Troelsenmccracken8134

The cell-cycle phase is a major determinant of repair pathway choice at DNA double strand breaks, non-homologous end joining (NHEJ), or homologous recombination (HR). Chk1 responds to genotoxic stress in S/G2 phase, but here, we report a role of Chk1 in directly promoting NHEJ repair in G1 phase. ASF1A is a histone chaperone, but it promotes NHEJ through a pathway independent of its histone-chaperone activity. Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. Chk1 deficiency suppresses all steps downstream of MDC1 following a DNA break in G1, namely histone ubiquitination, 53BP1 localization to the DNA break, and NHEJ. Thus, ASF1A phosphorylation by Chk1 is essential for DNA break repair by NHEJ in G1.Indoleamine 2,3-dioxygenases (IDOs) degrade l-tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments.Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence. Age-based analysis of human peripheral T cells reveals that levels of FOXO1 and its downstream target, TCF7, are inversely related to host age, whereas the opposite is found for AP-1 factors. These characteristics of aging also correlate with the formation of T cells manifesting features of cellular senescence. Our work illustrates a role for FOXO1 in the active maintenance of stem-like properties in T cells at the timescales of acute infection and organismal life span.Some scleractinian corals exhibit high thermal adaptability to climate changes, although the mechanism of their adaptation is unclear. This study investigated the adaptability of scleractinian coral Pocillopora damicornis to thermally variable reef environments by applying a nanopore-based RNA sequencing method to characterize different transcription responses that promote heat tolerance of P. damicornis. We identified 1414 novel genes and optimized 6256 mis-annotated loci. Based on full-length transcriptome data, we identified complex alternative polyadenylation and alternative splicing events, which can improve our understanding of the genome annotation and gene structures of P. damicornis. Furthermore, we constructed differentially expressed lncRNA-mRNA co-expression networks, which may play a crucial role in the P. damicornis thermal adaptive response. KEGG function enrichment analysis revealed that P. damicornis from the high-temperature pool had a lower metabolic rate than that from the low-temperature pool. We hypothesize that metabolic readjustment, in the form of a lower metabolic rate, positively correlated with increased heat tolerance in P. damicornis in thermally variable reef environments. Our study provides novel insights into lncRNAs that promote thermally tolerance of scleractinian corals in the thermally variable reef environment, suggesting potential mechanisms for their adaptation to global warming in the future.Astrocytes metabolically interact with neighboring neurons by providing multiple substances to neurons. How astrocytes regulate neural functions via altering the neuronal metabolic state remains elusive. Here, we demonstrate that astrocytic ApoE vectors a variety of microRNAs (miRNAs), and these miRNAs specifically silence genes involved in neuronal cholesterol biosynthesis, ultimately accounting for accumulation of the pathway-initiating substrate acetyl-CoA. Consequently, histone acetylation is promoted, and transcription is activated in neurons. Functionally, we demonstrate that ApoE-mediated neuronal histone acetylation leads to increased H3K27ac enrichment in the promoters of multiple neuronal immediate early genes and subsequently to enhanced memory consolidation in mice. Importantly, human ApoE4 vectors lower levels of miRNAs than ApoE3 and therefore is less capable of metabolic and epigenetic regulation in neurons. Collectively, our findings define an astrocytic ApoE-mediated neuronal epigenetic mechanism as a novel means through which astrocytes modulate brain connectivity and function.

We recently described the association between periodontal disease (PD) and stroke risk.

The purpose of this study was to test the association between PD, dental care utilization and incident atrial fibrillation (AF), as well as AF as a mediator to PD- stroke association.

In dental cohort of the Atherosclerosis Risk in Communities Study (ARIC), participants without prior AF underwent full-mouth periodontal measurements. PD was defined on an ordinal scale as healthy (referent), mild, moderate and severe. In ARIC main cohort, participants were classified as regular or episodic dental care users. ABT-869 chemical structure These patients were followed for AF, over 17 years. Cox proportional hazards models adjusted for AF risk factors were used to study relationships between PD severity, dental care utilization and AF. Mediation analysis was used to test if AF mediated the PD- stroke association.

In dental ARIC cohort, 5,958 were assessed without prior AF, 754 were found to have AF. Severe PD was associated with AF on both univariable (crude HR, 1.