[Pro-oxidation status of rotator cuff tissue and expression of Beclin-1 and mTOR in patients with rotator cuff injury].

OBJECTIVE: To explore pro-oxidative state of rotator cuff tissue and expression levels of Beclin-1 and mam-malian target of rapamycin(mTOR) in patients with acute and chronic rotator cuff injury, and then analyzed relationship between rotator cuff injury and oxidative stress and autophagy. METHODS: Forty patients with rotator cuff injury were seleceted from July 2019 to December 2020, and divided into male chronic injury group, male acute injury group, female chronic injury group, and female acute injury group, 10 patients in each group. All patients were performed rotator cuff repair under arthroscopy. The sample of tendon at the rotator cuff injury site of the patient was taken during operation, and total reactive oxygen species (ROS) and superoxide dismutase(SOD) were detected by detection kit;expression of Beclin-1 and mTOR mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR), and Western-blot was applied to detect protein expression of Beclin-1 and p-mTOR/mTOR. RESULTS: There were no significant difference in expression of ROS, SOD, Beclin-1mRNA and mTOR mRNA between male and female chronic injury groups, and between male and female acute injury groups (P>0.05); ROS, SOD and Beclin-1mRNA in male chronic injury group were higher than those in male chronic injury group, while mTOR mRNAand protein decreased (P<0.05);ROS, SOD and Beclin-1 mRNA in female chronic injury group were up-regulated compared with female acute injury group, while mTOR mRNA was down-regulated (P<0.05). CONCLUSION: Chronic rotator cuff injury is more likely to stimulate the pro-oxidation state of rotator cuff tissue than acute rotator cuff injury, which could up-regulating expression of autophagy factor Beclin-1 and down-regulating expression of mTOR. Therefore, patients with chronic rotator cuff injury may have higher levels of oxidative stress and autophagy.

Clinical efficacy and tendon integrity of patients with subscapularis tear by the technique of arthroscopic single external row repair.

Background: With the development of arthroscopic technology and equipment, arthroscopy can effectively repair the tear of the subscapular muscle. However, it is difficult to expose the subscapular muscle and operate it under a microscope. In this study, the SwiveLock® C external row anchor under arthroscopy was applied to repair the tear of the subscapular muscle in a single row, which is relatively easy to operate with reliable suture and fixation, and its efficacy was evaluated. Purpose: This study aimed to assess the clinical efficacy and the tendon integrity of patients who had subscapularis tears by adopting the single-row repair technique with a SwiveLock® C external row anchor. Methods: Patients who had the subscapular muscle tear either with or without retraction were included, and their follow-up time was at least 1 year. The degree of tendon injury was examined by magnetic resonance imaging (MRI) and confirmed by arthroscopy. The tendon was repaired in an arthroscopic manner by utilizing the single-row technique at the medial margin of the lesser tuberosity. One double-loaded suture SwiveLock® C anchor was applied to achieve a strong fixation between the footprint and tendon. The range of motion, pain visual simulation score, American Shoulder and Elbow Surgeons (ASES) score, and Constant score of shoulder joint were evaluated for each patient before the operation, 3 months after the operation, and at least 1 year after the operation. Results: In total, 110 patients, including 31 males and 79 females, with an average age of 68.28 ± 8.73 years were included. Arthroscopic repair of the subscapular tendon with SwiveLock® C external anchor can effectively improve the range of motion of the shoulder joint. At the last follow-up, the forward flexion of the shoulder joint increased from 88.97 ± 26.33° to 138.38 ± 26.48° (P < 0.05), the abduction range increased from 88.86 ± 25.27° to 137.78 ± 25.64° (P < 0.05), the external rotation range increased from 46.37 ± 14.48° to 66.49 ± 14.15° (P < 0.05), and the internal rotation range increased from 40.03 ± 9.01° to 57.55 ± 7.43° (P < 0.05). The clinical effect is obvious. The constant shoulder joint score increased from 40.14 ± 15.07 to 81.75 ± 11.00 (P < 0.05), the ASES score increased from 37.88 ± 13.24 to 82.01 ± 9.65 (P < 0.05), and the visual analog scale score decreased from 5.05 ± 2.11 to 1.01 ± 0.85 (P < 0.05). In the 6th month after the operation, two cases (1.81%) were confirmed to have re-tears via MRI. Conclusion: In this study, we repaired the subscapularis muscle with a single-row technique fixed by SwiveLock® C anchor and FiberWire® sutures and evaluated its efficacy. The results showed that the clinical effect of single-row arthroscopic repair was satisfactory and that reliable tendon healing could be achieved.

[Oxidative stress induces autophagy to inhibit the proliferation and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs)].

Objective To investigate the effect of H2O2-induced oxidative stress on autophagy and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs). Methods hBMSCs were isolated and cultured. The cells were divided into control group, 3-MA group, H2O2 group, H2O2 combined with 3-MA group. DCFH-DA staining was used to analyze the level of reactive oxygen species (ROS). hBMSCs were treated with 0, 50, 100, 200, 400 µmol/L H2O2, and then the cell viability was detected by CCK-8 assay. The level of autophagy was detected by monodansylcadaverine (MDC) staining and LysoTracker Red staining. The cell apoptosis was detected by flow cytometry. Western blotting was used to detect the expression of beclin 1, mTOR, phosphorylated mTOR (p-mTOR), cleaved caspase-3(c-caspase-3) and caspase-3 proteins. Results Compared with the control group and 3-MA group, ROS level and autophagosomes were increased and the proliferation and apoptosis were decreased in H2O2 group. The protein expression of beclin 1, mTOR, c-caspase-3 was up-regulated, while the p-mTOR was down-regulated. Compared with the 3-MA group, the H2O2 combined with 3-MA group also had an increased ROS level and autophagosomes, but not with significantly increased apoptosis rate; The protein expression of beclin 1, mTOR, c-caspase-3 was up-regulated, and the p-mTOR was down-regulated. Conclusion H2O2 can induce hMSCs to trigger oxidative stress response. It enhances the autophagy and inhibits the proliferation and apoptosis of hBMSCs.

Paired Oxidative and Reductive Catalysis: Breaking the Potential Barrier of Electrochemical C(sp3 )-H Alkenylation.

Due to the intrinsic inertness of alkanes, strong oxidative conditions are typically required to enable their C(sp3 )-H functionalization. Herein, a paired electrocatalysis strategy was developed by integrating oxidative catalysis with reductive catalysis in one cell without interference, in which earth-abundant iron and nickel are employed as the anodic and cathodic catalysts, respectively. This approach lowers the previously high oxidation potential required for alkane activation, enabling electrochemical alkane functionalization at the ultra-low oxidation potential of ≈0.25 V vs. Ag/AgCl under mild conditions. Structurally diverse alkenes, including challenging all-carbon tetrasubstituted olefins, can be accessed using readily available alkenyl electrophiles.

A century-long eddy-resolving simulation of global oceanic large- and mesoscale state.

Investigating oceanic variations at multiple spatial and temporal scales is vital for an in-depth understanding of the ocean response to global climate change. However, the available observational datasets contain uncertainties and deficiencies that leave them insufficient for investigating global ocean variability with long temporal scales and/or meso spatial scales. Here, we present a daily and century-long (1901-2010) global oceanic simulation dataset with high resolution (1/10° horizontal resolution and 55 vertical layers) forced by 6-hour atmospheric data from ERA-20C. Preliminary evaluations demonstrate that this simulation can realistically reproduce the large-scale global ocean circulation and capture the essential features of global surface mesoscale eddies. This long-running high-resolution simulation dataset provides temporally highly resolved oceanic and flux variables. Together with its good performance in simulating the global oceanic state, this eddy-resolving simulation has the potential to help toward a better understanding of ocean variability at multiple spatial and temporal scales.

Prognostic implications of the BRAF-V600E mutation in papillary thyroid carcinoma based on a new cut-off age stratification.

The BRAF-V600E mutation is the most common and specific oncogenic event known in papillary thyroid carcinoma (PTC). However, it remains controversial whether there is an association between the BRAF-V600E mutation and clinicopathologically aggressive characteristics of PTC. The purpose of the present retrospective study was to investigate the significance of the BRAF-V600E mutation in predicting prognostic and aggressive clinicopathological characteristics according to a new age-based stratification. Clinical data and the BRAF-V600E mutation status of 475 patients with PTC were downloaded from The Cancer Genome Atlas database. The association between BRAF-V600E status and clinicopathological characteristics was analyzed by χ2 test or Fisher's exact test. Recurrence-free survival rate (RFS) was analyzed using the Kaplan-Meier method. Aggressive clinicopathological factors associated with recurrence were analyzed by Cox multivariate regression. This study was conducted on 219 cases of patients with PTC with a known BRAF-V600E mutational status. In the ≥55 years age group, BRAF-V600E was found to be significantly associated with aggressive PTC characteristics, including tumor size, PTC subtype, radioactive iodine (RAI) dose, follow-up time, recurrence, recurrence risk stage, advanced T stage, advanced N stage and American Joint Committee on Cancer (III/IV) stage (all P<0.05). RFS was analyzed by the log-rank test and exhibited statistically significant differences in the ≥55 years group (P=0.041), but there was no significant difference in the <55 group (P=0.757), according to the BRAF-V600E mutation status. The BRAF-V600E gene was excluded from the recurrence Cox multivariate regression model. The BRAF-V600E mutation was found to better predict aggressive and recurrent PTC based on age stratification with the cut-off age of 55 years. The synergistic interaction between BRAF-V600E mutation and the new age stratification may help clinicians reach the optimal decision in terms of surgical approach and the extent of surgery.

Application of nomograms to predict overall and cancer-specific survival in patients with chordoma.

BACKGROUND: The survival prediction of patients with chordoma is difficult to make due to the rarity of this oncologic disease. Our objective was to apply a nomogram to predict survival outcomes in individuals with chordoma of the skull base, vertebral column, and pelvis. METHODS: A total of 558 patients with chordoma between 1973 and 2014 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors in patients with chordoma were identified via univariate and multivariate Cox analysis. Then these prognostic factors were incorporated into a nomogram to predict 3- and 5-year overall survival and cancer-specific survival rates. Internal and external data were used to validate the nomograms. Concordance indices (C-indices) were used to estimate the accuracy of this nomogram system. RESULTS: A total of 558 patients were randomly assigned into a training cohort (n = 372) and a validation cohort (n = 186). Age, surgical stage, tumor size, histology, primary site, and use of surgery were identified as independent prognostic factors via univariate and multivariate Cox analysis (all p < 0.05) and further included to establish the nomogram. The C-indices for overall survival and cancer-specific survival prediction of the training cohort were 0.775 (95% confidence interval, 0.770-0.779) and 0.756 (95% confidence interval, 0.749 -0.762). The calibration plots both showed an excellent consistency between actual survival and nomogram prediction. CONCLUSION: Nomograms were constructed to predict overall survival and cancer-specific survival for patients with chordoma of the skull base, vertebral column, and pelvis. The nomogram could help surgeons to identify high risk of mortality and evaluate prognosis in patients with chordoma.

Diffusion Tensor Magnetic Resonance Imaging in Chronic Spinal Cord Compression.

Chronic spinal cord compression is the most common cause of spinal cord impairment in patients with nontraumatic spinal cord damage. Conventional magnetic resonance imaging (MRI) plays an important role in both confirming the diagnosis and evaluating the degree of compression. However, the anatomical detail provided by conventional MRI is not sufficient to accurately estimate neuronal damage and/or assess the possibility of neuronal recovery in chronic spinal cord compression patients. In contrast, diffusion tensor imaging (DTI) can provide quantitative results according to the detection of water molecule diffusion in tissues. In the present study, we develop a methodological framework to illustrate the application of DTI in chronic spinal cord compression disease. DTI fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and eigenvector values are useful for visualizing microstructural pathological changes in the spinal cord. Decreased FA and increases in ADCs and eigenvector values were observed in chronic spinal cord compression patients compared to healthy controls. DTI could help surgeons understand spinal cord injury severity and provide important information regarding prognosis and neural functional recovery. In conclusion, this protocol provides a sensitive, detailed, and noninvasive tool to evaluate spinal cord compression.

Time course of diffusion tensor imaging metrics in the chronic spinal cord compression rat model.

BACKGROUND: Diffusion tensor imaging (DTI) provides information about water molecule diffusion in spinal cord. PURPOSE: This study was aimed to investigate DTI changes in the different stages of compressive spinal cord induced by water-absorbing material implantation. MATERIAL AND METHODS: The spinal cord compression was administered over the fourth cervical vertebral level in rat. Rat models were divided into five subgroups according to compression stages: sham group, group A: three-day compression rat models; group B: 12-day compression rat models; group C: 20-day compression rat models; group D: 60-day compression rat models. DTI including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the compressive spinal cord were collected. The relationship between the Basso, Beattie, and Bresnahan (BBB) scores and DTI metrics was further explored. RESULTS: Compared with the sham group, BBB scoring of rat model showed a decreased tendency from group A ( P < 0.05) to group B ( P < 0.05). Then the motor function of rat model hindlimbs was recovered in some degree from group C ( P < 0.05) to group D ( P < 0.05) but had significant motor defects when compared with the normal level ( P < 0.05). The DTI metrics results revealed that chronic spinal cord compression resulted in lower FA value and higher ADC value at the compressive spinal cord level assessed at all four time-points ( P < 0.05). DTI metrics also showed a close correlation with motor function ( P < 0.05). CONCLUSION: DTI is an optimal pre-clinical imaging tool to reflect locomotor performance and pathological status of compressive spinal cord epicenter in chronic spinal cord compression rat model.

Nomogram application to predict overall and cancer-specific survival in osteosarcoma.

PURPOSE: A prognostic nomogram was applied to predict survival in osteosarcoma patients. PATIENTS AND METHODS: Data collected from 2,195 osteosarcoma patients in the Surveillance, Epidemiology, and End Results (SEER) database between 1983 and 2014 were analyzed. Independent prognostic factors were identified via univariate and multivariate Cox analyses. These were incorporated into a nomogram to predict 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) rates. Internal and external data were used for validation. Concordance indices (C-indices) were used to estimate nomogram accuracy. RESULTS: Patients were randomly assigned into a training cohort (n=1,098) or validation cohort (n=1,097). Age at diagnosis, tumor site, histology, tumor size, tumor stage, use of surgery, and tumor grade were identified as independent prognostic factors via univariate and multivariate Cox analyses (all P<0.05) and then included in the prognostic nomogram. C-indices for OS and CSS prediction in the training cohort were 0.763 (95% CI 0.761-0.764) and 0.764 (95% CI 0.762-0.765), respectively. C-indices for OS and CSS prediction in the external validation cohort were 0.739 (95% CI 0.737-0.740) and 0.740 (95% CI, 0.738-0.741), respectively. Calibration plots revealed excellent consistency between actual survival and nomogram prediction. CONCLUSION: Nomograms were constructed to predict OS and CSS for osteosarcoma patients in the SEER database. They provide accurate and individualized survival prediction.

Identification of key target genes and biological pathways in multiple sclerosis brains using microarray data obtained from the Gene Expression Omnibus database.

OBJECTIVE: The purpose of this study was to investigate critical genes in multiple sclerosis (MS) using microarray data from brain tissue in MS. MATERIALS: The expression profile data set of MS (GSE38010) downloaded from the Gene Expression Omnibus database contained gene information from five plaque tissues from MS brains and two white matter tissues from healthy controls. An R package was applied to process these raw chip data. Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network analysis were performed to investigate interactions between differentially expressed genes (DEGs) in MS brain tissues. RESULTS: This study identified a total of 1065 DEGs, including 530 up-regulated genes and 535 down-regulated genes, in MS brain tissue samples compared to those in normal white matter tissue samples. GO and KEGG pathway enrichment analyses showed that the up-regulated DEGs were mainly related to neuron development, neuron projection morphogenesis and neuron differentiation. Furthermore, the down-regulated DEGs were largely related to axon ensheathment, ensheathment of neurons and nervous system development. Seven key genes were found as hub genes in the maintenance of the PPI network. CONCLUSION: Several key target genes and their GO and KEGG pathway enrichment identified in the present study may serve as feasible targets for MS therapies.

Application of Diffusion Tensor Imaging Cutoff Value to Evaluate the Severity and Postoperative Neurologic Recovery of Cervical Spondylotic Myelopathy.

BACKGROUND: Magnetic resonance imaging (MRI) plays an important role in the assessment of spinal cord status for cervical spondylotic myelopathy (CSM). Diffusion tensor imaging (DTI) also is a novel investigation tool with good sensitivity to detect changes in CSM, but it is not routinely used in spinal cord evaluation. METHODS: Sixty-six patients with CSM who required surgical decompression were included. All the patients were divided into 4 subgroups according to Japanese Orthopaedic Association (JOA) recovery rate. A 3.0T MR system was applied to obtain DTI of the spinal cord. Clinical assessment was performed with the JOA scores system. RESULTS: DTI data of 61 patients were available for further analysis in this study. No significant differences in age, sex, cervical curvature, surgical approach, and preoperative JOA score between the 4 subgroups were found (P > 0.05). Significant differences in apparent diffusion coefficient (ADC) (P < 0.0001), mean diffusivity (MD), (P < 0.0001), axial diffusivity (AD) (P = 0.0459), and radial diffusivity (RD) (P < 0.0001) values were found between the 4 groups. The ADC (P < 0.0001), MD (P < 0.0001), AD (P = 0.0434), and RD (P < 0.0001) values were significantly correlated with JOA recovery rate. Cutoff values of ADC, MD, AD, and RD in this study were 1.378*10-3, 1.378*10-3, 2.386*10-3, and 0.894*10-3 mm2/s, respectively. CONCLUSION: DTI was closely related to the severity of CSM, and cutoff values of DTI enabled the surgeons to predict the surgical outcomes in patients with CSM. These evaluation metrics may reflect the pathologic conditions of the spinal cord quantitatively, and potentially evaluate the functional status of spinal cords.

The Holocene temperature conundrum.

A recent temperature reconstruction of global annual temperature shows Early Holocene warmth followed by a cooling trend through the Middle to Late Holocene [Marcott SA, et al., 2013, Science 339(6124):1198-1201]. This global cooling is puzzling because it is opposite from the expected and simulated global warming trend due to the retreating ice sheets and rising atmospheric greenhouse gases. Our critical reexamination of this contradiction between the reconstructed cooling and the simulated warming points to potentially significant biases in both the seasonality of the proxy reconstruction and the climate sensitivity of current climate models.

Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.

OBJECTIVES: Few genetic mutations have been identified in pancreatic adenocarcinoma, whereas epigenetic changes that lead to gene silencing are known in several genes. Because SLC5A8 is regarded as a potential tumor suppressor gene that is down-regulated by epigenetic changes in several other cancers, we sought to characterize promoter methylation status and its relationship to SLC5A8 expression in pancreatic cancer. METHODS: Promoter methylation and expression of SLC5A8 were evaluated in pancreatic cancer cell lines, tumor, and adjacent nontumor tissues from pancreatic cancer patients using methylation-specific polymerase chain reaction analysis, quantitative real-time and semiquantitative reverse transcriptase-polymerase chain reaction, and bisulfate-modified sequencing. RESULTS: Complete or partial loss of SLC5A8 expression was observed in all tumor tissues. Bisulfite sequencing analysis on pancreatic cancer cell lines that did not express SLC5A8 detected dense methylation of the promoter region. SLC5A8 expression was reactivated by treatment with aza-deoxycytidine or trichostatin A. Methylation-specific polymerase chain reaction detected methylation in 7 of 10 pancreatic tumor tissues, whereas in only 3 of 28 adjacent nontumor tissues (P < 0.001). CONCLUSIONS: Our findings indicate loss of SLC5A8 expression as a result of aberrant promoter methylation in pancreatic adenocarcinoma. We suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis and progression of pancreatic cancer.

Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor.

BACKGROUND: The prostate gland is the most common site of cancer and the third leading cause of cancer mortality in men. Solute carrier family 5 (iodide transporter), member 8 (SLC5A8) was proposed as a potential tumor suppressor gene which is silenced by epigenetic changes in various tumors. The aim of this study was to investigate the significance of DNA methylation in SLC5A8 expression in prostate tumors. METHODS: DNA methylation status of the promoter region and expression of SLC5A8 were evaluated in prostate cancer cell lines, tumor and adjacent non-tumor prostate tissues from same prostate cancer patients, by using bisulphite-modified sequencing, RT-PCR and quantitative methylation-specific PCR (QMSP) analysis. RESULTS: The reduced or lost expression of SLC5A8 was observed in 70% of the tumor tissues. The bisulphite-modified sequencing analysis on the prostate cancer cell lines which do not express SLC5A8 detected the densely methylated SLC5A8 promoter region. SLC5A8 was reactivated by treatment with DNA methyl transferase inhibitor, 5-azacytidine but not by trichostatin A (TSA). Higher methylation at the promoter region of SLC5A8 in primary prostate tumor tissues was detected as compared with those in adjacent non-tumor tissues (7/10, 70%). CONCLUSIONS: These data suggested that DNA methylation in the SLC5A8 promoter region suppressed the expression of SLC5A8 in prostate tumor.

The autoimmune regulator directly controls the expression of genes critical for thymic epithelial function.

The autoimmune regulator (Aire) gene plays an essential role in negative selection of T cells and deletion of autoreactive T cells in the thymus. The defect in thymic selection in Aire(-/-) mice was attributed to the repressed expression of tissue-specific Ags in the thymic epithelial cells and defective Ag presentation; however, the molecular mechanism underlying these functions has been elusive. Using the chromatin immunoprecipitation technique, we demonstrate here that Aire binds in vivo to specific DNA sequence motifs and directly regulates thymic expression of genes important for thymic functions including expression of autoantigens, cytokines, transcription factors, and posttranslational modifiers. These results unambiguously established Aire as a key transcriptional regulator of the immune system.

Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulation of antigen-activated immune response and polymorphisms at the CTLA-4 gene have been shown to be associated with several autoimmune diseases including type-1 diabetes (T1D). The etiological mutation was mapped to the CT60-A/G single nucleotide polymorphism (SNP) that is believed to control the processing and production of soluble CTLA-4 (sCTLA-4). METHODS: We therefore determined sCTLA-4 protein levels in the sera from 82 T1D patients and 19 autoantibody positive (AbP) subjects and 117 autoantibody negative (AbN) controls using ELISA. The CT-60 SNP was genotyped for these samples by using PCR and restriction enzyme digestion of a 268 bp DNA segment containing the SNP. Genotyping of CT-60 SNP was confirmed by dye terminating sequencing reaction. RESULTS: Higher levels of sCTLA-4 were observed in T1D (2.24 ng/ml) and AbP (mean = 2.17 ng/ml) subjects compared to AbN controls (mean = 1.69 ng/ml) with the differences between these subjects becoming significant with age (p = 0.02). However, we found no correlation between sCTLA-4 levels and the CTLA-4 CT-60 SNP genotypes. CONCLUSION: Consistent with the higher serum sCTLA-4 levels observed in other autoimmune diseases, our results suggest that sCTLA-4 may be a risk factor for T1D. However, our results do not support the conclusion that the CT-60 SNP controls the expression of sCTLA-4.

Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes.

The lymphoid-specific phosphatase (LYP) encoded by PTPN22 is involved in preventing spontaneous T-cell activation by dephosphorylating and inactivating T-cell receptor-associated Csk kinase. We have genotyped 396 type 1 diabetic patients and 1,178 control subjects of Caucasian descent from north central Florida and report a strong association between type 1 diabetes and a polymorphism (R620W) in the PTPN22 gene. The homozygous genotype for the T allele encoding the 620W residue is associated with an increased risk for developing type 1 diabetes (odds ratio [OR] = 3.4, P < 0.008), and the heterozygous genotype C/T had an OR of 1.7 (P = 6 x 10(-6)). The C/C homozygous genotype is protective against type 1 diabetes (OR = 0.5, P = 6 x 10(-6)). Furthermore, transmission disequilibrium analysis of 410 affected sibpair and simplex families of Caucasian descent indicated that the type 1 diabetes-associated T allele is transmitted more often (57.2%) than randomly expected (P < 0.003). Together with previous reports of the association between PTPN22 and type 1 diabetes, as well as rheumatoid arthritis and systemic lupus erythematosus, these results provide compelling evidence that LYP is a critical player in multiple autoimmune disorders.

A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.