Abstract:   Lactate is a critical metabolite during the body’s adaption to exercise training, which effectively relieves anxiety-like disorders. The biological mechanism of lactate in the exercise-mediated anxiolytic effect has, however, not been comprehensively investigated. Here, we report that exercise-induced lactate markedly potentiates the lactylation of multiple synaptic proteins, among which synaptosome-associated protein 91 (SNAP91) is the critical molecule for synaptic functions. Both anatomical evidence and in vivo recording data showed that the lactylation of SNAP91 confers resilience against chronic restraint stress (CRS) via potentiating synaptic structural formation and neuronal activity in the medial prefrontal cortex (mPFC). More interestingly, exercise-potentiated lactylation of SNAP91 is necessary for the prevention of anxiety-like behaviors in CRS mice. These results collectively suggest a previously unrecognized non-histone lactylation in the brain for modulating mental functions and provide evidence for the brain’s metabolic adaption during exercise paradigms.

Yan L, Wang Y, Hu H, Yang D, Wang W, Luo Z, Wang Y, Yang F, So KF, Zhang L. Physical exercise mediates cortical synaptic protein lactylation to improve stress resilience. Cell Metab. 2024 Sep 3;36(9):2104-2117.e4. doi: 10.1016/j.cmet.2024.07.018. Epub 2024 Aug 19. PMID: 39163863.

https://pubmed.ncbi.nlm.nih.gov/39163863/

Abstract: Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1^−/Δmice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1^−/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1^−/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1^−/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.

Abstract

Yang H, Lu Z, Fu Y, Wu T, Hou Y. Stair climbing and risk of incident atrial fibrillation: Effect modulated by sex, genetic predisposition, and cardiorespiratory fitness. Nutr Metab Cardiovasc Dis. 2024 Oct 5:S0939-4753(24)00380-6. doi: 10.1016/j.numecd.2024.10.001. Epub ahead of print. PMID: 39448314.

https://pubmed.ncbi.nlm.nih.gov/39448314/

and

The role of exercise capacity in the health and longevity of centenarians

Venturelli M, Schena F, Richardson RS.: Maturitas. 2012 Aug 9;73(2):115–120. doi: 10.1016/j.maturitas.2012.07.009

https://pmc.ncbi.nlm.nih.gov/articles/PMC3618983/

Abstract: Both Alzheimer’s disease and vascular dementia are the result of disease processes that typically develop over several decades. Population studies have estimated that more than half of the risk for dementia is preventable or at least modifiable through behavioral adaptations. The association between these lifestyle factors and the risk of dementia is most evident for exposure in midlife. However, habits formed in middle age often reflect a lifetime of behavior patterns and living conditions. Therefore, individuals who, for example, are able to maintain healthy diets and regular exercise during their middle years are likely to benefit from these cognition-protective habits they have practiced throughout their lives. For numerous adult diseases, significant risks can often be traced back to early childhood. Suboptimal conditions during the perinatal period, childhood and adolescence can increase the risk of adult diseases, including stroke, heart disease, insulin resistance, hypertension and dementia. This review aims at summarizing some of the evidence for dementia risks from a life-time perspective with the goal of raising awareness for early dementia prevention and successful aging.

Kuhn HG, Skau S, Nyberg J. A lifetime perspective on risk factors for cognitive decline with a special focus on early events. Cereb Circ Cogn Behav. 2024 Mar 7;6:100217. doi: 10.1016/j.cccb.2024.100217. PMID: 39071743; PMCID: PMC11273094.

https://pubmed.ncbi.nlm.nih.gov/39071743/

Summary:

“A first-of-its-kind blood test that uses biomarkers to distinguish bipolar disorder from depression could slash the time it takes to get an accurate diagnosis from years to weeks, according to the company that developed the test — but some scientists have raised concerns about its validity. …”

https://www.nature.com/articles/d41586-024-03616-7

and

AI algorithm combined with RNA editing-based blood biomarkers to discriminate bipolar from major depressive disorders in an external validation multicentric cohort

Abstract:  “Bipolar disorder (BD) is a leading cause of disability worldwide, as it can lead to cognitive and functional impairment and premature mortality. The first episode of BD is usually a depressive episode and is often misdiagnosed as major depressive disorder (MDD). Growing evidence indicates that peripheral immune activation and inflammation are involved in the pathophysiology of BD and MDD. Recently, by developing a panel of RNA editing-based blood biomarkers able to discriminate MDD from depressive BD, we have provided clinicians a new tool to reduce the misdiagnosis delay observed in patients suffering from BD. The present study aimed at validating the diagnostic value of this panel in an external independent multicentric Switzerland-based cohort of 143 patients suffering from moderate to major depression. The RNA-editing based blood biomarker (BMK) algorithm developped allowed to accurately discriminate MDD from depressive BD in an external cohort, with high accuracy, sensitivity and specificity values (82.5 %, 86.4 % and 80.8 %, respectively). These findings further confirm the important role of RNA editing in the physiopathology of mental disorders and emphasize the possible clinical usefulness of the biomarker panel for optimization treatment delay in patients suffering from BD.”

Salvetat N, Checa-Robles FJ, Delacrétaz A, Cayzac C, Dubuc B, Vetter D, Dainat J, Lang JP, Gamma F, Weissmann D. AI algorithm combined with RNA editing-based blood biomarkers to discriminate bipolar from major depressive disorders in an external validation multicentric cohort. J Affect Disord. 2024 Jul 1;356:385-393. doi: 10.1016/j.jad.2024.04.022. Epub 2024 Apr 13. PMID: 38615844.

https://www.sciencedirect.com/science/article/pii/S0165032724006177

https://www.nature.com/immersive/d41586-024-03425-y/index.html

Significance: “Exposure to brighter nights and darker days causes circadian disruption, which accompanies poor health outcomes that increase mortality risk. Whether personal day and night light exposure predicts mortality risk is not known. This study captured ~13 million hours of data from light sensors worn by ~89,000 individuals who were over 40 y of age. Those with brighter nights and darker days had higher risk of premature mortality, after accounting for sociodemographic and lifestyle factors. Avoiding night light and seeking day light may promote optimal health and longevity, and this recommendation is both accessible and cost-effective.”

Windred DP, Burns AC, Lane JM, Olivier P, Rutter MK, Saxena R, Phillips AJK, Cain SW. Brighter nights and darker days predict higher mortality risk: A prospective analysis of personal light exposure in >88,000 individuals. Proc Natl Acad Sci U S A. 2024 Oct 22;121(43):e2405924121. doi: 10.1073/pnas.2405924121. Epub 2024 Oct 15. PMID: 39405349.

https://www.pnas.org/doi/10.1073/pnas.2405924121

Abstract:   Suicidal ideation (SI) is a significant precursor and risk marker for suicide behaviors in major depressive disorder (MDD). Exploration of SI trajectory from a longitudinal framework are essential for treatment guidelines and clinical management of suicide risk. This study sought to explore SI trajectories and its associated clinical, sociodemographic characteristics, and initial treatment among patients with MDD. We used data from a non-interventional, national multi-centered prospective cohort study. 1 461 patients with MDD were included in the growth mixture modeling using SI at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 6 months, 9 months, and 12 months as the indicator. A multinomial regression was employed with SI trajectory as the outcome and anhedonia, depressive symptoms, atypical depressive symptoms, pharmacological treatments, and other covariates as the predictors. Four distinct SI trajectories were identified: a consistently low SI trajectory(50.7%), a persistently mild SI trajectory(20.6%), a fast declined SI trajectory(8.9%), and a slowly declined trajectory(19.8%). Compared to those with a consistently low SI trajectory, a higher score of anhedonia was associated with an increased risk of experiencing persistently mild (RRR = 1.20, 95%CI: 1.05, 1.38) and slowly declined SI (1.54, 95%CI: 1.32, 1.80). Severity of depressive symptom was also positively associated with the risk of experiencing persistently mild (1.15, 95%CI: 1.13, 1.18) and slowly declined SI (1.17, 95%CI: 1.14, 1.21). And the risk of experiencing slowly declined SI was higher for those use SSRI(1.49, 95%CI: 1.02, 2.31), and for those use antidepressant and antipsychotic/mood stabilizer combined therapy (3.78, 95%CI: 1.48, 9.61). The findings of this study are potentially useful for clinical practice as critical indicators of profiles and interventions for prognosis among patients with MDD. Further research is warranted to explore potential modifiable factors and the association between SI trajectories and suicide behavior.

Ding R, Zhu X, Feng L, Xiao L, Zhang L, He P, Wang G. Trajectories and predictors of suicidal ideation in clinical characteristics and pharmacological treatments for major depressive disorder: a study based on a national multi-centered prospective cohort. Transl Psychiatry. 2024 Oct 6;14(1):422. doi: 10.1038/s41398-024-03115-3. PMID: 39370452; PMCID: PMC11456589.

https://pubmed.ncbi.nlm.nih.gov/39370452/

Abstract: 

Objective: Although Kawasaki disease (KD) is commonly regarded as a single disease entity, clinical subgroups have recently been described. We aimed to validate previous research on clinical subgroups and establish a KD subgroup differentiation model specific to China.

Methods: We analysed clinical data of 1682 patients diagnosed with KD at the Kunming Children’s Hospital from December 2014 to December 2022. We performed principal component analysis and hierarchical clustering on 13 continuous variables. Then, we grouped the patients based on the optimal number of clusters and analysed the clinical characteristics of each subgroup.

Results: We ultimately identified three subgroups. In cluster 1, younger patients predominantly exhibited the highest risk of coronary artery aneurysm and the lowest rate of intravenous immunoglobulin resistance. Cluster 2 was characterised by high inflammatory markers and a lowered risk of coronary artery aneurysm. Cluster 3 was characterised by liver involvement, with significant elevations in liver enzymes, gamma-glutamyl transferase and total bilirubin. We found a positive correlation between the ratio of the rising trend and intravenous immunoglobulin resistance. Cluster 1 and cluster 3 shared similarities with the previously identified younger age subgroup and liver subgroup, respectively, whereas cluster 2 was unique to our study.

Conclusions: Our study preliminarily validated a previous KD subgroup study and established a KD subgroup model in China.

Gong C, Liu K, Li B, Li Y, Gao H, Wang Z, Fu Y, Gao L, Hu L, Wang Y, Wang M, Zhao B, Liu X. Analysis and validation of clinical subgroups of Kawasaki disease in children in China: a retrospective study. BMJ Paediatr Open. 2024 Oct 15;8(1):e002650. doi: 10.1136/bmjpo-2024-002650. PMID: 39414342; PMCID: PMC11481108.

https://pubmed.ncbi.nlm.nih.gov/39414342/

Abstract:

Introduction: Kawasaki disease (KD), a common cause of acquired heart disease in children in developed countries, is primarily treated with intravenous immunoglobulin (IVIG), but some children demonstrate IVIG resistance with increased coronary artery injury risk. T cells have been demonstrated to be involved in the pathogenesis of KD and its treatment with IVIG. However, the role and mechanism of dual TCR T lymphocytes in the occurrence of KD and IVIG therapy remain unclear.

Methods: This study, based on scRNA-seq combined with TCR-seq technology, clustered the peripheral blood mononuclear cells of 3 healthy controls and 6 KD patients before and after IVIG treatment. Comparative analysis was conducted to investigate the differences in the proportion of single/dual receptor T cells, the characteristics of CDR3 repertoires, cell types, and the expression of transcription factors among the three groups. The study aimed to explore the correlation between dual TCR T cells and KD as well as IVIG treatment.

Results: In our experimental results, we observed the presence of dual TCR T cells in all three groups. However, compared to the healthy control group and the IVIG-treated group, the KD patients before IVIG treatment exhibited a lower proportion of dual TCR T cells, with variability between samples, ranging from 4% to 15%. Notably, after IVIG treatment, the proportion of dual TCR T cells significantly increased, stabilizing above 12%, and these T cells also exhibited clonal expansion and a preference for V gene usage. In addition we found differences in dual TCR T cell subsets among the three groups, for example, IVIG treatment increases the proportion of dual TCR Treg cells, but it still remains below that of healthy control groups, significantly higher proportions of both dual TCR CD8 central and effector memory T cells in IVIG-treated KD patients, and differences in the expression of transcription factors between single and dual TCR T cells. These results suggest dual TCR T cells correlate with KD and IVIG treatment.

Conclusion: Dual TCR T lymphocytes, especially dual TCR CD8 T cells and Treg cells, play crucial roles in the pathogenesis of KD and during IVIG treatment, providing strong support for further elucidating KD pathogenesis and optimizing treatment strategies.

Xu Y, Yuan Y, Mou L, Hui L, Zhang X, Yao X, Li J. scRNA+TCR-seq reveals the pivotal role of dual receptor T lymphocytes in the pathogenesis of Kawasaki disease and during IVIG treatment. Front Immunol. 2024 Oct 3;15:1457687. doi: 10.3389/fimmu.2024.1457687. PMID: 39421738; PMCID: PMC11484261.

https://pubmed.ncbi.nlm.nih.gov/39421738/