bluuebunny/crossref_metadata_2025 huggingface dataset:
High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology
Authors: Malysheva Valeriya , Ray-Jones Helen , Cazares Tareian A. , Clay Owen , Ohayon David , Artemov Pavel , Wayman Joseph A. , Rosa Monica Della , Petitjean Carmen , Booth Clarissa , Ellaway Joseph I.J. , Orchard William R. , Chen Xiaoting , Parameswaran Sreeja , Nagano Takashi , Fraser Peter , Schoenfelder Stefan , Weirauch Matthew T. , Kottyan Leah C. , Smith David F. , Powell Nick , Weimer Jill M. , Wallace Chris , Miraldi Emily R. , Waggoner Stephen , Spivakov Mikhail
Published: October 2022

Innate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries underlying ILC3 function, we used high-resolution Capture Hi-C to profile promoter-anchored chromosomal contacts in human primary ILC3s. Combining significant interaction detection with the Activity-By-Contact approach adapted to Capture Hi-C, we reveal a multitude of contacts between promoters and distal regulatory elements and obtain evidence for distinct regulatory wiring of alternative promoters. We find that promoter-interacting regions in ILC3s are enriched for genetic variants associated with multiple immune diseases. Focusing on Crohn’s disease (CD), in which ILC3s are established mediators, we devised a Bayesian approach that incorporates multivariate fine-mapping to link CD-associated genetic variants with putative target genes. We identify known and previously unimplicated genes in conferring genetic risk of CD through activity in ILC3s. This includes the CLN3gene that is mutated in most cases of the neurodegenerative disorder Batten disease. UsingCln3mutant mice, we show that CLN3 is a putative negative regulator of IL-17 production in an inflammatory subset of ILC3s. This finding suggests a functional role for CLN3 in ILC3 biology, with mechanistic implications for Crohn’s and Batten diseases.
Thermally Reversible Pattern Formation in Arrays of Molecular Rotors
Authors: DeLuca Marcello , Pfeifer Wolfgang G. , Randoing Benjamin , Huang Chao-Min , Poirier Michael G. , Castro Carlos E. , Arya Gaurav
Published: October 2022

Control over the mesoscale to microscale patterning of materials is of great interest to the soft matter community. Inspired by DNA origami rotors, we introduce a 2D nearest-neighbor lattice of spinning rotors that exhibit discrete orientational states and interactions with their neighbors. Monte Carlo simulations of rotor lattices reveal that they exhibit a variety of interesting ordering behaviors and morphologies that can be modulated through rotor design parameters. The rotor arrays exhibit diverse patterns including closed loops, radiating loops, and bricklayer structures in their ordered states. They exhibit specific heat peaks at very low temperatures for small system sizes, and some systems exhibit multiple order-disorder transitions depending on inter-rotor interaction design. We devise an energy-based order parameter and showviaumbrella sampling and histogram reweighting that this order parameter captures well the order-disorder transitions occurring in these systems. We fabricate real DNA origami rotors which themselves can orderviaprogrammable DNA base-pairing interactions and demonstrate both ordered and disordered phases, illustrating how rotor lattices may be realized experimentally and used for responsive organization. This work establishes the feasibility of realizing structural nanomaterials that exhibit locally mediated microscale patterns which could have applications in sensing and precision surface patterning.
Effect ofF. mosseaeon the expression of genes and proteins about sulfur nutrition in the continuous crop soybean roots
Authors: Zhang Xueqi , Lu Chengcheng , Liu Ronglin , Sun Zixin , Cai Baiyan
Published: October 2022

Soybean is a sulfur-loving oilseed crop, and continuous cropping can lead to soil sulfur deficiency, which can inhibit the growth and quality of soybean. This experiment used transcriptomic and proteomic sequencing techniques to analyse the changes in the expression of functional genes and related proteins in the root system of continuously cropped soybean and to reveal the molecular mechanism ofF. mosseaeinoculation on the soybean root system in response to sulfur nutrient supply at the molecular level. It was thus demonstrated thatF. mosseaecould enhance the uptake and transport of soil sulfur in continuously cropped soybean. This study, therefore, provides a theoretical basis for the application ofF. mosseaeas a biofertilizer in soybean production on sulfur-deficient soils.

One-sentence summary

F. mosseaeaffects soybean genes and proteins at the transcriptome and proteome levels.
ComprehensiveSMN1andSMN2profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
Authors: Chen Xiao , Harting John , Farrow Emily , Thiffault Isabelle , Kasperaviciute Dalia ,   Genomics England Research Consortium, Hoischen Alexander , Gilissen Christian , Pastinen Tomi , Eberle Michael A
Published: October 2022

Spinal muscular atrophy, a leading cause of early infant death, is caused by biallelic mutations of theSMN1gene. Sequence analysis ofSMN1is challenging due to high sequence similarity with its paralogSMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is impossible to identify silent carriers (2+0) with two copies ofSMN1on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-lengthSMN1andSMN2haplotypes, determines the gene copy numbers and calls phased variants using long-read PacBio HiFi data. TheSMN1andSMN2copy number calls by Paraphase are highly concordant with orthogonal methods (99.2% forSMN1and 100% forSMN2). We applied Paraphase to 438 samples across five ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified majorSMN1andSMN2haplogroups and characterized their co-segregation through pedigree-based analyses. We identified twoSMN1haplotypes that form a common two-copySMN1allele in African populations. Testing positive for these two haplotypes in an individual with two copies ofSMN1gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7-3.0%). Extending beyond simple copy number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers.
Efficienthyperactive piggyBactransgenesis inPlodiapantry moths
Authors: Heryanto Christa , Mazo-Vargas Anyi , Martin Arnaud
Published: October 2022

WhilepiggyBactransposon-based transgenesis is widely used in various emerging model organisms, its relatively low transposition rate in butterflies and moths has hindered its use for routine genetic transformation in Lepidoptera. Here, we tested the suitability of a codon-optimizedhyperactive piggyBactransposase (hyPBase) in mRNA form to deliver and integrate transgenic cassettes into the genome of the pantry mothPlodia interpunctella. Co-injection ofhyPBasemRNA with donor plasmids successfully integrated 1.5-4.4 kb expression cassettes driving the fluorescent markers EGFP, DsRed, or EYFP in eyes and glia with the3xP3promoter. Somatic integration and expression of the transgene in the G0injected generation was detectable from 72-hr embryos and onward in larvae, pupae and adults carrying a recessive white-eyed mutation. Overall, 2.5% of injected eggs survived into transgene-bearing adults with mosaic fluorescence. Subsequent outcrossing of fluorescent G0founders transmitted single-insertion copies of3xP3::EGFPand3xP3::EYFPand generated stable isogenic lines. Random in-crossing of a small cohort of G0founders expressing3xP3::DsRedyielded a stable transgenic line segregating for more than one transgene insertion site. We discuss howhyPBasecan be used to generate stable transgenic resources inPlodiaand other moths.
Evolutionary blocks to anthocyanin accumulation and the loss of an anthocyanin carrier protein in betalain-pigmented Caryophyllales
Authors: Pucker Boas , Walker-Hale Nathanael , Yim Won C. , Cushman John , Crum Alexandra , Yang Ya , Brockington Samuel
Published: October 2022

◻

The order Caryophyllales exhibits complex pigment evolution, with mutual exclusion of anthocyanin and betalain pigments. Given recent evidence for multiple shifts to betalain pigmentation, we re-evaluated potential mechanisms underpinning the exclusion of anthocyanins from betalain-pigmented lineages.

◻

We examined the evolution of the flavonoid pathway using transcriptomic and genomic datasets covering 309 species in 31 families. Orthologs and paralogs of known flavonoid synthesis genes were identified by sequence similarity, with gene duplication and gene loss inferred by phylogenetic and syntenic analysis. Relative transcript abundances were assessed to reveal broad-scale gene expression changes between betalain- and anthocyanin-pigmented lineages.

◻

Most flavonoid genes are retained and transcribed in betalain-pigmented lineages, and many also show evidence of extensive gene duplication within betalain-pigmented lineages. However, expression of several flavonoid genes is reduced in betalain-pigmented lineages, especially the late-stage genes dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). Notably flavonoid 3′,5′-hydroxylase (F3′5′H) homologs have been repeatedly lost in belatain-pigmented lineages, and Anthocyanin9 (AN9) homologs are undetectable in any betalain-pigmented lineages.

◻

Down-regulation ofANSandDFRhomolog expression (limiting synthesis) and reiterative loss ofAN9homologs (limiting transport), coincident with multiple shifts to betalain pigmentation, are likely crucial the loss of anthocyanins in betalain-pigmented Caryophyllales.
Prediction and scanning of IL-5 inducing peptides using alignment-free and alignment-based method
Authors: Devi Naorem Leimarembi , Sharma Neelam , Raghava Gajendra P. S.
Published: October 2022

Interleukin-5 (IL-5) is the key cytokine produced by T-helper, eosinophils, mast and basophils cells. It can act as an enticing therapeutic target due to its pivotal role in several eosinophil-mediated diseases. Though numerous methods have been developed to predict HLA binders and cytokines-inducing peptides, no method was developed for predicting IL-5 inducing peptides. All models in this study have been trained, tested and validated on experimentally validated 1907 IL-5 inducing and 7759 non-IL-5 inducing peptides obtained from IEDB. First, alignment-based methods have been developed using similarity and motif search. These alignment-based methods provide high precision but poor coverage. In order to overcome this limitation, we developed machine learning-based models for predicting IL-5 inducing peptides using a wide range of peptide features. Our random-forest model developed using selected 250 dipeptides achieved the highest performance among alignment-free methods with AUC 0.75 and MCC 0.29 on validation dataset. In order to improve the performance, we developed an ensemble or hybrid method that combined alignment-based and alignment-free methods. Our hybrid method achieved AUC 0.94 with MCC 0.60 on validation/ independent dataset. The best model developed in this study has been incorporated in the web server IL5pred (https://webs.iiitd.edu.in/raghava/il5pred/).

Key Points

IL-5 is a regulatory cytokine that plays a vital role in eosinophil-mediated diseases

BLAST-based similarity search against IL-5 inducing peptides was employed

A hybrid approach combines alignment-based and alignment-free methods

Alignment-free models are based on machine learning techniques

A web server ‘IL5pred’ and its standalone software have been developed

Authors’ Biography

Dr. Naorem Leimarembi Devi is currently working as a DBT-Research Associate in Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Neelam Sharma is pursuing her Ph.D. in Computational Biology from the Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Prof. G.P.S. Raghava is currently working as Professor and Head of Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
Antimicrobial resistance ofEnterococcus cecorum: ECOFF determination
Authors: Laurentie Jeanne , Mourand Gwenaelle , Grippon Pauline , Furlan Sylviane , Chauvin Claire , Jouy Eric , Serror Pascale , Kempf Isabelle
Published: October 2022

Enterococcus cecorum, a commensal Gram-positive bacterium of the chicken gut, has emerged as a worldwide cause of lameness in poultry, particularly in fast-growing broilers. It is responsible for osteomyelitis, spondylitis and femoral head necrosis, causing animal suffering, mortality and antimicrobial use. Research on the antimicrobial resistance ofE. cecorumclinical isolates in France is scarce, and epidemiological cut-off (ECOFF) values unknown. To determine tentative ECOFF (COWT) values forE. cecorumand to investigate the antimicrobial resistance patterns of isolates from mainly French broilers, we tested the susceptibility of a collection of commensal and clinical isolates (n=208) to 29 antimicrobials by the disc diffusion (DD) method. We also determined the minimum inhibitory concentrations (MICs) of 23 antimicrobials by the broth micro-dilution method. To detect chromosomal mutations conferring antimicrobial resistance, we investigated the genomes of 118E. cecorumisolates mainly obtained from infectious sites and previously described in the literature. We determined the COWTvalues for more than 20 antimicrobials and identified two chromosomal mutations explaining fluoroquinolone resistance. The DD method appears better suited for detectingE. cecorumantimicrobial resistance. Although tetracycline and erythromycin resistances were persistent in clinical and non-clinical isolates, we found little or no resistance to medically important antimicrobials.
A new method for a priori practical identifiability
Authors: Thompson Peter , Andersson Benjamin Jan , Sundqvist Nicolas , Cedersund Gunnar
Published: October 2022

Background and objective

Practical identifiability analysis – to determine whether a model property can be determined from given data – is central to model-based data analysis in biomedicine. The main approaches used today all require that the coverage of the parameter space be exhaustive, which is usually not possible. An attractive alternative could be to use structural identifiability methods, since they do not need such a parameter coverage. However, current structural methods are unsuited for practical identifiability analysis, since they assume that all higher-order derivatives of the measured variables are available, and we do not know the implications of this assumption. Herein, we provide new definitions and methods that allow for this assumption to be relaxed.

Methods

The new methods and definitions are valid for ordinary differential equations, and use a combination of differential algebra and modulus calculus, implemented in Maple.

Results

We introduce the concept of (ν1, …, νm)-identifiability, which differs from previous definitions in that it assumes that only the first νiderivatives of the measurement signalyiare available. This new type of identifiability can be determined using our new algorithm, as is demonstrated by applications to various published biomedical models. Our methods allow for identifiability of not only parameters, but of any model property, i.e. observability. These new results provide further strengthening of conclusions made in previous analysis of these models. Importantly, our analysis can for the first time quantify the impact of the assumption that all derivatives are available in specific examples. If one e.g. assumes that only up to third order derivatives, instead of all derivatives, are available, the number of identifiable parameters drops from 17 to 1 for a Drosophila model, and from 21 to 6 for an NF-κB model. In both these models, the previously obtained identifiability is present only if at least 20 derivatives of all measurement signals are available.

Conclusions

Our results demonstrate that the assumption regarding availability of derivatives done in traditional structural identifiability analysis causes a big overestimation regarding the number of parameters that can be estimated. Our new methods and algorithms allow for this assumption to be relaxed, which moves structural identifiability methodology one step closer to practical identifiability analysis.
Linking prokaryotic genome size variation to metabolic potential and environment
Authors: Rodríguez-Gijón Alejandro , Buck Moritz , Andersson Anders F. , Izabel-Shen Dandan , Nascimento Francisco J. A. , Garcia Sarahi L.
Published: October 2022

While theories and models have appeared to explain genome size as a result of evolutionary processes, little work has shown that genome sizes carry ecological signatures. Our work delves into the ecological implications of microbial genome size variation in benthic and pelagic habitats across environmental gradients of the brackish Baltic Sea. While depth is significantly associated with genome size in benthic and pelagic brackish metagenomes, salinity is only correlated to genome size in benthic metagenomes. Overall, we confirm that prokaryotic genome sizes in Baltic sediments (3.47 Mbp) are significantly bigger than in the water column (2.96 Mbp). While benthic genomes have a higher number of functions than pelagic genomes, the smallest genomes coded for a higher number of module steps per Mbp for most of the functions irrespective of their environment. Some examples of this functions are amino acid metabolism and central carbohydrate metabolism. However, we observed that nitrogen metabolism was almost absent in pelagic genomes and was mostly present in benthic genomes. Finally, we also show that Bacteria inhabiting Baltic sediments and water column not only differ in taxonomy, but also in their metabolic potential, such as the Wood-Ljungdahl pathway or the presence of different hydrogenases. Our work shows how microbial genome size is linked to abiotic factors in the environment, metabolic potential and taxonomic identity of Bacteria and Archaea within aquatic ecosystems.
Progressive decline in the levels of six miRNAs from parents to children in autism
Authors: Rassoulzadegan Minoo , Mehmetbeyoglu Ecmel , Yilmaz Zeynep , Taheri Serpil , Ozkul Yusuf
Published: October 2022

The growing burden of a gradual increase in births of children with autism has placed it at the center of the concerns of major laboratories. We have previously detected a decrease in the levels of six miRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) in parents and their children inherited at a lower level. Here, we suggest that down-regulation of each of these six miRNAs inherited from parents contributes to the development of children with autism. We compare their levels of distribution in each family between the autistic child and siblings. We find that the distribution of levels of these miRNAs in siblings (undiagnosed as autism) is not always higher than in autistic children, but it is at varying levels. These data support a model in which autistic behavior relies on low levels of the six miRNAs expressed in children potentially associated with autistic syndrome (ASD). The intimate link between miRNAs levels and behavioral characteristics suggests possibilities for understanding the basic circuitry involved in autism and thus advancing partial knowledge of brain functions. An early diagnosis of autism helps provide children an environment conducive to their development.

Graphical abstract
The male mouse meiotic cilium emanates from the mother centriole at zygotene prior to centrosome duplication
Authors: López-Jiménez P , Pérez-Martín S , Hidalgo I , Garcia-Gonzalo FR , Page J , Gómez R
Published: October 2022

Cilia are hair-like projections of the plasma membrane with an inner microtubule skeleton known as axoneme. Motile cilia and flagella beat to displace extracellular fluids, playing important roles in the airways and reproductive system, among others. Instead, primary cilia function as cell type-dependent sensory organelles, detecting chemical, mechanical or optical signals from the extracellular environment. Cilia dysfunction is associated with genetic diseases called ciliopathies, and with some types of cancer.

Cilia have been recently identified in zebrafish gametogenesis as an important regulator of thebouquetconformation and recombination. However, there is very little information about the structure and functions of cilia in mammalian meiosis. Here we describe the presence of cilia in male mouse meiotic cells. These solitary cilia form transiently in 20% of zygotene spermatocytes and reach considerable lengths (up to 15 μm). CEP164 and CETN3 localization studies indicate that these cilia emanate from the mother centriole, prior to centrosome duplication. In addition, the study of telomeric TFR2 suggests that these cilia are not directly related to thebouquetconformation during early male mouse meiosis. Instead, based on TEX14 labeling of intercellular bridges in spermatocyte cysts, we suggest that mouse meiotic cilia may have sensory roles affecting cyst function during prophase I.
The Network Basis for the Structural Thermostability and the Functional Thermoactivity of Aldolase B
Authors: Wang Guangyu
Published: October 2022

Thermostability is important for thermoactivity of proteins including enzymes. However, it is still challenging to pinpoint the specific structural factors for different temperature thresholds to initiate their specific structural and functional perturbations. Here, graph theory was used to investigate how the temperature-dependent noncovalent interactions as identified in the structures of aldolase B and its prevalent A149P mutant could form a systematic fluidic grid-like mesh network with topological grids to regulate the structural thermostability and the functional thermoactivity. The results showed that the biggest grid may determine the temperature thresholds for the changes in their secondary and tertiary structures and specific catalytic activities. Further, a highly conserved thermostable grid may serve as an anchor to secure the flexible active site to achieve the specific thermoactivity. Finally, higher grid-based systematic thermal instability may disfavor the thermoactivity. Thus, this computational study may provide critical clues for the structural thermostability and the functional thermoactivity of proteins including enzymes.
IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and disease status
Authors: Saikumar Jayalatha AK , Ketelaar ME , Hesse L , Badi YE , Zounemat-Kermani N , Brouwer S , Dijk FN , van den Berge M , Guryev V , Sayers I , Vonk JM , Adcock IM , Koppelman GH , Nawijn MC
Published: October 2022

Background

IL-33 can activate Th2 cells after binding to the IL-1RL1/IL-1RAcP receptor. However, it is unknown whether disease or genetic make-up regulate IL33 responsiveness of Th2 cells.

Objective

We investigated whetherIL-1RL1asthma risk haplotypes or asthma status influence IL-33-induced Th2 transcriptomic responsesin vitro.

Methods

CD4+T cells from 16 asthma patients and matched controls, stratified forIL-1RL1haplotype, were differentiated into Th2 effector cells, and re-stimulated in the presence or absence of IL-33, followed by RNA-sequencing and differential gene expression analysis. Association of IL-33-induced gene signatures with clinical parameters was tested in U-BIOPRED sputum transcriptomic data.

Results

Presence of IL-33 during Th2 cell re-stimulation results in extensive changes in gene expression, affecting a large proportion of the activated Th2 cell transcriptome. IL-33 induced more genes in Th2 cells from donors with asthma than in controls. However, the IL-33 effects were strongest in Th2 cells carrying theIL-1RL1risk haplotype, as evidenced by a significantly increased effect size compared to controls. A gene signature of IL-33 induced genes in Th2 cells showed a strong positive correlation with macrophage counts and pauci-granulocytic asthma in sputum transcriptomic data from the U-BIOPRED study.

Conclusion

The riskIL-1RL1haplotype strongly increases the sensitivity of Th2 effector cell for IL-33-mediated regulation of gene expression, while asthma status has an independent effect. The IL-33 gene signature was not associated with type-2 high or eosinophilic asthma in sputum transcriptomic data from U-BIOPRED.

Clinical Outcome

Cellular sensitivity to IL-33 depends on genetic makeup and asthma disease status.

Capsule summary

IL-33 strongly alters gene expression of activated Th2 cells, dependent on asthma disease status andIL-1RL1risk haplotype. IL-33 driven gene signature in sputum transcriptomic data identifies pauci-granulocytic asthma.
High-latitude marginal reefs support fewer but bigger corals than their tropical counterparts
Authors: Chong Fiona , Sommer Brigitte , Stant Georgia , Verano Nina , Cant James , Lachs Liam , Johnson Magnus L , Parsons Daniel R , Pandolfi John M , Salguero-Gómez Roberto , Spencer Matthew , Beger Maria
Published: October 2022

Aim

Despite the awareness that climate change impacts are typically detrimental to tropical coral reefs, the effect of increasing environmental stress and variability on the population size structure of coral species remains poorly understood. This gap in knowledge limits our ability to effectively conserve coral reef ecosystems because size specific dynamics are rarely incorporated. Our aim is to quantify variation in the size structure of coral populations along a tropical-to-subtropical environmental gradient.

Location

20 coral populations along a latitudinal gradient on the east coast of Australia (∼23°S to 30°S).

Time Period

Between 2010 and 2018.

Major taxa studied

Scleractinian corals.

Methods

We apply two methods to quantify the relationship between environmental covariates and coral population size structure along a latitudinal environmental gradient. First, we use linear regression with summary statistics, such as median size as response variables; a method frequently favoured by ecologists. The second method is compositional functional regression, a novel method using entire size-frequency distributions as response variables. We then predict coral population size structure with increasing environmental stress and variability.

Results

Compared to tropical reefs, we find fewer but larger coral colonies in marginal reefs, where environmental conditions are more variable and stressful for corals in the former. Our model predicts that coral populations may become gradually dominated by larger colonies (> 148 cm2) with increasing environmental stress.

Main conclusions

With increasing environmental stress and variability, we can expect shifts in coral population size structure towards more larger colonies. Fewer but bigger corals suggest low survival, slow growth, and poor recruitment. This finding is concerning for the future of coral reefs as it implies populations may have low recovery potential from disturbances. We highlight the importance and usefulness of continuously monitoring changes to population structure over large spatial scales.

Data availability

Data is supplied in the supplementary information, or upon request. Once accepted for publication it will be made openly available on Dryad.
TEINet: a deep learning framework for prediction of TCR-epitope binding specificity
Authors: Jiang Yuepeng , Huo Miaozhe , Li Shuai Cheng
Published: October 2022

The adaptive immune response to foreign antigens is initiated by T-cell receptor (TCR) recognition on the antigens. Recent experimental advances have enabled the generation of a large amount of TCR data and their cognate antigenic targets, allowing machine learning models to predict the binding specificity of TCRs. In this work, we present TEINet, a deep learning framework that utilizes transfer learning to address this prediction problem. TEINet employs two separately trained encoders to transform TCR and epitope sequences into numerical vectors, which are subsequently fed into a fully connected neural network to predict their binding specificities. A major challenge for binding specificity prediction is the lack of a unified approach to sample negative data. Here, we first assess the current negative sampling approaches comprehensively and suggest that theUnified Epitopeis the most suitable one. Subsequently, we compare TEINet with three baseline methods and observe that TEINet achieves an AUROC of 0.760, which outperforms baseline methods by 6.4-26%. Furthermore, we investigate the impacts of the pretraining step and notice that excessive pretraining can adversely affect model performance. Our results and analysis show that TEINet can make an accurate prediction using only the TCR sequence (CDR3β) and the epitope sequence, providing novel insights to understand the interactions between TCRs and epitopes. TEINet is available athttps://github.com/jiangdada1221/TEINet.
Tuning Strand Displacement Kinetics Enables Programmable ZTP Riboswitch Dynamic Rangein vivo
Authors: Bushhouse David Z. , Lucks Julius B.
Published: October 2022

Recent work has shown that transcriptional riboswitches function through internal strand displacement mechanisms that guide the formation of alternative structures which drive regulatory outcomes. Here we sought to investigate this phenomenon using theClostridium beijerinckii pflZTP riboswitch as a model system. Using functional mutagenesis within vivogene expression assays inE. coli, we show that mutations designed to slow strand displacement of the expression platform enable precise tuning of riboswitch dynamic range (2.4–34-fold), depending on the type of kinetic barrier introduced, and the position of the barrier relative to the strand displacement nucleation site. We also show that expression platforms from a range of differentClostridiumZTP riboswitches contain sequences that impose these barriers to affect dynamic range in these different contexts. Finally, we use sequence design to flip the regulatory logic of the riboswitch to create a transcriptional OFF-switch, and show that the same barriers to strand displacement tune dynamic range in this synthetic context. Together, our findings further elucidate how strand displacement can be manipulated to alter the riboswitch decision landscape, suggesting that this could be a mechanism by which evolution tunes riboswitch sequence, and providing an approach to optimize synthetic riboswitches for biotechnology applications.
Birds multiplex spectral and temporal visual information via retinal On- and Off-channels
Authors: Seifert Marvin , Roberts Paul A , Kafetzis George , Osorio Daniel , Baden Tom
Published: October 2022

Early retinal circuits divide incoming visual information into functionally opposite elementary signals: On and Off, transient and sustained, chromatic and achromatic. Together these signals can yield an efficient representation of the scene for transmission to the brain via the optic nerve. For example, primate On- and Off-parasol circuits are transient, while On- and Off-midget circuits are sustained. But this long-standing interpretation of retinal function is based on mammals, and it is unclear whether this functional arrangement is common to all vertebrates. Here we show that poultry chicks use a fundamentally different strategy to communicate information from the eye to the brain. Rather than using functionally opposite pairs of retinal output channels, chicks encode the polarity, timing, and spectral composition of visual stimuli in a highly correlated manner: fast achromatic information is encoded by Off-circuits, and slow chromatic information overwhelmingly by On-circuits. Moreover, most retinal output channels combine On- and Off-circuits to simultaneously encode, or multiplex, both achromatic and chromatic information.

Our results from birds conform to evidence from fish, amphibians, and reptiles which retain the full ancestral complement of four spectral types of cone photoreceptors. By contrast, mammals lost two of these cones early in their evolution, and we posit that this loss drove a radical simplification and reorganisation of retinal circuits, while birds and many other extant non-mammalian lineages retain the ancestral strategy for retinal image processing.

HIGHLIGHTS

First large-scale survey of visual functions in an avian retina

Off-circuits are fast and achromatic, On-circuits are slow and chromatic

Most avian RGCs are OnOff and encode both types of information

Colour and greyscale information can be decoded based on the kinetics
Infralimbic projections to the nucleus accumbens shell and amygdala regulate the encoding of cocaine extinction learning
Authors: Nett Kelle E. , Zimbelman Alexa R. , McGregor Matthew S. , Vera Vanessa Alizo , Harris Molly R. , LaLumiere Ryan T.
Published: October 2022

Prior evidence indicates that the infralimbic cortex (IL) mediates the ongoing inhibition of cocaine seeking following self-administration and extinction training in rats, specifically through projections to the nucleus accumbens (NA) shell. Our own data indicate that IL activity immediately following an unreinforced lever press is critical for encoding the extinction contingencies in such procedures. Whether extinction encoding requires activity in the IL exclusively or also activity in its outputs, such as those to the NAshell and amygdala, is unknown. To address this issue, we used a closed-loop optogenetic approach in female and male Sprague-Dawley rats to silence IL-NAshell or IL-amygdala activity following an unreinforced lever press during extinction training. Optical illumination (20 s) was given either immediately after a lever press or following a 20 s delay. IL-NAshell inhibition immediately following an unreinforced lever press increased lever pressing during extinction training and impaired retention of extinction learning, as assessed during subsequent extinction sessions without optical inhibition. Likewise, IL-amygdala inhibition given in the same manner impaired extinction retention during sessions without inhibition. Control experiments indicate that critical encoding of extinction learning does not require activity in these pathways beyond the initial 20 s post-lever press period, as delayed IL-NAshell and IL-amygdala inhibition had no effect on extinction learning. These results suggest that a larger network extending from the IL to the NAshell and amygdala is involved in encoding extinction contingencies following cocaine self-administration.

Significance Statement

Infralimbic cortex (IL) activity following an unreinforced lever press during extinction learning encodes the extinction of cocaine-seeking behavior. However, the larger circuitry controlling such encoding has not been investigated. Using closed-loop optogenetic pathway targeting, we found that inhibition of IL projections to the nucleus accumbens (NA) shell and to the amygdala impaired the extinction of cocaine seeking. Importantly, these effects were only observed when activity was disrupted during the first 20 s post-lever press and not when given following a 20 s delay. These findings suggest that successful cocaine extinction encoding requires activity across a larger circuit beyond simply inputs to the IL.
Single Cell lineage Tracing Identifies Cancer Testis Antigens as Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Afeworki Yohannes , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: October 2022

Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where dynamic regulation of key transcription factors can drive multiple populations of phenotypically different cells which contribute differentially to tumor dynamics. This tumor is characterized by a very low 2-year survival rate, high rates of metastasis, and rapid acquisition of chemoresistance. The heterogeneous nature of this tumor makes it difficult to study and to treat, as it is not clear how or when this heterogeneity arises. Here we describe temporal, single-cell analysis of SCLC to investigate tumor initiation and chemoresistance in both SCLC xenografts andin situSCLC mouse models. We identify an early population of tumor cells with high expression of AP-1 network genes that are critical for tumor growth. Furthermore, we have identified and validated the cancer testis antigens (CTAs) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have successfully been targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC.
Inherent envelope fluctuations in forward masking: Effects of age and hearing loss
Authors: Brennan Marc A. , Svec Adam , Farhadi Afagh , Maxwell Braden , Carney Laurel H.
Published: October 2022

Forward masking is generally greater for Gaussian noise (GN) than for low-fluctuation noise maskers, i.e., GN disruption. Because the minimal hearing loss that is associated with older age may affect GN disruption differently than more significant hearing loss, the current study explored the contribution of minimal hearing loss associated with older age to GN disruption. GN disruption was measured using three masker-signal delays (25, 75, and 150 ms) for three adult groups: younger participants with normal hearing, older participants with minimal hearing loss, and older participants with sensorineural hearing loss. The role of underlying mechanisms was tested using a computational model for midbrain neurons. The primary result suggests that older listeners with mild threshold elevations that typically occur with age may be more susceptible to the deleterious effects of masker-envelope fluctuations than younger listeners with normal hearing. Results from the computational model indicate that there may be a larger influence of efferent feedback and saturation of inner hair cells on forward masking and GN disruption than previously thought.
Reduced oriens-lacunosum/moleculare (OLM) cell model identifies biophysical current balances forin vivotheta frequency spiking resonance
Authors: Sun Zhenyang , Crompton David , Lankarany Milad , Skinner Frances K
Published: October 2022

Conductance-based models have played an important role in the development of modern neuroscience. These mathematical models are powerful “tools” that enable theoretical explorations in experimentally untenable situations, and can lead to the development of novel hypotheses and predictions. With advances in cell imaging and computational power, multi-compartment models with morphological accuracy are becoming common practice. However, as more biological details are added, they make extensive explorations and analyses more challenging largely due to their huge computational expense. Here, we focus on oriens-lacunosum/moleculare (OLM) cell models. OLM cells can contribute to functionally relevant theta rhythms in the hippocampus by virtue of their ability to express spiking resonance at theta frequencies, but what characteristics underlie this is far from clear. We converted a previously developed detailed multi-compartment OLM cell model into a reduced single compartment model that retained biophysical fidelity with its underlying ion currents. We showed that the reduced OLM cell model can capture complex output that includes spiking resonance inin vivo-like scenarios as previously obtained with the multi-compartment model. Using the reduced model, we were able to greatly expand ourin vivo-like scenarios. Applying spike-triggered average analyses, we were thus able to to determine that it is a combination of hyperpolarization-activated cation and muscarinic type potassium currents that specifically allow OLM cells to exhibit spiking resonance at theta frequencies. Further, we developed a robust Kalman Filtering (KF) method to estimate parameters of the reduced model in real-time. We showed that it may be possible to directly estimate conductance parameters from experiments since this KF method can reliably extract parameter values from model voltage recordings. Overall, our work showcases how the contribution of cellular biophysical current details could be determined and assessed for spiking resonance. As well, our work shows that it may be possible to directly extract these parameters from current clamp voltage recordings.
Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner
Authors: Yarur Hector E. , Casello Sanne M. , Tsai Valerie , Enriquez-Traba Juan , Kore Rufina , Wang Huikun , Arenivar Miguel , Tejeda Hugo A.
Published: October 2022

The medial prefrontal cortex (mPFC) controls emotional behaviors and cognition via connections with limbic excitatory afferents that engage various intra-mPFC inhibitory motifs The mPFC dynorphin (Dyn) / kappa-opioid receptor (KOR) system regulates affect and cognition and is implicated in neuropsychiatric disorders. However, it’s unclear how neuropeptides in the mPFC, including the Dyn / KOR system, control excitatory and inhibitory circuit motifs integral in information processing. Here, we provide a circuit-based framework wherein selective KOR expression in mPFC afferents or within mPFC feedforward and feedback inhibitory circuits gates how distinct limbic afferent inputs control mPFC neurons. Dyn/KOR signaling directly decreases the ability of KOR-expressing afferent inputs to drive mPFC cell activity. Dyn/KOR signaling also suppresses afferent-driven recruitment of inhibitory sub-networks via several mechanisms, disinhibiting KOR-negative excitatory afferent control of mPFC ensembles. Thus, the Dyn/KOR system toggles which afferent input controls mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function.

Highlight

Pathway-specific KOR expression confers selective filtering of mPFC afferents by dynorphin

Endogenous dynorphin release gates KOR-expressing inputs to both dynorphin-expressing and lacking mPFC neurons

Dynorphin / KOR modulation reveals parallel channels within amygdalo-cortical and cortical-cortical circuits

Dynorphin disinhibits mPFC pyramidal neurons via KOR-mediated suppression of distinct inhibitory circuit motifs that preferentially impact SST-mediated feedforward inhibition

Dynorphin / KOR signaling biases afferent control of mPFC principal cells away from KOR-positive and towards KOR-negative afferent inputs
Gammaretroviruses, novel viruses and pathogenic bacteria in Australian bats with neurological signs, pneumonia and skin lesions
Authors: Van Brussel Kate , Mahar Jackie E. , Hall Jane , Bender Hannah , Ortiz-Baez Ayda Susana , Chang Wei-Shan , Holmes Edward C. , Rose Karrie
Published: October 2022

More than 70 bat species are found in mainland Australia, including five species of megabat from a single genus (family Pteropodidae) and more than 65 species representing six families of microbats. The conservation status of these animals varies from least concern to endangered. Research directed at evaluating the impact of microorganisms on bat health has been generally restricted to surveillance for specific pathogens. While most of the current bat virome studies focus on sampling apparently healthy individuals, little is known about the infectome of diseased bats. We performed traditional diagnostic techniques and metatranscriptomic sequencing on tissue samples from 43 individual bats, comprising three flying fox and two microbat species experiencing a range of disease syndromes, including mass mortality, neurological signs, pneumonia and skin lesions. We identified reads from four pathogenic bacteria and two pathogenic fungi, includingPseudomonas aeruginosain lung samples from flying foxes with peracute pneumonia, and with dermatitis. Of note, we identified the recently discovered Hervey pteropid gammaretrovirus, with evidence of replication consistent with an exogenous virus, in a bat with lymphoid leukemia. In addition, one novel picornavirus, at least three novel astroviruses and bat pegiviruses were identified. We suggest that the most likely cause of peracute lung disease wasPseudomonas aeruginosa, while we suspect Hervey pteropid gammaretrovirus was associated with lymphoid leukemia. It is possible that any of the novel astroviruses could have contributed to the presentation of skin lesions in individual microbats. This study highlights the importance of studying the role of microorganisms in bat health and conservation.

IMPORTANCE

Bats have been implicated as reservoir hosts for zoonotic disease of concern, however, the burden of microorganism including viruses on bat health and disease is understudied. Here we incorporated veterinary diagnostics and RNA sequencing to identify the presence of microbes and viruses with possible pathogenic status in Australian bats with varying disease presentations. These techniques were able to effectively identify and describe several pathogenic species of bacteria and fungi in addition to known and novel viruses. This study emphasises the importance of screening pathogens in cases of bat mortality for the conservation of this diverse order.
Patterns in Medication Use for Treatment of Depression in Autistic Spectrum Disorder
Authors: Argonis Riley A. , Pedapati Ernest V. , Dominick Kelli C. , Harris Katherine , Lamy Martine , Fosdick Cara , Schmitt Lauren , Shaffer Rebecca C. , Smith Elizabeth , Will Meredith , McDougle Christopher J. , Erickson Craig A.
Published: October 2022

Depression impacts many individuals with autism spectrum disorder (ASD), carrying increased risk of functional impairment, hospitalization, and suicide. Prescribing medication to target depression in patients with ASD occurs despite limited available systematic data describing medication management of depression in this population. Drawing from a large clinical database describing the prescribing practices in patients with ASD, we identified 170 individuals with ASD (mean age 16.2±8.7 years old) who received medication targeting symptoms of depression. We report prescribing rates for specific drugs, drug treatment duration, and reasons for drug discontinuation when applicable. Sertraline, mirtazapine, and fluoxetine were the three most commonly prescribed medications to treat comorbid depression for this patient population. Among 247 drug starts, 121 (49%) drug treatments were continued at the final reviewed follow-up visit (average treatment duration of ±0.72 years). The most common reason for discontinuation across all medications prescribed was loss of or lack of effectiveness. This study raises concern that standard of care pharmacological treatments for depression in individuals with ASD may be less effective than in neurotypical populations. There remains a need to develop effective interventions for depression specifically tailored to the needs of individuals with ASD.