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Heterotopic ossification (HO) is the process by which ectopic bone forms at an extraskeletal site. Inflammatory conditions induce plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis, which regulates osteogenesis. In the present study, we investigated the roles of PAI-1 in the pathophysiology of HO induced by trauma/burn treatment using PAI-1-deficient mice. PAI-1 deficiency significantly promoted HO and increased the number of alkaline phosphatase (ALP)-positive cells in Achilles tendons after trauma/burn treatment. The mRNA levels of inflammation markers were elevated in Achilles tendons of both wild-type and PAI-1-deficient mice after trauma/burn treatment and PAI-1 mRNA levels were elevated in Achilles tendons of wild-type mice. PAI-1 deficiency significantly up-regulated the expression of Runx2, Osterix, and type 1 collagen in Achilles tendons 9 weeks after trauma/burn treatment in mice. In in vitro experiments, PAI-1 deficiency significantly increased ALP activity and mineralization in mouse osteoblasts. Moreover, PAI-1 deficiency significantly increased ALP activity and up-regulated osteocalcin expression during osteoblastic differentiation from mouse adipose-tissue-derived stem cells, but suppressed the chondrogenic differentiation of these cells. In conclusion, the present study showed that PAI-1 deficiency promoted HO in Achilles tendons after trauma/burn treatment partly by enhancing osteoblast differentiation and ALP activity in mice. Endogenous PAI-1 may play protective roles against HO after injury and inflammation.

This paper addresses truss topology optimization taking into account robustness to uncertainty in the truss geometry. Specifically, the locations of nodes are assumed not to be known precisely and the compliance in the worst case is attempted to be minimized. We formulate a semidefinite programming problem that serves as a safe approximation of this robust optimization problem. That is, any feasible solution of the presented semidefinite programming problem satisfies the constraints of the original robust optimization problem. Since a semidefinite programming problem can be solved efficiently with a primal-dual interior-point method, we can find a robust truss design efficiently with the proposed semidefinite programming approach. A notable property of the proposed approach is that the obtained truss is guaranteed to be stable. Numerical experiments are performed to illustrate that the optimal truss topology depends on the magnitude of uncertainty.

Dysbiosis of the oral microbiome has been implicated in the onset and progression of periodontal diseases. An altered oral microbiome can significantly affect the concentration and composition ratio of bacterial-derived metabolites, thereby contributing to disease development. However, there is limited research on the role of metabolites derived from the oral microbiota. This study aimed to identify specific bacteria-derived metabolites and their contributions to pathogenicity. Mouth-rinsed water was collected from 24 patients with periodontal disease and 22 healthy individuals. We conducted a correlation analysis between periodontal disease-associated bacteria and metabolites present in mouth-rinsed water. We evaluated the effects of these metabolites on human gingival epithelial cells analysis of oral bacteria culture supernatants confirmed the origin of these metabolites. We identified 20 metabolites associated with bacteria that are significantly more prevalent in periodontal disease. Notably, propionate, succinate, citrulline, and homoserine—metabolites derived from the oral microbiome—were identified as being associated with periodontal disease. These results suggested that metabolites derived from the oral microbiota are involved in periodontal disease.

Visualization of the surgically operated tissues is vital to improve surgical model animals including mouse. Urological surgeries for urethra include series of fine manipulations to treat the increasing number of birth defects such as hypospadias. Hence visualization of the urethral status is vital. Inappropriate urethral surgical procedure often leads to the incomplete wound healing and subsequent formation of urethro-cutaneous fistula or urethral stricture. Application of indocyanine green mediated visualization of the urethra was first performed in the current study. Indocyanine green revealed the bladder but not the urethral status in mouse. Antegrade injection of contrast agent into the bladder enabled to detect the urethral status in vivo. The visualization of the leakage of contrast agent from the operated region was shown as the state of urethral fistula in the current hypospadias mouse model and urethral stricture was also revealed. A second trial for contrast agent was performed after the initial operation and a tendency of accelerated urethral stricture was observed. Thus, assessment of post-surgical conditions of urogenital tissues can be improved by the current analyses on the urethral status.

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and thymic epithelial cells in such processes, the roles of stromal transcription factors in these remain incompletely understood. MafB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a transcription factor expressed in thymic stroma and its expression was induced a day after radiation exposure. Hence, the roles of mesenchymal MafB in the process of thymic regeneration offers an intriguing research topic also for radiation biology. The current study investigated whether MafB plays roles in the adult thymus. MafB /green fluorescent protein knock-in mutant ( MafB + / GFP ) mice showed impaired thymic regeneration after the sublethal irradiation, judged by reduced thymus size, total thymocyte number and medullary complexity. Furthermore, IL4 was induced after irradiation and such induction was reduced in mutant mice. The mutants also displayed signs of accelerated age-related thymic involution. Altogether, these results suggest possible functions of MafB in the processes of thymic recovery after irradiation, and maintenance during aging.

Graves’ disease (GD) is an organ-specific autoimmune thyroid disorder characterized by anti–thyrotropin receptor (TSH-R) antibodies (TRAb), with strong genetic susceptibility conferred by the HLA-DRB1*03:01 (DR3) allele. We investigated whether pre-immunization with the immunodominant TSH-R–derived peptide spanning residues 78–94 (ISRIYVSIDVTLQQLES; p37) could induce immune tolerance and prevent GD in DR3 transgenic mice. GD was induced by intramuscular injection of adenovirus encoding human TSH-R (Ad-TSH-R289). Mice were pretreated with p37 either as a single 50 μg dose or by step-up escalation protocol (0.05 μg, 0.5 μg, and 5 μg), with or without a final 50 μg dose. Ad-TSH-R289 immunization was performed in all groups three weeks after the final peptide administration. While the single-dose protocol failed to prevent disease, the step-up protocol, particularly when including the final 50 μg dose, significantly suppressed serum free thyroxine (FT4) and TRAb levels and prevented histopathological changes in the thyroid gland. These effects were accompanied by an increase in splenic regulatory T cells (CD4 + CD25 + FoxP3 + ), a reduction in CD4 + PD-1 + T cells, and an increase in CD8 + PD-1 + T cells. Depletion of Tregs using an anti-CD25 antibody abrogated the protective effect and elevated serum IFN-γ levels, underscoring the essential role of Tregs in mediating tolerance. In contrast, the weakly immunogenic variant of p37 (37m) provided limited protection, underscoring the necessity of the native peptide sequence. In conclusion, these findings demonstrate that step-up immunization with p37 induces antigen-specific immune tolerance and effectively prevents the development of GD in HLA-DR3 transgenic mice. This strategy represents a promising approach for antigen-specific immunotherapy in autoimmune thyroid disease.

The post-surgical fluid leakage from the tubular tissues is a critical symptom after gastrointestinal or urinary tract surgeries. Elucidating the mechanism for such abnormalities is vital in surgical and medical science. The exposure of the fluid such as peritonitis due to urinary or gastrointestinal perforation has been reported to induce severe inflammation to the surrounding tissue. However, there have been no reports for the tissue responses by fluid extravasation and assessment of post-surgical and injury complication processes is therefore vital. The current model mouse study aims to investigate the effect of the urinary extravasation of the urethral injuries. Analyses on the urinary extravasation affecting both urethral mesenchyme and epithelium and the resultant spongio-fibrosis/urethral stricture were performed. The urine was injected from the lumen of urethra exposing the surrounding mesenchyme after the injury. The wound healing responses with urinary extravasation were shown as severe edematous mesenchymal lesions with the narrow urethral lumen. The epithelial cell proliferation was significantly increased in the wide layers. The mesenchymal spongio-fibrosis was induced by urethral injury with subsequent extravasation. The current report thus offers a novel research tool for surgical sciences on the urinary tract.

Background Recent progress in molecular and signal analyses revealed essential functions of cellular signals including androgen and related growth factors such as Wnt regulators for external genitalia (ExG) development and its pathogenesis. Accumulated data showed their fundamental functions also for erectile tissue (corporal body) development and its abnormalities. The current review focuses on such signals from developmental and functional viewpoints. Methods Experimental strategies including histological and molecular signal analyses with conditional mutant mice for androgen and Wnt signals have been extensively utilized. Main findings Essential roles of androgen for the development of male‐type ExG and urethral formation are shown. Wnt signals are associated with androgen for male‐type ExG organogenesis. Androgen plays essential roles in the development of erectile tissue, the corporal body and it also regulates the duration time of erection. Wnt and other signals are essential for the regulation of mesenchymal cells of erectile tissue as shown by its conditional mutant mouse analyses. Stress signals, continuous erection, and the potential of lymphatic characteristics of the erectile vessels with sinusoids are also shown. Conclusion Reiterated involvement of androgen, Wnt, and other regulatory factors is stated for the development and pathogenesis of ExG and erectile tissues.

Purpose The pathophysiology of penis extends to erectile dysfunction (ED) to conditions including sexually transmitted diseases (STDs) and cancer. To date, there has been little research evaluating vascular drainage from the penis. We aimed to evaluate penile blood flow in vivo and analyze its possible relationship with the lymphatic maker. Materials and Methods We established an in vivo system designed to assess the dynamic blood outflow from the corpus cavernosum (CC) by dye injection. To analyze lymphatic characteristics in the CC, the expression of Lyve‐1, the key lymphatic endothelium marker, was examined by the in vitro system and lipopolysaccharide (LPS) injection to mimic the inflammatory conditions. Results A novel cavernography methods enable high‐resolution morphological and functional blood drainage analysis. The expression of Lyve‐1 was detected along the sinusoids. Furthermore, its prominent expression was also observed after penile LPS injection and in the erectile condition. Conclusions The current in vivo system will potentially contribute to the assessment of penile pathology from a novel viewpoint. In addition, current analyses revealed inducible Lyve‐1 expression for LPS injection and the erection state, which requires further analyses on penile lymphatic system. Dual expression domains of Lyve‐1 in the CC.