bluuebunny/crossref_metadata_2025_split huggingface dataset:
PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress
Authors: Hughes Daniel T. , Brar Karinder K. , Morris Jordan L. , Subramanian Kelly , Krishna Shivaani , Gao Fei , Rieder Lara-Sophie , Freeman Joshua , Smith Heather L. , Jukes-Jones Rebekkah , Nunnari Jodi , Prudent Julien , Butcher Adrian J. , Mallucci Giovanna R. 
Published: July 2022

AbstractWidespread repression of protein synthesis rates is a key feature of Endoplasmic Reticulum (ER) stress, mediated by the ER sensor kinase PERK. While select transcripts escape this repression, global translational down-regulation impacts crucial protein levels in all cellular compartments, beyond the ER. How the cell manages this paradox is unclear. PERK has a unique cytoplasmic loop within its kinase domain that binds PERK’s target, eIF2α. We identified the mitochondrial protein, ATAD3A, as a new interactor of the loop, binding to a highly conserved region within it. During ER stress, increased interaction between ATAD3A and PERK attenuates PERK signalling to eIF2α, removing the translational block on several mitochondrial proteins. This occurs at novel context-dependent, mitochondria-ER contact sites. The interaction provides a previously unknown mechanism for fine-tuning translational repression at a local level, mitigating the impact of ER stress on mitochondria. Further, it represents a new target for selective modulation of PERK-eIF2α signalling in diseases from cancer to neurodegeneration.Graphical Abstract
Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain
Authors: Caspi Yaki , Mazar Michael , Kushnir Yishai , Mazor Yoav , Katz Ben , Lev Shaya , Binshtok Alexander M 
Published: July 2022

AbstractActivity-dependent structural plasticity of axon initial segment (AIS) regulates neuronal excitability, thus fine-tuning neuronal and overall network output. Here using behavioral, immunohistochemical, electrophysiological and computational approaches, we describe the structural plasticity of AIS in rat’s superficial spinal cord dorsal horn (SDH) neurons, which underlies inflammatory pain. We show an inflammation-mediated distal shift of the AIS away from the soma in inhibitory but not excitatory SDH neurons, concomitant with the peak of inflammatory pain. This AIS translocation was accompanied by a decrease in excitability of the inhibitory neurons. Following recovery from inflammatory hyperalgesia, the AIS location and neuronal excitability reversed to baseline levels. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of differential inflammation-mediated AIS plasticity, reducing the excitability of inhibitory but not excitatory SDH neurons and contributing to inflammatory hyperalgesia.
Differential Regulation Analysis Quantifies Mirna Regulatory Roles and Context-Specific Targets
Authors: Ning Boting , Spira Tamar , Beane Jennifer E. , Lenburg Marc E. 
Published: July 2022

AbstractRewiring of transcriptional regulatory networks has been implicated in many biological and pathological processes. However, most current methods for detecting rewiring events (differential network connectivity) are not optimized for miRNA-mediated gene regulation and fail to systematically examine predicted target genes in study designs with multiple experimental or phenotypic groups. We developed a novel method to address these shortcomings. The method first estimates miRNA-gene expression correlations with Spatial Quantile Normalization to remove the mean-correlation relationship. Then, for each miRNA, genes are ranked by their correlation strength per experimental group. Enrichment patterns of predicted target genes are compared using the Anderson-Darling test and significance levels are estimated via permutation. Finally, context-specific target genes for each miRNA are identified with target prioritization based on the correlation strength between miRNA and predicted target genes within each group. In miR-155 KO RNA-seq data from four mice immune cell types, our method captures the known cell-specific regulatory differences of miR-155, and prioritized targets are involved in functional pathways with cell-type specificity. Moreover, in TCGA BRCA data, our method identified subtype-specific targets that were uniquely altered by miRNA perturbations in cell lines of the same subtype. Our work provides a new approach to characterize miRNA-mediated gene regulatory network rewiring across multiple groups from transcriptomic profiles. The method may offer novel insights into cell-type and cancer subtype-specific miRNA regulatory roles.
Age-related change in transient gamma band activity during working memory maintenance through adolescence
Authors: McKeon Shane D. , Calabro Finnegan , Thorpe Ryan V. , de la Fuente Alethia , Foran Will , Parr Ashley C. , Jones Stephanie R. , Luna Beatriz 
Published: July 2022

ABSTRACTAdolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, it did not appear to change during the delay period resulting in an increasing difference between the number of events during fixation and delay period with development, suggesting that as working memory develops there is greater specificity for gamma events supporting working memory. While average power of the transient gamma events was found to mediate age-related changes in total gamma power, the number of gamma events was unrelated to total power, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.
Positive indirect effects more than balance negative direct effects of ungulate grazers on population growth of a grassland herb
Authors: Richards Thomas J. , Thomann Michel , Ehrlén Johan , Ågren Jon 
Published: July 2022

AbstractHerbivores can affect plant population dynamics both directly because of the damage they inflict, and indirectly by moderating conditions for plant recruitment, competition and other biotic interactions. Still, the relative importance of indirect effects of herbivores on plant population dynamics is poorly known.We quantified direct and indirect effects of ungulate grazers on population growth rate of the short-lived perennial herb Primula farinosa, using integral projection models based on demographic data collected over 7 years in exclosures and open control plots at nine grassland sites in southern Sweden. In addition, we explored the mechanisms behind indirect effects with simulations.Grazers had negative direct effects on P. farinosa population growth rate, but these were more than balanced by positive indirect effects. The positive indirect effects were mainly linked to improved conditions for plant recruitment. Simulations indicated that indirect effects of ungulate grazers on population growth rate via interactions with pollinators, seed predators, and small herbivores were weak in this system.Synthesis. The results demonstrate that a full understanding of the effects of grazing on plant population dynamics requires that both direct and indirect effects are identified and quantified. Plant species vary considerably in their response to shifts in grazing regime. Our study sets an example for how the causes of such variation can be assessed, and thus providing a better understanding of the variable effects of herbivores on plant fitness, abundance and distribution.
Specific recognition and ubiquitination of slow-moving ribosomes by human CCR4-NOT
Authors: Absmeier Eva , Chandrasekaran Viswanathan , O’Reilly Francis J , Stowell James AW , Rappsilber Juri , Passmore Lori A 
Published: July 2022

AbstractEukaryotic messenger RNA (mRNA) decay is generally initiated by removal of the 3’ polyadenosine (poly(A)) tail by the CCR4-NOT complex. Yeast Ccr4-Not binds and ubiquitinates ribosomes stalled on mRNAs with sub-optimal codons to trigger deadenylation and decay of the associated transcript. However, the mammalian ortholog of the E3 ubiquitin ligase subunit, CNOT4, is not a constitutive component of human CCR4-NOT. It therefore remains unclear how the mammalian deadenylation machinery targets stalled ribosomes. Here, we reconstitute translational stalling on non-optimal codons. We find that human CCR4-NOT recognizes translating mammalian ribosomes and is required for stable CNOT4 association. Our cryoEM structure reveals that the CNOT3 subunit detects slow translation and locks the L1 stalk of the ribosome in an open conformation to impede further elongation. Using crosslinking mass spectrometry, we show that CNOT4 and CNOT11 also bind in the vicinity of the E site. Overall, our work defines how CCR4-NOT enforces ribosomal stalling in response to low codon optimality.
Comparisons of the rate of acute myocardial infarction between COVID-19 patients and individuals received COVID-19 vaccines: a population-based study
Authors: Chou Oscar Hou In , Chung Cheuk To , Satti Danish Iltaf , Zhou Jiandong , Lee Teddy Tai Loy , Wai Abraham Ka Chung , Liu Tong , Lee Sharen , Vassiliou Vassilios S , Cheung Bernard Man Yung , Tse Gary 
Published: July 2022

AbstractBackgroundBoth Coronavirus Disease-2019 (COVID-19) infection and COVID-19 vaccination have been associated with the development of acute myocardial infarction (AMI). This study compared the rates of AMI after COVID-19 infection and among the COVID-19 vaccinated populations in Hong Kong.MethodsThis was a population-based cohort study from Hong Kong, China. Patients with positive real time-polymerase chain reaction (RT-PCR) test for COVID-19 between January 1st, 2020 and June 30th, 2021 were included. The data of the vaccinated and unvaccinated population was obtained from the “Reference Data of Adverse Events in Public Hospitals” published by the local government. The individuals who were vaccinated with COVID-19 vaccination prior the observed period (December 6th, 2021 to January 2nd, 2022) in Hong Kong were also included. The vaccination data of other countries were obtained by searching PubMed using the terms [“COVID-19 vaccine” AND “Myocardial infarction”] from its inception to February 1st, 2022. The main exposures were COVID-19 test positivity or previous COVID-19 vaccination. The primary outcome was the development of AMI within 28 days observed period.ResultsThis study included 11441 COVID-19 patients, of whom 25 suffered from AMI within 28 days of exposure (rate per million: 2185; 95% confidence interval [CI]: 1481-3224). The rates of AMI were much higher than those who were not vaccinated by the COVID-19 vaccine before December 6th, 2021 (rate per million: 162; 95% CI: 147-162) with a rate ratio of 13.5 (95% CI: 9.01-20.2). Meanwhile, the rate of AMI was lower amongst the vaccinated population (rate per million: 47; 95% CI: 41.3-53.5) than COVID-19 infection with a rate ratio of 0.02 (0.01, 0.03). Regarding post-vaccination AMI, COVID-19 infection was associated with a significantly higher rate of AMI than post-COVID-19 vaccination AMI in other countries.ConclusionsCOVID-19 infection was associated with a higher rate of AMI than the vaccinated general population, and those immediately after COVID-19 vaccination.
CD3e-immunotoxin spares CD62LloTregs and reshapes organ-specific T-cell composition by preferentially depleting CD3ehiT cells
Authors: Kim Shihyoung , Shukla Rajni Kant , Yu Hannah , Baek Alice , Cressman Sophie G , Golconda Sarah , Lee Ga-Eun , Choi Hyewon , Reneau John C , Wang Zhirui , Huang Christene A. , Liyanage Namal P. M. , Kim Sanggu 
Published: July 2022

AbstractCD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissue-resident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of CD3e-IT treatment on these local cells, however, remains poorly understood. Here, using a new murine testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in CD3e-IT treatment. The surviving Tregs in CD3e-IT-treated mice were mostly the CD3edimCD62Lloeffector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface CD3e levels among tissue-resident T cells of different organs, and these variations drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes) also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment.
Neuronal Activity Alters Neuron to OPC Synapses
Authors: Moura  , Parvathaneni  , Sahagun  , Noguchi  , Brennan  , Tilton  , Brock  , Halladay  , Pleasure  , Cocas  
Published: July 2022

AbstractThe mechanisms that drive the timing and specificity of oligodendrocyte myelination during development, or remyelination after injury or immune attack are not well understood. Recent work has shown that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. We hypothesize that these connections are important both for correct myelination of neurons during development and for myelination during neuronal plasticity. We utilized chemogenetic tools and viral monosynaptic circuit tracing to analyze these neuroglial connections and to examine OPC proliferation, myelination, synapse formation, and neuronal-glial connectivity after increasing or decreasing neuronal activity in vivo. We found that increasing neuronal activity increased OPC activation, but not proliferation. We also found that altering neuronal activity altered neuronal-glial synaptic connections: while it did not impact the total number of neuronal inputs, or the number of inhibitory neuronal inputs, it did alter the number of excitatory neuron to OPC connections. We also found that increasing or decreasing neuronal activity impacted the ratio of excitatory and inhibitory synapses. Our data show that neuronal activity affects OPC activation, neuronal synapse formation onto OPCs, as well as the types of neuronal inputs to OPCs, indicating that neuronal activity is important for OPC circuit composition and function.
Synonymous polymorphism difference relating to codon degeneracy between co-transcribed genes in the genome ofEscherichia coli
Authors: Beura Pratyush Kumar , Sen Piyali , Aziz Ruksana , Chetia Chayanika , Dash Madhusmita , Satapathy Siddhartha Shankar , Ray Suvendra Kumar 
Published: July 2022

AbstractThe previous findings suggest that replication and transcription are two major reasons behind the different substitution patterns of mutations in genomic DNA. In the current work, we have compared the adjacent co-transcribed gene pairs regarding synonymous polymorphism in five different operons inEscherichia coli. It is interesting that the co-transcribed genes were different from each other regarding the polymorphism spectra. The transition to transversion ratio between gene pairs were different due to their compositional differences regarding two-fold degenerate codon and four-fold degenerate codons. Further, the polymorphism spectra difference between the gene pairs was more prominent in four-fold and six-fold degenerate codons than in the two-fold degenerate codons. In case ofrpoBandrpoC, the major difference was found at UCC, GUA, CCG, GCU, GGC and CGC codons. Similarly, in case of the other four pairs of co-transcribed genes, the difference was more prominent in the higher degenerate codons than the two-fold degenerate codons. It may be that the restriction of two-fold degenerate codons to transition substitutions only regarding synonymous polymorphism is making these codons different from the higher degeneracy codons in this study.
Validation of manifold-based direct control for a brain-to-body neural bypass
Authors: Losanno E. , Badi M. , Roussinova E. , Bogaard A. , Delacombaz M. , Shokur S. , Micera S. 
Published: July 2022

AbstractBrain-body interfaces (BBIs) are neuroprostheses that can restore the connection between brain activity and body movements. They have emerged as a radical solution for restoring voluntary hand control in people with upper-limb paralysis. The BBI module decoding motor commands to actuate the limb from brain signals should provide the user with intuitive, accurate, and stable control. Here, we present the design and demonstration in a monkey of a novel brain decoding strategy based on the direct coupling between the activity of intrinsic neural ensembles and output variables, meant to achieve ease of learning and long-term robustness. We identified once an intrinsic low-dimensional space (called manifold) capturing the co-variation patterns of the monkey’s neural activity associated to reach-to-grasp movements. We then tested the animal’s ability to directly control a computer cursor using cortical activation along the manifold axes and demonstrated rapid learning and stable high performance over 16 weeks of experiments. Finally, we showed that this brain decoding strategy can be effectively coupled to peripheral nerve stimulation to trigger hand movements. These results provide evidence that manifold-based direct control has promising characteristics for clinical applications of BBIs.
Prophylactic low-dose, bi-weekly benznidazole treatment fails to prevent Trypanosoma cruzi infection in dogs under intense transmission pressure
Authors: Bustamante Juan M. , Padilla Angel M. , White Brooke , Auckland Lisa D. , Busselman Rachel E. , Collins Stephanie , Malcolm Elizabeth L. , Wilson Briana F. , Saunders Ashley B. , Hamer Sarah A. , Tarleton Rick L. 
Published: July 2022

AbstractTrypanosoma cruzi naturally infects a wide variety of wild and domesticated mammals, in addition to humans. Depending on the infection dose and other factors, the acute infection can be life-threatening, and in all cases, the risk of chagasic heart disease is high in persistently infected hosts. Domestic, working, and semi-feral dogs in the Americas are at significant risk of T. cruzi and in certain settings in the southern United States, the risk of new infections can exceed 30% per year, even with the use of vector control protocols. In this study, we explored whether intermittent low-dose treatment with the trypanocidal compound benznidazole (BNZ) during the transmission season, could alter the number of new infections in dogs in an area of known, intense transmission pressure. Preliminary studies in mice suggested that twice-weekly administration of BNZ could prevent or truncate infections when parasites were delivered at the mid-point between BNZ doses. Pre-transmission season screening of 126 dogs identified 53 dogs (42.1%) as T. cruzi infection positive, based upon blood PCR and Luminex-based serology. Serial monitoring of the 67 uninfected dogs during the high transmission season (May to October) revealed 15 (22.4%) new infections, 6 in the untreated control group and 9 in the group receiving BNZ prophylaxis, indicating no impact of this prophylaxis regimen on the incidence of new infections. Although these studies suggest that rigorously timed and more potent dosing regimen may be needed to achieve an immediate benefit of prophylaxis, additional studies would be needed to determine if drug prophylaxis reduced disease severity despite this failure to prevent new infections.Author SummaryTrypanosoma cruzi, the parasite that causes Chagas disease, circulates extensively in the southern U.S. and working dog populations in south-central Texas are at very high risk of infection, and morbidity and early mortality due to this infection. In this study, we used low level administration of an FDA-approved drug during the transmission season to attempt to prevent new infections in these dogs. Although that effort failed, the study revealed new information about the transmission dynamics and generation of antibody responses and immune control of infection in this high-transmission setting.