Macrophages dying from ferroptosis promote microglia-mediated inflammatory responses during spinal cord injury.

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1ß, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1ß and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.

RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation.

OBJECTIVE: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms. METHODS: Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA­seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis. RESULTS: Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis. CONCLUSIONS: RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.

The association between body mass index and bone mineral density in older adults: a cross-sectional study of community population in Beijing.

BACKGROUND: Older subjects have a higher risk for vertebral compression fracture. Maintaining a higher bone mineral density (BMD) at this age can protect individuals from osteoporosis-related events. Body mass index (BMI) has been found to have a robust association with BMD. However, excessive BMI is detrimental to bone health and may cause systemic disorders. Therefore, the present study aimed to determine the association between BMI and BMD, and identify a reasonable BMI range. METHODS: A total of 961 participants were recruited from community-dwelling residents between August 2021 and May 2022. A weighted multivariate linear regression model was applied to identify the relationship between BMI and BMD. Meanwhile, subgroup stratified analysis by BMI quartile and gender was also performed. A non-linear relationship and threshold value were determined based on the smooth curve fittings and threshold effects analysis model. RESULTS: A robust relationship was found between BMI and BMD, which remained significant in subgroups stratified by gender and BMI quartile. The BMI inflection point values in lumbar BMD and femoral neck BMD were 25.2 kg/m2 and 27.3 kg/m2, respectively. For individuals with BMI < 25.2 kg/m2, an increase in BMI was related to an increase in lumbar BMD. For BMI > 25.2 kg/m2, an increase in BMI was associated with a decrease in lumbar BMD. For subjects with BMI < 27.3 kg/m2, the femoral neck BMD rose by 0.008 kg/m2 for each unit rise in BMI. However, when BMI exceeded 27.3 kg/m2, the femoral neck BMD increased only by 0.005 kg/m2. Fracture risk assessment based on the spinal deformity index (SDI) failed to determine the optimal BMI range. CONCLUSIONS: This study found an inflection point between BMI and lumbar/ femoral neck BMD in older community-dwelling subjects. An appropriate BMI but not an excessive BMI may allow older adults to have a better BMD.

The influence of HLA genetic variation on plasma protein expression.

Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.

The Role of Pelvic Compensation in Sagittal Balance and Imbalance: The Impact of Pelvic Compensation on Spinal Alignment and Clinical Outcomes Following Adult Spinal Deformity Surgery.

BACKGROUND AND OBJECTIVES: The Scoliosis Research Society (SRS)-Schwab system does not include a pelvic compensation (PC) subtype, potentially contributing to gaps in clinical characteristics and treatment strategy for deformity correction. It also remains uncertain as to whether PC has differing roles in sagittal balance (SB) or imbalance (SI) status. To compare radiological parameters and SRS-22r domains between patients with failed pelvic compensation (FPC) and successful pelvic compensation (SPC) based on preoperative SB and SI. METHODS: A total of 145 adult spinal deformity patients who received deformity correction were analyzed. Radiographic and clinical outcomes were collected for statistical analysis. Patients were classified into 4 groups based on the median value of PT/PI ratio (PTr) and the cutoff value of SB. Patients with low PTr and high PTr were defined as FPC and SPC, respectively. Radiographic and clinical characteristics of different groups were compared. RESULTS: Patients with SPC exhibited significantly greater improvements in lumbar lordosis, pelvic tilt, PTr, and T1 pelvic angle as compared to patients with FPC, irrespective of SB or SI. No apparent differences in any of SRS-22r domains were observed at follow-up when comparing the SB-FPC and SB-SPC patients. However, patients with SI-SPC exhibited significantly better function, self-image, satisfaction, and subtotal domains at follow-up relative to those with SI-FPC. When SI-FPC and SI-SPC patients were subdivided further based on the degree of PI-LL by adjusting for age, the postoperative function and self-image domains were significantly better in the group with overcorrection of PI-LL than undercorrection of PI-LL in SI-FPC patients. However, no differences in these SRS-22r scores were observed when comparing the subgroups in SI-SPC patients. CONCLUSION: Flexible pelvic rotation is associated with benefits to the correction of sagittal parameters, irrespective of preoperative SB or SI status. However, PC is only significantly associated with clinical outcomes under SI. Patients with SI-FPC exhibit poorer postoperative clinical outcomes, which should be recommended to minimize PI-LL.

Exploring the role of parthanatos in CNS injury: Molecular insights and therapeutic approaches.

BACKGROUND: Central nervous system (CNS) injury causes severe organ damage due to both damage resulting from the injury and subsequent cell death. However, there are currently no effective treatments for countering the irreversible loss of cell function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form of programmed cell death that is partly responsible for neural cell death. Consequently, the mechanism by which parthanatos promotes CNS injury has attracted significant scientific interest. AIM OF REVIEW: Our review aims to summarize the potential role of parthanatos in CNS injury and its molecular and pathophysiological mechanisms. Understanding the role of parthanatos and related molecules in CNS injury is crucial for developing effective treatment strategies and identifying important directions for future in-depth research. KEY SCIENTIFIC CONCEPTS OF REVIEW: Parthanatos (from Thanatos, the personification of death according to Greek mythology) is a type of programmed cell death that is initiated by the overactivation of PARP-1. This process triggers a cascade of reactions, including the accumulation of poly(ADP-ribose) (PAR), the nuclear translocation of apoptosis-inducing factor (AIF) after its release from mitochondria, and subsequent massive DNA fragmentation caused by migration inhibitory factor (MIF) forming a complex with AIF. Secondary molecular mechanisms, such as excitotoxicity and oxidative stress-induced overactivation of PARP-1, significantly exacerbate neuronal damage following initial mechanical injury to the CNS. Furthermore, parthanatos is not only associated with neuronal damage but also interacts with various other types of cell death. This review focuses on the latest research concerning the parthanatos cell death pathway, particularly considering its regulatory mechanisms and functions in CNS damage. We highlight the associations between parthanatos and different cell types involved in CNS damage and discuss potential therapeutic agents targeting the parthanatos pathway.

Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets' Perspective.

Open Targets, a consortium among academic and industry partners, focuses on using human genetics and genomics to provide insights to key questions that build therapeutic hypotheses. Large-scale experiments generate foundational data, and open-source informatic platforms systematically integrate evidence for target-disease relationships and provide dynamic tooling for target prioritization. A locus-to-gene machine learning model uses evidence from genome-wide association studies (GWAS Catalog, UK BioBank, and FinnGen), functional genomic studies, epigenetic studies, and variant effect prediction to predict potential drug targets for complex diseases. These predictions are combined with genetic evidence from gene burden analyses, rare disease genetics, somatic mutations, perturbation assays, pathway analyses, scientific literature, differential expression, and mouse models to systematically build target-disease associations (https://platform.opentargets.org). Scored target attributes such as clinical precedence, tractability, and safety guide target prioritization. Here we provide our perspective on the value and impact of human genetics and genomics for generating therapeutic hypotheses.

Activation of GPR81 by lactate drives tumour-induced cachexia.

Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gßγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.

Comparison of the clinical and radiographic outcomes of cortical bone trajectory and traditional trajectory pedicle screw fixation in transforaminal lumbar interbody fusion: a randomized controlled trial.

PURPOSE: To compare the clinical outcomes and radiographic outcomes of cortical bone trajectory (CBT) and traditional trajectory (TT) pedicle screw fixation in patients treated with single-level transforaminal lumbar interbody fusion (TLIF). METHODS: This trial included a total of 224 patients with lumbar spine disease who required single-level TLIF surgery. Patients were randomly assigned to the CBT and TT groups at a 1:1 ratio. Demographics and clinical and radiographic data were collected to evaluate the efficacy and safety of CBT and TT screw fixation in TLIF. RESULTS: The baseline characteristic data were similar between the CBT and TT groups. Back and leg pain for both the CBT and TT groups improved significantly from baseline to 24 months postoperatively. The CBT group experienced less pain than the TT group at one week postoperatively. The postoperative radiographic results showed that the accuracy of screw placement was significantly increased in the CBT group compared with the TT group (P < 0.05). The CBT group had a significantly lower rate of FJV than the TT group (P < 0.05). In addition, the rate of fusion and the rate of screw loosening were similar between the CBT and TT groups according to screw loosening criteria. CONCLUSION: This prospective, randomized controlled analysis suggests that clinical outcomes and radiographic characteristics, including fusion rates and caudal screw loosening rates, were comparable between CBT and TT screw fixation. Compared with the TT group, the CBT group showed advantages in the accuracy of screw placement and the FJV rate. CLINICAL TRIALS REGISTRATION: This trial has been registered at the US National Institutes of Health Clinical Trials Registry: NCT03105167.

Intestinal SURF4 is essential for apolipoprotein transport and lipoprotein secretion.

OBJECTIVE: Lipoprotein assembly and secretion in the small intestine are critical for dietary fat absorption. Surfeit locus protein 4 (SURF4) serves as a cargo receptor, facilitating the cellular transport of multiple proteins and mediating hepatic lipid secretion in vivo. However, its involvement in intestinal lipid secretion is not fully understood. In this study, we investigated the role of SURF4 in intestinal lipid absorption. METHODS: We generated intestine-specific Surf4 knockout mice and characterized the phenotypes. Additionally, we investigated the underlying mechanisms of SURF4 in intestinal lipid secretion using proteomics and cellular models. RESULTS: We unveiled that SURF4 is indispensable for apolipoprotein transport and lipoprotein secretion. Intestine-specific Surf4 knockout mice exhibited ectopic lipid deposition in the small intestine and hypolipidemia. Deletion of SURF4 impeded the transport of apolipoprotein A1 (ApoA1), proline-rich acidic protein 1 (PRAP1), and apolipoprotein B48 (ApoB48) and hindered the assembly and secretion of chylomicrons and high-density lipoproteins. CONCLUSIONS: SURF4 emerges as a pivotal regulator of intestinal lipid absorption via mediating the secretion of ApoA1, PRAP1 and ApoB48.

Diazo-carboxyl Click Derivatization Enables Sensitive Analysis of Carboxylic Acid Metabolites in Biosamples.

Carboxylic acids are central metabolites in bioenergetics, signal transduction, and post-translation protein regulation. However, the quantitative analysis of carboxylic acids as an indispensable part of metabolomics is prohibitively challenging, particularly in trace amounts of biosamples. Here we report a diazo-carboxyl/hydroxylamine-ketone double click derivatization method for the sensitive analysis of hydrophilic, low-molecular-weight carboxylic acids. In general, our method renders a 5- to 2000-fold higher response in mass spectrometry along with improved chromatographic separation. With this method, we presented the near-single-cell analysis of carboxylic acid metabolites in 10 mouse egg cells before and after fertilization. Malate, fumarate, and ß-hydroxybutyrate were found to decrease after fertilization. We also monitored the isotope labeling kinetics of carboxylic acids inside adherent cells cultured in 96-well plates during drug treatment. Finally, we applied this method to plasma or serum samples (5 µL) collected from mice and humans under pathological and physiological conditions. The double click derivatization method paves a way toward single-cell metabolomics and bedside diagnostics.

Correction: DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate zygotic transcriptional program.

[This corrects the article DOI: 10.1371/journal.pbio.3000324.].

Progress in understanding the role of cGAS-STING pathway associated with programmed cell death in intervertebral disc degeneration.

Nucleus pulposus (NP) inflammatory response can induce intervertebral disc degeneration (IVDD) by causing anabolic and catabolic disequilibrium of the extracellular matrix (ECM). This process is accompanied by the production of endogenous DNAs, then detectable by the DNA sensor cyclic GMP-AMP synthase (cGAS). cGAS recognizes these DNAs and activates the downstream adaptor protein, a stimulator of interferon genes (STING), initiating a cascade of inflammation responses through various cytokines. This evidence implies a crucial role of the cGAS-STING signaling pathway in IVDD. Additionally, it is suggested that this pathway could modulate IVDD progression by regulating apoptosis, autophagy, and pyroptosis. However, a detailed understanding of the role of cGAS-STING pathway in IVDD is still lacking. This review provides a comprehensive summary of recent advances in our understanding of the role of the cGAS-STING pathway in modulating inflammatory response in IVDD. We delve into the connection between the cGAS-STING axis and apoptosis, autophagy, and pyroptosis in IVDD. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING signaling pathway in IVDD treatment. Overall, this review aims to provide a foundation for future directions in IVDD treatment strategies.

The pathological mechanisms of circRNAs in mediating intervertebral disc degeneration.

Lower back pain (LBP) is a worldwide health problem associated with significant economic and social burden. Intervertebral disc degeneration (IVDD) is a leading cause of LBP. Several studies show that the death of nucleus pulposus cells (NPCs), abnormal metabolism of the extracellular matrix (ECM), and inflammatory response are the key mechanisms behind the pathogenesis of IVDD. Circular RNAs (circRNAs) are key regulators of gene expression and play a significant role in regulating NPCs death, ECM homeostasis, and inflammatory response by acting as microRNAs (miRNAs) sponges in IVDD. However, the regulatory role of circRNAs in mediating IVDD remains unknown. This review comprehensively describes the normal anatomic structure and function of IVD, the pathogenesis of IVDD, the characteristics, synthesis, mechanisms, and function of circRNAs. Moreover, we highlighted the 23 circRNAs that mediate ECM metabolism, 16 circRNAs that mediate NPCs apoptosis, circ_0004354 and circ_0040039 that mediate NPCs pyroptosis, and 5 circRNAs that mediate inflammatory response in IVDD. In addition, this review presents suggestions for future studies, such as the need for further investigation on ferroptosis-related circRNAs in IVDD. This review could provide novel insights into the pathogenesis and treatment of IVDD.

Irisin as an agent for protecting against osteoporosis: A review of the current mechanisms and pathways.

BACKGROUND: Osteoporosis is recognized as a skeletal disorder characterized by diminished bone tissue quality and density. Regular physical exercise is widely acknowledged to preserve and enhance bone health, but the detailed molecular mechanisms involved remain unclear. Irisin, a factor derived from muscle during exercise, influences bone and muscle. Since its discovery in 2012, irisin has been found to promote bone growth and reduce bone resorption, establishing a tangible link between muscle exertion and bone health. Consequently, the mechanism by which irisin prevents osteoporosis have attracted significant scientific interest. AIM OF THE REVIEW: This study aims to elucidate the multifaceted relationship between exercise, irisin, and bone health. Focusing on irisin, a muscle-derived factor released during exercise, we seek to understand its role in promoting bone growth and inhibiting resorption. Through a review of current research article on irisin in osteoporosis, Our review provides a deep dive into existing research on influence of irisin in osteoporosis, exploring its interaction with pivotal signaling pathways and its impact on various cell death mechanisms and inflammation. We aim to uncover the molecular underpinnings of how irisin, secreted during exercise, can serve as a therapeutic strategy for osteoporosis. KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Irisin, secreted during exercise, plays a vital role in bridging muscle function to bone health. It not only promotes bone growth but also inhibits bone resorption. Specifically, Irisin fosters osteoblast proliferation, differentiation, and mineralization predominantly through the ERK, p38, and AMPK signaling pathways. Concurrently, it regulates osteoclast differentiation and maturation via the JNK, Wnt/ß-catenin and RANKL/RANK/OPG signaling pathways. This review further delves into the profound significance of irisin in osteoporosis and its involvement in diverse cellular death mechanisms, including apoptosis, autophagy, ferroptosis, and pyroptosis.

Bibliometric analysis of research on neurodegenerative diseases and single-cell RNA sequencing: Opportunities and challenges.

Neurodegeneration, characterized by the progressive deterioration in neuronal structure or function, presents an elusive mechanism. The use of single-cell RNA sequencing (scRNA-seq) technology in the clinic is becoming increasingly prevalent in recent decades. This technology offers unparalleled cell-level insights into neurodegenerative diseases, establishing itself as a potent tool for elucidating these diseases underlying mechanisms. Here, we made a deep investigation for scRNA-seq research in neurodegenerative diseases using bibliometric analysis from 2009 to 2022. We observed a robust upward trajectory in the number of publications on this subject. The United States stood out as the principal contributor to this expanding field. Specifically, the University of California System exhibited notable research prowess in this field. Alzheimer disease and Parkinson disease were the diseases most frequently investigated. Key research hotspots include the creation of a molecular brain atlas and identification of vulnerable neuronal subpopulations and potential therapeutic targets at the transcriptomic level.

Behavior of organic components and the migration of heavy metals during sludge dewatering by different advanced oxidation processes via optical spectroscopy and molecular fingerprint analysis.

A comparative study of the different advanced oxidation processes (Fe(II)-Oxone, Fe(II)-H2O2, and Fe(II)-NaClO) was carried out herein to analyze the characteristics of organic components and the migration of heavy metals in waste activated sludge. With the Fe(II)-Oxone and Fe(II)-H2O2 treatments, sludge dewaterability was significantly improved, however, sludge dewaterability was deteriorated by the Fe(II)-NaClO treatment. The enhanced sludge dewaterability by the Fe(II)-Oxone and Fe(II)-H2O2 treatments was strongly correlated with the shifted organic components, particularly proteins, in soluble extracellular polymeric substances (S-EPS), while the deteriorated sludge dewaterability by the Fe(II)-NaClO treatment was strongly correlated with the over release of organic components from bound EPS (B-EPS) to S-EPS. For both the Fe(II)-Oxone and Fe(II)-H2O2 treatments, the radicals preferentially attacked humic acid-like organic components over the protein-like organic components in S-EPS, while for the Fe(II)-NaClO treatment, interestingly, the radicals preferentially attacked the protein-like organic components in both S-EPS and B-EPS. The hydrophilic functional groups like phenolic OH and CO of polysaccharides may be more preferentially migrated to S-EPS of sludge by the Fe(II)-NaClO treatment compared to the other two treatments. With the Fe(II)-Oxone and Fe(II)-H2O2 treatments, the proportion of aliphatic compounds as well as the much oxygenated organic components with a low desaturation and a low molecular weight increased. While with the Fe(II)-NaClO treatment, the proportion of low oxygenated organic components with a high desaturation and a high molecular weight increased. The concentration of total organic carbon, particularly the concentration of proteins, may be the key factor determining the shift of Zn and Cu from sludge solid to liquid phase, along with the high oxidation extent of organic components and close binding to CHOS and CHON compounds as indicated by density functional theory (DFT) calculation. This study systematically revealed the simultaneous sludge dewatering and migration of heavy metals when the role of organic components was factored into herein.

Can C7 Slope Accurately Substitute for an Invisible T1 Slope According to Age and Cervical Morphology in Cervical Lateral Radiographs?

STUDY DESIGN: A retrospective radiologic study. OBJECTIVES: To identify age-associated changes in T1 slope (T1S) and C7 slope (C7S), as well as the difference between T1S and C7S (△, which was defined as T1S minus C7S) and to explore the cervical morphology that C7S can be the most accurate alternative for the invisible T1S. METHODS: 625 asymptomatic Chinese volunteers received cervical lateral radiographs from August 2021 to May 2022. Occipito-C2 angle (O-C2), C2-7 angle (C2-7), cranial arch, caudal arch, C7S, and T1S were examined. Thereafter, the △ was established. The correlations among T1S, C7S, △ and other cervical sagittal parameters, and between age and other cervical sagittal parameters were evaluated with the Pearson correlation coefficient analysis. Then, analysis of variance (ANOVA) was conducted to compare variations in cervical sagittal parameters among volunteers aged 40 to 59 years, 60 to 64 years, 65 to 69 years, 70 to 74 years, and ≥75 years of age, and among volunteers with 1 lordotic morphology, 2 lordotic morphology, straight morphology, kyphotic morphology, 1 sigmoid morphology, and 2 sigmoid morphology. Linear regression modeling of the correlation between C7S and T1S in various cervical alignment patterns was then established. RESULTS: △ had the strongest correlation with caudal arch (r = .646), and weakest correlation with cranial arch (r = -.082). Age was significantly correlated with T1S (r = .250), C7S (r = .244), and △ (r = .112). Among them, △ was stable until 74 years after which it showed an elevation from 3.3° in the group 70-74 years to 4.1° in the group over 75 years. Moreover, there was marked variation between T1S and C7S at 1 lordotic, 2 lordotic, straight and 2 sigmoid alignment patterns, but no difference was seen between T1S and C7S at kyphotic and 1 sigmoid alignment patterns. CONCLUSIONS: There was a progressive increase in T1S, C7S, and △ with age. Linear regression equations for accurate prediction of T1S were developed based on the C7S in 1 lordotic, 2 lordotic, straight and 2 sigmoid alignment patterns. C7S may be a reliable proxy for T1S in kyphotic and 1 sigmoid alignment patterns.

E3 ligase MG53 suppresses tumor growth by degrading cyclin D1.

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.