bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular RNA as a potential activator of Neutrophil Extracellular Traps by Candida albicans biofilm
Authors: Smolarz Magdalena , Zawrotniak Marcin , Satała Dorota , Rapala-Kozik Maria 
Published: December 2021

Neutrophils represent the first line of innate host defense. The ability to inhibit the development of infections is associated with the involvement of several fighting strategies. The still poorly understood mechanism is netosis, involving the release of Extracellular Neutrophil Traps (NETs). NETs are complexes of chromosomal DNA and granule content. Such a web-like structure inhibits the spread of invaders.
Netosis plays a significant role in combating Candida albicans infections. It has been shown that several factors, composing C. albicans cell surface mediate NETs production. However, the development of difficult to eradicate fungal infection is associated with the formation of the biofilm structure, which partially protects the pathogen cells from contact with the host’s immune system. One of the reasons for the creation of a such protective environment is the production of the extracellular matrix (ECM). The major components of the C. albicans ECM layer are lipids, proteins, carbohydrates but also extracellular nucleic acids, among which we observed a significant RNA content.
Considering that the ECM consisting of RNA molecules is one of the first lines of contact between biofilms and neutrophils, our current studies aimed to assess the potential role of extracellular RNA in the triggering of the netosis process by human neutrophils in vitro. We showed that RNA purified from C. albicans biofilm structure and the whole cells have the capability to induction of ROS-dependent netosis pathway. Additionally, cell migration analysis indicate that RNA molecules may also be an effective chemotactic agent. This work was supported by NCN (2019/33/B/NZ6/02284).
Leukocyte cytokine responses in adult patients with mitochondrial DNA defects
Authors: Karan Kalpita R. , Trumpff Caroline , Cross Marissa , Englestad Kristin M. , Marsland Anna L. , McGuire Peter , Hirano Michio , Picard Martin 
Published: December 2021

AbstractPatients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n=21) and patients (n=12) with either the m.3243A>G mutation or single, large-scale mtDNA deletions, we examined: i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure, and ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74 - 79% lower responses for IL-6 and IL-1β (pIL-6=0.031, pIL-1β=0.009). Moreover, IL-6 response to LPS in presence of GC was also blunted in cells from patients with mtDNA deletions (pIL-6=0.006), but not in leukocytes from patients with the m.3243A>G mutation. Overall, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and glucocorticoid sensitivity. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes.
Cortical Temporal Integration Window for Binaural Cues accounts for Sluggish Auditory Spatial Perception
Authors: Singh Ravinderjit , Bharadwaj Hari M. 
Published: December 2021

AbstractThe auditory system has exquisite temporal coding in the periphery which is transformed into a rate-based code in central auditory structures like auditory cortex. However, the cortex is still able to synchronize, albeit at lower modulation rates, to acoustic fluctuations. The perceptual significance of this cortical synchronization is unknown. We estimated physiological synchronization limits of cortex (in humans with electroencephalography) and brainstem neurons (in chinchillas) to dynamic binaural cues using a novel system-identification technique, along with parallel perceptual measurements. We find that cortex can synchronize to dynamic binaural cues up to approximately 10 Hz, which aligns well with our measured limits of perceiving dynamic spatial information and utilizing dynamic binaural cues for spatial unmasking, i.e. measures of binaural sluggishness. We also find the tracking limit for frequency modulation (FM) is similar to the limit for spatial tracking, demonstrating that this sluggish tracking is a more general perceptual limit that can be accounted for by cortical temporal integration limits.
Lactate regulation of activation in CD8+ T cells
Authors: Barbieri Laura , Veliça Pedro , Gameiro Paulo A. , Cunha Pedro P. , Foskolou Iosifina P. , Bargiela David , Rundqvist Helene , Johnson Randall S. 
Published: December 2021

AbstractCD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in tissues can result in extended exposure of cytotoxic T cells to the metabolite lactate. Lactate can be immunosuppressive, at least in part due to its association with tissue acidosis. We show here that the lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and is capable of displacing glucose as a carbon source. Activation in the presence of a pH neutral form of lactate significantly alters the CD8+ T cell transcriptome, including the expression of key effector differentiation markers such as granzyme B and interferon-gamma. Our studies reveal the novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.
Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy
Authors: Hernandez Adriana , Liu Mei , Clark James , Le Tram , Biswas Biswajit , Bishop-Lilly Kimberly A. , Henry Matthew , Quinones Javier , Hamilton Theron , Schooley Robert , Salka Scott , Young Ry , Gill Jason 
Published: December 2021

AbstractIn 2016, a 68-year-old patient with a disseminated multi-drug resistant Acinetobacter baumannii infection was treated using lytic bacteriophages in one of the first modern human clinical uses of phage therapy in the United States. Due to the emergency nature of the treatment there was little time to thoroughly characterize the phages used in this intervention or the pathogen itself. Here we report the genomes of the nine phages used for treatment and three strains of A. baumannii isolated prior to and during treatment. The eight phages used in the initial treatment were found to be a group of closely related T4-like myophages; the ninth phage, AbTP3Φ1, was found to be an unrelated Fri1-like podophage. Analysis of 19 A. baumannii isolates collected before and during phage treatment showed that resistance to the T4-like phages appeared as early as two days following the start of treatment. Three A. baumannii strains (TP1, TP2 and TP3) collected before and during treatment were sequenced to closure, and all contained a 3.9 Mb chromosome of sequence type 570 with a KL116 capsule locus and identical 8.7 kb plasmids. Phage-insensitive mutants of A. baumannii strain TP1 were generated in vitro and the majority of identified mutations were located in the bacterial capsule locus. The presence of the same mutation in both the in vitro mutants and in phage-insensitive isolates TP2 and TP3, which evolved in vivo during phage treatment, indicate that in vitro investigations can produce results that are relevant and predictive for the in vivo environment.
QTQTN motif upstream of the furin-cleavage site plays key role in SARS-CoV-2 infection and pathogenesis
Authors: Vu Michelle N. , Lokugamage Kumari G. , Plante Jessica A. , Scharton Dionna , Johnson Bryan A. , Sotcheff Stephanea , Swetnam Daniele M. , Schindewolf Craig , Alvarado R. Elias , Crocquet-Valdes Patricia A. , Debbink Kari , Weaver Scott C. , Walker David H. , Routh Andrew L. , Plante Kenneth S. , Menachery Vineet D. 
Published: December 2021

AbstractThe furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing 1,2. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates 3. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS, and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated4, and disruption its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site – the FCS, loop length, and glycosylation – are required for efficient SARS-CoV-2 replication and pathogenesis.
An Explainable Self-Attention Deep Neural Network for Detecting Mild Cognitive Impairment Using Multi-input Digital Drawing Tasks
Authors: Ruengchaijatuporn Natthanan , Chatnuntawech Itthi , Teerapittayanon Surat , Sriswasdi Sira , Itthipuripat Sirawaj , Chotibut Thiparat , Chunharas Chaipat 
Published: December 2021

ABSTRACTMild cognitive impairment (MCI) is an early stage of age-inappropriate cognitive decline, which could develop into dementia – an untreatable neurodegenerative disorder. An early detection of MCI is a crucial step for timely prevention and intervention. To tackle this problem, recent studies have developed deep learning models to detect MCI and various types of dementia using data obtained from the classic clock-drawing test (CDT), a popular neuropsychological screening tool that can be easily and rapidly implemented for assessing cognitive impairments in an aging population. While these models succeed at distinguishing severe forms of dementia, it is still difficult to predict the early stage of the disease using the CDT data alone. Also, the state-of-the-art deep learning techniques still face the black-box challenges, making it questionable to implement them in the clinical setting. Here, we propose a novel deep learning modeling framework that incorporates data from multiple drawing tasks including the CDT, cube-copying, and trail-making tasks obtained from a digital platform. Using self-attention and soft-label methods, our model achieves much higher classification performance at detecting MCI compared to those of a well-established convolutional neural network model. Moreover, our model can highlight features of the MCI data that considerably deviate from those of the healthy aging population, offering accurate predictions for detecting MCI along with visual explanation that aids the interpretation of the deep learning model.
Sensory suppression and increased neuromodulation during actions disrupt memory encoding of unpredictable self-initiated stimuli
Authors: Paraskevoudi Nadia , SanMiguel Iria 
Published: December 2021

AbstractActions modulate sensory processing by attenuating responses to self- compared to externally-generated inputs, which is traditionally attributed to stimulus-specific motor predictions. Yet, suppression has been also found for stimuli merely coinciding with actions, pointing to unspecific processes that may be driven by neuromodulatory systems. Meanwhile, the differential processing for self-generated stimuli raises the possibility of producing effects also on memory for these stimuli, however, evidence remains mixed as to the direction of the effects. Here, we assessed the effects of actions on sensory processing and memory encoding of concomitant, but unpredictable sounds, using a combination of self-generation and memory recognition task concurrently with EEG and pupil recordings. At encoding, subjects performed button presses that half of the time generated a sound (motor-auditory; MA) and listened to passively presented sounds (auditory-only; A). At retrieval, two sounds were presented and participants had to respond which one was present before. We measured memory bias and memory performance by having sequences where either both or only one of the test sounds were presented at encoding, respectively. Results showed worse memory performance – but no differences in memory bias – and attenuated responses and larger pupil diameter for MA compared to A sounds. Critically, the larger the sensory attenuation and pupil diameter, the worse the memory performance for MA sounds. Nevertheless, sensory attenuation did not correlate with pupil dilation. Collectively, our findings suggest that sensory attenuation and neuromodulatory processes coexist during actions, and both relate to disrupted memory for concurrent, albeit unpredictable sounds.
Simple contextual cueing prevents retroactive interference in short-term perceptual training of orientation detection tasks
Authors: Huang Hui , Zhang Yangming , Li Sheng 
Published: December 2021

AbstractPerceptual training of multiple tasks suffers from interference between the trained tasks. Here, we conducted four psychophysical experiments with separate groups of participants to investigate the possibility of preventing the interference in short-term perceptual training. We trained the participants to detect two orientations of Gabor stimuli in two adjacent days at the same retinal location and examined the interference of training effects between the two orientations. The results showed significant retroactive interference from the second orientation to the first orientation (Experiments 1 and 2). Introducing a 6-hour interval between the pre-test and training of the second orientation did not eliminate the interference effect, excluding the interpretation of disrupted reconsolidation as the pre-test of the second orientation may reactivate and destabilize the representation of the first orientation (Experiment 3). Finally, the training of the two orientations was accompanied by fixations in two colors, each served as a contextual cue for one orientation. The results showed that the retroactive interference was not evident after introducing these passively perceived contextual cues (Experiment 4). Our findings suggest that the retroactive interference effect in short-term perceptual training of orientation detection tasks was likely the result of higher-level factors such as shared contextual cues embedded in the tasks. The effect of multiple perceptual training could be facilitated by associating the trained tasks with different contextual cues.
Spatially bivariate EEG-neurofeedback can manipulate interhemispheric rebalancing of M1 excitability
Authors: Hayashi Masaaki , Okuyama Kohei , Mizuguchi Nobuaki , Hirose Ryotaro , Okamoto Taisuke , Kawakami Michiyuki , Ushiba Junichi 
Published: December 2021

AbstractHuman behavior requires interregional crosstalk to employ the sensorimotor processes in the brain. Although some external neuromodulation tools have been used to manipulate interhemispheric sensorimotor activity, a central controversy concerns whether this activity can be volitionally controlled. Experimental tools lack the power to up- or down-regulate the state of the targeted hemisphere over a large dynamic range and, therefore, cannot evaluate the possible volitional control of the activity. We overcame this difficulty by using the recently developed method of spatially bivariate electroencephalography (EEG)-neurofeedback to systematically enable participants to manipulate their bilateral sensorimotor activities. Herein, we report that bi-directional changes in ipsilateral excitability to the imagined hand (conditioning hemisphere) affect interhemispheric inhibition (IHI) assessed by paired-pulse transcranial magnetic stimulation paradigm. In addition, participants were able to robustly manipulate the IHI magnitudes. Further physiological analyses revealed that the self-manipulation of IHI magnitude reflected interhemispheric connectivity in EEG and TMS, which was accompanied by intrinsic bilateral cortical oscillatory activities. Our results provide clear neuroscientific evidence regarding the inhibitory interhemispheric sensorimotor activity and IHI manipulator, thereby challenging the current theoretical concept of recovery of motor function for neurorehabilitation.
isomiRs-specific differential expression is the rule, not the exception: Are we missing hundreds of species in microRNA analysis?
Authors: Schmauch Eloi , Laitinen Pia , Turunen Tiia A. , Väänänen Mari-Anna , Malm Tarja , Kellis Manolis , Kaikkonen Minna U , Linna-Kuosmanen Suvi 
Published: December 2021

ABSTRACTMicroRNAs (miRNAs) are small RNA molecules that act as regulators of gene expression through targeted mRNA degradation. They are involved in many biological and pathophysiological processes and are widely studied as potential biomarkers and therapeutics agents for human diseases, including cardiovascular disorders. Recently discovered isoforms of miRNAs (isomiRs) exist in high quantities and are very diverse. Despite having few differences with their corresponding reference miRNAs, they display specific functions and expression profiles, across tissues and conditions. However, they are still overlooked and understudied, as we lack a comprehensive view on their condition-specific regulation and impact on differential expression analysis. Here, we show that isomiRs can have major effects on differential expression analysis results, as their expression is independent of their host miRNA genes or reference sequences. We present two miRNA-seq datasets from human umbilical vein endothelial cells, and assess isomiR expression in response to senescence and compartment-specificity (nuclear/cytosolic) under hypoxia. We compare three different methods for miRNA analysis, including isomiR-specific analysis, and show that ignoring isomiRs induces major biases in differential expression. Moreover, isomiR analysis permits higher resolution of complex signal dissection, such as the impact of hypoxia on compartment localization, and differential isomiR type enrichments between compartments. Finally, we show important distribution differences across conditions, independently of global miRNA expression signals. Our results raise concerns over the quasi exclusive use of miRNA reference sequences in miRNA-seq processing and experimental assays. We hope that our work will guide future isomiR expression studies, which will correct some biases introduced by golden standard analysis, improving the resolution of such assays and the biological significance of their downstream studies.
Semantic representations during language comprehension are affected by context
Authors: Deniz Fatma , Tseng Christine , Wehbe Leila , la Tour Tom Dupré , Gallant Jack L. 
Published: December 2021

AbstractThe meaning of words in natural language depends crucially on context. However, most neuroimaging studies of word meaning use isolated words and isolated sentences with little context. Because the brain may process natural language differently from how it processes simplified stimuli, there is a pressing need to determine whether prior results on word meaning generalize to natural language. fMRI was used to record human brain activity while four subjects (two female) read words in four conditions that vary in context: narratives, isolated sentences, blocks of semantically similar words, and isolated words. We then compared the signal-to-noise ratio (SNR) of evoked brain responses, and we used a voxelwise encoding modeling approach to compare the representation of semantic information across the four conditions. We find four consistent effects of varying context. First, stimuli with more context evoke brain responses with higher SNR across bilateral visual, temporal, parietal, and prefrontal cortices compared to stimuli with little context. Second, increasing context increases the representation of semantic information across bilateral temporal, parietal, and prefrontal cortices at the group level. In individual subjects, only natural language stimuli consistently evoke widespread representation of semantic information. Third, context affects voxel semantic tuning. Finally, models estimated using stimuli with little context do not generalize well to natural language. These results show that context has large effects on the quality of neuroimaging data and on the representation of meaning in the brain. Thus, neuroimaging studies that use stimuli with little context may not generalize well to the natural regime.Significance StatementContext is an important part of understanding the meaning of natural language, but most neuroimaging studies of meaning use isolated words and isolated sentences with little context. Here we examined whether the results of neuroimaging studies that use out-of-context stimuli generalize to natural language. We find that increasing context improves the quality of neuroimaging data and changes where and how semantic information is represented in the brain. These results suggest that findings from studies using out-of-context stimuli may not generalize to natural language used in daily life.
A recurring YYDRxG pattern in broadly neutralizing antibodies to a conserved site on SARS-CoV-2, variants of concern, and related viruses
Authors: Liu Hejun , Kaku Chengzi I. , Song Ge , Yuan Meng , Andrabi Raiees , Burton Dennis R. , Walker Laura M. , Wilson Ian A. 
Published: December 2021

ABSTRACTStudying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally and functionally characterized a potent human antibody ADI-62113 that also neutralizes SARS-CoV- 2 variants of concern and cross-reacts with many other sarbecoviruses. A YYDRxG motif encoded by IGHD3-22 in CDR H3 facilitates targeting to a highly conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences identified many antibodies with broad neutralization activity against SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to counteract sarbecoviruses. These findings also suggest an epitope targeting strategy to identify potent and broadly neutralizing antibodies that can aid in the design of pan-sarbecovirus vaccines and antibody therapeutics.Short SummaryDecryption of a recurrent sequence feature in anti-SARS-CoV-2 antibodies identifies how potent pan-sarbecovirus antibodies target a conserved epitope on the receptor binding domain.