bluuebunny/crossref_metadata_2025 huggingface dataset:
Segmentation of Pancreatic Ductal Adenocarcinoma (PDAC) and surrounding vessels in CT images using deep convolutional neural networks and texture descriptors
Authors: Mahmoudi Tahereh , Kouzahkanan Zahra Mousavi , Radmard Amir Reza , Kafieh Raheleh , Salehnia Aneseh , Davarpanah Amir H. , Arabalibeik Hossein , Ahmadian Alireza
Published: June 2021

Fully automated and volumetric segmentation of critical tumors may play a crucial role in diagnosis and surgical planning. One of the most challenging tumor segmentation tasks is localization of Pancreatic Ductal Adenocarcinoma (PDAC). Exclusive application of conventional methods does not appear promising. Deep learning approaches has achieved great success in the computer aided diagnosis, especially in biomedical image segmentation. This paper introduces a framework based on convolutional neural network (CNN) for segmentation of PDAC mass and surrounding vessels in CT images by incorporating powerful classic features, as well. First, a 3D-CNN architecture is used to localize the pancreas region from the whole CT volume using 3D Local Binary Pattern (LBP) map of the original image. Segmentation of PDAC mass is subsequently performed using 2D attention U-Net and Texture Attention U-Net (TAU-Net). TAU-Net is introduced by fusion of dense Scale-Invariant Feature Transform (SIFT) and LBP descriptors into the attention U-Net. An ensemble model is then used to cumulate the advantages of both networks using a 3D-CNN. In addition, to reduce the effects of imbalanced data, a new loss function is proposed as a weighted combination of three classic losses including Generalized Dice Loss (GDL), Weighted Pixel-Wise Cross Entropy loss (WPCE) and boundary loss. Due to insufficient sample size for vessel segmentation, we used the above-mentioned pre-trained networks and fin-tuned them. Experimental results show that the proposed method improves the Dice score for PDAC mass segmentation in portal-venous phase by 7.52% compared to state-of-the-art methods (from 53.08% to 60.6%) in term of DSC. Besides, three dimensional visualization of the tumor and surrounding vessels can facilitate the evaluation of PDAC treatment response.
Minimizer-space de Bruijn graphs
Authors: Ekim Barış , Berger Bonnie , Chikhi Rayan
Published: June 2021

DNA sequencing data continues to progress towards longer reads with increasingly lower sequencing error rates. We focus on the problem of assembling such reads into genomes, which poses challenges in terms of accuracy and computational resources when using cutting-edge assembly approaches, e.g. those based on overlapping reads using minimizer sketches. Here, we introduce the concept of minimizer-space sequencing data analysis, where the minimizers rather than DNA nucleotides are the atomic tokens of the alphabet. By projecting DNA sequences into ordered lists of minimizers, our key idea is to enumerate what we call k-min-mers, that are k-mers over a larger alphabet consisting of minimizer tokens. Our approach, mdBG or minimizer-dBG, achieves orders-of-magnitude improvement in both speed and memory usage over existing methods without much loss of accuracy. We demonstrate three uses cases of mdBG: human genome assembly, metagenome assembly, and the representation of large pangenomes. For assembly, we implemented mdBG in software we call rust-mdbg, resulting in ultra-fast, low memory and highly-contiguous assembly of PacBio HiFi reads. A human genome is assembled in under 10 minutes using 8 cores and 10 GB RAM, and 60 Gbp of metagenome reads are assembled in 4 minutes using 1 GB RAM. For pangenome graphs, we newly allow a graphical representation of a collection of 661,405 bacterial genomes as an mdBG and successfully search it (in minimizer-space) for anti-microbial resistance (AMR) genes. We expect our advances to be essential to sequence analysis, given the rise of long-read sequencing in genomics, metagenomics and pangenomics.
Landscape and climatic variations of the Quaternary shaped multiple secondary contacts among barn owls (Tyto alba) of the Western Palearctic
Authors: Cumer Tristan , Machado Ana Paula , Dumont Guillaume , Bontzorlos Vasileios , Ceccherelli Renato , Charter Motti , Dichmann Klaus , Martens Hans-Dieter , Kassinis Nicolaos , Lourenço Rui , Manzia Francesca , Prévost Laure , Rakovic Marko , Siverio Felipe , Roulin Alexandre , Goudet Jérôme
Published: June 2021

The combined actions of climatic variations and landscape barriers shape the history of natural populations. When organisms follow their shifting niches, obstacles in the landscape can lead to the splitting of populations, on which evolution will then act independently. When two such populations are reunited, secondary contact occurs in a broad range of admixture patterns, from narrow hybrid zones to the complete dissolution of lineages. A previous study suggested that barn owls colonized the Western Palearctic after the last glaciation in a ring-like fashion around the Mediterranean Sea, and conjectured an admixture zone in the Balkans. Here, we take advantage of whole-genome sequences of 94 individuals across the Western Palearctic to reveal the complex history of the species in the region using observational and modeling approaches. Even though our results confirm that two distinct lineages colonized the region, one in Europe and one in the Levant, they suggest that it predates the last glaciation and identify a narrow secondary contact zone between the two in Anatolia. Nonetheless, we also show that barn owls re-colonized Europe after the glaciation from two distinct glacial refugia: a western one in Iberia and an eastern one in Italy. Both glacial lineages now communicate via eastern Europe, in a wide and permeable contact zone. This complex history of populations enlightens the taxonomy of Tyto alba in the region, highlights the key role played by mountain ranges and large water bodies as barriers and illustrates the power of population genomics in uncovering intricate demographic patterns.
Detection of pigeon circoviruses in ticks of sheep and camels in Inner Mongolia, China
Authors: Kong Yunyi , Yan Chao , Zhang Gang , Cai Yurong , He Biao , Li Yong
Published: June 2021

Circovirus is one of the smallest known DNA viruses infecting animals. In this report, circovirus was detected in two tick species- Hyalomma asiaticum and Dermacentor nuttalli collected from sheep and camels in Inner Mongolia, China by high-throughput sequencing. The reverse semi-nested PCR assay revealed a complete genomic sequence of 2042 base pairs of cyclic single-stranded DNA (ssDNA). Evolutionary analysis further revealed that it belonged to circovirus with two major open read frames (ORFs) that putatively encode replicase and capsid proteins, respectively. Sequence and phylogenetic analysis suggested that the circovirus belonged to pigeon circovirus. The results demonstrated the presence of pigeon circovirus in ticks in Inner Mongolia, which provide the basis for future exploration of the prevalence of pigeon circovirus in Inner Mongolia and the pathogens carried by ticks in Inner Mongolia.
Heightened condition dependent expression of structural colouration in the faces, but not wings, of male and female flies
Authors: White Thomas E. , Locke Amy , Latty Tanya
Published: June 2021

Structurally coloured sexual signals are a conspicuous and widespread class of ornament used in mate choice, though the extent to which they encode information on the quality of their bearers is not fully resolved. Theory predicts that signalling traits under strong sexual selection as ‘honest’ indicators should evolve to be more developmentally integrated and exaggerated than nonsexual traits, thereby leading to heightened condition dependence. Here we test this prediction through examination of the sexually dimorphic faces and wings of the cursorial fly Lispe cana. Males and females possess structural UV-white and golden faces, respectively, and males present their faces and wings to females during close-range, ground-based courtship displays, thereby creating the opportunity for mutual inspection. Across a field-collected sample of individuals, we found that the appearance of the faces of both sexes scaled positively with individual condition, though along separate axes. Males in better condition expressed brighter faces as modelled according to conspecific flies, whereas condition scaled with facial saturation in females. We found no such relationships for their wing interference pattern nor abdomens, with the latter included as a nonsexual control. Our results suggest that the structurally coloured faces, but not the iridescent wings, of male and female Lispe cana are reliable guides to individual quality and support the broader potential for structural colours as honest signals. They also highlight the potential for mutual mate choice in this system, while arguing for one of several alternate signalling roles for wing interferences patterns among the myriad taxa which bear them.
Monitoring group activity of hamsters and mice as a novel tool to evaluate COVID-19 progression, convalescence and rVSV-ΔG-spike vaccination efficacy
Authors: Melamed Sharon , Politi Boaz , Grauer Ettie , Achdout Hagit , Aftalion Moshe , Gur David , Tamir Hadas , Yahalom-Ronen Yfat , Maimon Shlomy , Yitzhak Efi , Weiss Shay , Rosner Amir , Erez Noam , Yitzhaki Shmuel , Shapira Shmuel C , Paran Nir , Mamroud Emanuelle , Vagima Yaron , Israely Tomer
Published: June 2021

COVID-19 pandemic initiated a worldwide race toward the development of treatments and vaccines. Small animal models were the Syrian golden hamster and the K18-hACE2 mice infected with SARS-CoV-2 to display a disease state with some aspects of the human COVID-19. Group activity of animals in their home cage continuously monitored by the HCMS100 was used as a sensitive marker of disease, successfully detecting morbidity symptoms of SARS-CoV-2 infection in hamsters and in K18-hACE2 mice. COVID-19 convalescent hamsters re-challenged with SARS-CoV-2, exhibited minor reduction in group activity compared to naive hamsters. To evaluate rVSV-ΔG-spike vaccination efficacy against SARS-CoV-2, we used the HCMS100 to monitor group activity of hamsters in their home cage. Single-dose rVSV-ΔG-spike vaccination of immunized group showed a faster recovery compared to the non-immunized infected hamsters, substantiating the efficacy of rVSV-ΔG-spike vaccine. HCMS100 offers non-intrusive, hands-free monitoring of a number of home cages of hamsters or mice modeling COVID-19.
TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice
Authors: Gillis Noelle E. , Cozzens Lauren M. , Wilson Emily R. , Smith Noah M. , Tomczak Jennifer A. , Bolf Eric L. , Carr Frances E.
Published: June 2021

Thyroid hormone receptor beta (TRβ) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TRβ has been elucidated in several cancer types through re-expression models. Remarkably, the potential impact of selective activation of endogenous TRβ on tumor progression remains largely unexplored. We used cell-based andin vivoassays to evaluate the effects of the TRβ agonist Sobetirome (GC-1) on a particularly aggressive and dedifferentiated cancer, anaplastic thyroid cancer (ATC). Here we report that GC-1 reduced the tumorigenic phenotype, decreased cancer stem-like cell populations, and induced re-differentiation of the ATC cell lines with different mutational backgrounds. Of note, this selective activation of TRβ amplified the effects of therapeutic agents in blunting the aggressive cell phenotype and stem-cell growth. In xenograft assays, GC-1 alone inhibited tumor growth and was as effective as the kinase inhibitor, Sorafenib. These results indicate that selective activation of TRβ not only induces a tumor suppression programde novobut enhances the effectiveness of anti-cancer agents revealing potential novel combination therapies for ATC and other aggressive solid tumors.
FMRI multi-scale cortical spontaneous activity: 7T vs. 3T
Authors: Xing Xiu-Xia , Jiang Chao , Gao Xiao , Wang Yin-Shan , Zuo Xi-Nian
Published: June 2021

This paper describes the use of the Human Connectome Project (HCP) data for mapping the distribution of spontaneous activity in the human brain across different spatial scales, magnets and individuals. Specifically, the resting-state functional MRI signals acquired under the HCP 3 tesla (T) and 7T magnet protocols were measured by computational methods at multiple spatial scales across the cerebral cortex using: 1) an amplitude metric on a single measuring unit (ALFF), 2) a functional homogeneity metric on a set of neighboring measuring units (ReHo) and 3) a homotopic functional connectivity metric on pairs of symmetric measuring units between the two hemispheres (VMHC). Statistical assessments on these measurements revealed that all the raw metrics were enhanced by the higher magnetic field, highlighting their dependence on magnet field strength. Measurement reliability of these global measurements were moderate to high and comparable between between 3T and 7T magnets. The differences in these measurements introduced by the higher magnetic field were spatially dependent and varied according to specific cortical regions. Specifically, the spatial contrasts of ALFF were enhanced by the 7T magnet within the anterior cortex while weakened in the posterior cortex. This is opposite for ReHo and VMHC. This scale-dependent phenomena also held true for measurement reliabilities, which were enhanced by the 7T magnet for ReHo and VMHC and weakened for ALFF. These reliability differences were primarily located in high-order associate cortex, reflecting the corresponding changes of individual differences: higher between-subject variability and lower within-subject variability for ReHo and VMHC, lower between-subject variability and higher within-subject variability for ReHo and VMHC with respect to higher magnetic field strength. Our work, for the first time, demonstrates the spatial-scale dependence of spontaneous cortical activity measurements in the human brain and their test-retest reliability across different magnet strengths, and discussed about the statistical implications for experimental design using resting-state fMRI.
A dual allosteric pathway drives human mitochondrial Lon
Authors: Gesé Genís Valentín , Shahzad Saba , Pardo-Hernández Carlos , Wramstedt Anna , Falkenberg Maria , Hällberg B. Martin
Published: June 2021

The hexameric, barrel-forming, AAA+ protease Lon is critical for maintaining mitochondrial matrix protein homeostasis. Efficient substrate processing by Lon requires the coordinated action of six protomers. Despite Lon’s importance for human health, the molecular bases for Lon’s substrate recognition and processing remain unclear. Here, we use a combination of biochemistry and electron cryomicroscopy (cryo-EM) to unveil the structural and functional basis for full-length human mitochondrial Lon’s degradation of mitochondrial transcription factor A (TFAM). We show how opposing protomers in the Lon hexamer barrel interact through their N-terminal domains to give what resembles three feet above the barrel and help to form a triangular pore located just above the entry pore to the barrel. The interactions between opposing protomers constitute a primary allosteric regulation of Lon activity. A secondary allosteric regulation consists of an inter-subunit signaling element in the ATPase domains. By considering the ATP or ADP load in each protomer, we show how this dual allosteric mechanism in Lon achieves coordinated ATP hydrolysis and substrate processing. This mechanism enforces sequential anti-clockwise ATP hydrolysis resulting in a coordinated hand-over-hand translocation of the substrate towards the protease active sites.
Incorporating outlier information into diffusion MR tractogram filtering for robust structural brain connectivity and microstructural analyses
Authors: Sairanen Viljami , Ocampo-Pineda Mario , Granziera Cristina , Schiavi Simona , Daducci Alessandro
Published: June 2021

The white matter structures of the human brain can be represented using diffusion-weighted MRI tractography. Unfortunately, tractography is prone to find false-positive streamlines causing a severe decline in its specificity and limiting its feasibility in accurate structural brain connectivity analyses. Filtering algorithms have been proposed to reduce the number of invalid streamlines but the currently available filtering algorithms are not suitable to process data that contains motion artefacts which are typical in clinical research. We augmented the Convex Optimization Modelling for Microstructure Informed Tractography (COMMIT) filtering algorithm to adjust for these signal drop-out motion artifacts. We demonstrate with comprehensive Monte-Carlo whole brain simulations and in vivo infant data that our robust algorithm is capable in properly filtering tractography reconstructions despite these artefacts. We evaluated the results using parametric and non-parametric statistics and our results demonstrate that if not accounted for, motion artefacts can have severe adverse effect in the human brain structural connectivity analyses as well as in microstructural property mappings. In conclusion, the usage of robust filtering methods to mitigate motion related errors in tractogram filtering is highly beneficial especially in clinical studies with uncooperative patient groups such as infants. With our presented robust augmentation and open-source implementation, robust tractogram filtering is readily available.

Highlights

We present a novel augmentation to tractogram filtering method that accounts for subject motion related signal dropout artefacts in diffusion weighted images.

Our method is validated with realistic Monte-Carlo whole brain simulations and evaluated with in vivo infant data.

We show that even if data has 10% of motion corrupted slices our method is capable to mitigate their effect in structural brain connectivity analyses and microstructural mapping.
Quantifying spinal cord vascular permeability in the mouse using intravital imaging
Authors: Da Vitoria Lobo M.E. , Bates David O , Arkill Kenton P , Hulse R.P.
Published: June 2021

Sensory perception and motor dexterity is coordinated by in part distinct anatomical centres in the spinal cord. Importantly the spinal cord is the first modulatory relay hub for coordinating sensory and motor inputs to allow control of an organisms response to a sensory experience and to orientate proprioceptive outputs. This is whilst communicating with higher centres within the brain to undertake greater complex neurophysiological function such as pain perception. This begins to outline the complexity of the nervous system communication. To allow this integral system to function efficiently neuronal homeostasis needs to be maintained with energy expenditure matched by proficient delivery of nutrients. This factor introduces the vascular system that extensively interacts in a multifaceted manner with differing aspects of the nervous system. Part of this multi-factoral interaction is through the heterogenic cellular makeup of the vascular network that delivers and modulates the molecular transport of such nutrients to spinal cord tissues, but also controlling penetration and migration of harmful pathogens and agents. Therefore the spinal cord is susceptible to any alterations in the microvessel integrity (e.g. vascular leakage) and/or function (e.g. cessated blood flow) of this vascular network, which principally occurs in times of pathology. Typically investigations into microvessel function have utilised histological and/or tracer based in-vivo assays. Methodologies such as evans blue extravasation have been used inconjunction with in-vitro cell biology assays such as transwell assays to determine microvessel integrity or function that only provides snapshots of developing vasculopathy. Adopting in-vivo imaging approaches, allow for real time functional measurements of the ongoing physiological function within the spinal cord, providing direct measurement of the vascular processes in play, including vascular architecture, blood flow and/or permeability. This technique in mouse allow for direct visualisation of cellular and/or mechanistic influence upon vascular function through utilising disease, transgenic and/or viral approaches. This combination of attributes allows for in depth real time understanding of the function of the vascular network within the spinal cord.
The mating system affects the temperature sensitivity of male and female fertility
Authors: Baur Julian , Jagusch Dorian , Michalak Piotr , Koppik Mareike , Berger David
Published: June 2021

To mitigate effects of climate change it is important to understand species’ responses to increasing temperatures. This has often been done by studying survival or activity at temperature extremes. Before such extremes are reached, however, effects on fertility may already be apparent.

Sex differences in the thermal sensitivity of fertility (TSF) could impact species persistence under climate warming because female fertility is typically more limiting to population growth than male fertility. However, little is known about sex differences in TSF.

Here we first demonstrate that the mating system can strongly influence TSF using the seed beetle Callosobruchus maculatus. We exposed populations carrying artificially induced mutations to two generations of short-term experimental evolution under alternative mating systems, manipulating the opportunity for natural and sexual selection on the mutations. We then measured TSF in males and females subjected to juvenile or adult heat stress.

Populations kept under natural and sexual selection had higher fitness, but similar TSF, compared to control populations kept under relaxed selection. However, females had higher TSF than males, and strikingly, this sex difference had increased over only two generations in populations evolving under sexual selection.

We hypothesized that an increase in male-induced harm to females during mating had played a central role in driving this evolved sex difference, and indeed, remating under conditions limiting male harassment of females reduced both male and female TSF. Moreover, we show that manipulation of mating system parameters in C. maculatus generates intraspecific variation in the sex difference in TSF equal to that found among a diverse set of studies on insects.

Our study provides a causal link between the mating system and TSF. Sexual conflict, (re)mating rates, and genetic responses to sexual selection differ among ecological settings, mating systems and species. Our study therefore also provides mechanistic understanding for the variability in previously reported TSFs which can inform future experimental assays and predictions of species responses to climate warming.
A new behavioral and neural marker of social vision
Authors: Abassi Etienne , Papeo Liuba
Published: June 2021

Research on face perception has revealed highly specialized visual mechanisms such as configural processing, and provided markers of interindividual differences –including disease risks and alterations– in visuoperceptual abilities that traffic in social cognition. Is face perception unique in degree or kind of mechanisms, and in its relevance for social cognition? Combining functional MRI and behavioral methods, we address the processing of an uncharted class of socially relevant stimuli: minimal social scenes involving configurations of two bodies spatially close and face-to-face as if interacting (hereafter, facing dyads). We report category-specific activity for facing (vs. non-facing) two-body configurations in selective areas of the visual cortex. That activity shows face-like signatures of configural processing –i.e., stronger response, and greater susceptibility to stimulus inversion for facing (vs. non-facing) dyads–, and is predicted by performance-based measures of body-dyad perception (i.e., accuracy in a fast visual categorization task). Moreover, individual performance in body-dyad perception is reliable, stable-over-time and correlated with the individual social sensitivity, coarsely captured by the Autism-Spectrum Quotient. Further analyses clarify the relationship between single-body and body-dyad perception. We propose that facing dyads are processed through highly specialized mechanisms (and brain areas), analogously to other biologically/socially relevant stimuli such as faces. Like face perception, facing-dyad perception can reveal basic visual processes that lay the foundations for understanding others, their relationships and interactions.

Significance statement

With its specialization to faces and biological motion, vision houses the foundations of human social ability. Using a multimodal approach (meta-analysis, fMRI, visual-perception tasks and self-administered survey), we introduce a new class of visual stimuli –minimal social scenes with two face-to-face bodies–, whose processing highlights new behavioral and neural markers of visuoperceptual abilities that traffic in social cognition. Behavioral and neural effects of body-dyad perception reveal the recruitment of specialized configural processing, previously described for face perception. Furthermore, individual performance in body-dyad perception is stable over time, and predicts an individual’s social sensitivity, measured in terms of autism-spectrum traits. Thus, body-dyad perception reveals uncharted aspects of visual functioning and specialization, which may critically contribute to human social life.
Informing shigellosis prevention and control through pathogen genomics
Authors: Bengtsson Rebecca J. , Simpkin Adam J. , Pulford Caisey V. , Low Ross , Rasko David A. , Rigden Daniel J. , Hall Neil , Barry Eileen M. , Tennant Sharon M. , Baker Kate S.
Published: June 2021

Shigellaspp. are the leading bacterial cause of severe childhood diarrhoea in low- and middle-income countries (LMIC), are increasingly antimicrobial resistant and have no licensed vaccine. We performed genomic analyses of 1246 systematically collected shigellae from seven LMIC to inform control and identify factors that could limit the effectiveness of current approaches. We found thatS. sonneicontributes ≥20-fold more disease than otherShigellaspecies relative to its genomic diversity and highlight existing diversity and adaptative capacity amongS. flexnerithat may generate vaccine escape variants in <6 months. Furthermore, we show convergent evolution of resistance against the current recommended antimicrobial among shigellae. This demonstrates the urgent need to integrate existing genomic diversity into vaccine and treatment plans forShigella, and other pathogens.
pySuStaIn: a Python implementation of the Subtype and Stage Inference algorithm
Authors: Aksman Leon M. , Wijeratne Peter A. , Oxtoby Neil P. , Eshaghi Arman , Shand Cameron , Altmann Andre , Alexander Daniel C. , Young Alexandra L.
Published: June 2021

Progressive disorders are highly heterogeneous. Symptom-based clinical classification of these disorders may not reflect the underlying pathobiology. Data-driven subtyping and staging of patients has the potential to disentangle the complex spatiotemporal patterns of disease progression. Tools that enable this are in high demand from clinical and treatment-development communities. Here we describe the pySuStaIn software package, a Python-based implementation of the Subtype and Stage Inference (SuStaIn) algorithm. SuStaIn unravels the complexity of heterogeneous diseases by inferring multiple disease progression patterns (subtypes) and individual severity (stages) from cross-sectional data. The primary aims of pySuStaIn are to enable widespread application and translation of SuStaIn via an accessible Python package that supports simple extension and generalization to novel modelling situations within a single, consistent architecture.

Code metadata

Current code version v1.0

Permanent link to code/repository used of this code version https://github.com/ucl-pond/pySuStaIn

Legal Code License MIT

Code versioning system used git

Software code languages, tools, and services used Python

Compilation requirements, operating environments & dependencies Linux, Mac, Windows

Support email for questions leon.aksman@loni.usc.edu, p.wijeratne@ucl.ac.uk, alexandra.young@kcl.ac.uk
Nonlinear transient amplification in recurrent neural networks with short-term plasticity
Authors: Wu Yue Kris , Zenke Friedemann
Published: June 2021

To rapidly process information, neural circuits have to amplify specific activity patterns transiently. How the brain performs this nonlinear operation remains elusive. Hebbian assemblies are one possibility whereby symmetric excitatory connections boost neuronal activity. However, such Hebbian amplification is often associated with dynamical slowing of network dynamics, non-transient attractor states, and pathological run-away activity. Feedback inhibition can alleviate these effects but typically linearizes responses and reduces amplification gain. At the same time, other alternative mechanisms rely on asymmetric connectivity, in conflict with the Hebbian doctrine. Here we propose nonlinear transient amplification (NTA), a plausible circuit mechanism that reconciles symmetric connectivity with rapid amplification while avoiding the above issues. NTA has two distinct temporal phases. Initially, positive feedback excitation selectively amplifies inputs that exceed a critical threshold. Subsequently, short-term plasticity quenches the run-away dynamics into an inhibition-stabilized network state. By characterizing NTA in supralinear network models, we establish that the resulting onset transients are stimulus selective and well-suited for speedy information processing. Further, we find that excitatory-inhibitory co-tuning widens the parameter regime in which NTA is possible. In summary, NTA provides a parsimonious explanation for how excitatory-inhibitory co-tuning and short-term plasticity collaborate in recurrent networks to achieve transient amplification.
Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by Free Energy simulations
Authors: Jespers Willem , Heitman Laura H. , IJzerman Adriaan P. , Sotelo Eddy , van Westen Gerard J. P. , Åqvist Johan , Gutiérrez-de-Terán Hugo
Published: June 2021

Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A2AAR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.

Author Summary

The design of new ligands as chemical modulators of G protein-coupled receptors (GPCRs) has benefited considerably during the last years of advances in both the structural and computational biology disciplines. Within the last, area, the use of free energy calculation methods has arisen as a computational tool to predict ligand affinities to explain structure-affinity relationships and guide lead optimization campaigns. However, our comprehension of the structural determinants of ligands with different pharmacological profile is scarce, and knowledge of the chemical modifications associated with an agonistic or antagonistic profile would be extremely valuable. We herein report an original implementation of the thermodynamic cycles associated with free energy perturbation (FEP) simulations, to mimic the conformational equilibrium between active and inactive GPCRs, and establish a framework to describe pharmacological profiles as a function of the ligands selectivity for a given receptor conformation. The advantage of this method resides into its simplicity of use, and the only consideration of active and inactive conformations of the receptor, with no simulation of the transitions between them. This model can accurately predict the pharmacological profile of series of full and partial agonists as opposed to antagonists of the A2A adenosine receptor, and moreover, how certain mutations associated with modulation of basal activity can influence this pharmacological profiles, which enables our understanding of such clinically relevant mutations.
Towards the prediction of non-peptidic epitopes
Authors: Zierep P. F. , Vita R. , Blazeska N. , Greenbaum J. A. , Peters B. , Günther S.
Published: June 2021

In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. These compounds have not been systematically studied yet, and prediction approaches are lacking. The ability to predict the epitope activity of non-peptidic compounds could have vast implications; for example, for immunogenic risk assessment of the vast number of drugs and other xenobiotics. Here we present the first general attempt to predict the epitope activity of non-peptidic compounds using the Immune Epitope Database (IEDB) as a source for positive samples. The molecules stored in the Chemical Entities of Biological Interest (ChEBI) database were chosen as background samples. The molecules were clustered into eight homogeneous molecular groups, and classifiers were built for each cluster with the aim of separating the epitopes from the background. Different molecular feature encoding schemes and machine learning models were compared against each other. For those models where a high performance could be achieved based on simple decision rules, the molecular features were then further investigated. Additionally, the findings were used to build a web server that allows for the immunogenic investigation of non-peptidic molecules (http://tools-staging.iedb.org/np_epitope_predictor). The prediction quality was tested with samples from independent evaluation datasets, and the implemented method received noteworthy Receiver Operating Characteristic-Area Under Curve (ROC-AUC) values, ranging from 0.69-0.96 depending on the molecule cluster.
Open multimodal iEEG-fMRI dataset from naturalistic stimulation with a short audiovisual film
Authors: Berezutskaya Julia , Vansteensel Mariska J. , Aarnoutse Erik J. , Freudenburg Zachary V. , Piantoni Giovanni , Branco Mariana P. , Ramsey Nick F.
Published: June 2021

Intracranial human recordings are a valuable and rare resource that the whole neuroscience community can benefit from. Making such data available to the neuroscience community not only helps tackle the reproducibility issues in science, it also helps make more use of this valuable data. The latter is especially true for data collected using naturalistic tasks. Here, we describe a dataset collected from a large group of human subjects while they watched a short audiovisual film. The dataset is characterized by several unique features. First, it combines a large amount of intracranial data from 51 intracranial electroencephalography (iEEG) participants, who all did the same task. Second, the intracranial data are accompanied by fMRI recordings acquired for the same task in 30 functional magnetic resonance imaging (fMRI) participants. Third, the data were acquired using a rich audiovisual stimulus, for which we provide detailed speech and video annotations. This multimodal dataset can be used to address questions about neural mechanisms of multimodal perception and language comprehension as well as the nature of the neural signal acquired during the same task across brain recording modalities.
Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival
Authors: Sousa Abel , Dugourd Aurelien , Memon Danish , Petursson Borgthor , Petsalaki Evangelia , Saez-Rodriguez Julio , Beltrao Pedro
Published: June 2021

Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours has been extensively characterized, the measurements of protein activities has been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics measurements for 1,110 tumours and 77 cell lines that we used to estimate activity changes in 218 kinases and 292 TFs. Kinase activities are, on average, not strongly determined by protein abundance but rather by their phosphorylation state while the reverse is more common for TFs. Co-regulation of kinase and TF activities reflects previously known regulatory relationships and allows us to dissect genetic drivers of signalling changes in cancer. Loss-of-function mutation is not often associated with dysregulation of downstream targets, suggesting frequent compensatory mechanisms. Finally, we identified the activities most differentially regulated in cancer subtypes and showed how these can be linked to differences in patient survival. Our results provide broad insights into dysregulation of protein activities in cancer and their contribution to disease severity.
Anti-GD2 antibody therapy alters the neuroblastoma tumor microenvironment and extends survival in TH-MYCN mice
Authors: McNerney KO , Karageorgos S , Ferry G , Wolpaw A , Burudpakdee C , Khurana P , Vemu R , Vu A , Hogarty MD , Bassiri H
Published: June 2021

Background

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted.

Methods

TH-MYCN mice were treated with 14G2a (anti-GD2 antibody), isotype antibody, or phosphate buffered saline from day 14 of life until day 100 or signs of morbidity. Survival was recorded, and tumors were isolated in terminal surgeries for analysis of GD2 expression and immune cell frequencies. Tumors from untreated mice were explanted for generation into cell lines, and GD2 expression was recorded with serial passage in tissue culture. Immunocytology and immunoblotting were performed to evaluate for adrenergic and mesenchymal markers of neuroblasts. Survival curves compared using Kaplan-Meier method with a log-rank test for significance. Unpaired two-tailed Student’s t-tests used for comparison of groups in flow cytometry analysis.

Results

14G2a markedly extends survival in such TH-MYCN mice. Additionally, neuroblasts in 14G2a-treated mice have reduced GD2 expression and fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironments. Neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. The loss of GD2 expression ex vivo is associated with a transition from an adrenergic to mesenchymal state that is maintained when reimplanted in vivo.

Conclusions

Our findings support the utility of the TH-MYCN model to inform GD2-directed immunotherapy approaches for neuroblastoma as well as opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.
In silicostudy predicts a key role of RNA-binding domains 3 and 4 in nucleolin-miRNA interactions
Authors: San Avdar , Palmieri Dario , Saxena Anjana , Singh Shaneen
Published: June 2021

RNA binding proteins (RBPs) regulate many important cellular processes through their interactions with RNA molecules. RBPs are critical for post-transcriptional mechanisms keeping gene regulation in a fine equilibrium. Conversely, dysregulation of RBPs and RNA metabolism pathways is an established hallmark of tumorigenesis. Human nucleolin (NCL) is a multifunctional RBP that interacts with different types of RNA molecules, in part through its four RNA binding domains (RBDs). Particularly, NCL interacts directly with microRNAs (miRNAs) and is involved in their aberrant processing linked with many cancers, including breast cancer. Nonetheless, molecular details of the NCL-miRNA interaction remain obscure. In this study, we used anin silicoapproach to characterize how NCL targets miRNAs and whether this specificity is imposed by a definite RBD-interface. Here, we present structural models of NCL-RBDs and miRNAs, as well as predict scenarios of NCL- miRNA interactions generated using docking algorithms. Our study suggests a predominant role of NCL RBDs 3 and 4 (RBD3-4) in miRNA binding. We provide detailed analyses of specific motifs/residues at the NCL- substrate interface in both these RBDs and miRNAs. Finally, we propose that the evolutionary emergence of more than two RBDs in NCL in higher organisms coincides with its additional role/s in miRNA processing. Our study shows that RBD3-4 display sequence/structural determinants to specifically recognize miRNA precursor molecules. Moreover, the insights from this study can ultimately support the design of novel antineoplastic drugs aimed at regulating NCL-dependent biological pathways with a causal role in tumorigenesis.

Importance/impact of the study

Nucleolin is a multifunctional RNA binding protein that is often linked with many cancers. Similarly, microRNAs are often dysregulated in many cancers and linked to tumorigenesis. This study focuses on the interaction of nucleolin with microRNAs to identify previously unknown mechanistic details/specificity of these interactions. The insights from this study can ultimately support the design of novel drugs aimed at regulating NCL- dependent pathways implicated in tumorigenesis.
Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib
Authors: Lim Chaemin , Dismuke Taylor , Malawsky Daniel , Ramsey Jacob D. , Hwang Duhyeong , Godfrey Virginia L. , Kabanov Alexander V. , Gershon Timothy R. , Sokolsky-Papkov Marina
Published: June 2021

CDK4/6 inhibitors hold promise for brain tumor treatment, but efficacy has been limited by recurrence in both preclinical models and clinical trials. To address recurrence, we tested a nanoparticle formulation of the CDK4/6 inhibitor palbociclib (POx-palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma. We then analyzed medulloblastomas in mice receiving palbociclib treatment, and compared the efficacy of combining palbociclib with specific inhibitors suggested by our analysis. POx-Palbo showed reduced toxicity compared to conventional palbociclib, was tolerable in parenteral administration, improved CNS pharmacokinetics, and extended survival of mice with medulloblastoma. Recurrence, however, remained problematic as fractions of tumor cells proliferated during therapy. ScRNA-seq identified a gene expression pattern unique to proliferating medulloblastoma cells in POx-Palbo-treated mice, marked by up-regulation of the glutamate transporterSlc1a2and down-regulation of diverse ribosomal genes. Reduced mTORC1 signaling, suggested by ribosomal suppression in POx-Palbo-treated tumors was confirmed by decreased 4EBP1 phosphorylation (p4EBP1). Further reducing mTORC1 activity by combining POx-Palbo with the mTORC1 inhibitor sapanisertib produced mutually enhancing effects, with increased suppression of both pRB and p4EBP1, and prolonged mouse survival compared to either agent alone. In contrast, targeting cell cycle progression by combining POx-Palbo with the SHH-pathway inhibitor vismodegib, or with the replication-targeting agents gemcitabine or etoposide, failed to enhance efficacy. Our data show the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment, and identify POx-palbo plus sapanisertib as effective combinatorial therapy for SHH medulloblastoma. This combination may be appropriate for testing in patients with recurrence, who need new options.
Hepatocyte androgen receptor in females mediates androgen-induced hepatocellular glucose mishandling and systemic insulin resistance
Authors: Andrisse Stanley , Feng Mingxiao , Wang Zhiqiang , Awe Olubusayo , Yu Lexiang , Zhang Haiying , Bi Sheng , Wang Hongbing , Li Linhao , Joseph Serene , Heller Nicola , Mauvais-Jarvis Franck , Wong Guang William , Segars James , Wolfe Andrew , Divall Sara , Ahima Rexford , Wu Sheng
Published: June 2021

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl) and LivARKO (ARfl/fl; Cre+/-) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Further, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.