bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification ofYAB11-NGAL1controlling leaf serrations through enhanced genome-wide association studies ofPopulus
Authors: Liu Peng , Bu Chenhao , Chen Panfei , Zhang Deqiang , Song Yuepeng
Published: April 2022

Leaf margins are complex plant morphological features and contribute to the diversity of leaf shapes which effect on plant structure, yield and adaptation. Although several regulators of leaf margins have been identified, the genetic basis of natural variation therein has not been fully elucidated. We first profiled two distinct types (serration and smooth) of leaf morphology using the persistent homology mathematical framework (PHMF) in poplar. Combined genome-wide association studies (GWAS) and expression quantitative trait nucleotide (eQTN) mapping to create a module of leaf morphology controlling using data fromPopulus tomentosaandP. simoniiassociation population, respectively. Natural variation of leaf margins is associated with transcript abundances ofYABBY11(YAB11) in poplar. InP. tomentosa,PtoYAB11carries premature stop codon (PtoYAB11PSC) resulting in lost its positive regulation inPtoNGAL-1,PtoRBCL,PtoATPA,PtoATPE, andPtoPSBB. Overexpression ofPtoYAB11PSCserrated leaf margin, enlarged leaves, promoted photosynthesis and increased biomass. Overexpression ofPsiYAB11inP. tomentosacould rescue leaf margin serration and increase stomatal density and light damage repair ability. In poplar, YAB11-NGAL1is sensitive to environmental conditions and play positive regulator of leaf margin serration. It might be important regulator which bridge environment signaling to leaf morphological plasticity.
Hairy root transformation system as a tool for CRISPR/Cas9-directed genome editing in oilseed rape (Brassica napus)
Authors: Jedličková Veronika , Mácová Kateřina , Štefková Marie , Butula Jan , Staveníková Jana , Sedláček Marek , Robert Hélène S.
Published: April 2022

Our study examined the mutation efficiency of the CRISPR/Cas9 method for tryptophan aminotransferase BnaTAA1 genes involved in the auxin biosynthesis pathway. We made nine CRISPR/Cas9 constructs with various promoters driving the expression of a Cas9 from Staphylococcus aureus (SaCas9) or a plant codon-optimized Streptococcus pyogenes Cas9 (pcoCas9). We developed a fast and efficient system for evaluating the variety and frequency of mutations caused by each construct using Brassica napus hairy roots. We showed that pcoCas9 is more efficient in mutating the targeted loci than SaCas9 and the presence of the NLS signal enhanced the chance of mutagenesis by 25%. The mutations were studied further in regenerated lines, and we determined the BnaTAA1 gene expression and heritability of the gene modifications in transgenic plants. Hairy root transformation combined with CRISPR/Cas9-mediated gene editing represents a fast and straightforward system for studying target gene function in the important oilseed crop Brassica napus.

One-sentence summary

The hairy root transformation system of Brassica napus generates stable transformants and is a tool for efficiently identifying CRISPR/Cas9-induced genome editing.
Mapping CAR T-cell design space using agent-based models
Authors: Prybutok Alexis N. , Yu Jessica S. , Leonard Joshua N. , Bagheri Neda
Published: April 2022

Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating liquid cancers and increasingly for solid tumors as well. While potential design strategies exist to address translational challenges, including the lack of unique tumor antigens and the presence of an immunosuppressive tumor microenvironment, testing all possible design choicesin vitroandin vivois prohibitively expensive, time consuming, and laborious. To address this gap, we extended the modeling framework ARCADE (Agent-based Representation of Cells And Dynamic Environments) to include CAR T-cell agents (CAR T-cell ARCADE, or CARCADE). We conductedin silicoexperiments to investigate how clinically relevant design choices and inherent tumor features—CAR T-cell dose, CD4+:CD8+CAR T-cell ratio, CAR-antigen affinity, cancer and healthy cell antigen expression—individually and collectively impact treatment outcomes. Our analysis revealed that tuning CAR affinity modulates IL-2 production by balancing CAR T-cell proliferation and effector function. It also identified a novel multi-feature tuned treatment strategy for balancing selectivity and efficacy and provided insights into how spatial effects can impact relative treatment performance in different contexts. CARCADE facilitates deeper biological understanding of treatment design and could ultimately enable identification of promising treatment strategies to accelerate solid tumor CAR T-cell design-build-test cycles.
Spring haul-out behavior of seals in the Bering and Chukchi seas
Authors: London Josh M. , Conn Paul B. , Koslovsky Stacie M. , Richmond Erin L. , Ver Hoef Jay M. , Cameron Michael F. , Crawford Justin A. , Von Duyke Andrew L. , Quakenbush Lori , Boveng Peter L.
Published: April 2022

Ice-associated seals rely on sea ice for a variety of activities, including pupping, breeding, molting, and resting. In the Arctic, many of these activities occur in spring (April – June) as sea ice begins to melt and retreat northward. Rapid acceleration of climate change in Arctic ecosystems is therefore of concern as the quantity and quality of suitable habitat is forecast to decrease. Improved estimates of seal population abundance are needed to properly monitor the impacts of these changes over time. In this paper, we use hourly percent-dry data from satellite-linked bio-loggers deployed between 2005 and 2021 to quantify the proportion of seals hauled out on ice. This information is needed to accurately estimate abundance from aerial survey counts of ice-associated seals (i.e., to correct for the proportion of animals that are in the water while surveys are conducted). In addition to providing essential data for survey ‘availability’ calculations, our analysis also provides insights into the seasonal timing and environmental factors affecting haul-out behavior by ice-associated seals. We specifically focused on bearded (Erignathus barbatus), ribbon (Histriophoca fasciata), and spotted seals (Phoca largha) in the Bering and Chukchi seas. Because ringed seals (Phoca (pusa) hispida) can be out of the water but hidden from view in snow lairs analysis of their ‘availability’ to surveys requires special consideration; therefore,they were not included in this analysis. Using generalized linear mixed pseudo-models to properly account for temporal autocorrelation, we fit models with covariates of interest (e.g., day-of-year, solar hour, age-sex class, wind speed, barometric pressure, temperature, precipitation) to examine their ability to explain variation in haul-out probability. We found evidence for strong diel and within-season patterns in haul-out behavior, as well as strong weather effects (particularly wind and temperature). In general, seals were more likely to haul out on ice in the middle of the day and when wind speed was low and temperatures were higher. Haul-out probability increased through March and April, peaking in May and early June before declining again. The timing and frequency of haul-out events also varied based on species and age-sex class. For ribbon and spotted seals, models with year effects were highly supported, indicating that the timing and magnitude of haul-out behavior varied among years. However, we did not find broad evidence that haul-out timing was linked to annual sea-ice extent. Our analysis emphasizes the importance of accounting for seasonal and temporal variation in haul-out behavior, as well as associated environmental covariates, when interpreting the number of seals counted in aerial surveys.
Intestinal inflammation reversibly alters the microbiota to drive susceptibility to Clostridioides difficile colonization in a mouse model of colitis
Authors: Barron Madeline R. , Sovacool Kelly L. , Abernathy-Close Lisa , Vendrov Kimberly C. , Standke Alexandra K. , Bergin Ingrid L. , Schloss Patrick D. , Young Vincent B.
Published: April 2022

Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10-/- mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germ-free animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients.

Importance

Patients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germ-free mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile.
Can neurogenesis act as a neural regularizer?
Authors: Tran Lina M. , Santoro Adam , Liu Lulu , Josselyn Sheena A. , Richards Blake A. , Frankland Paul W.
Published: April 2022

New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naïve synapses. Viewed from this perspective, these new neurons may represent a significant source of ‘wiring’ noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data, and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of neurons in a chosen hidden layer were re-initialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise-injection, expanding on the roles that neurogenesis may have in cognition.

Author Summary

In deep neural networks, various forms of noise injection are used as regularization techniques to prevent overfitting and promote generalization on unseen test data. Here, we were interested in whether adult neurogenesis– the lifelong production of new neurons in the hippocampus– might similarly function as a regularizer in the brain. We explored this question computationally, assessing whether implementing a neurogenesis-like process in a hidden layer within a convolutional neural network trained in a category learning task would prevent overfitting and promote generalization. We found that neurogenesis regularization was as least as effective as, or more effective than, conventional regularizers (i.e., dropout, weight decay and neural noise) in improving model performance. These results suggest that optimal levels of hippocampal neurogenesis may improve memory-guided decision making by preventing overfitting, thereby promoting the formation of more generalized memories that can be applied in a broader range of circumstances. We outline how these predictions may be evaluated behaviorally in rodents with altered hippocampal neurogenesis.
The multi-BRCT domain protein DDRM2 is required for homologous recombination in plants
Authors: Wang Lili , Yu Chen , Hou Longhui , Huang Yongchi , Cui Xiaoyu , Xu Shijun , Yan Shunping
Published: April 2022

DNA double-strand breaks (DSBs) are the most toxic DNA damage for cells. Homologous recombination (HR) is a precise DSB repair mechanism as well as a basis for gene targeting using genome-editing techniques. Despite the importance of HR, the HR mechanism in plants is poorly understood. In a genetic screen for DNA Damage Response Mutants (DDRMs), we find that the Arabidopsisddrm2mutant is hypersensitive to DSB-inducing reagents. DDRM2 encodes a protein with four BRCA1 C-terminal (BRCT) domains and is highly conserved in plants including the earliest land plant linage, bryophytes. The plant-specific transcription factor SOG1 binds to the promoter ofDDRM2and activates its expression, suggesting thatDDRM2is a direct target of SOG1. In consistence, the expression ofDDRM2is induced by DSBs in a SOG1-dependent manner. Epistasis analysis indicates that DDRM2 functions downstream of SOG1. Similar to thesog1mutant, theddrm2mutant shows dramatically reduced HR efficiency. Our study suggests that the SOG1-DDRM2 module is required for HR, providing new insights into the HR mechanisms in plants and a potential target for improving the efficiency of gene targeting.

One Sentence Summary

A genetic screen in Arabidopsis reveals that the multi-BRCT domain protein DDRM2 is required for homologous recombination and is targeted by the master DNA damage response regulator SOG1.
Traits of soil bacteria predict plant responses to soil moisture
Authors: Bolin Lana G. , Lennon Jay T. , Lau Jennifer A.
Published: April 2022

Microbes can promote beneficial plant and animal responses to abiotic environments, but the ecological drivers of this benefit remain elusive. Here we investigated byproduct benefits, which occur when traits that increase the fitness of one species provide incidental benefits to another species with no direct cost to the provider species. In experimental mesocosms, microbial traits predicted plant responses to soil moisture such that bacteria with self-beneficial traits in drought increased plant early growth, size at reproduction, and chlorophyll concentration under drought, while bacteria with self-beneficial traits in well-watered environments increased these same plant traits in well-watered environments. Thus, microbial traits that promote microbial success in different soil moisture environments also promote plant success in these same environments. Our results show that the concept of byproduct benefits, originally conceived to explain the evolution of cooperation in pairwise mutualisms, also applies to interactions between plants and non-symbiotic soil microbes.
Liver-secreted fluorescent blood plasma markers enable chronic imaging of microcirculation
Authors: Wang Xiaowen , Delle Christine , Asiminas Antonis , Akther Sonam , Vittani Marta , Brøgger Peter , Kusk Peter , Vo Camilla Trang , Konno Ayumu , Hirai Hirokazu , Fukuda Masahiro , Weikop Pia , Goldman Steven A , Nedergaard Maiken , Hirase Hajime
Published: April 2022

Studying blood microcirculation is vital for gaining insights into vascular diseases. Acute administration of fluorescent tracers is currently used for deep tissue blood flow imaging. This is invasive, and the plasma fluorescence decreases within an hour of administration. We report a novel approach for the longitudinal study of vasculature. Using a single systemic administration of viral vectors, we express fluorescent secretory albumin-fusion proteins in the liver to label the blood in mice. All segments of the vasculature in brain and peripheral tissue are observable by two-photon microscopy within two weeks of vector administration. This approach allows for observation of circulation without the need for repeated administration for several months. We demonstrate the chronic assessment of vascular functions at micro-and mesoscopic scales. This genetic plasma labeling approach represents a versatile and cost-effective method for the chronic investigation of vasculature functions across the body in health and disease.
Functionally and structurally distinct fusiform face area(s) in over 1000 participants
Authors: Chen Xiayu , Liu Xingyu , Parker Benjamin J. , Zhen Zonglei , Weiner Kevin S.
Published: April 2022

The Fusiform Face Area (FFA) is a widely studied region causally involved in face perception. Even though cognitive neuroscientists have been studying the FFA for over two decades, answers to foundational questions regarding the structure, function, and connectivity of the FFA from a large (N>1000) group of participants are still lacking. To fill this gap, we quantified structural, functional, and connectivity features of fusiform face-selective regions in 1080 participants in the Human Connectome Project (HCP). After manually defining over 4,000 fusiform face-selective regions, we report five main findings. First, 68.94% of hemispheres have two cortically separate regions (pFus-faces/FFA-1 and mFus-faces/FFA-2). Second, in 26.48% of hemispheres, pFus-faces/FFA-1 and mFus-faces/FFA-2 are spatially contiguous, yet functionally and structurally distinct. Third, pFus-faces/FFA-1 is more face-selective than mFus-faces/FFA-2, and the two regions have distinct functional connectivity fingerprints. Fourth, pFus-faces/FFA-1 is cortically thinner and more heavily myelinated than mFus-faces/FFA-2. Fifth, face-selective patterns and functional connectivity fingerprints of each region were more similar in monozygotic than dizygotic twins and more so than structural gradients. As we share our areal definitions with the field, future studies can explore how structural and functional features of these regions will inform theories regarding how visual categories are represented in the brain.
NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data
Authors: Bahl Ethan , Chatterjee Snehajyoti , Mukherjee Utsav , Elsadany Muhammad , Vanrobaeys Yann , Lin Li-Chun , McDonough Miriam , Resch Jon , Giese K Peter , Abel Ted , Michaelson Jacob J.
Published: April 2022

Neuronal activity-dependent transcription directs molecular processes that regulate synaptic plasticity, brain circuit development, behavioral adaptation, and long-term memory. Single cell RNA-sequencing technologies (scRNAseq) are rapidly developing and allow for the interrogation of activity-dependent transcription at cellular resolution. Here, we present NEUROeSTIMator, a deep learning model that integrates transcriptomic signals to estimate neuronal activation in a way that we demonstrate is associated with Patch-seq electrophysiological features and that is robust against differences in species, cell type, and brain region. We demonstrate this method’s ability to accurately detect neuronal activity in previously published studies of single cell activity-induced gene expression. Further, we applied our model in a spatial transcriptomic study to identify unique patterns of learning-induced activity across different brain regions. Altogether, our findings establish NEUROeSTIMator as a powerful and broadly applicable tool for measuring neuronal activation, whether as a critical covariate or a primary readout of interest.
Acquired resistance to anti-PD1 therapy in patients with NSCLC reveals changes in T cell phenotypes and MET amplification
Authors: Hiltbrunner Stefanie , Cords Lena , Kasser Sabrina , Freiberger Sandra N. , Kreutzer Susanne , Toussaint Nora C. , Grob Linda , Opitz Isabelle , Messerli Michael , Zoche Martin , Soltermann Alex , Rechsteiner Markus , van den Broek Maries , Bodenmiller Bernd , Curioni-Fontecedro Alessandra
Published: April 2022

The treatment of non-small cell lung cancer (NSCLC) patients with immune checkpoint inhibitors has prolonged their survival dramatically. However, some patients develop resistance after initial response. Here, we used imaging mass cytometry and whole exome and RNA sequencing to analyze matching tumor samples from a cohort of NSCLC patients who initially responded to immune checkpoint inhibitor therapy and later developed acquired resistance. We detected two patterns of resistance: One group of patients had reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group showed high CD8+ T cell infiltration and high expression of PD-L1 and markedly elevated expression of other immune-inhibitory molecules. In two cases, we detected downregulation of type I and II IFN pathways after resistance developed, which could lead to an impaired anti-tumor immune response. This study adds to our knowledge of the mechanisms that cause resistance to immunotherapy in NSCLC patients.
Pneumococcus suppresses host inflammatory response through COMMD2 mediated NF-κB degradation by aggrephagy
Authors: Connor Michael G. , Sanchez Lisa , Chevalier Christine , Carvalho Filipe , Eldridge Matthew G. , Chaze Thibault , Matondo Mariette , Weight Caroline M. , Dufour Sara , Impens Francis , Baumgarten Sebastian , Enninga Jost , Hamon Melanie A.
Published: April 2022

NF-κB driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-κB tunes the epithelial response toStreptococcus pneumoniaeacross the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate that TIGR4 both blunts and antagonizes NF-κB activation. We identified, through comparative mass spectrometry of the p65 interactome, that the 6B ST90 isolate drives a non-canonical NF-κB RelB cascade, whereas TIGR4 induces p65 degradation though aggrephagy. Mechanistically, TIGR4 challenge triggers a novel interaction of COMMD2 with p65 and p62. This complex mediates export of p65 for degradation and is necessary for repressing host inflammatory transcription. With these results, we reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 mediated turnover of p65, and present a paradigm for diverging NF-κB responses to pneumococcus.
RetroSnake: a Modular End-to-End Pipeline for Detection of Human Endogenous Retrovirus (HERV) Transposable Elements in Next Generation Sequencing (NGS) Data
Authors: Kabiljo Renata , Bowles Harry , Marriott Heather , Jones Ashley R. , Dobson Richard JB , Quinn John P , Swanson Chad M , Al-Chalabi Ammar , Iacoangeli Alfredo
Published: April 2022

Human Endogenous Retroviruses (HERVs) integrated into the genome of vertebrates as a result of ancient exogenous infections and currently comprise ∼8% of our genome. The majority of these elements have accumulated mutations rendering them inactive. The most recently acquired members, HERV-K have potential to produce viral particles and have been linked to a wide range of diseases including cancer and neurodegeneration. Although a range of tools for HERV discovery exist, most of them lack wet-lab validation of their results and are not end-to-end as they do not cover all steps of the analysis. These factors greatly limit their use. Here we describe RetroSnake, an end-to-end, modular, computationally efficient and customisable pipeline for the discovery of HERVs in short-read NGS data. RetroSnake presents important advantages with respect to other available tools. For instance, it is the only pipeline based on an extensively wet-lab validated protocol, and it is the most complete transposable elements detection pipeline, producing annotated insertions presented as an interactive html file, easy enough to use by life scientists without substantial computational training.

Availability and implementation

The Pipeline and an extensive documentation are available at https://github.com/KHP-Informatics/RetroSnake

Contact

alfredo.iacoangeli@kcl.ac.uk
Multitrait diversification in marine diatoms in constant and warmed environments
Authors: Hinners Jana , Argyle Phoebe A. , Walworth Nathan G. , Doblin Martina A. , Levine Naomi M. , Collins Sinéad
Published: April 2022

Phytoplankton are photosynthetic marine microbes that affect food webs, nutrient cycles, and climate regulation. Their roles are determined by a correlated set of phytoplankton functional traits including cell size, chlorophyll content, and cellular composition. Here, we explore how interrelated trait values and correlations evolve. Because both chance events and natural selection contribute to phytoplankton trait evolution, we used population bottlenecks to diversify six genotypes of Thalassiosirid diatoms. We then evolved them in two environments where natural selection could act on this diversity. Interspecific variation and within-species evolution were visualized for nine traits and their correlations using reduced axes (a trait-scape). Shifts in both trait values and correlations, resulting in movement of evolving populations on the trait-scape, occurred in both environments, and were more frequent under environmental change. Which trait correlations evolved was strain-specific, but greater departures from ancestral trait correlations were associated with lower population growth rates. There was no single master trait that could be used to understand multitrait evolution. Instead, repeatable multitrait evolution occurred along a major axis of variation defined by several diatom functional traits and trait relationships. Because trait-scapes capture changes in trait correlations and values together, they offer an insightful way to study multitrait variation.
The GUN mutants: new weapons to unravel ascospore germination regulation in the model fungus Podospora anserina
Authors: Demoor Alexander , Lacaze Isabelle , Ferrari Roselyne , Lalanne Christophe , Silar Philippe , Brun Sylvain
Published: April 2022

In Podospora anserina as in many other ascomycetes, ascospore germination is a regulated process that requires breaking of dormancy. Despite its importance in survival and dispersal, ascospore germination in filamentous fungi has been poorly investigated and little is known about its regulation and genetic control. We have designed a positive genetic screen that led to the isolation of mutants showing uncontrolled germination, the GUN mutants. In this paper, we report on the characterization of GUN1SG. We show that GUN1SG is mutated in Pa_6_1340, the ortholog of Magnaporthe oryzae Pth2, which encodes a Carnitine-acetyltransferase (CAT) involved in the shuttling of acetyl-CoA between peroxisomes and mitochondria and which is required for appressorium-development. Bioinformatic analysis revealed that the mutated residue (I441) is highly conserved among the Fungi, and that the mutation has a deleterious impact on the protein function. We show that GUN1 is essential for ascospore germination and that the protein is localized both in mitochondria and in peroxisomes. Finally, epistasis studies allowed us to place GUN1 upstream of the PaMpk2 MAPK pathway and the PaNox2/PaPls1 complex in the regulation of ascospore germination. The identification of GUN1, the ortholog of Pth2, in ascospore germination, strengthens the idea of a common genetic regulation governing both appressorium development and melanized ascospore germination. In addition, we characterize the second CAT encoded in P. anserina genome, Pa_3_7660/GUP1, and we show that the function of both CATs is conserved in P. anserina.
Wax worm saliva and the enzymes therein are the key to polyethylene degradation by Galleria mellonella
Authors: Sanluis-Verdes A. , Colomer-Vidal P. , Rodríguez-Ventura F. , Bello-Villarino M. , Spinola-Amilibia M. , Ruiz-López E. , Illanes-Vicioso R. , Castroviejo P. , Cigliano R. Aiese , Montoya M. , Falabella P. , Pesquera C. , González-Legarreta L. , Arias-Palomo E. , Solà M. , Torroba T. , Arias C.F. , Bertocchini F.
Published: April 2022

Plastic degradation by biological systems with re-utilization of the by-products can be the future solution to the global threat of plastic waste accumulation. We report that the saliva of Galleria mellonella larvae (wax worms) is capable of oxidizing and depolymerizing polyethylene (PE), one of the most produced and sturdy polyolefin-derived plastics. This effect is achieved after a few hours’ exposure at room temperature and physiological conditions (neutral pH). The wax worm saliva can indeed overcome the bottleneck step in PE biodegradation, that is the initial oxidation step. Within the saliva, we identified two enzymes that can reproduce the same effect. This is the first report of enzymes with this capability, opening up the way to new ground-breaking solutions for plastic waste management through bio-recycling/up-cycling.
Dietary and Reproductive Traits of Two Brachyuran Crab Species
Authors: Potter Ben , Cannizzo Zachary J. , Griffen Blaine D.
Published: April 2022

Many animals have flexible morphological traits that allow them to succeed in differing circumstances with differing diets available to them. For brachyuran crabs, claw height and gut size are diet-specific and largely reflect foraging strategies, while abdomen width reflects relative levels of fecundity. However, the link between claw size and diet has largely been documented only for primarily carnivorous crabs, while the link between diet and fecundity is strong in herbivorous crabs. We sought to determine the nature of the intraspecific relationship between claw size, dietary habits, and fecundity for two primarily herbivorous crab species, Hemigrapsus sanguineus and Aratus pisonii. Specifically, we examined whether claw size and/or abdomen width can be used as reliable measures of individual diet strategy. To test these hypotheses, we collected crabs and measured the dimensions of their claws, abdomens, and guts. By comparing these dimensions for each individual, we found that strongly predictive relationships do not exist between these traits for the primarily herbivorous species in our study. Thus, identifying external morphological features that can be used to assess diets of primarily herbivorous crabs remains elusive.
Soil water consumption characteristics in rain-fed apple orchards and wheat fields
Authors: Zhang Lu , Wang Yiquan , Sun Zenghui
Published: April 2022

Agricultural production in Weibei rain-fed highland, Northwest China, is facing severe drought and water shortages. Here, soil water consumption characteristics in rain-fed orchards and farmlands were explored to ascertain the rationality of planting orchards in Weibei. Soil moisture dynamics was monitored in the 0–150-cm soil profiles of different aged ‘Red Fuji’ apple orchards (young: 7 years, mature: 13 years, and old: 22 years), and in long-term cultivated winter wheat fields during the growing season of apple trees. The over-consumption and consumption of soil water were analyzed to evaluate water stress and differential water consumption by distinct vegetation, respectively. Soil desiccation index was used to determine the occurrence of dry soil layers. Generally, there was no water stress in the 0–150-cm orchard soil profiles, while water stress was observed at the 0–70-cm soil depths in the old orchards (mid-June) and farmlands (mid-May–mid-July). Water consumption took place at deeper depths for longer periods in the older orchards than in the younger orchards. Soil desiccation was not observed in the young orchards, while mild desiccation occurred at the 0–80-cm soil depths in the mature and old orchards in mid-June. The desiccation intensity was mild at the 0–60-cm soil depths in mid-April–mid-May, intense at the soil 0–150-cm depths in mid-June, and moderate at the 20–150-cm soil depths in mid-July. In conclusion, conversion from wheat fields to apple orchards could reduce soil water stress, reduce dry soil layers, and mitigate soil desiccation in the rain-fed highland area.
Hemispheric Asymmetries of Individual Differences in Functional Connectivity
Authors: Perez Diana C. , Dworetsky Ally , Braga Rodrigo M. , Beeman Mark , Gratton Caterina
Published: April 2022

Resting-state fMRI studies have revealed that individuals exhibit stable, functionally meaningful divergences in large-scale network organization. The locations with strongest deviations (called network ‘variants’) have a characteristic spatial distribution, with qualitative evidence from prior reports suggesting that this distribution differs across hemispheres. Hemispheric asymmetries can inform us on constraints guiding the development of these idiosyncratic regions. Here, we used data from the Human Connectome Project to systematically investigate hemispheric differences in network variants. Variants were significantly larger in the right hemisphere, particularly along the frontal operculum and medial frontal cortex. Variants in the left hemisphere appeared most commonly around the temporoparietal junction. We investigated how variant asymmetries vary by functional network and how they compare with typical network distributions. For some networks, variants seemingly increase group-average network asymmetries (e.g., the group-average language network is slightly bigger in the left hemisphere and variants also appeared more frequently in that hemisphere). For other networks, variants counter the group-average network asymmetries (e.g., the default mode network is slightly bigger in the left hemisphere, but variants were more frequent in the right hemisphere). Intriguingly, left- and right-handers differed in their network variant asymmetries for the cinguloopercular and frontoparietal networks, suggesting that variant asymmetries are connected to lateralized traits. These findings demonstrate that idiosyncratic aspects of brain organization differ systematically across the hemispheres. We discuss how these asymmetries in brain organization may inform us on developmental constraints of network variants, and how they may relate to functions differentially linked to the two hemispheres.
Capped nascent RNA sequencing reveals novel therapy-responsive enhancers in prostate cancer
Authors: Cotter Kellie A. , Shah Sagar R. , Paramo Mauricio I. , Lou Shaoke , Yao Li , Rubin Philip D. , Chen You , Gerstein Mark , Rubin Mark A. , Yu Haiyuan
Published: April 2022

Mounting evidence suggests that enhancer RNA (eRNA) transcription start sites (TSSs) provide higher sensitivity and specificity for enhancer identification than histone modifications and chromatin accessibility. The extent to which changes in eRNA transcription correspond to changes in enhancer activity, however, remains unclear. Here, we used precision run-on and capped RNA sequencing (PRO-cap) to assess changes in enhancer activity in response to treatment with the androgen receptor signaling inhibitor, enzalutamide (ENZ). We identified 6,189 high-confidence candidate enhancers in the human prostate cancer cell line, LNCaP; 853 of which demonstrated significant changes in activity in response to drug treatment. Notably, we found that 67% and 54% of drug-responsive enhancers did not show similar changes in activity in previous studies that utilized ChIP-seq and ATAC-seq, respectively. Strikingly, 79% of regions with increased eRNA transcription showed no other biochemical alterations, implying that PRO-cap can capture a set of precise changes in enhancer activity that classical approaches lack the sensitivity to detect. We performed in vivo functional validations of candidate enhancers and found that CRISPRi targeting of PRO-cap-specific drug-responsive enhancers impaired ENZ regulation of downstream target genes, suggesting that changes in eRNA TSSs mark true biological changes in enhancer activity with high sensitivity. Our study highlights the utility of using PRO-cap as a complementary approach to canonical biochemical methods for detecting precise changes in enhancer activity and, in particular, for better understanding disease progression and responses to treatment.
Mutational scan inferred binding energetics and structure in intrinsically disordered protein CcdA
Authors: Chandra Soumyanetra , Manjunath Kavyashree , Asok Aparna , Varadarajan Raghavan
Published: April 2022

Unlike globular proteins, mutational effects on the function of Intrinsically Disordered Proteins (IDPs) are not well-studied. Deep Mutational Scanning of a yeast surface displayed mutant library yields insights into sequence-function relationships in the CcdA IDP. The approach enables facile prediction of interface residues and local structural signatures of the bound conformation. In contrast to previous titration-based approaches which use a number of ligand concentrations, we show that use of a single rationally chosen ligand concentration can provide quantitative estimates of relative binding constants for large numbers of protein variants. This is because the extended interface of IDP ensures that energetic effects of point mutations are spread over a much smaller range than for globular proteins. Our data also provides insights into the much-debated role of helicity and disorder in partner binding of IDPs. Based on this exhaustive mutational sensitivity dataset, a model was developed to predict mutational effects on binding affinity of IDPs that form alpha-helical structures upon binding.
Cannabinoid 1/2 Receptor Activation Induces Strain-Dependent Behavioral and Neurochemical Changes in GAERS and NEC rats
Authors: De Deurwaerdère Philippe , Casarrubea Maurizio , Cassar Daniel , Radic Manuela , Puginier Emilie , Chagraoui Abdeslam , Crescimanno Giuseppe , Crunelli Vincenzo , Di Giovanni Giuseppe
Published: April 2022

Childhood absence epilepsy (CAE) is characterized by absence seizures which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with ASs are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities.

Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg, i.p.) has a strain-dependent effect on anxiety-like and motor behavior and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal-Pattern analysis, we found that WIN 55,212-2 did not affect the emotional status of GAERS but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS are more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats.

These data support the view of a strain-dependent alteration of the endocannabinoid system by adding evidence of lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.
A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Authors: Kelly Michael R. , Wisniewska Kamila , Regner Matthew J. , Lewis Michael W. , Perreault Andrea A. , Davis Eric S. , Phanstiel Douglas H. , Parker Joel S. , Franco Hector L.
Published: April 2022

The human genome contains regulatory elements, such as enhancers, that are often rewired by cancer cells for the activation of genes that promote tumorigenesis and resistance to therapy. This is especially true for cancers that have little or no known driver mutations within protein coding genes, such as ovarian cancer. Herein, we have utilized an integrated set of genomic and epigenomic datasets to identify clinically relevant super-enhancers that are preferentially amplified in ovarian cancer patients. We have systematically probed the top 86 super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to RNA-sequencing, to nominate two salient super-enhancers that drive proliferation and migration of cancer cells. Utilizing Hi-C, we constructed chromatin interaction maps that enabled the annotation of direct target genes for these super-enhancers and later confirmed their activity specifically within the cancer cell compartment of human tumors using single-cell genomics data. Together, our multi-omic approach has examined a number of fundamental questions about how regulatory information encoded into super-enhancers drives gene expression networks that underlie the biology of ovarian cancer.
Brain resident memory T cells rapidly expand and initiate neuroinflammatory responses following CNS injury and viral infection
Authors: Ayasoufi K , Wolf DM , Namen SL , Tritz ZP , Jin F , Pfaller CK , Goddery EN , Fain CE , Gulbicki LR , Khadka RH , Yokanovich LT , Hansen MJ , Johnson AJ
Published: April 2022

The contribution of circulating verses tissue resident memory T cells (TRM) to clinical neuropathology is an enduring question due to a lack of mechanistic insights. The prevailing view is TRM cells are protective against pathogens in the brain. However, the extent antigen-specific TRM cells can induce neuropathology upon reactivation has not been determined. Using the described phenotype of TRMs, we found that brains of naïve mice harbor populations of CD69+ CD103− T cells. Notably, numbers of CD69+ CD103− TRM cells rapidly increase following neurological insults of physical, cancerous, or viral origins. This TRM expansion precedes infiltration of virus specific CD8 T cells and is due to proliferation of T cells within the brain. In contrast, the CD69+ CD103+ TRMs in the brain are generated after the initial expansion of CD69+ CD103− cells following injury and are antigen-specific. We next evaluated the capacity of antigen-specific TRMs in the brain to induce significant neuroinflammation post virus clearance, including infiltration of inflammatory monocytes, activation of T cells in the brain, and significant blood brain barrier disruption. These neuroinflammatory events were induced by TRMs, as depletion of peripheral T cells or blocking T cell trafficking using FTY720 did not change the neuroinflammatory course. Reactivation of antigen-specific TRMs in the brain also induced profound lymphopenia within the blood compartment. We have therefore determined that antigen-specific TRMs can induce significant neuroinflammation, neuropathology, and peripheral immune suppression. Importantly, understanding functions of brain TRMs is crucial in investigating their role in neurodegenerative disorders, CNS cancers, and long-term complications associated with viral infections including COVID-19.

Graphical Abstract

Healthy brain harbors populations of resident memory T cells (TRM). These TRM cells rapidly proliferate in response to CNS insults of various origins. Following clearance of the insult, populations of TRM cells in the brain decline, but an antigen-specific TRM subset remains within the brain. Antigen-specific reactivation of brain TRMs mediates neuroinflammatory sequalae involving activation and blasting of resident T cells, infiltration of inflammatory monocytes and blood brain barrier disruption. Severe neuroinflammation within the brain following antigen-specific TRM reactivation is concurrent with profound lymphopenia within the blood compartment.
Pan-cancer quantification of neoantigen-mediated immunoediting in cancer evolution
Authors: Wu Tao , Wang Guangshuai , Wang Xuan , Wang Shixiang , Zhao Xiangyu , Wu Chenxu , Ning Wei , Tao Ziyu , Chen Fuxiang , Liu Xue-Song
Published: April 2022

Immunoediting, which includes three temporally distinct stages, termed elimination, equilibrium, and escape, has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion signal in untreated cancer has been debated. Here we developed a distribution pattern based method for quantifying neoantigen mediated negative selection in cancer evolution. Our method provides a robust and reliable quantification for immunoediting signal in an individual cancer patient. The prevalence of immunoediting signal in immunotherapy untreated cancer genome has been demonstrated with this method. Importantly, the elimination and escape stages of immunoediting can be quantified separately, tumor types with strong immunoediting-elimination tend to have weak immunoediting-escape signal, and vice versa. Quantified immunoediting-elimination signal predicts cancer immunotherapy clinical response. Immunoediting quantification provides an evolutional perspective for evaluating the antigenicity of neoantigen, and reveals a potential biomarker for cancer precision immunotherapy.