Mutations spike in a reservoir of compromised immunity.

The hierarchy of immunosuppression predicts SARS-CoV-2 time to clearance and intrahost viral evolution.

O-GlcNAcylation of RIPK1 rescues red blood cells from necroptosis.

Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which O-GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that O-GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that O-GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in Ripk1 -/- MEFs. Thus, our study demonstrates that RIPK1 O-GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.

Self-forgiveness is associated with increased volumes of fusiform gyrus in healthy individuals.

Self-forgiveness (SF) involves a process through which negative moral emotions directed at the self are replaced by benevolence and acceptance. Lower SF scores can be associated with less self-compassion, higher psychological distress, and lower life dissatisfaction. However, neural correlates of SF have not been investigated yet. We enrolled a total of 79 healthy individuals. The Self-Forgiveness Scale (SFS), Self-Compassion Scale (SCS), Connor-Davidson Resilience Scale (CD-RISC), Beck Depression Inventory-II (BDI-II), and Beck Anxiety Inventory (BAI) were evaluated. Voxel-wise correlational analyses showed a significant positive correlation between the total SFS scores and gray matter volumes (GMVs) in the fusiform gyrus (FG). In addition, the GMVs in the FG were significantly positively associated with the total SCS and CD-RISC scores and negatively correlated with the total BDI-II and BAI scores. These findings suggest that the FG related to the mirror neuron system might be a neural correlate of SF. Furthermore, its increased volumes of FG in healthy individuals can be associated with the capacity to overcome stressful life events.

In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington's Disease.

White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington's disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4.

MTFMT deficiency correlates with reduced mitochondrial integrity and enhanced host susceptibility to intracellular infection.

Mitochondria behave as functional and structural hubs for innate defense against intracellular infection. While the mitochondrial membrane serves as a platform for the assembly of signaling complexes activated by intracellular infection, various danger molecules derived from impaired mitochondria activate innate signaling pathways. Using methionyl-tRNA formyl transferase (MTFMT)-deficient cells, which exhibit impaired mitochondrial activity, we examined the role of mitochondrial integrity in regulating innate defense against infection. Since MTFMT functions at the early steps of mitochondrial translation, its loss was expected to cause defects in mitochondrial activity. Under transient MTFMT gene silencing conditions, we observed shortened mitochondria along with reduced activity. MTFMT-silenced cells were more susceptible to intracellular infection, as examined by infection with RNA viruses and the intracellular bacterium Shigella flexneri. In support of this observation, MTFMT-silenced cells possessed lowered basal NF-κB activity, which remained low after S. flexneri infection. In addition, the mitochondrial accumulation of evolutionarily conserved signaling intermediate in Toll pathway (ECSIT), an adaptor protein for NF-κB activation, was significantly decreased in MTFMT-silenced cells, explaining the reduced NF-κB activity observed in these cells. Since impaired mitochondria likely release mitochondrial molecules, we evaluated the contribution of mitochondrial N-formyl peptides to the regulation of bacterial infection. Transient transfection of mitochondrial-derived N-formyl peptides favored S. flexneri infection, which was accompanied by enhanced bacterial survival, but did not affect host cell viability. However, transient transfection of mitochondrial-derived N-formyl peptides did not affect basal NF-κB activity. Altogether, these data suggest that the integrity of mitochondria is essential to their proper function in protecting against infection, as intact mitochondria not only block the release of danger molecules but also serve as signaling hubs for the downstream NF-κB pathway.

O-Linked N-Acetylglucosamine Modification of Mitochondrial Antiviral Signaling Protein Regulates Antiviral Signaling by Modulating Its Activity.

Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. Several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been identified; however, the direct regulatory mechanisms linking O-GlcNAcylation with antiviral RIG-I-like receptor signaling are not fully understood. In this study, we found that cellular levels of O-GlcNAcylation decline in response to infection with Sendai virus. We identified a heavily O-GlcNAcylated serine-rich region between amino acids 249-257 of the mitochondrial antiviral signaling protein (MAVS); modification at this site disrupts MAVS aggregation and prevents MAVS-mediated activation and signaling. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-ß. Taken together, these results suggest that O-GlcNAcylation of MAVS may be a master regulatory event that promotes host defense against RNA viruses.

Induction of Neurorestoration From Endogenous Stem Cells.

Neural stem cells (NSCs) persist in the subventricular zone lining the ventricles of the adult brain. The resident stem/progenitor cells can be stimulated in vivo by neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and/or physical exercise. In both animals and humans, the differentiation and survival of neurons arising from the subventricular zone may also be regulated by the trophic factors. Since stem/progenitor cells present in the adult brain and the production of new neurons occurs at specific sites, there is a possibility for the treatment of incurable neurological diseases. It might be feasible to induce neurogenesis, which would be particularly efficacious in the treatment of striatal neurodegenerative conditions such as Huntington's disease, as well as cerebrovascular diseases such as ischemic stroke and cerebral palsy, conditions that are widely seen in the clinics. Understanding of the molecular control of endogenous NSC activation and progenitor cell mobilization will likely provide many new opportunities as therapeutic strategies. In this review, we focus on endogenous stem/progenitor cell activation that occurs in response to exogenous factors including neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and an enriched environment. Taken together, these findings suggest the possibility that functional brain repair through induced neurorestoration from endogenous stem cells may soon be a clinical reality.

CTR9, a component of PAF complex, controls elongation block at the c-Fos locus via signal-dependent regulation of chromatin-bound NELF dissociation.

PAF complex (PAFc) is an RNA polymerase II associated factor that controls diverse steps of transcription. Although it is generally associated with actively transcribed genes, a repressive PAFc has also been suggested. Here, we report that PAFc regulates the transition from transcription initiation to transcription elongation. PAFc repressed IL-6-induced, but not TNF-α-induced, immediate early gene expression. PAFc constitutively associated with the 5'-coding region of the c-Fos locus, then transiently dissociated upon IL-6 stimulation. When CTR9, a component of PAFc, was depleted, higher levels of serine 5-phosphorylated or serine 2-phosphorylated forms of RNA Polymerase II were associated with the unstimulated c-Fos locus. We also observed an increased association of CDK9, a kinase component of the pTEF-b elongation factor, with the c-Fos locus in the CTR9-depleted condition. Furthermore, association of negative elongation factor, NELF, which is required to proceed to the elongation phase, was significantly reduced by CTR9 depletion, whereas elongation factor SPT5 recruitment was enhanced by CTR9 depletion. Finally, the chromatin association of CTR9 was specifically controlled by IL-6-induced kinase activity, because a JAK2 kinase inhibitor, AG-490, blocked its association. In conclusion, our data suggest that PAFc controls the recruitment of NELF and SPT5 to target loci in a signal- and locus-specific manner.

High-performance ambipolar transistors and inverters from an ultralow bandgap polymer.

High mobility ambipolor organic thin-film transistors based on an ultralow bandgap polymer are presented together with their morphological and optical properties. Hole and electron mobilities of this polymer are of 1.0 cm(2) V(-1) s(-1) and 0.7 cm(2) V(-1) s(-1), respectively. The inverter based on two identical ambipolar transistors exhibits a gain around 35.