The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reac Show more
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. Show less
Microtubule and actin crosslinking factor 1 (MACF1) plays a critical role in cytoskeletal regulation. Pathogenic variants in We identified two Chinese patients with Our findings broaden the phenotypic Show more
Microtubule and actin crosslinking factor 1 (MACF1) plays a critical role in cytoskeletal regulation. Pathogenic variants in We identified two Chinese patients with Our findings broaden the phenotypic spectrum of The online version contains supplementary material available at 10.1186/s40246-026-00917-y. Show less
We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In Show more
We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA. Show less
BRAF, when mutated at V600E, is a well-known potent early oncogenic driver in papillary thyroid carcinoma (PTC), with potential prognostic and therapeutic implications. Non-V600E mutations are less co Show more
BRAF, when mutated at V600E, is a well-known potent early oncogenic driver in papillary thyroid carcinoma (PTC), with potential prognostic and therapeutic implications. Non-V600E mutations are less common and without clear functional or therapeutic significance. One class of non-V600E mutations is BRAF gene fusions, which typically involve the C-terminal kinase domain of BRAF joined to a wide repertoire of potential N-terminal fusion partners. The aim of this study was to employ a sequential algorithmic approach to identify patients with BRAF fusions based on an integrated analysis of histologic, immunohistochemistry (IHC), and molecular (NGS) features of BRAF-rearranged PTCs. Nine patients with PTC previously scrutinized as BRAF V600E negative by IHC were analyzed by NGS. The studied 9 cases showed conventional PTC growth; 2 cases displayed a minor high-grade component (tall cell and hobnailing, < 20%), 1 case qualified as high-grade differentiated thyroid carcinoma (presence of necrosis and mitotic activity > 5 MF/ 2 mm Show less
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and ga Show more
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and gain-of-function assays using shRNA-mediated knockdown and ectopic overexpression of MACF1 and NR2F1 in LUAD cell lines (H1299 and Calu-3). Cell proliferation, adhesion, and migration were assessed by CCK-8, EdU, crystal violet, and Transwell assays. In vivo tumor growth and metastasis were evaluated using subcutaneous and tail vein xenograft models in nude mice. RNA-seq and GSEA were performed to identify MACF1-regulated pathways, followed by nuclear-cytoplasmic fractionation, dual-luciferase reporter assays, and immunofluorescence to assess WNT/β-catenin activity. ChIP-qPCR and ChIP-seq data from ENCODE were used to validate NR2F1 binding to the MACF1 promoter. MACF1 knockdown significantly suppressed LUAD cell proliferation, DNA replication, adhesion, and migration, and reduced tumor burden and lung metastases in vivo. Mechanistically, MACF1 activated WNT/β-catenin signaling by promoting CTNNB1 nuclear translocation, which upregulated focal adhesion genes (Paxillin, FAK, ITGB1). CTNNB1 agonist TWS119 restored focal adhesion in MACF1-deficient cells. Bioinformatic prediction and ChIP validation identified NR2F1 as a transcription factor directly targeting the MACF1 promoter. NR2F1 deficiency reduced MACF1 expression and phenocopied its functional loss, while MACF1 overexpression rescued the impaired phenotype. Our study uncovers a previously unrecognized NR2F1-MACF1-WNT axis that drives focal adhesion formation and LUAD progression. Targeting this regulatory circuit may offer new avenues for anti-metastatic therapy in lung adenocarcinoma. 1. NR2F1 is identified as a direct upstream transcription factor that activates MACF1 expression in LUAD. 2. MACF1 promotes LUAD cell proliferation, adhesion, and migration by enhancing focal adhesion assembly. 3. MACF1 activates the WNT/CTNNB1 signaling cascade, facilitating CTNNB1 nuclear translocation and downstream target expression. 4. Loss of MACF1 impairs focal adhesion formation and metastatic potential both in vitro and in xenograft and tail vein models. 5. The NR2F1-MACF1-WNT axis represents a novel regulatory circuit driving LUAD metastasis and offers potential therapeutic targets. Show less
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidate Show more
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidated. This study aims to examine the prognostic significance of genes associated with immune-stromal scores and to explore their underlying mechanisms in ccRCC. Data from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) were subjected to analysis to compute immune and stromal scores utilizing the ESTIMATE algorithm. The weighted gene co-expression network analysis (WGCNA) was employed to identify gene modules associated with these scores. Differentially expressed genes were assessed using the limma package. Prognostic biomarkers were subsequently identified through univariate, LASSO, and multivariate Cox regression analyses, culminating in the development of a risk score model. Gene expression was confirmed in ccRCC cell lines (786-O, Caki-1) and tumor tissues. Functional assays, such as wound healing and Transwell assays, were employed to evaluate tumor invasion and migration. The prognostic accuracy was assessed through ROC curve analysis, and a nomogram integrating risk scores with clinical variables was constructed. Analyses of immune infiltration, human leukocyte antigen (HLA) expression, immune checkpoint expression, immunophenoscore (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and responses to six targeted therapies were conducted across different risk groups. Twelve critical prognostic markers, including CAPRIN1, CXCR3, FERMT3, HAPLN3, HBP1, MACF1, MPEG1, OSCAR, STAT1, UBA7, VAMP1, and VSIG4, were identified. The risk score model exhibited a high degree of predictive accuracy for survival outcomes in ccRCC. Immune profiling revealed significant differences in the TME between risk groups, with high-risk patients displaying elevated expression of HLA and immune checkpoints. Drug sensitivity analyses suggested that high-risk patients had a better response to erlotinib, temsirolimus, axitinib, and sunitinib, whereas low-risk patients demonstrated greater sensitivity to pazopanib. Variability in immunotherapy responsiveness between groups was observed based on IPS and TIDE analyses. This study highlights the prognostic value and TME-related mechanisms of immune-stromal score signatures in ccRCC, developing a risk score model and nomogram for predicting patient prognosis. Show less
The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
Microtubule-actin cross-linking factor 1 (MACF1), also known as actin cross-linking family protein 7 (ACF7), is a giant cytolinker protein with multiple conserved domains that can orchestrate cytoskel Show more
Microtubule-actin cross-linking factor 1 (MACF1), also known as actin cross-linking family protein 7 (ACF7), is a giant cytolinker protein with multiple conserved domains that can orchestrate cytoskeletal networks of actin and microtubules. MACF1 is involved in various biological processes, including cell polarity, cell-cell connection, cell proliferation, migration, vesicle transport, signal transduction, and neuronal development. In this review, we updated the physiological and pathological roles of MACF1, highlighting the components and signaling pathways involved. Novel evidence showed that MACF1 is involved in diverse human diseases, including multiple neuronal diseases, congenital myasthenic syndrome, premature ovarian insufficiency, spectraplakinopathy, osteoporosis, proliferative diabetic retinopathy, and various types of cancer. We also reviewed the physiological roles of MACF1, including its involvement in adhesome formation, bone formation, neuronal aging, and tooth development. In addition, MACF1 plays other roles, functioning as a biomarker for the prediction of infections in patients with burns and as a marker for genome selection breeding. These studies reinforce the idea that MACF1 is a bona fide versatile, multifaceted giant protein. Identifying additional MACF1 functions would finally help with the treatment of diseases caused by MACF1 defects. Show less
Accurate skin lesion classification is crucial for the early detection of malignant lesions, including melanoma, as well as improved patient outcomes. While convolutional neural networks (CNNs) excel Show more
Accurate skin lesion classification is crucial for the early detection of malignant lesions, including melanoma, as well as improved patient outcomes. While convolutional neural networks (CNNs) excel at capturing local morphological features, they struggle with global context modeling essential for comprehensive lesion assessment. Vision transformers address this limitation but suffer from quadratic computational complexity O(n Show less
Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spect Show more
Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spectraplakin protein to the central nervous system and Wnt signaling. In the early 2000's, genetic alterations of MACF1 were identified in several cancers suggesting that this cytoskeletal crosslinker was involved in tumor development and progression, while preclinical studies provided evidence that MACF1 is a potential diagnostic and prognostic biomarker and therapeutic target in glioblastomas, a central nervous system cancer derived from astrocytes and neural progenitor stem cells. Furthermore, investigations in glioblastomas demonstrated that genetic inhibitory targeting of this spectraplakin protein alone and in combination with DNA damaging agents had synergistic antitumorigenic effects. The established role of MACF1 in Wnt signaling, a known mechanistic driver of central nervous system development and pro-tumorigenic cell behavior in glioblastomas, provide a premise for addressing the potential of this spectraplakin protein as a novel oncoprotein in cancers with origins in the nervous system. The present review provides a summary of the role and function of MACF1 in the central nervous system, Wnt signaling and cancer development, specifically as an oncoprotein that underlie the transformation and oncogenic properties of glioblastomas. Show less
Cytoskeletal dynamics, the interplay of actin, microtubules, and septins, is a highly coordinated and tightly regulated process. Defects in the proteins involved can result in a wide range of cellular Show more
Cytoskeletal dynamics, the interplay of actin, microtubules, and septins, is a highly coordinated and tightly regulated process. Defects in the proteins involved can result in a wide range of cellular consequences. Hearing loss is the most common sensory defect and exhibits extraordinary genetic and phenotypic heterogeneity. Currently, there are more than 170 genes casually linked to non-syndromic hearing loss (NSHL), of which more than 60 are associated with autosomal dominant inheritance. Here, we add to this growing number by implicating Show less
To investigate the genetic etiology of ventriculomegaly (VM) in fetuses by analyzing chromosomal aberrations and genetic variations through high-throughput sequencing. Clinical data and samples (amnio Show more
To investigate the genetic etiology of ventriculomegaly (VM) in fetuses by analyzing chromosomal aberrations and genetic variations through high-throughput sequencing. Clinical data and samples (amniotic fluid or miscarriage tissue) were collected from fetuses with ventricular width >10 mm, diagnosed at Shanxi Children's Hospital between 2020 and 2023. All samples underwent copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further analyzed by whole exome sequencing (WES) to identify single-gene variants. Chromosomal abnormalities and monogenic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were tracked. Among 73 VM fetuses, 23 (31.5%) cases exhibited chromosomal aberrations via CNV-seq, including 4 aneuploidies, 12 pathogenic CNVs, 2 likely pathogenic CNVs, and 8 variants of unknown significance. The incidence of chromosomal abnormalities was significantly higher in non-isolated VM fetuses compared to isolated VM (p < 0.05). WES analysis of 33 CNV-negative cases identified single-gene defects in 16 (48.5%) fetuses, including SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1, and PURA gene, with 10 novel variants reported. Fetal VM is associated with heterogeneous neurodevelopmental outcomes, and genetic etiology plays an important role in its pathogenesis. WES enhances the efficiency of diagnosis, particularly for VM fetuses without detectable aneuploidy or CNVs. Identifying the genetic etiology of fetal VM is is crucial for informing birth defect prevention strategies and improving the overall health of the newborn population. Show less
While heterozygous Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domain Clustering revealed two Show more
While heterozygous Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domain Clustering revealed two distinct phenotypic signatures, suggesting domain-specific effects. Variants outside the GAR domain associate with broader neurodevelopmental phenotypes and variable craniofacial and skeletal expressivity. Additionally, enrichment analysis (p < 0.001) using OMIM HPO sets supported these findings. In contrast to the GAR domain's strong correlation with lissencephaly and brainstem malformations, biallelic non-GAR domain These results expand the phenotypic spectrum of Show less
Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-s Show more
Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. Show less
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at th Show more
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50). Show less
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expr Show more
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less
A ketogenic diet is used in children with drug-resistant epilepsy but predictors for efficacy are largely lacking. Our aim was to evaluate if causative genetic variants could predict seizure response Show more
A ketogenic diet is used in children with drug-resistant epilepsy but predictors for efficacy are largely lacking. Our aim was to evaluate if causative genetic variants could predict seizure response to the ketogenic diet. A cohort study of 226 children with refractory epilepsy and classic ketogenic diet treatment for at least 3 months (76.9% of the 294 who started) was performed. The median age at diet start was 5.1 years (range 0.1-17.8), 118 were girls and 108 boys. They had previous trials of a median of 6.0 anti-seizure medications (range 0-12) and intellectual disability was found in 87%. Seizure response (≥50% reduction) was found in 138/226 patients (61.1%) at 3 months, 121 (53.5%) at 6 months, 107 (47.3%) at 1 year and in 80 (37.0%) at 2 years follow-up of ketogenic diet. Age of epilepsy onset was lower and combined epilepsy type less common in responders compared to non-responders but no differences were found for specific seizure types, ketogenic ratio or beta-hydroxybutyric acid blood levels. A causative pathogenic/likely pathogenic variant was detected in 107/153 = 69.9% in 48 different genes. Next generation sequencing was used in 91/226 (40%) cases with a diagnostic yield of 58.2% (53/91). In comparison with cases without a revealed genetic aetiology, patients with a causative genetic variant had less atonic seizures and epileptic spasms and a better seizure response with 17.3% seizure free and 25% with >90% seizure reduction at 2-year follow-up. Causative variants in Show less
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA i Show more
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA in tumor diagnosis have gradually attracted the attention of researchers. However, methylation detection, which is more advantageous than mutation detection in tumor diagnosis, has not been widely practiced in EV DNA, and its value in PCa diagnosis also remains underexplored. This study aims to establish and optimize an EV DNA methylation detection system and evaluate its diagnostic and classification potential for PCa. We characterized EV DNA biological properties, optimized pretreatment strategies, validated its correlation with genomic DNA methylation, and explored urine EV DNA methylation targets in 86 benign prostatic hyperplasia (BPH) and 109 PCa patients across three cohorts (screening: 30 BPH/33 PCa; training: 27 BPH/30 PCa; validation: 29 BPH/46 PCa). Heterogeneous biological characteristics were observed among DNA from different subtypes of EV, but methylation profiles remained consistent across subtypes and post-DNase I treatment. EV DNA accurately reflected the methylation state of source cell genomic DNA. By combining our screening results with data from the TCGA database and previously reported, we developed a panel consisting of 667 PCa-specific methylation targets for detection. Among these, six methylation sites (MACF1、LINC01359-1、LINC01359-2、ADCY4、GAPLINC、C19orf25) demonstrated high diagnostic value for PCa, enabling construction of PCa and aggressive PCa differential diagnosis model with AUCs up to 0.74 and 0.91 respectively. The diagnostic value of these six markers was further confirmed using methylight PCR in the validation cohort which also displayed promising performance as a tool for diagnosing PCa. This study highlights the potential of urine EV DNA methylation as a novel diagnostic marker for PCa and lays a foundation for future EV DNA research. Show less
The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 mic Show more
The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 microduplication syndrome results from the duplication of 16p13.11 chromosome copies and is associated with various neurodevelopmental and physiological abnormalities. Both MACF1 and 16p13.11 microduplication have significant impacts on neural development, potentially leading to nerve damage or neurological diseases. This study presents a unique case of a patient simultaneously experiencing a de novo MACF1 mutation and a hereditary 16p13.11 microduplication, which has not been reported previously. In this report, we describe a Chinese preterm newborn girl exhibiting the typical characteristics of 16.13.11 microduplication syndrome. These features include developmental delay, respiratory issues, feeding problems, muscle weakness, excessive joint movement, and multiple congenital abnormalities. Through whole-exome sequencing, we identified a disease-causing mutation in the MACF1 gene (c.15266T > C / p. Met5089Thr). Additionally, after microarray analysis, we confirmed the presence of a 16p13.11 microduplication (chr16:14,916,289 - 16,315,688), which was inherited from the mother. The patient's clinical presentation, marked by muscle weakness and multiple birth defects, may be attributed to both the de novo MACF1 mutation and the 16p13.11 duplication, which could have further amplified her severe symptoms. Genetic testing for individuals with complex clinical manifestations can offer valuable insights for diagnosis and serve as a reference for genetic counseling for both patients and their families. Show less
Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while a Show more
Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments. Show less
Skeletal myofibers are syncytia made from the fusion of dozens or hundreds of mononuclear progenitor cells. Along myogenesis, the arriving nuclei from the progenitor cells have a long journey before b Show more
Skeletal myofibers are syncytia made from the fusion of dozens or hundreds of mononuclear progenitor cells. Along myogenesis, the arriving nuclei from the progenitor cells have a long journey before being positioned at the periphery of a mature myofiber. Once at the periphery, nuclei are regularly spaced and each nucleus is transcriptionally responsible for its surrounding proportion of cytoplasm, known as the myonuclear domain. Disruption of these domains can be observed in various myopathies, suggesting their importance for skeletal muscle functionality. However, little is known about mechanisms regulating the myonuclear domain stability and organization. Here we take the example of MACF1, a microtubule-associated protein, as an essential actor in myonuclear domain organization, to highlight the potential role of microtubules and their associated proteome network for the stability of these domains and hence for proper myofiber functionality. Show less
As the prevalence of Type 2 Diabetes Mellitus (T2DM) and Glioblastoma (GBM) rises globally, the relationship between T2DM and GBM remains controversial. This study aims to investigate whether genetica Show more
As the prevalence of Type 2 Diabetes Mellitus (T2DM) and Glioblastoma (GBM) rises globally, the relationship between T2DM and GBM remains controversial. This study aims to investigate whether genetically predicted T2DM is causally associated with GBM. We performed bidirectional Mendelian randomization (MR) analysis using data from genome-wide studies on T2DM (N = 62,892) and GBM (N = 218,792) in European populations. The results of the inverse-variance weighted (IVW) approach served as the primary outcomes. We applied Cochran's Q test and MR-Egger regression for heterogeneity assessment. Leave-one-out analysis was used to evaluate whether any single SNP significantly influenced the observed effect. Our findings reveal a significant causal association between T2DM and an increased risk of GBM (OR [95% CI] 1.70 [1.09, 2.65], P = 0.019). Conversely, the reverse association between T2DM and GBM was insignificant (OR [95% CI] 1.00 [0.99, 1.01], P = 0.408) (P > 0.40). Furthermore, the results from Cochran's Q-test and funnel plots in the MR-Egger method indicated no evidence of pleiotropy between the SNPs and GBM. Additionally, we mapped causal SNPs to genes and identified 10 genes, including MACF1, C1orf185, PTGFRN, NOTCH2, ABCB10, GCKR, THADA, RBMS1, SPHKAP, and PPARG, located on chromosomes 1, 2, and 3. These genes are involved in key biological processes such as the BMP signaling pathway and various metabolic pathways relevant to both conditions. This study provides robust evidence of a significant causal relationship between T2DM and an increased risk of GBM. The identified SNP-mapped genes highlight potential biological mechanisms underlying this association. Show less
Lung adenocarcinoma (LUAD) is the most common and aggressive cancer with a high incidence. N1-specific pseudouridine methyltransferase (EMG1), a highly conserved nucleolus protein, plays an important Show more
Lung adenocarcinoma (LUAD) is the most common and aggressive cancer with a high incidence. N1-specific pseudouridine methyltransferase (EMG1), a highly conserved nucleolus protein, plays an important role in the biological development of ribosomes. However, the role of EMG1 in the progression of LUAD is still unclear. The expression of EMG1 in LUAD cells, and LUAD tissues, and adjacent noncancerous tissues was quantified using real-time polymerase chain reaction (PCR) and western blotting. The roles of EMG1 in LUAD cell proliferation, migration, invasion and tumorigenicity were explored in vitro and in vivo. Western blot analysis to underlying molecular mechanism of EMG1 regulating the biological function of LUAD. EMG1 expression and its impact on tumor prognosis were analyzed using a range of databases including GEPIA, UALCAN, cBioPortal, LinkedOmics, and Kaplan-Meier Plotter. EMG1 expression was elevated in LUAD patients compared to normal tissues, and EMG1 expression was strongly correlated with prognosis in LUAD patients. EMG1 expression correlated with age, gender, N stage, T stage, and pathologic stage. EMG1 expression was strongly positively correlated with MRPL51, PHB2, SNRPG, ATP5MD, and TPI1, and strongly negatively correlated with MACF1, DOCK9, RAPGEF2, SYNJ1, and KIDINS220, the major enrichment pathways for EMG1 and related genes include Cell cycle, DNA Replication and Pathways in cancer signaling pathways. EMG1 expression level was significantly increased in LUAD cell lines and tissues. Knockdown of EMG1 could inhibit LUAD cell proliferation, migration, invasion, and tumorigenicity. Besides, EMG1 overexpression could promote LUAD cell proliferation, migration, and invasion. High expression of EMG1 predicts poor prognosis in LUAD patients, and EMG1 may play an oncogenic role in the tumor microenvironment by participating in the infiltration of LUAD immune cells. EMG1 regulated various functions in LUAD by directly mediating Akt/mTOR/p70s6k signaling pathways activation. The results suggest that EMG1 may be a novel biomarker for assessing prognosis and immune cell infiltration in LUAD. Show less
Biomarker discovery is a challenging task due to the massive search space. Quantum computing and quantum Artificial Intelligence (quantum AI) can be used to address the computational problem of biomar Show more
Biomarker discovery is a challenging task due to the massive search space. Quantum computing and quantum Artificial Intelligence (quantum AI) can be used to address the computational problem of biomarker discovery from genetic data. We propose a Quantum Neural Networks architecture to discover genetic biomarkers for input activation pathways. The Maximum Relevance-Minimum Redundancy criteria score biomarker candidate sets. Our proposed model is economical since the neural solution can be delivered on constrained hardware. We demonstrate the proof of concept on four activation pathways associated with CTLA4, including (1) CTLA4-activation stand-alone, (2) CTLA4-CD8A-CD8B co-activation, (3) CTLA4-CD2 co-activation, and (4) CTLA4-CD2-CD48-CD53-CD58-CD84 co-activation. The model indicates new genetic biomarkers associated with the mutational activation of CLTA4-associated pathways, including 20 genes: CLIC4, CPE, ETS2, FAM107A, GPR116, HYOU1, LCN2, MACF1, MT1G, NAPA, NDUFS5, PAK1, PFN1, PGAP3, PPM1G, PSMD8, RNF213, SLC25A3, UBA1, and WLS. We open source the implementation at: https://github.com/namnguyen0510/Biomarker-Discovery-with-Quantum-Neural-Networks . Show less