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eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Amelia E Hinman ◽  
Charul Jani ◽  
Stephanie C Pringle ◽  
Wei R Zhang ◽  
Neharika Jain ◽  
...  

For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes TB pathogenesis in both macrophage and murine infection models.


2021 ◽  
Author(s):  
Amelia E. Hinman ◽  
Charul Jani ◽  
Stephanie C. Pringle ◽  
Wei R. Zhang ◽  
Neharika Jain ◽  
...  

For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included TNF. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes TB pathogenesis in both macrophage and murine infection models.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Furkan Asan ◽  
Ayşegül Gündüz ◽  
Meral E. Kızıltan
Keyword(s):  

2021 ◽  
Vol 22 (19) ◽  
pp. 10513
Author(s):  
Aaron D. Kaplan ◽  
Humberto C. Joca ◽  
Liron Boyman ◽  
Maura Greiser

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF’s incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets. Over the past 20 years, a large body of research has shown that intracellular Ca2+ handling is dramatically altered in AF. While some of these changes are arrhythmogenic, other changes counteract cellular arrhythmogenic mechanisms (Calcium Signaling Silencing). The intracellular Na+ concentration ([Na+])i is a key regulator of intracellular Ca2+ handling in cardiac myocytes. Despite its importance in the regulation of intracellular Ca2+ handling, little is known about [Na+]i, its regulation, and how it might be changed in AF. Previous work suggests that there might be increases in the late component of the atrial Na+ current (INa,L) in AF, suggesting that [Na+]i levels might be high in AF. Indeed, a pharmacological blockade of INa,L has been suggested as a treatment for AF. Here, we review calcium signaling silencing and changes in intracellular Na+ homeostasis during AF. We summarize the proposed arrhythmogenic mechanisms associated with increases in INa,L during AF and discuss the evidence from clinical trials that have tested the pharmacological INa,L blocker ranolazine in the treatment of AF.


2020 ◽  
Author(s):  
Edgar Bermudez-Contreras ◽  
Andrea Gomez-Palacio Schjetnan ◽  
Artur Luczak ◽  
Majid H. Mohajerani

AbstractIn response to sensory stimulation, the cortex exhibits an early transient response followed by a late and slower activation pattern. Recent studies suggest that the early component represents features of the stimulus while the late component is associated with stimulus perception. In this work we study how patterns of evoked activity are modified by experience at meso and microcircuit scales using voltage and extracellular glutamate transient recordings over widespread regions of mice dorsal neocortex or single-unit activity recordings with multi-shank silicon probes in rat cortex. We find that repeated tactile or auditory stimulation selectively modifies the spatiotemporal patterns of activity mainly of the late evoked response at the mesoscale and microcircuit levels. This modification results not only in an increase in amplitude of the late response, but also in an increased similarity between the spatiotemporal patterns of the early and late evoked activity across trials. These changes are only present in the sensory area corresponding to the modality that received the repeated stimulation and they persisted up to one hour. Thus, this selective long-lasting spatiotemporal modification of the cortical activity patterns provides new insights about how perception-related cortical activity changes with sensory experience at multiple scales.


2020 ◽  
Vol 41 (7) ◽  
pp. 1759-1764
Author(s):  
Meral E. Kızıltan ◽  
Ayşegül Gündüz

2019 ◽  
Author(s):  
Peng Zan ◽  
Alessandro Presacco ◽  
Samira Anderson ◽  
Jonathan Z. Simon

AbstractAging is associated with an exaggerated representation of the speech envelope in auditory cortex. The relationship between this age-related exaggerated response and a listener’s ability to understand speech in noise remains an open question. Here, information-theory-based analysis methods are applied to magnetoencephalography (MEG) recordings of human listeners, investigating their cortical responses to continuous speech, using the novel non-linear measure of phase-locked mutual information between the speech stimuli and cortical responses. The cortex of older listeners shows an exaggerated level of mutual information, compared to younger listeners, for both attended and unattended speakers. The mutual information peaks for several distinct latencies: early (∼50 ms), middle (∼100 ms) and late (∼200 ms). For the late component, the neural enhancement of attended over unattended speech is affected by stimulus SNR, but the direction of this dependency is reversed by aging. Critically, in older listeners and for the same late component, greater cortical exaggeration is correlated with decreased behavioral inhibitory control. This negative correlation also carries over to speech intelligibility in noise, where greater cortical exaggeration in older listeners is correlated with worse speech intelligibility scores. Finally, an age-related lateralization difference is also seen for the ∼100 ms latency peaks, where older listeners show a bilateral response compared to younger listeners’ right-lateralization. Thus, this information-theory-based analysis provides new, and less coarse-grained, results regarding age-related change in auditory cortical speech processing, and its correlation with cognitive measures, compared to related linear measures.New & NoteworthyCortical representations of natural speech are investigated using a novel non-linear approach based on mutual information. Cortical responses, phase-locked to the speech envelope, show an exaggerated level of mutual information associated with aging, appearing at several distinct latencies (∼50, ∼100 and ∼200 ms). Critically, for older listeners only, the ∼200 ms latency response components are correlated with specific behavioral measures, including behavioral inhibition and speech comprehension.


2018 ◽  
Vol 115 (41) ◽  
pp. 10499-10504 ◽  
Author(s):  
Yin Yan ◽  
Li Zhaoping ◽  
Wu Li

Early sensory cortex is better known for representing sensory inputs but less for the effect of its responses on behavior. Here we explore the behavioral correlates of neuronal responses in primary visual cortex (V1) in a task to detect a uniquely oriented bar—the orientation singleton—in a background of uniformly oriented bars. This singleton is salient or inconspicuous when the orientation contrast between the singleton and background bars is sufficiently large or small, respectively. Using implanted microelectrodes, we measured V1 activities while monkeys were trained to quickly saccade to the singleton. A neuron’s responses to the singleton within its receptive field had an early and a late component, both increased with the orientation contrast. The early component started from the outset of neuronal responses; it remained unchanged before and after training on the singleton detection. The late component started ∼40 ms after the early one; it emerged and evolved with practicing the detection task. Training increased the behavioral accuracy and speed of singleton detection and increased the amount of information in the late response component about a singleton’s presence or absence. Furthermore, for a given singleton, faster detection performance was associated with higher V1 responses; training increased this behavioral–neural correlate in the early V1 responses but decreased it in the late V1 responses. Therefore, V1’s early responses are directly linked with behavior and represent the bottom-up saliency signals. Learning strengthens this link, likely serving as the basis for making the detection task more reflexive and less top-down driven.


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