Supramolecular Aggregation of Carbon Nanodots.

Supramolecular aggregation has provided the archetype concept to understand the variants in an emerging systems property. Herein, we have achieved the supramolecular assembly of carbon nanodots (CDs) for the first time and employ supramolecular aggregation to understand their alteration in photophysical properties. In detail, we have employed the CDs as a block to construct the supramolecular assembly of aggregates in the CDs' antisolvent of ethanol. The CD-based aggregates exhibit complex and organized morphologies with another long-wavelength excitation-dependent emission band. The experimental results and density functional theoretical calculations reveal that the supramolecular assembly of CDs can decrease the energy gap between the ground and excited states, contributing to the new long-wavelength excitation-dependent emission. The supramolecular aggregation can be employed as one universal strategy to manipulate and understand the luminescence of CDs. These findings cast new light to build the emerging systems and understand the light emission of CDs through supramolecular chemistry.

In Situ Confining Citric Acid-Derived Carbon Dots for Full-Color Room-Temperature Phosphorescence.

Room-temperature phosphorescence has received much attention owing to its potential applications in information encryption and bioelectronics. However, the preparation of full-color single-component-derived phosphorescent materials remains a challenge. Herein, a facile in situ confining strategy is proposed to achieve full-color phosphorescent carbon dots (CDs) through rapid microwave-assisted carbonization of citric acid in NaOH. By tuning the mass ratio of citric acid and NaOH, the obtained CDs exhibit tunable phosphorescence wavelengths ranging from 483 to 635 nm and alterable lifetimes from 58 to 389 ms with a synthesis yield of up to 83.7% (>30 g per synthesis). Theoretical calculations and experimental results confirm that the formation of high-density ionic bonds between cations and CDs leads to efficient afterglow emission via the dissociation of CD arrangement, and the evolution of the aggregation state of CDs results in redshifted phosphorescence. These findings provide a strategy for the synthesis of new insights into achieving and manipulating room-temperature phosphorescent CDs, and prospect their applications in labeling and information encryption.

Relationship between filtering bleb vascularization and surgical outcomes after trabeculectomy: an optical coherence tomography angiography study.

PURPOSE: To explore the relationship between the bleb vasculature and surgical outcome after trabeculectomy (TRAB) using optical coherence tomography angiography (OCT-A). METHODS: A prospective study was conducted, which included 26 eyes of 26 primary glaucoma patients in the final analysis. Thereinto, six patients underwent TRAB combined 5-FU and 12 patients received subconjunctival 5-FU injection postoperation. The bleb vessel was evaluated using OCT-A 1 week, 2 weeks, 1 month, 3 months, and 6 months after TRAB. Intraocular pressure (IOP), filtering bleb height, and bleb wall thickness were recorded at the same time. Pearson's correlation analysis and linear regression analysis were performed to determine the correlation of the vessel area data with other parameters. RESULTS: Compared with vessel area 1 week after surgery, there was significant increase of the vessel area (△vessel area) 2 weeks (11.13 ± 11.91%, p < 0.05) and 1 month (16.91 ± 14.85%, p < 0.0001) after surgery in all patients. The △vessel area was significantly greater in acute angle closure (AAC) and primary angle closure glaucoma (PACG) 1-month post-TRAB as compared with that 1 week (p < 0.05). The results indicated that the △vessel area 1-month post-TRAB was positive correlated with IOP 6-month post-TRAB (ß = 3.88, p = 0.042). CONCLUSIONS: Filtering bleb vascularization evaluation using OCT-A could potentially predict IOP 6-month post-TRAB. Surgery effect predicted by filtering bleb vascularization detection is conducive to the select specific postoperative intervention to improve the success rate of TRAB.

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.

Zinc tungstate encapsulated into a scarce Zn(II)-viologen framework with photochromic, electrochromic and chemochromic properties.

Smart chromic materials reacting to physicochemical stimuli are widely applied in optical switches, smart windows, and chemical sensors. Currently, most materials only respond to a single stimulus, but those that respond to multiple external stimuli are still in the minority. Herein, we report a novel porous zinc tungstate@metaloxoviologen framework [Zn3(Bcbpy)6(H2O)2]-[ZnW12O40]·6H2O (ZnW12@MV, H2BcbpyCl2 = 1,1'-bis(3-carboxybenzyl)-4,4'-bipyridinium dichloride), which shows multiple stimulus-responsive properties due to a combination of different functional motifs, namely, viologen electron acceptors, luminescent zinc-oxygen-clusters, porous cationic frameworks, and ZnW12O406- electron donors. Generally, the large-sized polyoxometalate (POM) anions serving as structure-directing agents can easily direct the formation of the oligomeric metaloxoviologen cations, mainly because POMs may break down some linkages leaving larger spaces for themselves. The large ZnW12O406- anions in ZnW12@MV are encapsulated into three-dimensional (3D) metaloxoviologen frameworks built up from the linkages of trinuclear zinc-oxygen clusters and Bcbpy viologens, which offer the first example of a 3D metaloxoviologen framework induced by large-sized POM anions. ZnW12@MV shows a reversible chromic response to X-ray/UV and electricity via different stimulus-induced electron transfers between electron-rich POM anions and electron-deficient metaloxoviologen frameworks, whereas the coloration changes are ascribed to the formation of radical and mixed-valence colored state ZnW12O406- species. The photochromic behavior is accompanied by photoluminescence quenching. The discriminative response to different-sized amines is attributed to the formation of viologen radicals through host-guest electron transfer. These results indicate that the multi-stimulus response ZnW12@MV can be applied in electrochromic devices, inkless erasable printing, and the detection of amines.

Tunable photo/thermochromic properties of Cd(II)-viologen coordination polymers modulated by coordination modes for flexible imaging films and anti-counterfeiting.

Two photochromic Cd(II)-CPs were obtained based on the viologen ligand using different synthetic routes, named {[Cd4(p-BDC)4(CPB)2(H2O)2]·2H2O·EtOH}n (1) and {[Cd(p-BDC)(CPB)(H2O)]·(L)·DMF}n (2) (p-H2BDC = 1,4-benzene-dicarboxylate, HCPB·Cl = 1-(4-carboxyphenyl)-4,4'-bipyridinium·Cl, L = 2,4-dinitrochlorobenzene, and DMF = N,N-dimethylformamide), respectively. Due to different coordination modes, the two Cd(II)-CPs show different structures. Compound 1 exhibits a three-dimensional (3D) framework with bimetallic nodes, while compound 2 displays a 2-fold interpenetrated (4,4) net topology. Notably, the two Cd(II)-CPs exhibit substantial disparities in photo/thermochromism, which can be attributed to variations in donor-acceptor (D-A) distances arising from structural differences. Compound 1 showed visually sensitive photo- and thermochromic behavior due to multi-pathway electron transfer and short D-A distances, which is relatively rare in electron-transfer type photochromic systems. In contrast, 2 only demonstrates insensitive photochromic behavior, with a slight deepening of the color observed after 2 hours of UV light, which is due to the mono-pathway electron transfer and long D-A distance. Moreover, we first combined Cd(II)-viologen CPs with polydimethylsiloxane (PDMS) to prepare a 1@PDMS flexible UV imaging film. 1@PDMS exhibits excellent bendability and stretchability and maintains good photochromic properties after 100 bending cycles. To demonstrate the rapid color response and distinct color contrast of 1, its application in anti-counterfeiting is also demonstrated.

Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.

Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.

Photooxidation triggered ultralong afterglow in carbon nanodots.

It remains a challenge to obtain biocompatible afterglow materials with long emission wavelengths, durable lifetimes, and good water solubility. Herein we develop a photooxidation strategy to construct near-infrared afterglow carbon nanodots with an extra-long lifetime of up to 5.9 h, comparable to that of the well-known rare-earth or organic long-persistent luminescent materials. Intriguingly, size-dependent afterglow lifetime evolution from 3.4 to 5.9 h has been observed from the carbon nanodots systems in aqueous solution. With structural/ultrafast dynamics analysis and density functional theory simulations, we reveal that the persistent luminescence in carbon nanodots is activated by a photooxidation-induced dioxetane intermediate, which can slowly release and convert energy into luminous emission via the steric hindrance effect of nanoparticles. With the persistent near-infrared luminescence, tissue penetration depth of 20 mm can be achieved. Thanks to the high signal-to-background ratio, biological safety and cancer-specific targeting ability of carbon nanodots, ultralong-afterglow guided surgery has been successfully performed on mice model to remove tumor tissues accurately, demonstrating potential clinical applications. These results may facilitate the development of long-lasting luminescent materials for precision tumor resection.

Chemiluminescent carbon nanodots for dynamic and guided antibacteria.

Advanced antibacterial technologies are needed to counter the rapid emergence of drug-resistant bacteria. Image-guided therapy is one of the most promising strategies for efficiently and accurately curing bacterial infections. Herein, a chemiluminescence (CL)-dynamic/guided antibacteria (CDGA) with multiple reactive oxygen species (ROS) generation capacity and chemiexcited near-infrared emission has been designed for the precise theranostics of bacterial infection by employing near-infrared emissive carbon nanodots (CDs) and peroxalate as CL fuels. Mechanistically, hydrogen peroxide generated in the bacterial microenvironment can trigger the chemically initiated electron exchange between CDs and energy-riched intermediate originated from the oxidized peroxalate, enabling bacterial induced inflammation imaging. Meanwhile, type I/II photochemical ROS production and type III ultrafast charge transfer from CDs under the self-illumination can inhibit the bacteria proliferation efficiently. The potential clinical utility of CDGA is further demonstrated in bacteria infected mice trauma model. The self-illuminating CDGA exhibits an excellent in vivo imaging quality in early detecting wound infections and internal inflammation caused by bacteria, and further are proven as efficient broad-spectrum antibacterial nanomedicines without drug-resistance, whose sterilizing rate is up to 99.99%.

Endoscopic Partial Plantar Fasciotomy via 2 Medial Portals vs Mini-Open Procedure for Refractory Plantar Fasciitis.

BACKGROUND: The treatment of plantar fasciitis may require surgical intervention in patients with ineffective response to conservative treatment. There is a lack of evidence regarding the differences in clinical outcomes between the endoscopic and the mini-open procedures. The purpose of this study was to compare the clinical outcomes of the endoscopic partial plantar fasciotomy via 2 medial portals with mini-open partial plantar fasciotomy for treating refractory plantar fasciitis. METHODS: A retrospective analysis was carried out on 62 patients with refractory plantar fasciitis from January 2015 to July 2017. Thirty-three patients received endoscopic partial plantar fasciotomy, while the other 29 received mini-open procedure by patient preference. Two medial portals were used in the endoscopic group while single mini-medial method was used in the open group. All patients were followed up for 24 months. The pain visual analog scale (VAS), the American Orthopaedic Foot & Ankle Society (AOFAS) score, the calcaneodynia score (CS), and the 36-item Short Form Health Survey questionnaire (SF-36) were employed to evaluate the clinical outcomes of the 2 groups. RESULTS: There was increase in the functional scores (eg, VAS, AOFAS, CS, and SF-36) in both groups recorded at 3 months, 6 months, 1 year, and 2 years after surgery. The patients in the endoscopic group had better VAS, AOFAS, CS, and SF-36 scores at 3 months after the surgery compared with those of the open group. During the 6-month follow-up, although the 2 groups showed similar VAS and AOFAS, the CS and SF-36 scores of the endoscopic group were significantly higher than those of the open group. During the 1-year and 2-year follow-ups, the endoscopic group gained equivalent VAS, AOFAS, CS, and SF-36 scores compared with those of the open group. The recurrence rate was similar in both groups. Moreover, the patients in the endoscopic group achieved earlier recovery in comparison to those in the open group. CONCLUSION: For refractory plantar fasciitis, endoscopic partial plantar fasciotomy via 2 medial portals produced better short-term and equivalent long-term subjective outcomes than the mini-open surgery. LEVEL OF EVIDENCE: Level II, comparative study.

Lung cancer pathogenesis and poor response to therapy were dependent on driver oncogenic mutations.

AIMS: Lung cancer was the most fatal malignancy, dominated the cancer related mortality list for years, and we tried to distinguish the lung adenocarcinoma patients at higher risk from those bearing lower therapy resistance and recurrence risk. MATERIALS: Patients information from clinical Sequencing Cohorts and from the Regional Medical Center of the Middle-West China were included. The whole-exome sequencing was analyzed for risk evaluation. KEY FINDINGS: We found that Smoking stimulated the oncogenic genes mutations, and the most frequently mutated genes of EGFR, KRAS, and TP53 (E/K/P) were identified. Different N stage affected the survival prognosis of patients bearing E/K/P mutations, but the T stage and AJCC stage did not. Radiation failed to prolong survival of phase II/III patients who didn't receive surgery. In those received surgery, radiation also failed to prolong survival of phase II/III patients. Radiation did not improve the prognosis in patients bearing E/K/P mutation burdens, whose differences were identified in gender or smoking-history classified groups. SIGNIFICANCE: Smoking status and history contributed to oncogenic mutation burdens associated therapy resistance, and the aggressive treatment, especially to radiation, may lead to worse therapy response to current and past smoking behavior.

[Effects of long-term different fertilization regimes on the abundance and community structure of ammonia oxidizers in paddy soils]. / 长期不同施肥制度对水稻土氨氧化微生物数量和群落结构的影响.

Ammonia oxidation, driven by the ammonia oxidizers, is the rate-limiting step of nitrification and plays a key role in soil nitrogen cycling. In this study, real-time PCR and Illumina MiSeq sequencing approaches were used to investigate the effects of long-term different fertilization regimes on the abundance and community structure of ammonia oxidizers, targeting the amoA genes, in a 30-year located experimental paddy soil in Ningxiang County, Hunan Province. Four treatments were compared, including control without fertilizer (CK), fertilizers NPK (CF), 70% NPK plus 30% manure (CFM1), and 40% NPK plus 60% manure (CFM2). The results showed that the abundance of amoA genes in AOA and AOB was in the range of 3.09×107-8.37×107 and 1.04×107-7.03×107 copies·g-1 dry soil, respectively. Fertilization significantly increased the AOA and AOB abundances. However, no significant difference was observed in AOB abundance between CFM2 and CK. Manure fertilization rate greatly affected the α diversity index of AOB rather than AOA. The Shannon index of AOA and ACE and Chao1 indexes of AOB observed in CFM1 were significantly higher than that in CK, respectively. Thaumarchaeota and Crenarchaeota were the predominant AOA phyla and Nitrosospira, environmental_samples_norank, Bacteria_unclassified and Nitrosomonadales_unclassified were the main AOB genus groups which accounted for 83.4% and 97.8% of the total AOA and AOB amoA gene reads, respectively. Venn diagram indicated that manure fertilization rate had a stronger effect on the OTU number of AOB amoA gene than that of AOA in different treatments, but it slightly altered the proportion of shared AOA and AOB amoA gene reads. Furthermore, there were pronounced differences in the community structure of AOB among different treatments than that of AOA. These results suggested that manure fertilization rate significantly affected the abundance, diversity and community structure of AOA and AOB. The Shannon index of AOA and the abundance and ACE and Chao1 indexes of AOB in CFM1 were significantly higher than that in the rest treatments, respectively. Our results provided basis for further exploring the response mechanism of ammonia oxidizers to different fertilization strategies and the roles of ammonia oxidizers in nitrogen transformation in agricultural systems.

Overexpression of Csk-binding protein decreases growth, invasion, and migration of esophageal carcinoma cells by controlling Src activation.

AIM: To investigate the mechanisms by which Csk-binding protein (CBP) inhibits tumor progression in esophageal carcinoma. METHODS: A CBP overexpressing esophageal carcinoma cell line (TE-1) was established. The growth, invasion, and migration of CBP-TE-1 cells, as well as the expression of Src were then determined and compared with those in normal TE-1 cells. RESULTS: The expression of Src was decreased by the overexpression of CBP in TE-1 cells. The growth, invasion, and migration of TE-1 cells were decreased by the overexpression of CBP. CONCLUSION: This study indicates that CBP may decrease the metastasis of esophageal carcinoma by inhibiting the activation of Src. CBP may be a potential tumor suppressor and targeting the CBP gene may be an alternative strategy for the development of therapies for esophageal carcinoma.

Vitamin D receptor BsmI polymorphism and colorectal cancer risk: an updated analysis.

BACKGROUND: Previous studies have investigated the association between the vitamin D receptor (VDR) BsmI polymorphism and colorectal cancer (CRC) susceptibility, but the results were conflicting. The aim of this study is to quantitatively summarize the relationship between this polymorphism and CRC risk. MATERIALS AND METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure (CNKI) and Chinese Biomedicine databases for studies published before November 2013. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) for VDR BsmI polymorphism and CRC were calculated in a fixed- effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. RESULTS: This meta-analysis included 14 case-control studies, which included 10,822 CRC cases and 11,779 controls. Overall, the variant genotype (BB) of the BsmI was associated with a lower CRC risk when compared with the wild-type bb homozygote (OR=0.66, 95%CI: 0.49-0.88). Similarly, a decreased CRC risk was also found in the dominant and recessive models. When stratifying for ethnicity, source of controls, and study sample size, associations were observed among Caucasians, population-based studies and studies with large study sample size (>1000 subjects). Limiting the analysis to the studies within Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study. CONCLUSIONS: This updated meta-analysis suggests that the VDR BsmI polymorphism may be associated with a moderate protective effect against CRC.

[Expression of Csk-binding protein in esophageal carcinoma and its possible implications].

OBJECTIVE: To investigate the expression of Csk-binding protein (CBP) in esophageal carcinoma and its association with the tumorigenesis and progression of esophageal cancer. METHODS: RT-PCR and Western blotting were employed to determine the expressions of CBP at the mRNA and protein levels in 50 pairs of fresh esophageal carcinoma tissue and the adjacent normal tissues. RESULTS: CBP mRNA and protein expressions in normal tissues were 1.43- and 1.28-fold higher than those in the cancer tissues, respectively (P<0.05). The expressions of CBP mRNA and protein were positively correlated (P=0.015). The decreased expressions of CBP were significantly correlated to lymph node metastasis of esophageal cancer (P<0.05). CONCLUSION: The expression of CBP gene is decreased in esophageal carcinoma, which might contribute to the tumorigenesis and progression of this malignancy.

[Combination of dexamethasone with IL-2 selectively induces the expansion of CD4(+)CD25(+)FOXP3(+) regulatory T cells in vivo and suppresses graft versus host disease.].

OBJECTIVE: To establish a method for increasing T regulatory cells (Treg) in the graft by using in vivo treatment with dexamethasone (Dex) plus IL-2 and observe its suppressing effect on graft-versus-host-disease (GVHD) in mice. METHODS: After treatment of male C57BL/6N mice (donor) with Dex (5 mgxkg(-1)xd(-1)) combined with IL-2 (300 000 IUxmouse(-1)xday(-1)) for three days, spleen mononuclear cells were isolated for flow cytometry analysis of CD4(+)CD25(+) POXP3(+) Treg cells. The allogeneic lymphocytes were transplanted from male C57BL/6N mice to female BALB/c mice aged 8-12 weeks. GVHD and survival time were investigated after transplantation. Donor-derived hematopoiesis reconstituted in recipient mice was detected by Y-chromosome-specific PCR and H-2K(b) by flow cytometry. RESULTS: Administration of Dex and IL-2 markedly expanded functional CD4(+)CD25(+)FOXP3(+) Treg cells in murine spleen, the number of which in treated group was (24.2 +/- 7.6)% while in control group was (4.0 +/- 0.8)% (P = 0.01). The ratio of Treg to effector T cells (Teff) increased obviously in the treated group (0.43 +/- 0.15 vs 0.14 +/- 0.01, P = 0.01). In a murine allogeneic lymphocyte transplantation model, the grafts from donor with combined treatment of Dex and IL-2 led to a longer survival time than that from the control group (median survival time > 60 d vs 12 d, P = 0.0045), while the mortality rate was decreased (29.4% vs 71.4%, P < 0.05). CONCLUSION: Costimulation with Dex and IL-2 can selectively expand the functional CD4(+)CD25(+)FOXP3(+) Treg in vivo, which can suppress acute GVHD.

Neuronal regulated cell death in aging-related neurodegenerative diseases: key pathways and therapeutic potentials.

Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP + /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.