Machine Learning-Derived Active Sleep as an Early Predictor of White Matter Development in Preterm Infants.

White matter dysmaturation is commonly seen in preterm infants admitted to the neonatal intensive care unit (NICU). Animal research has shown that active sleep is essential for early brain plasticity. This study aimed to determine the potential of active sleep as an early predictor for subsequent white matter development in preterm infants. Using heart and respiratory rates routinely monitored in the NICU, we developed a machine learning-based automated sleep stage classifier in a cohort of 25 preterm infants (12 females). The automated classifier was subsequently applied to a study cohort of 58 preterm infants (31 females) to extract active sleep percentage over 5-7 consecutive days during 29-32 weeks of postmenstrual age. Each of the 58 infants underwent high-quality T2-weighted magnetic resonance brain imaging at term-equivalent age, which was used to measure the total white matter volume. The association between active sleep percentage and white matter volume was examined using a multiple linear regression model adjusted for potential confounders. Using the automated classifier with a superior sleep classification performance [mean area under the receiver operating characteristic curve (AUROC) = 0.87, 95% CI 0.83-0.92], we found that a higher active sleep percentage during the preterm period was significantly associated with an increased white matter volume at term-equivalent age [ß = 0.31, 95% CI 0.09-0.53, false discovery rate (FDR)-adjusted p-value = 0.021]. Our results extend the positive association between active sleep and early brain development found in animal research to human preterm infants and emphasize the potential benefit of sleep preservation in the NICU setting.

Relationship between changes in the triglyceride glucose-body mass index and frail development trajectory and incidence in middle-aged and elderly individuals: a national cohort study.

BACKGROUND: Insulin resistance is linked to an increased risk of frailty, yet the comprehensive relationship between the triglyceride glucose-body mass index (TyG-BMI), which reflects weight, and frailty, remains unclear. This relationship is investigated in this study. METHODS: Data from 9135 participants in the China Health and Retirement Longitudinal Study (2011-2020) were analysed. Baseline TyG-BMI, changes in the TyG-BMI and cumulative TyG-BMI between baseline and 2015, along with the frailty index (FI) over nine years, were calculated. Participants were grouped into different categories based on TyG-BMI changes using K-means clustering. FI trajectories were assessed using a group-based trajectory model. Logistic and Cox regression models were used to analyse the associations between the TyG-BMI and FI trajectory and frail incidence. Nonlinear relationships were explored using restricted cubic splines, and a linear mixed-effects model was used to evaluate FI development speed. Weighted quantile regression was used to identify the primary contributing factors. RESULTS: Four classes of changes in the TyG-BMI and two FI trajectories were identified. Individuals in the third (OR = 1.25, 95% CI: 1.10-1.42) and fourth (OR = 1.83, 95% CI: 1.61-2.09) quartiles of baseline TyG-BMI, those with consistently second to highest (OR = 1.49, 95% CI: 1.32-1.70) and the highest (OR = 2.17, 95% CI: 1.84-2.56) TyG-BMI changes, and those in the third (OR = 1.20, 95% CI: 1.05-1.36) and fourth (OR = 1.94, 95% CI: 1.70-2.22) quartiles of the cumulative TyG-BMI had greater odds of experiencing a rapid FI trajectory. Higher frail risk was noted in those in the fourth quartile of baseline TyG-BMI (HR = 1.42, 95% CI: 1.28-1.58), with consistently second to highest (HR = 1.23, 95% CI: 1.12-1.34) and the highest TyG-BMI changes (HR = 1.58, 95% CI: 1.42-1.77), and those in the third (HR = 1.10, 95% CI: 1.00-1.21) and fourth quartile of cumulative TyG-BMI (HR = 1.46, 95% CI: 1.33-1.60). Participants with persistently second-lowest to the highest TyG-BMI changes (ß = 0.15, 0.38 and 0.76 respectively) and those experiencing the third to fourth cumulative TyG-BMI (ß = 0.25 and 0.56, respectively) demonstrated accelerated FI progression. A U-shaped association was observed between TyG-BMI levels and both rapid FI trajectory and higher frail risk, with BMI being the primary factor. CONCLUSION: A higher TyG-BMI is associated with the rapid development of FI trajectory and a greater frail risk. However, excessively low TyG-BMI levels also appear to contribute to frail development. Maintaining a healthy TyG-BMI, especially a healthy BMI, may help prevent or delay the frail onset.

Imbalance of T follicular helper cell subsets trigger the differentiation of pathogenic B cells in idiopathic membranous nephropathy.

OBJECTIVE: This study aims to elucidate the role of T follicular helper (Tfh) cells and their subsets in idiopathic membranous nephropathy (IMN). METHODS: The frequencies of Tfh cell subsets and B cell subsets in peripheral blood (PB) were detected in both IMN patients and healthy controls (HCs). The involvement of Tfh cells in the disease pathogenesis was examined by coculturing human Tfh cells with B cells. The dynamic changes of Tfh cells in PB or spleen were monitored in passive Heymann nephritis (PHN) rats. RESULTS: The frequencies of circulating Tfh (cTfh) cells, cTfh2 cells, and plasmablasts were enriched in the PB of patients with IMN. cTfh cells expressed higher ICOS, and lower BTLA than healthy counterparts. The frequency of ICOS + cTfh2 was associated with the severity of IMN, including 24h urine protein, IgG4 concentration and the IgG4: IgG ratio. Positive correlations were also observed between the frequency of cTfh2 cells with plasmablasts, serum IL-21 and IL-4 levels. Importantly, cTfh cells isolated from IMN patients were able to induce the differentiation of B cells to memory B cells (MBC) and plasmablasts, this process could be substantially attenuated by blocking the IL-21. Similar increases of ICOS + cTfh cells were also detected in spleen of PHN rats, concomitant with elevated urine protein levels. CONCLUSIONS: Collectively, our results demonstrate that the imbalance of cTfh cell subsets play a crucial pathogenic role in IMN by inducing the differentiation of B cells through IL-21, and cTfh2 cells might serve as useful markers to evaluate the progression of IMN.

[Effect and mechanism of Jiedu Huoxue Decoction in regulating YAP/ACSL4 pathway to inhibit ferroptosis in treatment of acute kidney injury].

Jiedu Huoxue Decoction(JDHX), first recorded in the Correction on Errors in Medical Works by WANG Qing-ren, is an effective formula screened out from ancient formulas by the traditional Chinese medicine(TCM) master ZHANG Qi to treat acute kidney injury(AKI) caused by heat, toxicity, stasis, and stagnation. This paper elucidated the therapeutic effect of JDHX on AKI and probed into the potential mechanism from ferroptosis. Thirty-two male C57BL/6 mice were randomized into four groups(n=8): normal, model, and low-and high-dose JDHX. Since the clinical treatment of AKI depends on supportive or alternative therapies and there is no specific drug, this study did not include a positive drug group. The low dose of JDHX corresponded to half of clinically equivalent dose, while the high dose corresponded to the clinically equivalent dose. Mice were administrated with JDHX by gavage daily for 7 consecutive days, while those in the normal group and the model group were administered with the corresponding volume of distilled water. On day 5 of drug administration, mice in other groups except the normal group were injected intraperitoneally with cisplatin solution at a dose of 20 mg·kg~(-1) to induce AKI, and the normal group was injected with saline. All of the mice were sacrificed 72 h after modeling, blood and kidney samples were collected for subsequent analysis. The levels of serum creatine(Scr) and blood urea nitrogen(BUN) were measured by the commercial kits. The expression level of kidney injury molecule 1(KIM-1) in the serum was measured by enzyme-linked immunosorbent assay. Hematoxylin-eosin(HE) staining, periodic acid-Schiff(PAS) staining, and Prussian blue staining were employed to observe the pathological changes, glycogen deposition, and iron deposition, respectively, in the renal tissue. In addition, the levels of glutathione(GSH), superoxide dismutase(SOD), and catalase(CAT) in the renal tissue were examined by biochemical colorimetry. Western blot was performed to determine the protein levels of acyl-CoA synthetase long chain family member 4(ACSL4), lysophosphatidylcholine acyltransferase 3(LPCAT3), and Yes-associated protein(YAP, a key molecule in the Hippo pathway) in the renal tissue. Immunohistochemistry was then employed to detect the location and expression of YAP in the renal tissue. Real-time fluorescence quantitative polymerase chain reaction(qRT-PCR) was performed to measure the mRNA levels of ACSL4 and glutathione peroxidase 4(GPX4). Compared with the normal group, the model group showed elevated serum levels of Scr, BUN, and KIM-1. In the AKI model group, the tubular epithelial cells underwent atrophy and necrotic detachment, disappearance of brush border, and some tubules became protein tubules or experienced vacuole-like degeneration. In addition, this group presented widening of the interstitium or even edema, increased renal tubule injury score, and obvious glycogen and iron deposition in parts of the renal tissue. Moreover, the model group had lower GSH, SOD, and CAT levels, higher ASCL4 and LPCAT3 levels, and lower GPX4 expression and higher YAP expression than the normal group. Compared with the model group, high dose of JDHX effectively protected renal function, lowered the levels of Scr, BUN and KIM-1, alleviated renal pathological injury, reduced glycogen and iron deposition, and elevated the GSH, SOD, and CAT levels in the renal tissue. Furthermore, JDHX down-regulated the protein levels of ACSL4, LPCAT3, and YAP and up-regulated the level of GPX4, compared with the model group. In conclusion, JDHX can protect mice from cisplatin-induced AKI by inhibiting ferroptosis via regulating the YAP/ACSL4 signaling pathway.

HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1.

HPGD encodes 15-Hydroxyprostaglandin dehydrogenase catalyzing the decomposition of prostaglandin E2 and has not been reported in multiple sclerosis (MS). We previously found that Nr4a1 regulated microglia polarization and inhibited the progression of experimental autoimmune encephalomyelitis (EAE). Bioinformatics analysis suggested that HPGD might be regulated by Nr4a1. Therefore, this study aimed to explore the role of HPGD in microglia polarization and determine whether HPGD mediates the inhibition of EAE by Nr4a1. C57BL/6 mice were treated with MOG35-55 peptide to induce EAE. BV-2 cells were treated with LPS/IL-4 to induce M1/M2 polarization. We then analyzed the pathological changes of spinal cord tissue, detected the expression levels of M1/M2 genes in tissues and cells, and explored the effect of HPGD on PPARγ activation to clarify the role of HPGD in EAE. The interaction between HPGD and Nr4a1 was verified by ChIP and pull-down assay. HPGD was downregulated in the spinal cord of EAE mice and HPGD overexpression alleviated the progression of EAE. Experiments in vitro and in vivo revealed that HPGD inhibited M1 polarization, promoted M2 polarization and increased PPARγ-DNA complex level. Nr4a1 could bind to the promoter of HPGD and its overexpression increased HPGD level. HPGD overexpression (or knockdown) reversed the effect of Nr4a1 knockdown (or overexpression) on M1/2 polarization. HPGD is regulated by Nr4a1 and inhibits the progression of EAE through shifting the M1/M2 polarization and promoting the activation of PPARγ signaling pathway. This study provides potential targets and basis for the development of MS therapeutic drugs.

A review and new perspective on oral bacteriophages: manifestations in the ecology of oral diseases.

Objective: To explore the manifestations of bacteriophages in different oral disease ecologies, including periodontal diseases, dental caries, endodontic infections, and oral cancer, as well as to propel phage therapy for safer and more effective clinical application in the field of dentistry. Methods: In this literature review, we outlined interactions between bacteriophages, bacteria and even oral cells in the oral ecosystem, especially in disease states. We also analyzed the current status and future prospects of phage therapy in the perspective of different oral diseases. Results: Various oral bacteriophages targeting at periodontal pathogens as Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola and Aggregatibacter actinomycetemcomitans, cariogenic pathogen Streptococcus mutans, endodontic pathogen Enterococcus faecalis were predicted or isolated, providing promising options for phage therapy. In the realm of oral cancer, aside from displaying tumor antigens or participating in tumor-targeted therapies, phage-like particle vaccines demonstrated the potential to prevent oral infections caused by human papillomaviruses (HPVs) associated with head-and-neck cancers. Conclusion: Due to their intricate interactions with bacteria and oral cells, bacteriophages are closely linked to the progression and regression of diverse oral diseases. And there is an urgent need for research to explore additional possibilities of bacteriophages in the management of oral diseases.

Novel insights into the protective effects of leonurine against acute kidney injury: Inhibition of ER stress-associated ferroptosis via regulating ATF4/CHOP/ACSL4 pathway.

Acute kidney injury (AKI) is a common and serious global health problem with high risks of mortality and the development of chronic kidney diseases. Leonurine is a unique bioactive component from Leonurus japonicus Houtt. and exerts antioxidant, antiapoptotic or anti-inflammatory properties. This study aimed to explore the benefits of leonurine on AKI and the possible mechanisms involved, with a particular foc on the regulation of ferroptosis and endoplasmic reticulum (ER) stress. Our results showed that leonurine exhibited prominent protective effects against AKI, as evidenced by the amelioration of histopathological alterations and reduction of renal dysfunction. In addition, leonurine significantly suppressed ferroptosis in AKI both in vivo and in vitro by effectively restoring ultrastructural abnormalities in mitochondria, decreasing ASCL4 and 4-HNE levels, scavenging reactive oxygen species (ROS), as well as increasing GPX4 and GSH levels. In parallel, leonurine also markedly mitigated ER stress via down-regulating PERK, eIF-2α, ATF4, CHOP and CHAC1. Further studies suggested that ER stress was closely involved in erastin-induced ferroptosis, and leonurine protected tubular epithelial cells in vitro by inhibiting ER stress-associated ferroptosis via regulating ATF4/CHOP/ASCL4 signalling pathway. Mechanistically, ATF4 silencing in vitro regulated CHOP and ACSL4 expressions, ultimately weakening both ER stress and ferroptosis. Notably, analyses of single-cell RNA sequencing data revealed that ATF4, CHOP and ASCL4 in renal tubular cells were all abnormally upregulated in patients with AKI compared to healthy controls, suggesting their contributions to the pathogenesis of AKI. Altogether, these findings suggest that leonurine alleviates AKI by inhibiting ER stress-associated ferroptosis via regulating ATF4/CHOP/ASCL4 signalling pathway, thus providing novel mechanisms for AKI treatment.

Oral microbiome sequencing revealed the enrichment of Fusobacterium sp., Porphyromonas sp., Campylobacter sp., and Neisseria sp. on the oral malignant fibroma surface of giant panda.

Introduction: Microbial community composition is closely associated with host disease onset and progression, underscoring the importance of understanding host-microbiota dynamics in various health contexts. Methods: In this study, we utilized full-length 16S rRNA gene sequencing to conduct species-level identification of the microorganisms in the oral cavity of a giant panda (Ailuropoda melanoleuca) with oral malignant fibroma. Results: We observed a significant difference between the microbial community of the tumor side and non-tumor side of the oral cavity of the giant panda, with the latter exhibiting higher microbial diversity. The tumor side was dominated by specific microorganisms, such as Fusobacterium simiae, Porphyromonas sp. feline oral taxon 110, Campylobacter sp. feline oral taxon 100, and Neisseria sp. feline oral taxon 078, that have been reported to be associated with tumorigenic processes and periodontal diseases in other organisms. According to the linear discriminant analysis effect size analysis, more than 9 distinct biomarkers were obtained between the tumor side and non-tumor side samples. Furthermore, the Kyoto Encyclopedia of Genes and Genomes analysis revealed that the oral microbiota of the giant panda was significantly associated with genetic information processing and metabolism, particularly cofactor and vitamin, amino acid, and carbohydrate metabolism. Furthermore, a significant bacterial invasion of epithelial cells was predicted in the tumor side. Discussion: This study provides crucial insights into the association between oral microbiota and oral tumors in giant pandas and offers potential biomarkers that may guide future health assessments and preventive strategies for captive and aging giant pandas.

Association between sleep stages and brain microstructure in preterm infants: Insights from DTI analysis.

STUDY OBJECTIVES: The aim of this study was to investigate the relationship between sleep stages and neural microstructure - measured using diffusion tensor imaging - of the posterior limb of the internal capsule and corticospinal tract in preterm infants. METHODS: A retrospective cohort of 50 preterm infants born between 24 + 4 and 29 + 3 weeks gestational age was included in the study. Sleep stages were continuously measured for 5-7 consecutive days between 29 + 0 and 31 + 6 weeks postmenstrual age using an in-house-developed, and recently published, automated sleep staging algorithm based on routinely measured heart rate and respiratory rate. Additionally, a diffusion tensor imaging scan was conducted at term equivalent age as part of standard care. Region of interest analysis of the posterior limb of the internal capsule was performed, and tractography was used to analyze the corticospinal tract. The association between sleep and white matter microstructure of the posterior limb of the internal capsule and corticospinal tract was examined using a multiple linear regression model, adjusted for potential confounders. RESULTS: The results of the analyses revealed an interaction effect between sleep stage and days of invasive ventilation on the fractional anisotropy of the left and right posterior limb of the internal capsule (ß = 0.04, FDR-adjusted p = 0.001 and ß = 0.04, FDR-adjusted p = 0.02, respectively). Furthermore, an interaction effect between sleep stage and days of invasive ventilation was observed for the radial diffusivity of the mean of the left and right PLIC (ß = -4.1e-05, FDR-adjusted p = 0.04). CONCLUSIONS: Previous research has shown that, in very preterm infants, invasive ventilation has a negative effect on white matter tract maturation throughout the brain. A positive association between active sleep and white matter microstructure of the posterior limb of the internal capsule, may indicate a protective role of sleep in this vulnerable population.

Inhibition of Streptococcus mutans growth and biofilm formation through protein acetylation.

Numerous cellular processes are regulated in response to the metabolic state of the cell, and one such regulatory mechanism involves lysine acetylation. Lysine acetylation has been proven to play an important role in the virulence of Streptococcus mutans, a major cariogenic bacterial species. S. mutans' glucosyltransferases (Gtfs) are responsible for synthesizing extracellular polysaccharides (EPS) and contributing to biofilm formation. One of the most common nonsteroidal anti-inflammatory drugs is acetylsalicylic acid (ASA), which can acetylate proteins through a nonenzymatic transacetylation reaction. Herein, we investigated the inhibitory effects of ASA on S. mutans. ASA treatment was observed to impede the growth of S. mutans, leading to a reduction in the production of water-insoluble EPS and the formation of biofilm. Moreover, ASA decreased the enzyme activity of Gtfs while increasing the protein acetylation level. The in vivo anticaries efficacy of ASA has further been proved using the rat caries model. In conclusion, ASA as an acetylation agent attenuated the cariogenic virulence of S. mutans, suggesting the potential value of protein acetylation on antimicrobial and anti-biofilm applications to S. mutans.

Analysis of the chemical constituents and their metabolites in Orthosiphon stamineus Benth. via UHPLC-Q exactive orbitrap-HRMS and AFADESI-MSI techniques.

BACKGROUND: Known for its strong diuretic properties, the perennial herbaceous plant Orthosiphon stamineus Benth. is believed to preserve the kidney disease. This study compared the boiling water extract with powdered Orthosiphon stamineus Benth. and used a highly sensitive and high resolution UHPLC-Q-Exactive-Orbitrap-HRMS technology to evaluate its chemical composition. RESULTS: Furthermore, by monitoring the absorption of prototype components in rat plasma following oral treatment, the beneficial ingredients of the Orthosiphon stamineus Benth. decoction was discovered. Approximately 92 substances underwent a preliminary identification utilizing relevant databases, relevant literature, and reference standards. As the compound differences between the powdered Orthosiphon stamineus Benth. and its water decoction were analyzed, it was found that boiling produced additional compounds, 48 of which were new. 45 blood absorption prototype components and 49 OS metabolites were discovered from rat serum, and a kidney tissue homogenate revealed an additional 28 prototype components. Early differences in the distribution of ferulic acid, cis 4 coumaric acid, and rosmarinic acid were shown using spatial metabolomics. It was elucidated that the renal cortex region is where rosmarinic acid largely acts, offering a theoretical foundation for further studies on the application of OS in the prevention and treatment of illness as well as the preservation of kidney function. SIGNIFICANCE: In this study, UHPLC-Q Exactive Orbitrap-HRMS was employed to discern OS's chemical composition, and a rapid, sensitive, and broad-coverage AFADESI-MSI method was developed to visualize the spatial distribution of compounds in tissues.

The pathogenic mechanism of monosodium urate crystal-induced kidney injury in a rat model.

Objective: (MSU) crystals usually in the kidney tubules especially collecting ducts in the medulla. Previous animal models have not fully reproduced the impact of MSU on kidneys under non-hyperuricemic conditions. Methods: In the group treated with MSU, the upper pole of the rat kidney was injected intrarenally with 50 mg/kg of MSU, while the lower pole was injected with an equivalent volume of PBS solution. The body weight and kidney mass of the rats were observed and counted. H&E staining was used to observe the pathological damage of the kidney and to count the number of inflammatory cells. Masoon staining was used to observe the interstitial fibrosis in the kidneys of the rat model. Flow cytometric analysis was used for counting inflammatory cells in rats. ElISA was used to measure the concentration of serum and urine uric acid, creatinine and urea nitrogen in rats. Results: At the MSU injection site, a significantly higher infiltration of inflammatory cells and a substantial increase in the area of interstitial fibrosis compared to the control group and the site of PBS injection were observed. The serum creatinine level was significantly increased in the MSU group. However, there were no significant differences in the rats' general conditions or blood inflammatory cell counts when compared to the control group. Conclusion: The injection of urate crystals into the kidney compromised renal function, caused local pathological damage, and increased inflammatory cell infiltration and interstitial fibrosis. Intrarenal injection of MSU crystals may result in urate nephropathy. The method of intrarenal injection did not induce surgical infection or systemic inflammatory response.

O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.

Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification ß-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively. Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses. Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression. Conclusion: Collectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month old) and aged (23-month old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. To better assess the impact of chronic alcohol exposure, we fed young and aged mice alcohol for four weeks before completing Morris Water and Barnes Maze spatial memory testing. The aged mice showed worse spatial memory on both tests. While alcohol feeding slightly impaired spatial memory in the young mice, it had little effect or even slightly improved spatial memory in the aged mice. These findings suggest that aging is a far more important driver of spatial memory impairment and reduced autophagy flux than alcohol consumption.

Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change.

Background: Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer's disease (AD). Objective: To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association. Methods: We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1-5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and tangle burden. Results: In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate. Conclusions: As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect.