Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory T-cells

Objective: Atherosclerosis is an age-related disease characterised by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence a potential causative role of telomerase in atherogenesis is critically debated. Approach and Results: In this study we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent, as oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase-knock-out mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase (TERT) deficiency had no effect on Treg numbers in vivo or suppressive function ex vivo. Adoptive transfer of TERT-/- Tregs into Rag2-/- ApoE-/- double knock out mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. Conclusions: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.This study was supported, in part, by British Heart Foundation Project Grants PG/15/85/31744 and PG/12/47/29681 (www.BHF.org.uk) as well as the Newcastle Healthcare Charity (www.newcastle-hospitals. org.uk/patient-guides/charity-matters-at-newcastle-hospitals_charitable- funds.aspx). N.M. Al Zhrany was funded by a stipend from the Government of Saudi Arabia

Electrophysiological correlates of selective attention: A lifespan comparison

<p>Abstract</p> <p>Background</p> <p>To study how event-related brain potentials (ERPs) and underlying cortical mechanisms of selective attention change from childhood to old age, we investigated lifespan age differences in ERPs during an auditory oddball task in four age groups including 24 younger children (9–10 years), 28 older children (11–12 years), 31 younger adults (18–25), and 28 older adults (63–74 years). In the Unattend condition, participants were asked to simply listen to the tones. In the Attend condition, participants were asked to count the deviant stimuli. Five primary ERP components (N1, P2, N2, P3 and N3) were extracted for deviant stimuli under Attend conditions for lifespan comparison. Furthermore, Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) were computed as difference waves between deviant and standard tones, whereas Early and Late Processing Negativity (EPN and LPN) were calculated as difference waves between tones processed under Attend and Unattend conditions. These four secondary ERP-derived measures were taken as indicators for change detection (MMN and LDN) and selective attention (EPN and LPN), respectively. To examine lifespan age differences, the derived difference-wave components for attended (MMN and LDN) and deviant (EPN and LPN) stimuli were specifically compared across the four age groups.</p> <p>Results</p> <p>Both primary and secondary ERP components showed age-related differences in peak amplitude, peak latency, and topological distribution. The P2 amplitude was higher in adults compared to children, whereas N2 showed the opposite effect. P3 peak amplitude was higher in older children and younger adults than in older adults. The amplitudes of N3, LDN, and LPN were higher in older children compared with both of the adult groups. In addition, both P3 and N3 peak latencies were significantly longer in older than in younger adults. Interestingly, in the young adult sample P3 peak amplitude correlated positively and P3 peak latency correlated negatively with performance in the Identical Picture test, a marker measure of fluid intelligence.</p> <p>Conclusion</p> <p>The present findings suggest that patterns of event-related brain potentials are highly malleable within individuals and undergo profound reorganization from childhood to adulthood and old age.</p

Good vibrations, bad vibrations: Oscillatory brain activity in the attentional blink

The attentional blink (AB) is a deficit in reporting the second (T2) of two targets (T1, T2) when presented in close temporal succession and within a stream of distractor stimuli. The AB has received a great deal of attention in the past two decades because it allows to study the mechanisms that influence the rate and depth of information processing in various setups and therefore provides an elegant way to study correlates of conscious perception in supra-threshold stimuli. Recently evidence has accumulated suggesting that oscillatory signals play a significant role in temporally coordinating information between brain areas. This review focuses on studies looking into oscillatory brain activity in the AB. The results of these studies indicate that the AB is related to modulations in oscillatory brain activity in the theta, alpha, beta, and gamma frequency bands. These modulations are sometimes restricted to a circumscribed brain area but more frequently include several brain regions. They occur before targets are presented as well as after the presentation of the targets. We will argue that the complexity of the findings supports the idea that the AB is not the result of a processing impairment in one particular process or brain area, but the consequence of a dynamic interplay between several processes and/or parts of a neural network

Auditory event-related potentials

Auditory event related potentials are electric potentials (AERP, AEP) and magnetic fields (AEF) generated by the synchronous activity of large neural populations in the brain, which are time-locked to some actual or expected sound event

Electrical Brain Responses to an Auditory Illusion and the Impact of Musical Expertise

The presentation of two sinusoidal tones, one to each ear, with a slight frequency mismatch yields an auditory illusion of a beating frequency equal to the frequency difference between the two tones; this is known as binaural beat (BB). The effect of brief BB stimulation on scalp EEG is not conclusively demonstrated. Further, no studies have examined the impact of musical training associated with BB stimulation, yet musicians' brains are often associated with enhanced auditory processing. In this study, we analysed EEG brain responses from two groups, musicians and non-musicians, when stimulated by short presentation (1 min) of binaural beats with beat frequency varying from 1 Hz to 48 Hz. We focused our analysis on alpha and gamma band EEG signals, and they were analysed in terms of spectral power, and functional connectivity as measured by two phase synchrony based measures, phase locking value and phase lag index. Finally, these measures were used to characterize the degree of centrality, segregation and integration of the functional brain network. We found that beat frequencies belonging to alpha band produced the most significant steady-state responses across groups. Further, processing of low frequency (delta, theta, alpha) binaural beats had significant impact on cortical network patterns in the alpha band oscillations. Altogether these results provide a neurophysiological account of cortical responses to BB stimulation at varying frequencies, and demonstrate a modulation of cortico-cortical connectivity in musicians' brains, and further suggest a kind of neuronal entrainment of a linear and nonlinear relationship to the beating frequencies

Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory T-cells

Objective: Atherosclerosis is an age-related disease characterised by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence a potential causative role of telomerase in atherogenesis is critically debated. Approach and Results: In this study we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent, as oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase-knock-out mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase (TERT) deficiency had no effect on Treg numbers in vivo or suppressive function ex vivo. Adoptive transfer of TERT-/- Tregs into Rag2-/- ApoE-/- double knock out mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. Conclusions: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.This study was supported, in part, by British Heart Foundation Project Grants PG/15/85/31744 and PG/12/47/29681 (www.BHF.org.uk) as well as the Newcastle Healthcare Charity (www.newcastle-hospitals. org.uk/patient-guides/charity-matters-at-newcastle-hospitals_charitable- funds.aspx). N.M. Al Zhrany was funded by a stipend from the Government of Saudi Arabia

An orthogonal proteomic survey uncovers novel Zika virus host factors.

Zika virus (ZIKV) has recently emerged as a global health concern owing to its widespread diffusion and its association with severe neurological symptoms and microcephaly in newborns(1). However, the molecular mechanisms that are responsible for the pathogenicity of ZIKV remain largely unknown. Here we use human neural progenitor cells and the neuronal cell line SK-N-BE2 in an integrated proteomics approach to characterize the cellular responses to viral infection at the proteome and phosphoproteome level, and use affinity proteomics to identify cellular targets of ZIKV proteins. Using this approach, we identify 386 ZIKV-interacting proteins, ZIKV-specific and pan-flaviviral activities as well as host factors with known functions in neuronal development, retinal defects and infertility. Moreover, our analysis identified 1,216 phosphorylation sites that are specifically up-or downregulated after ZIKV infection, indicating profound modulation of fundamental signalling pathways such as AKT, MAPK-ERK and ATM-ATR and thereby providing mechanistic insights into the proliferation arrest elicited by ZIKV infection. Functionally, our integrative study identifies ZIKV host-dependency factors and provides a comprehensive framework for a system-level understanding of ZIKV-induced perturbations at the levels of proteins and cellular pathways