Downregulation of Lnc-ABCA12-3 modulates UBQLN1 expression and protein homeostasis pathways in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.

Diagnostic value of expressions of cancer stem cell markers for adverse outcomes of hepatocellular carcinoma and their associations with prognosis: A Bayesian network meta­analysis.

The expression of cancer stem cell (CSC) markers adversely affect the survival prognosis of patients with hepatocellular carcinoma (HCC), but it is not clear which cancer stem cell marker has the best predictive effect on the survival prognosis and diagnostic value indicators of patients with HCC. Therefore, the present study performed a network meta-analysis to compare the prognostic and diagnostic value of the expressions of several CSC markers for patients with HCC and to identify the most efficient CSC marker. Studies on the associations of positive CSC markers with the overall survival (OS) rate, disease-free survival (DFS) rate, recurrence-free survival (RFS) rate, recurrence rate, differentiation, microvascular invasion and metastasis in patients with HCC were included in the network meta-analysis following searches on the PubMed, Embase, Elsevier and The Cochrane Library databases from January 1, 2013 to November 17, 2023. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the quality assessment of studies, and R (version 4.3.1), Stata (version 15.0) and Review Manager (version 5.3) were used for analysis. A total of 37 studies involving 3,980 participants were included. For patients with HCC, simultaneous positivity of cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM) was the strongest predictor of the OS rate [surface under the cumulative ranking curve (SUCRA), 78.65%], positive keratin 19 (K19) was the strongest predictor of the RFS and DFS rates (SUCRA, 98.93 and 84.95%, respectively), and simultaneous positivity of EpCAM and cluster of differentiation (CD)90 was the strongest predictor of the recurrence rate (SUCRA, 5.61%). In addition, positivity of CD56, K19 and CD133 had the best diagnostic efficacy for poor differentiation [superiority index, 7.4498; 95% confidence interval (CI): 0.3333, 13.0000], microvascular invasion (superiority index, 8.4777; 95% CI: 0.2308, 17.0000), and metastasis (superiority index, 5.6097; 95% CI: 0.3333, 11.0000), respectively. In conclusion, no single CSC marker possessed the best predictive effect on all indexes of survival prognosis and diagnosis of patients with HCC. In terms of survival prognosis, simultaneous positivity of CK19 and EpCAM demonstrated the strongest predictive effect on the OS rate, suggesting an association with a low OS rate in patients with HCC; positive K19 revealed the strongest predictive effect on the RFS rate and DFS rate, suggesting an association with low RFS and DFS rates in patients with HCC; and simultaneous positivity of EpCAM and CD90 had the strongest predictive effect on the recurrence rate, suggesting a high recurrence rate in patients with HCC patients. In terms of diagnostic value, CD56, K19 and CD133 were the strongest predictors of poor differentiation, microvascular invasion and metastasis, respectively. In the future, well-designed randomized controlled trials are required to further confirm these findings.

Protective role of serum albumin in dementia: a prospective study from United Kingdom biobank.

Background: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis. Methods: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis. Results: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = -0.024, SE = 0.004, p < 0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta = 0.003, SE = 3.30E-04, p < 0.001). No significant associations were found between albumin levels and the risk of PD or ALS. Conclusion: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials.

Reduced PTPRS expression promotes epithelial-mesenchymal transition of Schwann cells in NF1-related plexiform neurofibromas.

Plexiform neurofibromas (PNFs) are a prevalent and severe phenotype associated with NF1, characterized by a high teratogenic rate and potential for malignant transformation. The growth and recurrence of PNFs are attributed to aberrant proliferation and migration of Nf1-deficient Schwann cells. Protein tyrosine phosphatase receptor S (PTPRS) is believed to modulate cell migration and invasion by inhibiting the EMT process in NF1-derived malignant peripheral nerve sheath tumors. Nevertheless, the specific role of PTPRS in NF1-derived PNFs remains to be elucidated. The study utilized the GEO database and tissue microarray to illustrate a decrease in PTPRS expression in PNF tissues, linked to tumor recurrence. Furthermore, the down- and over-expression of PTPRS in Nf1-deficient Schwann cell lines resulted in the changes of cell migration and EMT processes. Additionally, RTK assay and WB showed that PTPRS knockdown can promote EGFR expression and phosphorylation. The restoration of EMT processes disrupted by alterations in PTPRS levels in Schwann cells can be achieved through EGFR knockdown and EGFR inhibitor. Moreover, high EGFR expression has been significantly correlated with poor prognosis. These findings underscore the potential role of PTPRS as a tumor suppressor in the recurrence of PNF via the regulation of EGFR-mediated EMT processes, suggesting potential targets for future clinical interventions.

Identifying Novel Proteins for Chronic Pain: Integration of Human Brain Proteomes and Genome-wide Association Data.

Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained elusive. We sought to identify key genes modulating chronic pain risk by regulating brain protein expression. We integrated brain proteomic data with the largest genome-wide dataset for multisite chronic pain (N = 387,649) in a proteome-wide association study (PWAS) using discovery and confirmatory proteomic datasets (N = 376 and 152) from the dorsolateral prefrontal cortex. Leveraging summary data-based Mendelian randomization and Bayesian colocalization analysis, we pinpointed potential causal genes, while a transcriptome-wide association study integrating 452 human brain transcriptomes investigated whether cis-effects on protein abundance extended to the transcriptome. Single-cell RNA-sequencing data and single-nucleus transcriptomic data revealed cell-type-specific expression patterns for identified causal genes in the dorsolateral prefrontal cortex and dorsal root ganglia (DRG), complemented by RNA microarray analysis of expression profiles in other pain-related brain regions. Of the 22 genes cis-regulating protein abundance identified by the discovery PWAS, 18 (82%) were deemed causal by summary data-based Mendelian randomization or Bayesian colocalization analysis analyses, with 7 of these 18 genes (39%) replicating in the confirmatory PWAS, including guanosine diphosphate-mannose pyrophosphorylase B, which also associated at the transcriptome level. Several causal genes exhibited selective expression in excitatory and inhibitory neurons, oligodendrocytes, and astrocytes, while most identified genes were expressed across additional pain-related brain regions. This integrative proteogenomic approach identified 18 high-confidence causal genes for chronic pain, regulated by cis-effects on brain protein levels, suggesting promising avenues for treatment research and indicating a contributory role for the DRG. PERSPECTIVE: The current post genome-wide association study analyses identified 18 high-confidence causal genes regulating chronic pain risk via cis-modulation of brain protein abundance, suggesting promising avenues for future chronic pain therapies. Additionally, the significant expression of these genes in the DRG indicated a potential contributory role, warranting further investigation.

Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.

BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS. METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival. RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039). CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.

Alzheimer's disease and oral manifestations: a bi-directional Mendelian randomization study.

Background: Epidemiological studies have provided evidence suggesting an association between Alzheimer's disease (AD) and various oral manifestations. However, conflicting conclusions have been drawn, and whether a causal association truly exists remains unclear. Methods: In order to investigate the potential causal association between AD and prevalent oral diseases, we conducted a bi-directional two-sample Mendelian randomization analysis based on summary statistics from genome-wide association studies of AD (N = 63,926), as well as mouth ulcer (N = 461,103), oral cavity cancer (N = 4,151), and periodontal disease (N = 527,652). Results: We identified that one standard increase in the risk of AD was causally associated with a reduced risk of oral cavity cancer (OR = 0.76, 95% CI: 0.63-0.92, p = 3.73 × 10-3). In the opposite direction, oral conditions were not causally associated with risk of AD. Conclusion: The present findings contributed to a better understanding of the correlation between AD and oral conditions, specifically oral cavity cancer. These results also identified new avenues for exploring the underlying mechanisms of oral cavity cancer.

Calcium channel blockers and Parkinson's disease: a systematic review and meta-analysis.

Background: The calcium channel has been considered to have great potential as a drug target for neuroprotective therapy in Parkinson's disease (PD), but previous studies yielded inconsistent results. Objectives: This study aimed to conduct a systematic review and meta-analysis to assess the relationship between using calcium channel blockers (CCBs) and the risk and progression of PD. Data sources and methods: The terms such as 'Parkinson's disease', 'PD', 'calcium channel blockers', and 'CCB' were used to search the literature published before 1 May 2023 in English databases, including PubMed, Embase, and Cochrane Library, for studies on CCB and PD. Data analysis was performed using Review Manager 5.3 software. Results: A total of 190 works of literature were preliminarily retrieved, and 177 works of literature were excluded by eliminating duplicates, reading abstracts, and reading full texts. A total of nine studies were finally included in the meta-analysis of the CCB and the risk of PD, and five studies were included in the systematic review of the CCB and the progression of PD. A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62-0.99). Conclusion: CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study. Registration: PROSPERO: CRD42024508242.

Sleep characteristics and risk of Alzheimer's disease: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Alzheimer's disease (AD) is on the rise in our aging society, making it crucial to identify additional risk factors to mitigate its increasing incidence. This systematic review and meta-analysis aimed to provide updated evidence regarding the association between sleep and AD. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE, and Web of Science databases from inception to July 2023 to identify longitudinal studies. Adjusted relative risks were pooled for each sleep characteristic, and a dose-response analysis was performed specifically for sleep duration. RESULTS: A total of 15,278 records were initially retrieved, and after screening, 35 records were ultimately included in the final analysis. The results showed that insomnia (RR, 1.43; 95%CI, 1.17-1.74), sleep-disordered breathing (RR, 1.22; 95%CI, 1.07-1.39), as well as other sleep problems, including sleep fragmentation and sleep-related movement disorders, were associated with a higher risk of developing AD, while daytime napping or excessive daytime sleepiness (RR, 1.18; 95%CI, 1.00-1.40) only exhibited a trend toward a higher risk of AD development. Furthermore, our analysis revealed a significant association between self-reported sleep problems (RR, 1.34; 95%CI, 1.26-1.42) and the incidence of AD, whereas this association was not observed with sleep problems detected by objective measurements (RR, 1.14; 95%CI, 0.99-1.31). Moreover, both quite short sleep duration (< 4 h) and long duration (> 8 h) were identified as potential risk factors for AD. CONCLUSIONS: Our study found the association between various types of sleep problems and an increased risk of AD development. However, these findings should be further validated through additional objective device-based assessments. Additional investigation is required to establish a definitive causal connection between sleep problems and AD.

Predictors for survival in patients with Alzheimer's disease: a large comprehensive meta-analysis.

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

Genome-wide DNA methylation analysis related to ALS patient progression and survival.

BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.

The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms underlying this neuronal cell death remain unclear. Numerous studies demonstrate abnormally elevated and active p53 in the central nervous system of ALS patients. Activation of p53-regulated pro-apoptotic signaling pathways may trigger motor neuron death. We previously reported decreased expression of the long non-coding RNA NR3C2-8:1 (Lnc-NR3C) in leukocytes of ALS patients. Here, we show lnc-NR3C promotes p53-mediated cell death in ALS by upregulating USP10 and promoting lnc-NR3C-triggered p53 activation, resulting in cell death. Conversely, lnc-NR3C knockdown inhibited USP10-triggered p53 activation, thereby protecting cells against oxidative stress. As a competitive endogenous RNA, lnc-NR3C competitively binds miR-129-5p, regulating the usp10/p53 axis. Elucidating the link between Lnc-NR3C and the USP10/p53 axis in an ALS cell model reveals a role for long non-coding RNAs in activating apoptosis. This provides new therapeutic opportunities in ALS.

Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.

Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer.

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.

Generation of induced pluripotent stem cell line LNDWCHi001-A from a patient with early-onset Parkinson's disease carrying the homozygous c.1898C > T (p. A633V) mutation in the PLA2G6 gene.

A variant of the phospholipase A2 group VI gene (PLA2G6, PARK14) has been found to cause early-onset Parkinson's disease (EOPD). In this study, we reprogrammed peripheral blood mononuclear cells from a 39-year-old patient with EOPD carrying a homozygous PLA2G6 mutation c.1898C > T (p. A633V) to generate the human induced pluripotent stem cell line LNDWCHi001-A. This cell line was identified based on pluripotent markers and displayed differentiation capacity, providing an essential model for studying the pathogenesis of EOPD and drug screening.

Lnc-HIBADH-4 Regulates Autophagy-Lysosome Pathway in Amyotrophic Lateral Sclerosis by Targeting Cathepsin D.

Amyotrophic lateral sclerosis (ALS) is the most prevalent and lethal class of severe motor neuron diseases (MND) with no efficacious treatment. The pathogenic mechanisms underlying ALS remain unclear. Nearly 90% of patients exhibit sporadic onset (sALS). Therefore, elucidating the pathophysiology of ALS is imperative. Long non-coding RNA (lncRNA) is a large class of non-coding RNAs that regulate transcription, translation, and post-translational processes. LncRNAs contribute to the pathogenesis of diverse neurodegenerative disorders and hold promise as targets for interference in the realm of neurodegeneration. However, the mechanisms of which lncRNAs are involved in ALS have not been thoroughly investigated. We identified and validated a downregulated lncRNA, lnc-HIBADH-4, in ALS which correlated with disease severity and overall survival. Lnc-HIBADH-4 acted as a "molecular sponge" regulating lysosomal function through the lnc-HIBADH-4/miR-326/CTSD pathway, thereby impacting autophagy-lysosome dynamics and the levels of cell proliferation and apoptosis. Therefore, this study discovered and revealed the role of lnc-HIBADH-4 in the pathogenesis of ALS. With further research, lnc-HIBADH-4 is expected to provide a new biomarker in the diagnosis and treatment of ALS.

Unraveling intratumoral complexity in metastatic dermatofibrosarcoma protuberans through single-cell RNA sequencing analysis.

Dermatofibrosarcoma protuberans (DFSP) stands as a rare and locally aggressive soft tissue tumor, characterized by intricated molecular alterations. The imperative to unravel the complexities of intratumor heterogeneity underscores effective clinical management. Herein, we harnessed single-cell RNA sequencing (scRNA-seq) to conduct a comprehensive analysis encompassing samples from primary sites, satellite foci, and lymph node metastases. Rigorous preprocessing of raw scRNA-seq data ensued, and employing t-distributed stochastic neighbor embedding (tSNE) analysis, we unveiled seven major cell populations and fifteen distinct subpopulations. Malignant cell subpopulations were delineated using infercnv for copy number variation calculations. Functional and metabolic variations of diverse malignant cell populations across samples were deciphered utilizing GSVA and the scMetabolism R packages. Additionally, the exploration of differentiation trajectories within diverse fibroblast subpopulations was orchestrated through pseudotime trajectory analyses employing CytoTRACE and Monocle2, and further bolstered by GO analyses to elucidate the functional disparities across distinct differentiation states. In parallel, we segmented the cellular components of the immune microenvironment and verified the presence of SPP1+ macrophage, which constituted the major constituent in lymph node metastases. Remarkably, the CellChat facilitated a comprehensive intercellular communication analysis. This study culminates in an all-encompassing single-cell transcriptome atlas, propounding novel insights into the multifaceted nature of intratumor heterogeneity and fundamental molecular mechanisms propelling metastatic DFSP.