Efficacy of longevity interventions in C. elegans is determined by early life activity of RNA splicing factors

Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using in vivo mini gene reporters in isogenic C. elegans, we show that alternative splicing of mRNAs related to lipid metabolism in young animals is coupled to subsequent life expectancy. Further, activity of RNA splicing factors REPO-1 and SFA-1 early in life modulates effectiveness of specific longevity interventions via POD-2/ACC1 and regulation of lipid utilization. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together these data suggest that activity of RNA splicing factors and the metabolic landscape early in life can modulate responsiveness to longevity interventions and may explain variance in efficacy between individuals.

NF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells

The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells (NPCs). Here, we provide evidence that the NF-κB pathway plays also a fundamental role during the differentiation of NPCs into astrocytes. First, we show that the NF-κB pathway is essential to initiate astrocytic differentiation as its early inhibition induces NPC apoptosis and impedes their differentiation. Second, we demonstrate that persistent NF-κB activation affects NPC-derived astrocyte differentiation. Tumor necrosis factor (TNF)-treated NPCs show NF-κB activation, maintain their multipotential and proliferation properties, display persistent expression of immature markers and inhibit astrocyte markers. Third, we analyze the effect of NF-κB activation on the main known astrocytic differentiation pathways, such as NOTCH and JAK-STAT. Our findings suggest that the NF-κB pathway plays a dual fundamental role during NPC differentiation into astrocytes: it promotes astrocyte specification, but its persistent activation impedes their differentiation.

Increased circulating microparticles and inflammatory factors aggravate coronavirus disease 2019 (COVID-19)

Background The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed tremendous challenges to the world's public health. The conditions of some patients can quickly progress to acute respiratory distress syndrome and even death. Current studies suggest that an outbreak of inflammatory response known as cytokine storm may play a key role in the process. This study was performed to investigate the relativity of the production of circulating microparticles (cMPs) and the expression of inflammatory factors (interleukin [IL]-6, IL-8 and IL-10) expression in the blood on the degree of COVID-19. Methods A total of 89 patients infected with SARS-CoV-2 were divided into four groups, namely, mild, moderate, severe and critically ill groups, according to China's COVID-19 Diagnosis and Treatment Program (6th trial version), and 30 healthy persons were selected as the control group. The groups were compared in terms of cMP production and IL-6, IL-8 and IL-10 levels in their blood, and the correlation between cMP production and the expression of inflammatory factors with the degree of COVID-19 were analysed. Results Differences in cMP production and IL-6, IL-8 and IL-10 expression levels among the five groups were statistically significant (P<0.05). Pearson correlation analysis showed a positive correlation between cMP production or the expression of IL-6, IL-8 and IL-10 and the degree of COVID-19 (cMP, r=0.981; IL-6, r=0.954; IL-8, r=0.863; IL-10, r=0.895; P<0.05). Conclusion Increased levels of cMP, IL-6, IL-8 and IL-10 aggravate COVID-19. cMP production and the expression of IL-6, IL-8 and IL-10 may predict the degree of COVID-19 to a certain extent. The early inhibition of cMP overproduction and IL-6, IL-8 and IL-10 expression may be an important therapeutic target for the prevention of COVID-19 progression.

Cue-inhibited ventrolateral periaqueductal gray neurons signal fear output and threat probability in male rats

The ventrolateral periaqueductal gray (vlPAG) is proposed to mediate fear responses to imminent danger. Previously we reported that vlPAG neurons showing short-latency increases in firing to a danger cue – the presumed neural substrate for fear output – signal threat probability in male rats (Wright et al., 2019). Here, we scrutinize the activity vlPAG neurons that decrease firing to danger. One cue-inhibited population flipped danger activity from early inhibition to late excitation: a poor neural substrate for fear output, but a better substrate for threat timing. A second population showed differential firing with greatest inhibition to danger, less to uncertainty and no inhibition to safety. The pattern of differential firing reflected the pattern of fear output, and was observed throughout cue presentation. The results reveal an expected vlPAG signal for fear output in an unexpected, cue-inhibited population.