bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting frequency-dependent selection through the effects of genotype similarity on fitness components
Authors: Sato Yasuhiro , Takahashi Yuma , Xu Chongmeng , Shimizu Kentaro K.
Published: August 2022

Frequency-dependent selection (FDS) drives an evolutionary regime that maintains or disrupts polymorphisms. Despite the increasing feasibility of genetic association studies on fitness components, there are a few methods to uncover the loci underlying FDS. Based on a simplified model of pairwise genotype–genotype interactions, we propose a linear regression that can infer FDS from observed fitness. The key idea behind our method is the inclusion of genotype similarity as a pseudo-trait in selection gradient analysis. Single-locus analysis of Arabidopsis and damselfly data could detect known negative FDS on visible polymorphism that followed Mendelian inheritance with complete dominance. By extending the singlelocus analysis to genome-wide association study (GWAS), our simulations showed that the regression coefficient of genotype similarity can distinguish negative or positive FDS without confounding other forms of balancing selection. Field GWAS of the branch number further revealed that negative FDS, rather than positive FDS, was enriched among the top-scoring single nucleotide polymorphisms (SNPs) in Arabidopsis thaliana. These results showed the wide applicability of our method for FDS on both visible polymorphism and genome-wide SNPs. Our study provides an effective method for selection gradient analysis to understand the maintenance or loss of polymorphism.
EEG signature of breaks in embodiment in VR
Authors: Porssut Thibault , Iwane Fumiaki , Chavarriaga Ricardo , Blanke Olaf , Millán José del R. , Boulic Ronan , Herbelin Bruno
Published: August 2022

The brain mechanism of embodiment in a virtual body has grown a scientific interest recently, with a particular focus on providing optimal virtual reality (VR) experiences. Disruptions from an embodied state to a less- or non-embodied state, denominated Breaks in Embodiment (BiE), are however rarely studied despite their importance for designing interactions in VR. Here we use electroencephalography (EEG) to monitor the brain’s reaction to a BiE, and investigate how this reaction depends on previous embodiment conditions. The experimental protocol consisted of two sequential steps; an induction step where participants were either embodied or non-embodied in an avatar, and a monitoring step where, in some cases, participants saw the avatar’s hand move while their hand remained still. Our results show the occurrence of error-related potentials linked to observation of the BiE event in the monitoring step. Importantly, this EEG signature shows amplified potentials following the non-embodied condition, which is indicative of an accumulation of errors across steps. These results provide neurophysiological indications on how progressive disruptions impact the expectation of embodiment for a virtual body.
TRPM3 as novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain
Authors: Aloi Vincenzo Davide , Pinto Silvia , van Bree Rita , Luyten Katrien , Voets Thomas , Vriens Joris
Published: August 2022

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is an adverse effect observed in up to 80% of cancer patients upon treatment with cytostatic drugs including paclitaxel and oxaliplatin. CIPNP can be so severe that it limits dose and choice of chemotherapy, and has a significant negative consequences on the quality of life of survivors. Current treatments for CIPNP are limited and unsatisfactory. TRPM3 is a Ca2+-permeable ion channel functionally expressed in peripheral sensory neurons involved in the detection of thermal stimuli. Here, we focus on the possible involvement of TRPM3 in acute oxaliplatin-induced mechanical allodynia and cold hypersensitivity. In vitro calcium microfluorimetry and whole-cell patch-clamp experiments showed that TRPM3 is functionally upregulated in both heterologous and homologous expression systems after acute (24h) oxaliplatin treatment, while direct application of oxaliplatin was without effect. In vivo behavioral studies using an acute oxaliplatin model for CIPNP showed the development of cold and mechano-hypersensitivity in control mice, which was lacking in TRPM3 deficient mice. In addition, the levels of pERK, a marker for neuronal activity, were significantly reduced in DRG neurons derived from TRPM3 deficient mice compared to control after oxaliplatin administration. Moreover, intraperitoneal injection of a TRPM3 antagonist, isosakuranetin, effectively reduced the oxaliplatin-induced pain behavior in response to cold and mechanical stimulation in mice with an acute form of oxaliplatin-induced peripheral neuropathy. In summary, TRPM3 thus represents a potential new target for the treatment of neuropathic pain in patients undergoing chemotherapy.
Retinoid acid receptor β mechanically regulates the activity of pancreatic cancer cells
Authors: Matellan Carlos , Lachowski Dariusz , Cortes Ernesto , Thorpe Stephen , del Río Hernández Armando E.
Published: August 2022

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, characterised by stromal remodelling, elevated matrix stiffness and high metastatic rate. Retinoids, compounds derived from vitamin A, have a history of clinical use in cancer for their anti-proliferative and differentiation effects, and more recently have been explored as anti-stromal therapies in PDAC for their ability to induce mechanical quiescence in cancer associated fibroblasts. Here we demonstrate that retinoic acid receptor β (RAR-β) transcriptionally represses myosin light chain 2 (MLC-2) expression, a key regulatory component of the contractile actomyosin machinery. In turn, MLC-2 downregulation results in decreased cytoskeletal stiffness and traction force generation, impaired response to mechanical stimuli via mechanosensing and reduced ability to invade through the basement membrane.
Direct Observation of Competing Prion Protein Fibril Populations with Distinct Structures and Kinetics
Authors: Sun Yuanzi , Jack Kezia , Ercolani Tiziana , Sangar Daljit , Hosszu Laszlo , Collinge John , Bieschke Jan
Published: August 2022

In prion diseases, fibrillar assemblies of misfolded prion protein (PrP) self-propagate by incorporating PrP monomers. Using total internal reflection and transient amyloid binding super-resolution microscopy, our study analyses elongation of single PrP fibrils to reveal polymorphic populations, featuring structural and dynamic heterogeneity similar to prion strains, which were previously hidden in ensemble measurements. PrP fibrils elongated along a preferred direction by an intermittent ‘stop- and-go’ mechanism. Fibrils fell into three main populations, which each displayed distinct elongation mechanisms incorporating different monomer structures and which maintained their properties even under elongation conditions favouring a different fibril type. Elongation of RML and ME7 prion rods likewise exhibited unique kinetic features. The discovery of polymorphic fibril populations of amyloid and prions growing in competition suggests that prions may present as quasispecies of structural isomorphs and that the replication environment may tilt the balance between prion isomorphs and amyloid species.

Highlights

Synthetic prion fibril populations contain structurally distinct fibril types

Fibril types faithfully elongate by different mechanisms

Fibril types compete for substrate depending on environment

Fibril populations model quasi-species behavior of prion strains

eTOC

Replication of different prion strains causes distinct disease phenotypes. Sun et al. analyzed the growth of individual synthetic prion protein fibrils by super-resolution microscopy and found populations of structurally distinct fibril types, which grew in competition to each other as a quasi-species, recapitulating basic prion strain characteristics in vitro.
Ageing in a collective: The impact of ageing individuals on social network structure
Authors: Siracusa Erin R. , Pereira André S. , Brask Josefine Bohr , Negron-Del Valle Josué E. , Phillips Daniel ,   Cayo Biobank Research Unit, Platt Michael L. , Higham James P. , Snyder-Mackler Noah , Brent Lauren J. N.
Published: August 2022

Ageing affects many phenotypic traits, but its consequences for social behaviour have only recently become apparent. Social networks emerge from associations between individuals. The changes in sociality that occur as individuals get older are thus likely to impact network structure, yet this remains unstudied. Here we use empirical data from free-ranging rhesus macaques and an agent-based model to test how age-based changes in social behaviour feed up to influence: (1) an individual’s level of indirect connectedness in their network; and (2) overall patterns of network structure. Our empirical analyses revealed that female macaques became less indirectly connected as they aged for some, but not all network measures examined, suggesting that indirect connectivity is affected by ageing, and that ageing animals can remain well integrated in some social contexts. Surprisingly, we did not find evidence for a relationship between age distribution and the structure of female macaque networks. We used an agent-based model to gain further understanding of the link between age-based differences in sociality and global network structure, and under which circumstances global effects may be detectable. Overall, our results suggest a potentially important and underappreciated role of age in the structure and function of animal collectives, which warrants further investigation.
scMEGA: Single-cell Multiomic Enhancer-based Gene Regulatory Network Inference
Authors: Li Zhijian , Nagai James S , Kuppe Christoph , Kramann Rafael , Costa Ivan G
Published: August 2022

The increasing availability of single-cell multi-omics data allows to quantitatively characterize gene regulation. We here describe scMEGA (Single-cell Multiomic Enhancer-based Gene Regulatory Network Inference) to infer gene regulatory networks by combining single-cell gene expression and chromatin accessibility profiles. This enables to study of complex gene regulation mechanisms for dynamic biological processes, such as cellular differentiation and disease-driven cellular remodeling. We provide a case study on gene regulatory networks controlling myofibroblast activation in human myocardial infarction
K978C CFTR restores essential epithelial function with greater efficiency than wildtype CFTR when expressed in CF airway cells
Authors: Woodall Maximillian , Tarran Robert , Lee Rhianna , Anfishi Hafssa , Prins Stella , Counsell John , Vergani Paola , Hart Stephen , Baines Deborah
Published: August 2022

Class Ia/b CFTR variants cause severe cystic fibrosis (CF) lung disease in ~10% of CF patients and are untreatable with small molecule pharmaceuticals. Genetic replacement strategies offer a potential cure for all patients but so far, have displayed limited efficiency in vivo.

We hypothesised that increasing protein abundance and/or activity of introduced CFTRs would more effectively restore function to CF bronchial epithelial cells (CFBE) in the presence of CF sputum (CFS) than wildtype (WT)-CFTR. We investigated codon optimised CFTR (hCAI), increased open probability CFTR (K978C) and codon optimised plus K978C (h^K978C) as candidates for gene therapy. Transfection of HEK293T with hCAI and h^K978C produced ~10-fold more CFTR protein than WT or K978C CFTRs. hCAI and h^K978C also displayed ~4-fold greater anion transport than WT in a halide-sensitive YFP quenching assay. However, functionality of modified CFTR cDNAs expressed in CFBE were profoundly different. 10% transduction of CFBE with K978C, compared to 22% transduction with WT, restored Cl- transport to similar levels as that recorded from non-CF cells. K978C increased ASL height and pH more effectively than WT-CFTR, while hCAI and h^K978C had limited impact. Further investigation indicated that codon optimised CFTRs mis-localised in CFBE and compromised vectoral Cl- transport.

These data provide further evidence that codon optimised CFTR cDNAs may be unsuitable for gene therapy practices that employ high activity promoters. However, increased activity CFTR cDNAs such as K978C, that potentially mimic the effect of potentiators, may provide more potent recovery of function than WT-CFTR cDNA in CF airways.

Significance Statement

Cystic fibrosis (CF) disease is associated with genetic malfunction of the Cl- channel CFTR, leading to dehydration and decreased pH in the fluid lining the airways. Replacement of CFTR by gene therapy/gene editing offers potential therapeutic benefit but efficiency is poor. We show that gain of activity K978C CFTR under the control of a high activity promoter fully restored Cl- transport, hydration and pH to CF bronchial epithelial cells (CFBE) in the presence of CF sputum and more efficiently than wild type CFTR. Codon optimised forms of CFTR were much less effective and proteins were mis-localised/mis-processed in CFBE. Thus, K978C could offer improved therapeutic potential.
Glycation-lowering compounds inhibit ghrelin signaling to reduce food intake, lower insulin resistance, and extend lifespan
Authors: Wimer Lauren , Kaneshiro Kiyomi R. , Ramirez Jessica , Bose Neelanjan , Valdearcos Martin , Shanmugam Muniesh Muthaiyan , Farrera Dominique O. , Singh Parminder , Beck Jennifer , Sellegounder Durai , Enqriquez Najera Lizbeth , Melov Simon , Ellerby Lisa , Cho Soo-Jin , Newman John C. , Koliwad Suneil , Galligan James , Kapahi Pankaj
Published: August 2022

Non-enzymatic reactions in glycolysis lead to the accumulation of methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity, diabetes and aging-associated pathologies. A combination of nicotinamide, α-lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low) lowered deleterious effects of glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduced food consumption, decreased body weight, improved insulin sensitivity, and increased survival in leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Transcriptional, protein, and functional analyses demonstrated that Gly-Low inhibited appetite-stimulating ghrelin signaling and enhanced the appetite-satiating mTOR pathways within the hypothalamus. Consistent with these molecular findings, Gly-Low inhibited ghrelin-mediated hunger responses. When administered as a late-life intervention, Gly-Low slowed hypothalamic aging signatures, improved glucose homeostasis and motor coordination, and increased lifespan, suggesting its potential benefits in ameliorating age-associated decline.

Graphical Abstract
A framework evaluating the utility of multi-gene, multi-disease population-based panel testing that accounts for uncertainty in penetrance estimates
Authors: Liang Jane W. , Christensen Kurt D. , Green Robert C. , Kraft Peter
Published: August 2022

Panel germline testing allows for efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well-understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency; estimated penetrances; and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly-penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities, and should account for uncertainties around these factors.
Endocannabinoid-dependent persistent decrease of GABAergic transmission on dopaminergic neurons underlies gene-environment interaction-induced susceptibility to cocaine sensitization
Authors: Serra Valeria , Traccis Francesco , Aroni Sonia , Bortolato Marco , Melis Miriam
Published: August 2022

Vulnerability to develop cocaine use disorder depends upon an unpredictable combination of genetic and non-genetic risk factors. Early life adversity and adolescence are critical non-genetic risk factors, and haplotypes of the monoamine oxidase (MAO) genes are among genetic variations increasing the risk of drug-related problems. However, data on the interactions between inheritable risk factors and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model containing both genetic (low-activity alleles of theMAO Agene; MAOANeo) and environmental (i.e., ES) variables displays a long lasting increased sensitivity to repeatedin vivococaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from MAOANeoES mice treated repeatedly with cocaine. Activation of either dopamine D2 or CB1 receptors is required for cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next,in vivopharmacological enhancement of 2-AG signaling during repeated cocaine exposure occludes its actions bothin vivoandex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene by environment interaction in VTA dopamine neurons of male pre-adolescent mice, contributing to our understanding of neural mechanisms of vulnerability for early onset cocaine use disorder.
Local brain oscillations and inter-regional connectivity differentially serve sensory and expectation effects on pain
Authors: Bott Felix S. , Nickel Moritz M. , Hohn Vanessa D. , May Elisabeth S. , Gil Ávila Cristina , Tiemann Laura , Gross Joachim , Ploner Markus
Published: August 2022

Pain emerges from the integration of sensory information about threats and contextual information such as an individual’s expectations. However, how sensory and contextual effects on pain are served by the brain is not fully understood so far. To address this question, we applied brief painful stimuli to 40 healthy human participants and independently varied stimulus intensity and expectations. Concurrently, we recorded electroencephalography. We assessed local oscillatory brain activity and inter-regional functional connectivity in a network of six brain regions playing key roles in the processing of pain. We found that sensory information predominantly influenced local brain oscillations. In contrast, expectations exclusively influenced inter-regional connectivity. Specifically, expectations altered connectivity at alpha (8-12 Hz) frequencies from prefrontal to somatosensory cortex. Moreover, discrepancies between sensory information and expectations, i.e., prediction errors, influenced connectivity at gamma (60-100 Hz) frequencies. These findings reveal how fundamentally different brain mechanisms serve sensory and contextual effects on pain.

Teaser

Sensory and expectation effects on pain are implemented by fundamentally different brain mechanisms.
Tip-links serve as force-pass filter to fulfil the role of gating-springs
Authors: Arora Nisha , Hazra Jagadish P. , Roy Sandip , Bhati Gaurav K. , Gupta Sarika , Chaudhuri Abhishek , Sagar Amin , Rakshit Sabyasachi
Published: August 2022

Tip-links as gating-spring in the mechanotransduction in hearing is still a debate. While the molecular elasticity of individual tip-link proteins warrants its candidature, the apparent rigidity from the heterotetrameric tip-links assembly refutes the claim. Using force-clamp experiments and simulations, we report that the heterotetrameric assembly is the natural selection for the gating-springs. Tip-links follow slip-ideal-slip bonds with increasing force. While in slip, the complex dissociates monotonously, ideal-bond interface responds indifferently to various auditory inputs. Insensitivity to forces renders tip-links as low-force pass filter, characteristic of gating-spring. Individual tip-links, however, forms slip-catch-slip bonds under tension. While catch bonds turn stronger with force from loud sound, our Langevin dynamics indicated the transition from slip-catch to slip-ideal bonds as cooperative effect of the dimers of individual protein complexes in tip-links. From molecular dynamics, we deciphered the molecular mechanism of catch bonds and its importance in deafness.
Optimizing InterProScan representation generates a surprisingly good protein function prediction method
Authors: Tiittanen Henri , Holm Liisa , Törönen Petri
Published: August 2022

Motivation

Automated protein Function Prediction (AFP) is an intensively studied topic. Most of this research focuses on methods that combine multiple data sources, while fewer articles look for the most efficient ways to use a single data source. Therefore, we wanted to test how different preprocessing methods and classifiers would perform in the AFP task when we process the output from the InterProscan (IPS). Especially, we present novel preprocessing methods, less used classifiers and inclusion of species taxonomy. We also test classifier stacking for combining tested classifier results. Methods are tested with in-house data and CAFA3 competition evaluation data.

Results

We show that including IPS localisation and taxonomy to the data improves results. Also the stacking improves the performance. Surprisingly, our best performing methods outperformed all international CAFA3 competition participants in most tests. Altogether, the results show how preprocessing and classifier combinations are beneficial in the AFP task.

Contact

petri.toronen(AT)helsinki.fi

Supplementary information

Supplementary text is available at the project web site http://ekhidna2.biocenter.helsinki.fi/AFP/ and at the end of this document.
A vast space of compact strategies for highly efficient decisions
Authors: Ma Tzuhsuan , Hermundstad Ann M
Published: August 2022

When foraging in dynamic and uncertain environments, animals can benefit from basing their decisions on smart inferences about hidden properties of the world. Typical theoretical approaches to understand the strategies that animals use in such settings combine Bayesian inference and value iteration to derive optimal behavioral policies that maximize total reward given changing beliefs about the environment. However, specifying these beliefs requires infinite numerical precision; with limited resources, this problem can no longer be separated into optimizing inference and optimizing action selections. To understand the space of behavioral policies in this constrained setting, we enumerate and evaluate all possible behavioral programs that can be constructed from just a handful of states. We show that only a small fraction of the top-performing programs can be constructed by approximating Bayesian inference; the remaining programs are structurally or even functionally distinct from Bayesian. To assess structural and functional relationships among all programs, we developed novel tree embedding algorithms; these embeddings, which are capable of extracting different relational structures within the program space, reveal that nearly all good programs are closely connected through single algorithmic “mutations”. We demonstrate how one can use such relational structures to efficiently search for good solutions via an evolutionary algorithm. Moreover, these embeddings reveal that the diversity of non-Bayesian behaviors originates from a handful of key mutations that broaden the functional repertoire within the space of good programs. The fact that this diversity of behaviors does not significantly compromise performance suggests a novel approach for studying how these strategies generalize across tasks.
Unified access to up-to-date residue-level annotations from UniProt and other biological databases for PDB data via PDBx/mmCIF files
Authors: Choudhary Preeti , Anyango Stephen , Berrisford John , Varadi Mihaly , Tolchard James , Velankar Sameer
Published: August 2022

More than 58,000 proteins have up-to-date correspondence between their amino acid sequence (UniProtKB) and their 3D structures (PDB), enabled by the Structure Integration with Function, Taxonomy and Sequences (SIFTS) resource. In addition to this fundamental mapping, SIFTS incorporates residue-level annotations from other biological resources such as Pfam, InterPro, SCOP, SCOP2, CATH, IntEnz, GO, PubMed, Ensembl, NCBI taxonomy database and Homologene. The SIFTS data is exported in XML format per individual PDB entry and is also accessible via the PDBe REST API. These mappings have always been maintained separately from the structure data (PDBx/mmCIF file) in the PDB archive. In this current work, taking advantage of the extensibility of the core PDBx/mmCIF framework, we extended the wwPDB PDBx/mmCIF data dictionary with additional categories to accommodate SIFTS data and added the UniProt, Pfam, SCOP2, and CATH mapping information directly into the PDBx/mmCIF files from the PDB archive. The integration of mapping data in the PDBx/mmCIF files provides consistent numbering of residues in different PDB entries allowing easy comparison of structure models. The extended PDBx/mmCIF format yields a more consistent, standardised metadata description without altering the core PDB information. This development enables up-to-date cross-reference information at residue level resulting in better data interoperability, supporting improved data analysis and visualisation.

Availability and implementation

We expanded the PDBe release pipeline with a process that adds SIFTS annotations to the PDBx/mmCIF files for individual structures in the PDB archive. The scientific community can download these updated PDBx/mmCIF files from the PDBe entry pages

(https://pdbe.org/7dr0) and through direct URLs

(https://www.ebi.ac.uk/pdbe/static/entry/7o9f_updated.cif), using the PDBe download service

(https://www.ebi.ac.uk/pdbe/download/api) or from the EMBL-EBI FTP area

(https://ftp.ebi.ac.uk/pub/databases/msd/updated_mmcif/).
“It’s my job”: A qualitative study of the mediatization of science within the scientist-journalist relationship
Authors: Moorhead Laura L. , Fleerackers Alice , Maggio Lauren A.
Published: August 2022

Through 19 interviews with scientists, this study examines scientists’ use of media logic and their relationships with journalists using research as the focal point. The authors identified that the scientists shared a basic understanding of media logic classified in three patterns. Two patterns were previously identified by Olesk: 1) adaption (ability to explain research in a simple, engaging fashion but with a reactive approach to journalist interaction) and 2) adoption (proactively create and manage media interactions for strategic aims through a more active use of media logic). The other emerged as a new, third pattern, affiliation (enthusiastic contributors to journalists’ production practices and desire to engage in public outreach).
Automatic identification of drug-induced liver injury literature using natural language processing and machine learning methods
Authors: Oh Jung Hun , Tannenbaum Allen , Deasy Joseph O.
Published: August 2022

Drug-induced liver injury (DILI) is an adverse hepatic drug reaction that can potentially lead to life-threatening liver failure. Previously published work in the scientific literature on DILI has provided valuable insights for the understanding of hepatotoxicity as well as drug development. However, the manual search of scientific literature in PubMed is laborious. Natural language processing (NLP) techniques have been developed to decipher and understand the meaning of human language by extracting useful information from unstructured text data. In particular, NLP along with artificial intelligence (AI) / machine learning (ML) techniques may allow automatic processing of the DILI literature, but useful methods are yet to be demonstrated. To address this challenge, we have developed an integrated NLP/ML classification model to identify DILI-related literature using only paper titles and abstracts. We used 14,203 publications provided by the Critical Assessment of Massive Data Analysis (CAMDA) challenge, employing word vectorization techniques in NLP coupled with machine learning methods. Classification modeling was performed using 2/3 of the data for training and the remainder for testing in internal validation. The best performance was achieved using a linear support vector machine (SVM) model that combined vectors derived from term frequency-inverse document frequency (TF-IDF) and Word2Vec, achieving an accuracy of 95.0% and an F1-score of 95.0%. The final SVM model built using all 14,203 publications was tested on independent datasets, resulting in accuracies of 92.5%, 96.3%, and 98.3%, and F1-scores of 93.5%, 86.1%, and 75.6% for three test sets (T1-T3). The SVM model was tested on four external validation sets (V1-V4), resulting in accuracies of 92.0%, 96.2%, 98.3%, and 93.1%, and F1-scores of 92.4%, 82.9%, 75.0%, and 93.3%.
KAS-pipe2: a flexible toolkit for exploring KAS-seq and spKAS-seq data
Authors: Lyu Ruitu , Wu Tong , Park Gayoung , He Yu-Ying , He Chuan , Chen Mengjie
Published: August 2022

Kethoxal-assisted ssDNA sequencing (KAS-seq) is gaining popularity as a robust and effective approach to study the dynamics of transcriptionally engaged RNA polymerases through profiling of genome-wide single-stranded DNA (ssDNA). Its latest variant, spKAS-seq, a strand-specific version of KAS-seq, has been developed to map genome-wide R-loop structures by detecting imbalances of ssDNA on two strands. However, user-friendly, open-source analysis pipelines for KAS-seq data are still lacking. Here we present KAS-pipe2 as a flexible and integrated toolkit to facilitate the analysis and interpretation of KAS-seq data. KAS-pipe2 can perform standard analyses such as quality control, read alignment, and differential RNA polymerase activity analysis. In addition, KAS-pipe2 introduces many novel features, including, but not limited to: calculation of transcriptional indexes, identification of single-stranded transcribing enhancers, and high-resolution mapping of R-loops. We use benchmark datasets to demonstrate that KAS-pipe2 provides a powerful framework to study transient transcriptional regulatory programs. KAS-pipe2 is available at https://github.com/Ruitulyu/KAS-pipe2.
Screening the Medicines for Malaria Pandemic Response Box chemical library onCaenorhabditis elegansidentifies re-profiled candidate anthelmintic drug leads
Authors: Nick Marina , Partridge Frederick A , Forman Ruth , Bataille Carole JR , Else Kathryn J , Russell Angela J , Sattelle David B
Published: August 2022

The 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organismCaenorhabditis elegans. The 400 compound Medicines for Malaria Pandemic Response Box library was screened with each compound tested initially at 1.0 × 10−4M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth / motility assay and in an L4 motility assay. For vorapaxar, an EC50of 5.7 × 10−7M was observed, a value comparable to some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematodeC. elegansmakes this a useful approach to identify chemical leads and complement the often lower-throughput experiments on parasitic nematode models.
3D Direttissima: A V1 Heresy
Authors: Arathorn David W
Published: August 2022

The heretical conjecture offered here is that a 3-space scene reconstruction of sequences of visual fixations is constructed directly in V1 in a head-centered frame. “Direttissima” is a climbing term designating the shortest, most direct route to the objective of a climb. The “heresy” here is the claim that the construction of the first 3D representation of the scene before one’s eyes takes place in V1 rather than further up the visual pathways. The inputs to the neural process proposed for such construction are the V1 retinotopic projections from each eye and the vergence angle. Absolute disparities are not encoded as a separate data set in a distinct set of neurons, but rather are emergent properties of the neurons that implement the construction of the 3D representation of one or a sequence of fixations on elements of the scene. In this conjecture, the conscious “picture” we take as vision is a projection of the 3D construction, not a view of the retinal image. One of the critical psychophysical clues to the nature of such a mechanism is the well known visual size constancy phenomenon. Another property of the proposed mechanism is that it is plausibly fast enough to enable such spatially and temporally demanding tasks as a human batting a fastball or a bobcat swatting the head of a striking rattlesnake.
Widespread perturbation of ETS factor binding sites in cancer
Authors: Carrasco Pro S , Hook H , Bray D , Berenzy D , Moyer D , Yin M , Labadorf AT , Tewhey R , Siggers T , Fuxman Bass JI
Published: August 2022

Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.
Seasonal polyphenism of wing colors and its influence on sulphur butterfly diversification
Authors: Fenner Jennifer , Ficarrotta Vincent , Colombara Alexandra , Smith Heather , Evans Kymberlee , Range Ryan , Counterman Brian A.
Published: August 2022

Seasonal variation of color patterns on butterfly wings are iconic examples of developmentally plastic traits that can influence adaptation and speciation. Yet, there are few examples of such seasonal polyphenisms that have characterized the environmental cues, ecological consequences, or genetic mechanisms involved in generating the plastic variation of wing color. Further, there is a lack of support that such plasticity may impact the adaptive diversification of butterfly wing patterns. Here, we report a case of seasonal polyphenism in pigment and structurally-based color patterns ofZerene cesoniathat are strikingly similar to the color pattern divergence seen on the wings of sulphur butterflies. We show that (i) coordinated changes in temperature and photoperiod drive the plasticity, (ii) the plastic color changes impact how fast the butterflies can warm, (iii) identifyspaltas likely be involved in the genetic coupling of the pigment and structurally-based color plastic response. We further show that this plastic wing changes phenocopy wing pattern divergence betweenZerenespecies, as well as the color pattern differences known to be commonly involved in sexual selection and speciation across sulphur butterflies. Together, our results demonstrate that shared environmental cues and genetic basis for pigment and structural color plasticity may result in conditions that may have facilitated species diversification of sulphur butterflies.
RatInABox: A toolkit for modelling locomotion and neuronal activity in continuous environments
Authors: George Tom M , Rastogi Mehul , de Cothi William , Clopath Claudia , Stachenfeld Kimberly , Barry Caswell
Published: August 2022

Generating synthetic locomotory and neural data is a useful yet cumbersome step commonly required to study theoretical models of the brain’s role in spatial navigation. This process can be time consuming and, without a common framework, makes it difficult to reproduce or compare studies which each generate test data in different ways. In response we present RatInABox, an open-source Python toolkit designed to model realistic rodent locomotion and generate synthetic neural data from spatially modulated cell types. This software provides users with (i) the ability to construct one-or two-dimensional environments with configurable barriers and visual cues, (ii) a physically realistic random motion model fitted to experimental data, (iii) rapid online calculation of neural data for many of the known self-location or velocity selective cell types in the hippocampal formation (including place cells, grid cells, boundary vector cells, head direction cells) and (iv) a framework for constructing custom cell types, multi-layer network models and data-or policy-controlled motion trajectories. The motion and neural models spatially and temporally continuous as well as topographically sensitive to boundary conditions and walls. We demonstrate that out-of-the-box parameter settings replicate many aspects of rodent foraging behaviour such as velocity statistics and the tendency of rodents to over-explore walls. Numerous tutorial scripts are provided, including examples where RatInABox is used for decoding position from neural data or to solve a navigational reinforcement learning task. We hope this tool significantly streamline computational research into the brain’s role in navigation.
Hepatitis D virus infection of stem cell-derived hepatocytes triggers an IFN- and NFκB-based innate immune response unable to clear infection
Authors: Lange Frauke , Garn Jonathan , Anagho Holda , von Hahn Thomas , Pietschmann Thomas , Carpentier Arnaud
Published: August 2022

Human pluripotent stem cell-derived hepatocyte-like cells (HLCs) are a valuable model to investigate host-pathogen interactions of hepatitis viruses in a mature and authentic environment. Here, we investigated the susceptibility of HLCs to the Hepatitis D Virus (HDV), a virus that in co-infection with HBV is responsible for the most severe form of viral hepatitis. Cells undergoing hepatic differentiation became susceptible to HDV infection after acquiring expression of the Na+-taurocholate cotransporting polypeptide (NTCP), the receptor mediating HBV and HDV entry. Inoculation of mature HLCs with HDV lead to increasing amounts of intracellular HDV RNA and accumulation of the HDV antigen in the cells. The infection was abrogated when using known entry inhibitors targeting NTCP or by disrupting genome replication using the nucleoside analogue Ribavirin. Upon infection, the HLCs mounted an innate immune response based on induction of the interferons IFNB and L, but not IFNA, and were associated with an upregulation of interferon-stimulated genes. The intensity of this immune response positively correlated with the level of viral replication and was dependant on both the JAK/STAT and NFκB pathway activation. Importantly, neither this innate immune response nor an exogenous treatment of IFNα2b inhibited HDV replication. However, pre-treatment of the HLCs with IFNα2b reduced viral infection, suggesting that ISGs may limit early stages of infection.

This novel HDV in vitro infection model represents a valuable tool for studying HDV replication and investigating candidate antiviral drugs in cells displaying mature hepatic functions.

Lay summary

HDV can infect stem cell-derived hepatocytes through an NTCP-mediated entry process. Infection triggers an IFN and NFκB dependent innate immune response. However, viral replication seems unaffected by this innate response or by exogenous IFN treatment.

Graphical abstract
A TCF4/BRD4-dependent regulatory network confers cross-resistance to targeted and immune checkpoint therapy in melanoma
Authors: Pozniak Joanna , Pedri Dennis , Landeloos Ewout , Herck Yannick Van , Antoranz Asier , Karras Panagiotis , Nowosad Ada , Makhzami Samira , Bervoets Greet , Dewaele Michael , Vanwynsberghe Lukas , Cinque Sonia , Kint Sam , Vandereyken Katy , Voet Thierry , Vernaillen Frank , Annaert Wim , Lambrechts Diether , Boecxstaens Veerle , van den Oord Joost , Bosisio Francesca , Leucci Eleonora , Rambow Florian , Bechter Oliver , Marine Jean-Christophe
Published: August 2022

Primary resistance drastically limits the clinical success of immune checkpoint blockade (ICB) in melanoma. Resistance to ICB may also develop when tumours relapse after targeted therapy. To identify cancer cell-intrinsic mechanisms driving resistance to ICB, we generated single-cell RNA-sequencing (scRNA-seq) data from a prospective longitudinal cohort of patients on ICB therapy, including an early time point obtained after only one cycle of treatment. Comparing these data with murine scRNA-seq datasets, we established a comprehensive view of the cellular architecture of the treatment-naïve melanoma ecosystem, and defined 6 evolutionarily conserved melanoma transcriptional metaprograms (Melanocytic or MEL, Mesenchymal-like or MES, Neural Crest-like, Antigen Presentation, Stress (hypoxia response) and Stress (p53 response)). Spatial multi-omics revealed a non-random geographic distribution of cell states that is, at least partly, driven by the tumour microenvironment. The single-cell data allowed unambiguous discrimination between melanoma MES cells and cancer-associated fibroblasts bothin silicoandin situ, a long-standing challenge in the field. Importantly, two of the melanoma transcriptional metaprograms were associated with divergent clinical responses to ICB. While the Antigen Presentation cell population was more abundant in tumours from patients who exhibited a clinical response to ICB, MES cells were significantly enriched in early on-treatment biopsies from non-responders, and their presence significantly predicted lack of response. Critically, we identified TCF4 (E2-2) as a master regulator of the MES program and suppressor of both MEL and Antigen Presentation programs. TargetingTCF4expression in MES cells either genetically or pharmacologically using a bromodomain inhibitor increased immunogenicity and sensitivity to targeted therapy. This study describes an increasingly complex melanoma transcriptional landscape and its rapid evolution under ICB. It also identifies a putative biomarker of early response to ICB and an epigenetic therapeutic strategy that increases both immunogenicity of ICB-refractory melanoma and their sensitivity to targeted therapy.
Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma
Authors: Gaglia Giorgio , Burger Megan L. , Ritch Cecily C. , Rammos Danae , Dai Yang , Crossland Grace E. , Tavana Sara Z. , Warchol Simon , Jaeger Alex M. , Naranjo Santiago , Coy Shannon , Nirmal Ajit J. , Krueger Robert , Lin Jia-Ren , Pfister Hanspeter , Sorger Peter K , Jacks Tyler , Santagata Sandro
Published: August 2022

Lymphocytes play a key role in immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. Here, we used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of tumor-bearing lung tissues from a Kras/p53 (KP) mouse model and human resections. Networks of directly interacting lymphocytes (‘lymphonets’) emerge as a distinctive feature of the anti-cancer immune response. Lymphonets nucleate from small T-cell clusters and incorporate B cells with increasing size. CXCR3-mediated trafficking modulates lymphonet size and number, but neoantigen expression directs intratumoral localization. Lymphonets preferentially harbor TCF1+/PD1+ progenitor CD8 T cells involved in responses to immune checkpoint blockade (ICB). Upon treatment of mice with ICB therapy or a neoantigen-targeted vaccine, lymphonets retain progenitor and gain cytotoxic CD8 T-cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8 T-cell anti-tumor responses.
FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation
Authors: Chen Dailu , Wosztyl Aleksandra , Mullapudi Vishruth , Bali Sofia , Vaquer-Alicea Jaime , Melhem Shamiram , Seelaar Harro , van Swieten John C. , Diamond Marc I. , Joachimiak Lukasz A.
Published: August 2022

Amyloid deposition of the microtubule-associated protein tau is a unifying theme in a multitude of neurodegenerative diseases. Disease-associated missense mutations in tau are associated with frontotemporal dementia (FTD) and enhance tau aggregation propensity. However, the molecular mechanism of how mutations in tau promote tau assembly into amyloids remains obscure. There is a need to understand how tau folds into pathogenic conformations to cause disease. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation. We use recombinant protein and synthetic peptide systems, computational modeling, cross-linking mass spectrometry, and cell models to investigate the mechanism of spontaneous aggregation of the S320F FTD-tau mutant. We discover that the S320F mutation drives the stabilization of a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif. We identify a suppressor mutation that reverses the S320F aggregation phenotype through the reduction of S320F-based hydrophobic clustering in vitro and in cells. Finally, we use structure-based computational design to engineer rapidly aggregating tau sequences by optimizing nonpolar clusters in proximity to the S320 site revealing a new principle that governs the regulation of tau aggregation. We uncover a mechanism for regulating aggregation that balances transient nonpolar contacts within local protective structures or in longer-range interactions that sequester amyloid motifs. The introduction of a pathogenic mutation redistributes these transient interactions to drive spontaneous aggregation. We anticipate deeper knowledge of this process will permit control of tau aggregation into discrete structural polymorphs to aid design of reagents that can detect disease-specific tau conformations.