimulation in one human subject and quantified 1) evoked cortical responses to single pulses of varying intensity, and 2) evoked cortical facilitation and suppression to paired pulses at varying intervals. In the presence of a gamma-Aminobutyric acid (GABA) agonist or antagonist, we found that 1) cortical response to single pulses and 2) cortical facilitation decreased and increased, respectively. Additionally, using trains of opto-pulses in mice in the presence of a GABA agonist, we found increased resilience to the induction of seizures. With this study, we provide evidence for a tight correlation between cortical excitability and resilience, exploring a range of cortical dynamics, from physiological excitability, to pathological discharges. Our study carried out with two different stimulation methods in two species suggests that varying cortical excitability can be tracked with simple protocols involving minute short-lived perturbative stimuli.
Improving Generalizability of Protein Sequence Models with Data Augmentations
Authors: Shen Hongyu , Price Layne C. , Bahadori Taha , Seeger Franziska 
Published: February 2021

AbstractWhile protein sequence data is an emerging application domain for machine learning methods, small modifications to protein sequences can result in difficult-to-predict changes to the protein’s function. Consequently, protein machine learning models typically do not use randomized data augmentation procedures analogous to those used in computer vision or natural language, e.g., cropping or synonym substitution. In this paper, we empirically explore a set of simple string manipulations, which we use to augment protein sequence data when fine-tuning semi-supervised protein models. We provide 276 different comparisons to the Tasks Assessing Protein Embeddings (TAPE) baseline models, with Transformer-based models and training datasets that vary from the baseline methods only in the data augmentations and representation learning procedure. For each TAPE validation task, we demonstrate improvements to the baseline scores when the learned protein representation is fixed between tasks. We also show that contrastive learning fine-tuning methods typically outperform masked-token prediction in these models, with increasing amounts of data augmentation generally improving performance for contrastive learning protein methods. We find the most consistent results across TAPE tasks when using domain-motivated transformations, such as amino acid replacement, as well as restricting the Transformer attention to randomly sampled sub-regions of the protein sequence. In rarer cases, we even find that information-destroying augmentations, such as randomly shuffling entire protein sequences, can improve downstream performance.
CTCF association with episomal HPV16 genomes regulates viral oncogene transcription and splicing
Authors: Groves Ian J , Tang George , Pentland Ieisha , Parish Joanna L , Coleman Nicholas 
Published: February 2021

AbstractHuman papillomavirus 16 (HPV16) is a high-risk alphapapillomavirus that is associated with cancers of mucosal epithelia. The virus genome exists in cells as an episome but can integrate and overexpress theE6andE7viral oncogenes. In related high-risk family members HPV18 and HPV31, host proteins including CTCF, an insulator, and SMC1A, a component of the cohesion complex, are known to interact with the viral genome and alter transcriptional activity, splicing patterns and episome amplification. However, the roles of these two proteins during HPV16 infection has not yet been fully examined. Here, we show during differentiation of the episomal HPV16-containing W12 cell line that CTCF association increases with the virus genome at the knownE2binding site, whilst additional CTCF binding now occurs at the putativeL2binding site, with SMC1A association occurring unchanged here. While expression of virus late transcripts (E4^L1, L2, L1) is stimulated, early transcript levels decrease by 48 hours, with the exception of the E6*IV spliced transcript. Conversely, in undifferentiated, monolayer W12 cells, CTCF knockdown increases the level of all early transcripts, whereas E6*IV level increases. Additionally, CTCF ablation as well as SMC1A knockdown results in decreases to HPV16 genome copy number. Taken together, this supports the model that while CTCF and SMC1A have a role in HPV16 genome maintenance, CTCF plays a greater part in regulating HPV16 oncogene splicing and expression during the natural lifecycle of the virus, and may be involved in a reduced risk of cancer development during episomal HPV16 infections.