bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundIL-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.ObjectiveWe investigated whetherIL-1RL1asthma risk haplotypes or asthma status influence IL-33-induced Th2 transcriptomic responsesin vitro.MethodsCD4+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.ResultsPresence 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.ConclusionThe 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 OutcomeCellular sensitivity to IL-33 depends on genetic makeup and asthma disease status.Capsule summaryIL-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

AbstractAimDespite 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.Location20 coral populations along a latitudinal gradient on the east coast of Australia (∼23°S to 30°S).Time PeriodBetween 2010 and 2018.Major taxa studiedScleractinian corals.MethodsWe 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.ResultsCompared 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 conclusionsWith 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 availabilityData 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

AbstractThe 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

ABSTRACTRecent 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

SUMMARYEarly 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.HIGHLIGHTSFirst large-scale survey of visual functions in an avian retinaOff-circuits are fast and achromatic, On-circuits are slow and chromaticMost avian RGCs are OnOff and encode both types of informationColour 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

AbstractPrior 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 StatementInfralimbic 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

AbstractSmall 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

ABSTRACTForward 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

ABSTRACTConductance-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

SummaryThe 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.HighlightPathway-specific KOR expression confers selective filtering of mPFC afferents by dynorphinEndogenous dynorphin release gates KOR-expressing inputs to both dynorphin-expressing and lacking mPFC neuronsDynorphin / KOR modulation reveals parallel channels within amygdalo-cortical and cortical-cortical circuitsDynorphin disinhibits mPFC pyramidal neurons via KOR-mediated suppression of distinct inhibitory circuit motifs that preferentially impact SST-mediated feedforward inhibitionDynorphin / 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

ABSTRACTMore 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.IMPORTANCEBats 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.