Injectable, pH-responsive hybrid hydrogels for the treatment of periodontitis.

Anti-inflammatory hydrogels have demonstrated great potential in the treatment of periodontitis. However, intelligent removal of reactive oxygen species (ROS) remains significantly challenging. In this study, a novel pH-responsive anti-inflammatory hydrogel was designed to treat periodontitis. We synthesized methacrylated alginate modified with a unique pH-sensitive phenylboronic acid through a one-step synthesis and then incorporated polydopamine particles loaded with minocycline to obtain a novel hydrogel under ultraviolet irradiation. Infrared and ultraviolet tests confirmed the successful preparation of the hydrogel. In environments with low pH, drug release rates significantly increased. In addition, in vitro cell experiments demonstrated excellent biocompatibility of the hydrogels. Furthermore, ROS detection revealed that the hydrogel effectively reduced cellular ROS levels and displayed excellent anti-inflammatory properties. These results strongly suggest that this novel pH-responsive anti-inflammatory hydrogel platform has tremendous potential for the treatment of periodontitis.

The effect of radioiodine treatment on the characteristics of TRAb in Graves' disease.

BACKGROUND: Graves' disease (GD) is one of the most common autoimmune thyroid diseases (AITDs) in humans, and thyrotropin receptor antibody (TRAb) is a characterized autoantibody in GD. The use of radioactive iodine therapy (RAI) for GD treatment is increasing. OBJECTIVES: We studied the biological properties of TRAb and evaluated the effect of RAI therapy on TRAb in GD patients. METHODS: In total, 225 patients (22 onset GD patients without 131I therapy, 203 GD patients treated with 131I therapy) and 20 healthy individuals as normal controls were included in this study. Clinical assessments were performed, and we examined in vitro the biological properties of TRAb in the 22 onset GD patients and 20 controls as well as 84 GD patients with 131I therapy. RESULTS: Serum TRAb and thyroid peroxidase antibody (TPOAb) levels increased in the initial year of RAI treatment, and both antibodies decreased gradually after one year. After 5 years from radioiodine treatment, TRAb and TPOAb levels decreased in 88% and 65% of GD patients, respectively. The proportion of patients positive for thyroid-stimulatory antibody (TSAb) was significantly higher in the 7-12-month group, and thyroid-blocking antibody (TBAb) levels were elevated after one year in half of the patients who received 131I treatment. CONCLUSIONS: Treatment of GD patients with radioiodine increased TPOAb and TRAb (their main biological properties were TSAbs) within the first year after therapy, and the main biological properties of elevated TRAb were TBAbs after 1 year.

Research on Fault Extraction Method of Variational Mode Decomposition Based on Immunized Fruit Fly Optimization Algorithm.

In recent years, a new method of fault diagnosis, named variational mode decomposition (VMD), has been widely used in industrial production, but the decomposition accuracy of VMD is determined by two parameters, which are respectively the decomposition layer number k and the penalty factor α, if the parameters are not properly selected, there will be over-decomposition or under-decomposition. In order to find an approach to determine the parameters adaptively, a method to optimize VMD by using the immune fruit fly optimization algorithm (IFOA) is proposed in this paper. In this method, permutation entropy is used as the fitness function, firstly, the immune fruit fly optimization algorithm is used to search the combined parameters of k and α in VMD, searching for the best combination parameters of k and α by iteration, and then uses the combined parameters to perform VMD, finally, the center frequency is determined through frequency spectrum analysis. The method mentioned is applied to the fault extraction of a simulated signal and a measured signal of a wind turbine gearbox, and the fault frequency is successfully extracted. Using ensemble empirical mode decomposition (EEMD) and singular spectrum decomposition (SSD) to compare with the proposed method, which validated feasibility of the proposed method.

A New Fuzzy Logic Classifier Based on Multiscale Permutation Entropy and Its Application in Bearing Fault Diagnosis.

The self-organizing fuzzy (SOF) logic classifier is an efficient and non-parametric classifier. Its classification process is divided into an offline training stage, an online training stage, and a testing stage. Representative samples of different categories are obtained through the first two stages, and these representative samples are called prototypes. However, in the testing stage, the classification of testing samples is completely dependent on the prototype with the maximum similarity, without considering the influence of other prototypes on the classification decision of testing samples. Aiming at the testing stage, this paper proposed a new SOF classifier based on the harmonic mean difference (HMDSOF). In the testing stage of HMDSOF, firstly, each prototype was sorted in descending order according to the similarity between each prototype in the same category and the testing sample. Secondly, multiple local mean vectors of the prototypes after sorting were calculated. Finally, the testing sample was classified into the category with the smallest harmonic mean difference. Based on the above new method, in this paper, the multiscale permutation entropy (MPE) was used to extract fault features, linear discriminant analysis (LDA) was used to reduce the dimension of fault features, and the proposed HMDSOF was further used to classify the features. At the end of this paper, the proposed fault diagnosis method was applied to the diagnosis examples of two groups of different rolling bearings. The results verify the superiority and generalization of the proposed fault diagnosis method.

A dense mapping study of six European AITD susceptibility regions in a large Chinese Han Cohort of Graves' disease.

OBJECTIVE: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN: Dense mapping studies based on GWAS. PATIENTS: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS: Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS: After the first replication stage, four SNPs from three regions with Pfirst  < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined  = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined  = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.

Research on Fault Diagnosis of Gearbox with Improved Variational Mode Decomposition.

Variational Mode Decomposition (VMD) can decompose signals into multiple intrinsic mode functions (IMFs). In recent years, VMD has been widely used in fault diagnosis. However, it requires a preset number of decomposition layers K and is sensitive to background noise. Therefore, in order to determine K adaptively, Permutation Entroy Optimization (PEO) is proposed in this paper. This algorithm can adaptively determine the optimal number of decomposition layers K according to the characteristics of the signal to be decomposed. At the same time, in order to solve the sensitivity of VMD to noise, this paper proposes a Modified VMD (MVMD) based on the idea of Noise Aided Data Analysis (NADA). The algorithm first adds the positive and negative white noise to the original signal, and then uses the VMD to decompose it. After repeated cycles, the noise in the original signal will be offset to each other. Then each layer of IMF is integrated with each layer, and the signal is reconstructed according to the results of the integrated mean. MVMD is used for the final decomposition of the reconstructed signal. The algorithm is used to deal with the simulation signals and measured signals of gearbox with multiple fault characteristics. Compared with the decomposition results of EEMD and VMD, it shows that the algorithm can not only improve the signal to noise ratio (SNR) of the signal effectively, but can also extract the multiple fault features of the gear box in the strong noise environment. The effectiveness of this method is verified.

Application of Improved Singular Spectrum Decomposition Method for Composite Fault Diagnosis of Gear Boxes.

Aiming at the problem that the composite fault signal of the gearbox is weak and the fault characteristics are difficult to extract under strong noise environment, an improved singular spectrum decomposition (ISSD) method is proposed to extract the composite fault characteristics of the gearbox. Singular spectrum decomposition (SSD) has been proved to have higher decomposition accuracy and can better suppress modal mixing and pseudo component. However, noise has a great influence on it, and it is difficult to extract weak impact components. In order to improve the limitations of SSD, we chose the minimum entropy deconvolution adjustment (MEDA) as the pre-filter of the SSD to preprocess the signal. The main function of the minimum entropy deconvolution adjustment is to reduce noise and enhance the impact component, which can make up for the limitations of SSD. However, the ability of MEDA to reduce noise and enhance the impact signal is greatly affected by its parameter, the filter length. Therefore, to improve the shortcomings of MEDA, a parameter adaptive method based on Cuckoo Search (CS) is proposed. First, construct the objective function as the adaptive function of CS to optimize the MEDA algorithm. Then, the pre-processed signal is decomposed into singular spectral components (SSC) by SSD, and the meaningful components are selected by Correlation coefficient. For the existing modal mixing phenomenon, the SSC component is reconstructed to eliminate the misjudgment of the result. Then, the frequency spectrum analysis is performed to obtain the frequency information for fault diagnosis. Finally, the effectiveness and superiority of ISSD are validated by simulation signals and applying to compound faults of a Gear box test rig.

Modified Singular Spectrum Decomposition and Its Application to Composite Fault Diagnosis of Gearboxes.

Under the strong noise environment, the composite fault signal of gearbox is weak, which makes it difficult to extract fault features. For this problem, based on noise-assisted method, we propose a novel method called Modified Singular Spectrum Decomposition (MSSD). Singular Spectrum Decomposition (SSD) has many advantages such as high decomposition precision and strong ability to restrain mode mixing, etc. However, the ability of SSD to extract a weak signal is not ideal, the decomposition results usually contain a lot of redundant noise and mode mixing caused by intermittency, which is also a troubling problem. In order to improve the decomposition efficiency and make up for the defects of SSD, the new method MSSD adds an adaptive and particular noise in every SSD decomposition stage for each trial, and in addition, whenever the input signal is decomposed to obtain an intrinsic module function (IMF), a unique residual is obtained. After multiple decomposition, the average value of the residual is used as input to the next stage, until the residual cannot continue to decompose, which means that the residual component has, at most, one extreme value. Finally, analyzing simulated signals to explain the advantages of MSSD compared to ensemble empirical mode decomposition (EEMD) and complete ensemble local mean decomposition with adaptive noise (CEEMDAN). In order to further prove the effectiveness of MSSD, this new method, MSSD, is applied to the fault diagnosis of an engineering gearbox test stand in an actual engineer project case. The final results show that MSSD can extract more fault feature information, and mode mixing has been improved and suffers less interference compared to SSD.

Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Role of speckle tracking imaging in the assessment of myocardial regional ventricular function in experimental blunt cardiac injury.

PURPOSE: To evaluate the usefulness and information collecting ability of speckle tracking imaging techniques in the assessment of myocardial regional ventricular contractility in a rabbit model with blunt cardiac injury. METHODS: Fifteen healthy New Zealand rabbits weighing (2.70 ±0.28) kg were anesthetized (3% pentobarbital sodium/i.v) and impacted using the BIM-II biological impact machine to induce myocardial contusion (MC). Hemodynamic parameters, such as heart rate, systolic pressure, mean arterial pressure, diastolic pressure and central venous pressure, were determined before and after MC. Further, parameters reflecting left ventricular functions, such as left ventricular end systolic pressure, left ventricular end diastolic pressure, isovolumic pressure (IP) and the maximal increasing/decreasing rate of left intraventricular pressure (±dp/dtmax), were also determined before and after MC. Left ventricular functions were determined either by two dimensional transthoracic echocardiography or by speckle tracking imaging for segmental abnormal ventricular wall motions. RESULTS: Heart rate, systolic pressure, diastolic pressure and mean arterial pressure decreased significantly but transiently, while central venous pressure markedly increased after MC. In contrast to significant changes in diastolic functions, there was no significant change in cardiac systolic functions after MC. The speckle tracking imaging demonstrated that strain values of different myocardial segment significantly decreased post impact, and that of the ventricular segment decreased from segment to segment. CONCLUSION: Speckle tracking imaging is useful and informative to assess myocardial regional dysfunctions post MC.

Identification of BACH2 as a susceptibility gene for Graves' disease in the Chinese Han population based on a three-stage genome-wide association study.

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.

Effects of harvest stages and lactic acid bacteria additives on the nutritional quality of silage derived from triticale, rye, and oat on the Qinghai-Tibet Plateau.

Background: Triticale (×Triticosecale Wittmack L.), rye (Secale cereale L.), and oat (Avena sativa L.) are the main forage crops on the Qinghai-Tibet Plateau, but there has been relatively little research on the silage produced from these three species. Methods: Plants were harvested at the heading, flowering, grouting, milky, and dough stages and then used to produce silage with and without additives (Sila-Max and Sila-Mix). The nutritional quality of the resulting silages was analyzed. Results: Triticale was revealed to be more suitable than oat or rye for producing silage on the Qinghai-Tibet Plateau. On the basis of the dry matter yield (DMY), triticale and rye should be harvested at the milky stage to optimize silage quality, whereas oat should be harvested at the dough stage. The lactic acid bacteria additives Sila-Max and Sila-Mix had no significant effect on the nutritional quality of the three silages regardless of when the samples were harvested. Overall, triticale produced higher quality silage than oat or rye. More specifically, triticale variety 'Gannong No.2' harvested at the milky stage is ideal for silage production.

Response of nine triticale genotypes to different salt concentrations at the germination and early seedling stages.

Salinity stress poses a major challenge to agricultural productivity worldwide, and understanding their responses at the early growth stage is vital for devising strategies to cope with this stress. Therefore, to improve triticale productivity, this study investigated the salinity stress tolerance of different salt-tolerant triticale genotypes aiming to cultivate them on saline soils. To this end, salinity stress impacts on nine triticale genotypes, i.e., Zhongsi 1084, Gannong No. 2, Gannong No. 4, Shida No. 1, C6, C16, C23, C25 and C36 at germination and early seedling stages was evaluated. Each genotype was subjected to six treatments inducing control, 40, 80, 120, 160, and 200 mM NaCl treatments to study their effect on seedling and termination traits of the nine genotypes. Compared to the overall mean seedling vigor index, the seedling vigor index was higher in the genotypes Zhongsi 1084 and C6 (39% and 18.1%, respectively) and lower in Gannong No.2 (41%). Increasing NaCl concentrations negatively affected germination and seedling traits. Compared to other genotypes, Zhongsi 1084 had the highest mean germination rate, germination vigor index, germination percentage, mean daily germination and germination energy. It also showed the lowest relative salt injury. The relative salt injury was higher in the genotype Shida No. 1 than those in Gannong No. 2, Gannong No. 4, Shida No. 1, C16, and C36 genotypes. All genotypes exhibited desirable mean germination time except for line C6. High significant positive correlations were observed among germination rate, germination vigor index, germination percentage, mean daily germination, seedling vigor index, and root length. Principal component analysis (PCA) grouped the most desirable genotypes into two clusters. Our study determined salt stress tolerance of nine triticale genotypes at germination and early seedling stages. to select salt-tolerant genotypes that can be cultivated on saline soil or after salt irrigation.

Triticale Improvement: Mining of Genes Related to Yellow Rust Resistance in Triticale Based on Transcriptome Sequencing.

Yellow (stripe) rust caused by Puccinia striiformis f. sp. tritici (Pst) is a major destructive fungal disease of small grain cereals, leading to large yield losses. The breeding of resistant varieties is an effective, sustainable way to control yellow rust. Elucidation of resistance mechanisms against yellow rust and identification of candidate genes associated with rust resistance are thus crucial. In this study, seedlings of two Triticosecale Wittmack cultivars, highly resistant Gannong No. 2 and susceptible Shida No. 1, were inoculated with Pst race CYR34. Transcriptome sequencing (RNA-seq) was then used to investigate their transcriptional responses against pathogen infection before and after the appearance of symptoms-10 and 20 days after inoculation, respectively. According to the RNA-seq data, the number of upregulated and downregulated differentially expressed genes (DEGs) in the resistant cultivar was greater than in the susceptible cultivar. A total of 2,560 DEGs commonly expressed in the two cultivars on two sampling dates were subjected to pathway analysis, which revealed that most DEGs were closely associated with defense and metabolic activities. Transcription factor enrichment analysis indicated that the expressions of NAC, WRKY, and FAR1 families were also significantly changed. Further in-depth analysis of resistance genes revealed that almost all serine/threonine-protein kinases were upregulated in the resistant cultivar. Other genes related to disease resistance, such as those encoding disease-resistance- and pathogenesis-related proteins were differentially regulated in the two cultivars. Our findings can serve as a resource for gene discovery and facilitate elucidation of the complex defense mechanisms involved in triticale resistance to Pst.

Porphyromonas gingivalis­derived lipopolysaccharide inhibits brown adipocyte differentiation via lncRNA­BATE10.

Epidemiological studies have suggested an association between obesity and periodontal disease. Brown adipose tissue (BAT) has an anti-obesity effect. However, the effects of periodontitis on obesity and BAT remain unclear. Therefore, the present study aimed to determine the effects of lipopolysaccharide derived from Porphyromonas gingivalis (P. gingivalis LPS) on brown adipocytes. For this purpose, the present study examined the effects of the intravenous administration of Porphyromonas gingivalis (P. gingivalis) in mice, the treatment of brown adipocytes with P. gingivalis LPS during differentiation, and the administration of small interfering RNA targeting interferon on brown preadipocytes by assessing the expression of genes involved in differentiation, using a long non-coding (lnc)RNA, and pro-inflammatory factors using reverse transcription-quantitative PCR. In addition, the accumulation of lipid droplets was examined using Oil Red O staining. P. gingivalis LPS reduced the expression of uncoupling protein 1 (UCP1) and lncRNA-BATE10 in brown adipocytes during differentiation. Consistent with this finding, P. gingivalis reduced UCP1 and lncRNA-BATE10 expression in the BAT of mice. lncRNA-BATE10 may thus be involved in the regulation of UCP1 expression that occurs during the differentiation of brown adipocytes treated with P. gingivalis LPS. Thus, P. gingivalis LPS may inhibit BAT differentiation by reducing lncRNA-BATE10 expression.

Phenotypic Heterogeneity and Fertility Potential of Patients With 17-Hydroxylase/17,20-lyase Deficiency.

CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by a human CYP17A1 gene mutation and has the classical phenotype of hypertension, hypokalemia, sexual infantilism, and primary amenorrhea in females (46,XX) and disorders of sexual development in males (46,XY). To date, few cases of 17OHD have been reported, and the likelihood of pregnancy has rarely been explored. OBJECTIVE: To study the clinical characteristics, phenotype heterogeneity, genotyping, and the likelihood of pregnancy of patients with 17OHD. DESIGN: Genotype analysis was performed by direct sequencing of the CYP17A1 gene and next-generation sequencing in nonclassical patients. In vitro enzyme activity assays and 3-dimensional structure observations were used to assess the function of 3 missense mutations of the CYP17A1 gene. Progestin-primed ovarian stimulation (PPOS) was chosen for ovulation induction in 2 patients. RESULTS: Eight mutations were identified from 13 patients, including the homozygous mutations p. N395D and p. R496C and compound heterozygous mutations p. Y329fs/p. A421A and p. I332T/p. D487_F489del in 4 nonclassical patients. For the 3 missense mutations, an in vitro functional study showed mild impairment of 17α-hydroxylase activities 15.3-25.0% but residual 17,20-lyase activities 6.6%-9.4%. Two 46,XX females succeeded in pregnancy and delivery by combined PPOS, in vitro fertilization embryo transfer (IVF-ET), and the use of low-dose glucocorticoids. CONCLUSIONS: Partial 17OHD present nonclassical clinical features, without hypertension and hypokalemia. Successful pregnancy in such 46,XX patients could be attained by the appropriate choice of ovulation induction regimen, precise dose of glucocorticoid to reduce progesterone levels, and the use of IVF-ET.

Short-term effect of radioactive iodine therapy on CXCL-10 production in Graves' disease.

PURPOSE: To observe the short-term dynamic change in serum CXC chemokine ligand-10 (CXCL10) levels in patients with Graves' disease (GD) before and after iodine therapy and to analyze the relationship between CXCL10 levels and clinical disease indices. METHODS: ELISA was used to determine serum levels of CXCL10 in 43 patients with GD shortly before radioiodine therapy and on days six, 14, and 60, post-therapy. RESULTS: Patients with newly diagnosed GD showed significantly higher levels of serum CXCL10 compared with the control group (P < 0.01). The serum CXCL10 level increased slightly on day six after treatment of radioactive iodine (P < 0.01). There was no significant statistical difference in serum CXCL10 levels pre-treatment and on day 14 post-treatment. A significant reduction in serum CXCL10 level was observed on day 60 (P < 0.01). GD patients with exophthalmia showed higher serum CXCL10 level than GD patients without exophthalmia. No correlation was found between levels of CXCL10 and FT3, FT4 or TSH at any time point, but significant positive correlation was shown between thyroid peroxidase antibodies (TPOAb) and CXCL10 (r=0.50, P < 0.01). CONCLUSION: CXCL10 participates in the early inflammatory response after radioactive iodine therapy in patients with Graves' disease and shows a strong association with the autoimmune process.

Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism.

The transcription factor GLIS3 is an important factor in hormone biosynthesis and thyroid development, and mutations in GLIS3 are relatively rare. Deletions of more than one of the 11 exons of GLIS3 occur in most patients with various extrathyroidal abnormalities and congenital hypothyroidism (CH), and only 18 missense variants of GLIS3 related to thyroid disease have been reported. The aim of this study was to report the family history and molecular basis of patients with CH who carry GLIS3 variants. Three hundred and fifty-three non-consanguineous infants with CH were recruited and subjected to targeted exome sequencing of CH-related genes. The transcriptional activity and cellular localization of the variants in GLIS3 were investigated in vitro. We identified 20 heterozygous GLIS3 exonic missense variants, including eight novel sites, in 19 patients with CH. One patient carried compound heterozygous GLIS3 variants (p.His34Arg and p.Pro835Leu). None of the variants affected the nuclear localization. However, three variants (p.His34Arg, p.Pro835Leu, and p.Ser893Phe) located in the N-terminal and C-terminal regions of the GLIS3 protein downregulated the transcriptional activation of several genes required for thyroid hormone (TH) biosynthesis. This study of patients with CH extends the current knowledge surrounding the spectrum of GLIS3 variants and the mechanisms by which they cause TH biosynthesis defects.

The effect of femoral head size on edge loading in metal-on-metal hip joint replacement under dynamic separation conditions.

Edge loading that occurs in hip joint replacements due to dynamic separation of the joint bearings has been shown to cause severe wear for meal-on-metal bearings. In the present study, the multibody dynamics model for metal-on-metal (MoM) hip joints with a medial-lateral translational mismatch in the centers of rotation of the cup and head has been developed to predict the dynamic separation and contact force of edge loading under gait loading conditions. The effects of larger head diameters (28-55 mm), in combination with the translational mismatch (0-4 mm) and varied cup inclination angles (45°-65°), on edge loading of MoM bearings have been computationally investigated. For the given translational mismatch, increasing head diameters results in negligible effects on the dynamic separation, contact force and severity of edge loading. Increasing head size also leads to increased offset loading torque which has been found to reach at the level that may cause cup loosening under larger translational mismatch at 4 mm. The result highlights the importance of the cup inclination angle of 45° and a lower translational mismatch to avoid severe edge loading.

A Novel c.125 T>G (p.Val42Gly) Mutation in The Human INS Gene Leads to Neonatal Diabetes Mellitus via a Decrease in Insulin Synthesis.

BACKGROUND: Neonatal diabetes mellitus is likely caused by monogenic mutations, several of which have been identified. INS mutations have a broad spectrum of clinical presentations, ranging from severe neonatal onset to mild adult onset, which suggests that the products of different mutant INS alleles behave differently and utilize distinct mechanisms to induce diabetes. In this study, a neonatal diabetes mellitus patient's INS gene was sequenced, and functional experiments were conducted. METHODS: The neonatal diabetes mellitus patient's genomic DNA was extracted, and the patient's KCNJ11, ABCC8, and INS genes were sequenced. A novel mutation was identified in INS, and the open reading frame of this human mutant INS gene was inserted into the pMSCV-PIG plasmid. The constructed pMSCV-PIG plasmid was combined with VSV-g and Gag-pol and transfected into 293T cells to package the lentivirus. To stably overexpress the mutant gene, INS-1 cells were infected with the virus. The levels of insulin in the cell culture medium and cytoplasm were determined by ELISA and immunocytochemistry, respectively. RESULTS: A heterozygous mutation, c.125T>G (p. Val42Gly), was identified in a neonatal diabetes mellitus patient's INS gene. The human mutant INS open reading frame was overexpressed in INS-1 cells, and the mutant insulin was undetectable in the cell culture medium and cytoplasm. CONCLUSIONS: The novel heterozygous activating mutation c.125 T>G (p.Val42Gly) impairs the synthesis of insulin by pancreatic beta cells, resulting in diabetes.