bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter-animal variability in activity phase is constrained by synaptic dynamics in an oscillatory network
Authors: Anwar Haroon , Martinez Diana , Bucher Dirk , Nadim Farzan 
Published: January 2022

AbstractThe levels of voltage-gated and synaptic currents in the same neuron type can vary substantially across individuals. Yet, the phase relationships between neurons in oscillatory circuits are often maintained, even in the face of varying oscillation frequencies. We examined whether synaptic and intrinsic currents are matched to maintain constant activity phases across preparations, using the lateral pyloric (LP) neuron of the stomatogastric ganglion of the crab, Cancer borealis. LP produces stable oscillatory bursts upon release from inhibition, with an onset phase that is independent of oscillation frequency. We quantified the parameters that define the shape of the synaptic current inputs across preparations and found no linear correlations with voltage-gated currents. However, several synaptic parameters were correlated with oscillation period and burst onset phase, suggesting they may play a role in phase maintenance. We used the dynamic clamp to apply artificial synaptic inputs and found that those synaptic parameters correlated with phase and period were ineffective in influencing burst onset. Instead, parameters that showed the least variability across preparations had the greatest influence. Thus, parameters that influence circuit phasing are constrained across individuals, while those that have little effect simply co-vary with phase and frequency.
An organoid CRISPRi screen revealed that SOX9 primes human fetal lung tip progenitors to receive WNT and RTK signals
Authors: Sun Dawei , Batlle Oriol Llora , van den Ameele Jelle , Thomas John C. , He Peng , Lim Kyungtae , Tang Walfred , Xu Chufan , Meyer Kerstin B. , Teichmann Sarah A. , Marioni John C. , Jackson Stephen P. , Brand Andrea H. , Rawlins Emma L. 
Published: January 2022

ABSTRACTThe balance between self-renewal and differentiation in human fetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID we place SOX9 at the centre of a transcriptional network which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new approach for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.HighlightsA pooled CRISPRi screen in human fetal lung organoids identified transcription factors controlling progenitor cell self-renewal.SOX9 promotes tip progenitor cell proliferation and supresses precocious airway differentiation.Targeted DamID (TaDa) identified SOX9 direct binding targets, revealing that SOX9 lies at the intersection of WNT and RTK signalling.SOX9 and ETVs co-regulate the human fetal lung progenitor self-renewal programme.
ArabidopsisCONSERVED BINDING OF EIF4E1 negatively regulates the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D
Authors: George Jeoffrey , Stegmann Martin , Monaghan Jacqueline , Zipfel Cyril 
Published: January 2022

SummaryCell-surface pattern recognition receptors sense invading pathogens by binding microbial or endogenous elicitors to activate plant immunity. These responses are under tight control to avoid excessive or untimely activation of cellular responses, which may otherwise be detrimental to host cells. How this fine-tuning is accomplished is an area of active study. We previously described a suppressor screen that identifiedArabidopsis thalianamutants with regained immune signaling in the immunodeficient genetic backgroundbak1-5, which we namedmodifier of bak1-5(mob)mutants. Here, we report thatbak1-5 mob7restores elicitor-induced signaling. Using a combination of map-based cloning and whole-genome resequencing, we identifiedMOB7asCONSERVED BINDING OF EIF4E1(CBE1), a plant-specific protein that interacts with highly-conserved eukaryotic translation initiation factor eIF4E1. Our data demonstrate that CBE1 regulate the accumulation of RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD), the NADPH oxidase responsible for elicitor-induced apoplast reactive oxygen species (ROS) production. Furthermore, several mRNA decapping and translation initiation factors co-localize with CBE1 and similarly regulate immune signaling. This study thus identifies a novel regulator of immune signaling and provides new insights into ROS regulation, and more generally translational control during plant stress responses.
Knockout of OsSWEET15 impaired rice embryo formation and seed-setting
Authors: Tang Zhenjia , Yang Jing , Bao Shuhui , Hu Zhi , Xia Huihuang , Ma Lai , Zheng Qingsong , Yang Fang , Zhang Dechun , Wang Tai , Sun Shubin , Hu Yibing 
Published: January 2022

Abstractwe show that the knockout of a sugar transporter gene OsSWEET15 led to a significant drop in rice fertility because near half of the knockout mutant spikelets bore blighted or empty grains. The rest spikelets bore fertile grains with slightly reduced weight. Notably, the ovaries in the blighted grains of the ossweet15 mutants expanded after flowering but terminated development before the endosperm cellularization stage and aborted subsequently. GUS and GFP representing OsSWEET15 expression showed that the protein was strongly expressed in the embryo surrounding region (ESR) which was supposed to supply nutrients for the embryo development. These results joined with the protein’s sucrose transport capacity and plasma membrane localization suggest that OsSWEET15 plays a prominent role during the caryopsis formation stage probably by releasing sucrose from the ESR to support the embryo development. By contrast, the empty grains were probably caused by the reduced pollen viability of the ossweet15 mutants. Investigation of the makeup of ossweet11 mutant grains revealed similar phenotypes that were observed in the ossweet15 mutants. These results indicate that both OsSWETT15 and OsSWEET11 play important and similar roles during rice pollen development, caryopsis formation, and seed-setting in addition to their function in seed-filling that was demonstrated previously.
Discovering highly potent antimicrobial peptides with deep generative model HydrAMP
Authors: Szymczak Paulina , Możejko Marcin , Grzegorzek Tomasz , Jurczak Radosław , Bauer Marta , Neubauer Damian , Sikora Karol , Michalski Michał , Sroka Jacek , Setny Piotr , Kamysz Wojciech , Szczurek Ewa 
Published: January 2022

AbstractAntimicrobial peptides emerge as compounds that can alleviate the global health hazard of antimicrobial resistance, prompting a need for novel computational approaches to peptide generation. Here, we propose HydrAMP, a conditional variational autoencoder that learns lower-dimensional, continuous representation of peptides and captures their antimicrobial properties. The model disentangles the learnt representation of a peptide from its antimicrobial conditions and leverages parameter-controlled creativity. HydrAMP is the first model that is directly optimized for diverse tasks, including unconstrained and analogue generation and outperforms other approaches in these tasks. An additional preselection procedure based on ranking of generated peptides and molecular dynamics simulations increases experimental validation rate. Wet-lab experiments on five bacterial strains confirm high activity of nine peptides generated as analogues of clinically relevant prototypes, as well as six analogues of an inactive peptide. HydrAMP enables generation of diverse and potent peptides, making a step towards resolving the antimicrobial resistance crisis.
Multiscale Entropy Analysis of Retinal Signals Reveals Reduced Complexity in a Mouse Model of Alzheimer’s Disease
Authors: Araya-Arriagada Joaquín , Garay Sebastián , Rojas Cristóbal , Duran-Aniotz Claudia , Palacios Adrián G. , Chacón Max , Medina Leonel E. 
Published: January 2022

ABSTRACTAlzheimer’s disease (AD) is one of the most significant health challenges of our time, affecting a growing number of the elderly population. In recent years, the retina has received increased attention as a candidate for AD biomarkers since it appears to manifest the pathological signatures of the disease. Therefore, its electrical activity may hint at AD-related physiological changes. However, it is unclear how AD affects retinal electrophysiology and what tools are more appropriate to detect these possible changes. In this study, we used entropy tools to estimate the complexity of the dynamics of healthy and diseased retinas at different ages. We recorded microelectroretinogram responses to visual stimuli of different nature from retinas of young and adult, wild-type and 5xFAD –an animal model of AD– mice. To estimate the complexity of signals, we used the multiscale entropy approach, which calculates the entropy at several time scales using a coarse graining procedure. We found that young retinas had more complex responses to different visual stimuli. Further, the responses of young, wild-type retinas to natural-like stimuli exhibited significantly higher complexity than young, 5xFAD retinas. Our findings support a theory of complexity-loss with aging and disease and can have significant implications for early AD diagnosis.
DNA uptake by cell wall-deficient bacteria reveals a putative ancient macromolecule uptake mechanism
Authors: Kapteijn Renée , Shitut Shraddha , Aschmann Dennis , Zhang Le , de Beer Marit , Daviran Deniz , Roverts Rona , Akiva Anat , van Wezel Gilles P. , Kros Alexander , Claessen Dennis 
Published: January 2022

SUMMARYHorizontal gene transfer in bacteria is widely believed to occur via three main mechanisms: conjugation, transduction and transformation. These mechanisms facilitate the passage of DNA across the protective cell wall using sophisticated machinery. We present here a new mechanism of DNA uptake that is independent of canonical DNA uptake machineries and is used by bacteria that live without a cell wall. We show that the cell wall-deficient bacteria engulf extracellular material, whereby intracellular vesicles are formed, and DNA is internalized. This mechanism is not specific to DNA, and allows uptake of other macromolecules and even 125 nm lipid nanoparticles (LNPs). Uptake was prevented by molecules known to inhibit eukaryotic endocytosis, suggesting this to be an energy-dependent process. Given that cell wall-deficient bacteria are considered a model for early life forms, our work provides a possible mechanism for primordial cells to acquire new genetic material or food before invention of the bacterial cell wall.
Innate immune cell response to host-parasite interaction in a human intestinal tissue microphysiological system
Authors: Humayun Mouhita , Ayuso Jose M , Park Keon Young , Di Genova Bruno Martorelli , Skala Melissa , Kerr Sheena C , Knoll Laura J. , Beebe David J. 
Published: January 2022

AbstractProtozoan parasites that infect humans are widespread, and lead to varied clinical manifestations, including life-threatening illnesses in immunocompromised individuals. Animal models have provided insight into innate immunity against parasitic infections, however, species-specific differences and complexity of innate immune responses make translation to humans challenging. Thus, there is a need for novelin vitrosystems that can elucidate mechanisms of immune control and parasite dissemination. We have developed a human microphysiological system of intestinal tissue to evaluate parasite-immune-specific interactions during infection, which integrates primary intestinal epithelial cells and immune cells to investigate the role of innate immune cells during epithelial infection by the protozoan parasite, Toxoplasma gondii, which affects billions of people worldwide. Our data indicate that epithelial-infection by parasites stimulates a broad range of effector functions in neutrophils and NK cell-mediated cytokine production that play immunomodulatory roles, demonstrating the potential of our system for advancing the study of human-parasite interactions.TeaserNovel engineered model of human intestinal tissue for study of dissemination and immune control of parasitic infections.
Inflammasome mediated neuronal-microglial crosstalk: a therapeutic substrate for the familialC9orf72variant of the frontotemporal dementia/amyotrophic lateral sclerosis
Authors: Trageser Kyle J. , Smith Chad , Yang Eun-Jeong , Iban-Arias Ruth , Oguchi Tatsunori , Sebastian-Valverde Maria , Iqbal Umar Haris , Wu Henry , Estill Molly , Rahim Md Al , Raval Urdhva , Herman Francis J , Zhang Yong Jie , Petrucelli Leonard , Pasinetti Giulio Maria 
Published: January 2022

AbstractIntronic G4C2hexanucleotide repeat expansions (HRE) ofC9orf72are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2HREs inC9orf72undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly(GR) model ofC9orf72FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model ofC9orf72FTD/ALS we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1β and upregulation ofCxcl10in the brain ofC9orf72FTD/ALS mice. Excitingly, we find that genetic ablation ofNlrp3significantly improved survival, protected behavioral deficits and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in theC9orf72variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.
Design in the DARK: Learning Deep Generative Models for De Novo Protein Design
Authors: Moffat Lewis , Kandathil Shaun M. , Jones David T. 
Published: January 2022

AbstractThe design of novel protein sequences is providing paths towards the development of novel therapeutics and materials. At the forefront is the challenging field of de novo protein design, which looks to design protein sequences unlike those found in nature using general design methodologies. In this work, we develop a tool for de novo design, based on a deep generative sequence model, that rapidly samples novel protein sequences with diverse and ordered structures. To build this tool we develop a framework, called DARK, that trains the underlying generative model on an iteratively expanding set of synthetic sequences. The resulting model generalizes where models trained on natural sequences struggle and greatly improves on the efficiency of comparable sampling-based approaches. We further show how it can generate high quality candidates for de novo design problems and aid in the development of further novel design methods, in all, providing another step, amongst others, towards truly automated and intelligent protein design.
NGSEP 4: Efficient and Accurate Identification of Orthogroups and Whole-Genome Alignment
Authors: Tello Daniel , Gonzalez-Garcia Laura Natalia , Gomez Jorge , Zuluaga-Monares Juan Camilo , Garcia Rogelio , Angel Ricardo , Mahecha Daniel , Duarte Erick , del Rosario Leon Maria , Reyes Fernando , Escobar-Velásquez Camilo , Linares-Vásquez Mario , Cardozo Nicolas , Duitama Jorge 
Published: January 2022

ABSTRACTWhole-genome alignment allows researchers to understand the genomic structure and variations among the genomes. Approaches based on direct pairwise comparisons of DNA sequences require large computational capacities. As a consequence, pipelines combining tools for orthologous gene identification and synteny have been developed. In this manuscript, we present the latest functionalities implemented in NGSEP 4, to identify orthogroups and perform whole genome alignments. NGSEP implements functionalities for identification of clusters of homologus genes, synteny analysis and whole genome alignment, and visualization. Our results showed that the NGSEP algorithm for ortholog identification has competitive accuracy and better efficiency in comparison to commonly used tools. The implementation also includes a visualization of the whole genome alignment based on synteny of the orthogroups that were identified, and a reconstruction of the pangenome based on frequencies of the orthogroups among the genomes. Finally, our software includes a new graphical user interface. We expect that these new developments will be very useful for several studies in evolutionary biology and population genomics.
Macrophages regulate gastrointestinal motility through complement component 1q
Authors: Pendse Mihir , Li Yun , Salinas Cristine N. , Quinn Gabriella , Vo Nguyen , Propheter Daniel C. , Dende Chaitanya , Crofts Alexander A. , Koo Eugene , Hassell Brian , Ruhn Kelly A. , Raj Prithvi , Obata Yuuki , Hooper Lora V. 
Published: January 2022

ABSTRACTPeristaltic movement of the intestine propels food down the length of the gastrointestinal tract to promote nutrient absorption. Interactions between intestinal macrophages and the enteric nervous system regulate gastrointestinal motility, yet we have an incomplete understanding of the molecular mediators of this crosstalk. Here we identify complement component 1q (C1q) as a macrophage product that regulates gut motility. Macrophages were the predominant source of C1q in the mouse intestine and most extraintestinal tissues. Although C1q mediates complement-mediated killing of bacteria in the bloodstream, we found that C1q was not essential for immune defense of the intestine. Instead, C1q-expressing macrophages were localized to the intestinal submucosal plexus where they closely associated with enteric neurons and expressed surface markers characteristic of nerve-adjacent macrophages in other tissues. Mice with a macrophage-specific deletion ofC1qashowed changes in enteric neuronal gene expression, increased peristaltic activity, and accelerated intestinal transit. Our findings identify C1q as a key regulator of gastrointestinal motility and provide enhanced insight into the crosstalk between macrophages and the enteric nervous system.
Selective Ablation of 3’ RNA ends and Processive RTs Facilitate Direct cDNA Sequencing of Full-length Host Cell and Viral Transcripts
Authors: Gallardo Christian M. , Nguyen Anh-Viet T. , Routh Andrew L. , Torbett Bruce E. 
Published: January 2022

AbstractAlternative splicing (AS) is necessary for viral proliferation in host cells and a critical regulatory component of viral gene expression. Conventional RNA-seq approaches provide incomplete coverage of AS due to their short read-lengths and are susceptible to biases and artifacts introduced in prevailing library preparation methodologies. Moreover, viral splicing studies are often conducted separately from host cell transcriptome analysis, precluding an assessment of the viral manipulation of host splicing machinery. To address current limitations, we developed a quantitative full-length direct cDNA sequencing strategy to simultaneously profile viral and host cell transcripts. This nanopore-based approach couples processive reverse transcriptases with a novel one-step chemical ablation of 3’ RNA ends (termed CASPR) which decreases ribosomal RNA reads and enriches for poly-adenylated coding sequences. We extensively validate our approach using synthetic reference transcripts and show CASPR doubles the breadth of coverage per transcript and increases detection of long transcripts (>4kb), while being functionally equivalent to PolyA+ selection for transcript quantification. We used our approach to interrogate host cell and HIV-1 transcript dynamics during viral reactivation and identified novel putative HIV-1 host factors containing exon skipping or novel intron retentions and delineated the HIV-1 transcriptional state associated with these differentially regulated host factors.
Integrated pretraining with evolutionary information to improve RNA secondary structure prediction
Authors: Yan Zichao , Hamilton William , Blanchette Mathieu 
Published: January 2022

AbstractRNA secondary structure prediction is a fundamental task in computational and molecular biology. While machine learning approaches in this area have been shown to improve upon traditional RNA folding algorithms, performance remains limited for several reasons such as the small number of experimentally determined RNA structures and suboptimal use of evolutionary information. To address these challenges, we introduce a practical and effective pretraining strategy that enables learning from a larger set of RNA sequences with computationally predicted structures and in the meantime, tapping into the rich evolutionary information available in databases such as Rfam. Coupled with a flexible and scalable neural architecture that can navigate different learning scenarios while providing ease of integrating evolutionary information, our approach significantly improves upon state-of-the-art across a range of benchmarks, including both single sequence and alignment based structure prediction tasks, with particularly notable benefits on new, less well-studied RNA families. Our source code, data and packaged RNA secondary structure prediction software RSSMFold can be accessed at https://github.com/HarveyYan/RSSMFold.