KAT6A/YAP/TEAD4 pathway modulates osteoclastogenesis by regulating the RANKL/OPG ratio on the compression side during orthodontic tooth movement.

BACKGROUND: Orthodontic tooth movement (OTM) is a dynamic equilibrium of bone remodeling, involving the osteogenesis of new bone and the osteoclastogenesis of old bone, which is mediated by mechanical force. Periodontal ligament stem cells (PDLCSs) in the periodontal ligament (PDL) space can transmit mechanical signals and regulate osteoclastogenesis during OTM. KAT6A is a histone acetyltransferase that plays a part in the differentiation of stem cells. However, whether KAT6A is involved in the regulation of osteoclastogenesis by PDLSCs remains unclear. RESULTS: In this study, we used the force-induced OTM model and observed that KAT6A was increased on the compression side of PDL during OTM, and also increased in PDLSCs under compression force in vitro. Repression of KAT6A by WM1119, a KAT6A inhibitor, markedly decreased the distance of OTM. Knockdown of KAT6A in PDLSCs decreased the RANKL/OPG ratio and osteoclastogenesis of THP-1. Mechanistically, KAT6A promoted osteoclastogenesis by binding and acetylating YAP, simultaneously regulating the YAP/TEAD axis and increasing the RANKL/OPG ratio in PDLSCs. TED-347, a YAP-TEAD4 interaction inhibitor, partly attenuated the elevation of the RANKL/OPG ratio induced by mechanical force. CONCLUSION: Our study showed that the PDLSCs modulated osteoclastogenesis and increased the RANKL/OPG ratio under mechanical force through the KAT6A/YAP/TEAD4 pathway. KAT6A might be a novel target to accelerate OTM.

Elastic modulus of hydrogel regulates osteogenic differentiation via liquid-liquid phase separation of YAP.

Craniofacial bone defects induced by congenital malformations, trauma, or diseases frequently challenge the orthodontic or restorative treatment. Stem cell-based bone regenerative approaches emerged as a promising method to resolve bone defects. Microenvironment physical cues, such as the matrix elastic modulus or matrix topography, regulate stem cell differentiation via multiple genes. We constructed gelatin methacryloyl (GelMA), a well-known scaffold, to investigate the impact of elastic modulus on osteogenic differentiation in a three-dimensional environment. Confocal microscope was used to observe and assess the condensates fission and fusion. New bone formation was evaluated by micro-computed tomography at 6 weeks in calvarial defect rat. We found that the light curing increased elastic modulus of GelMA, and the pore size of GelMA decreased. The expression of osteogenic markers was inhibited in hBMSCs cultured in the low-elastic-modulus GelMA. In contrast, the expression of YAP, TAZ and TEAD was increased in the hBMSCs in the low-elastic-modulus GelMA. Furthermore, YAP assembled via liquid-liquid phase separation (LLPS) into condensates that were sensitive to 1'6-hexanediol. YAP recruit TAZ and TEAD4, but not RUNX2 into the condensates. In vivo, we also found that hBMSCs in high-elastic-modulus GelMA was more apt to form new bone. This study provides new insight into the mechanism of osteogenic differentiation. Reagents that can regulate the elastic modulus of substrate or LLPS may be applied to promote bone regeneration.

Macrophages with Different Polarization Phenotypes Influence Cementoblast Mineralization through Exosomes.

Root resorption is a common dental challenge that can lead to tooth loosening or even tooth loss. Among the cells involved in root resorption, cementoblasts are responsible for laying down the cementum, while macrophages with different phenotypes have also been shown to have bidirectional effects on root resorption. However, the relationship between macrophages and cementoblasts remains largely unknown. In this study, we examined the effect of macrophages with different polarization phenotypes on the mineralization of cementoblasts. Using the transwell coculture system and a conditioned medium-based coculture system, we found that compared with M0 (unpolarized macrophages), M1-polarized macrophages attenuated cementoblast mineralization, while M2-polarized macrophages enhanced cementoblast mineralization. Furthermore, by extracting M0/M1/M2 macrophage exosomes and examining their effects on the mineralization of cementoblasts, we found that the effects of macrophages on cementoblast mineralization were, at least partially, exerted by exosomes. Moreover, in vivo studies also indicated that an increased M1/M2 ratio could suppress cementoblast mineralization and bring about root resorption. During mechanical force-induced orthodontic tooth movement (OTM), root resorption was evident on the compression side of periodontal tissue, and a higher M1/M2 ratio and weaker cementoblast mineralization were observed on the compression side than on the tension side. We also used localized lipopolysaccharide (LPS) injection to increase the M1/M2 ratio around the roots of maxillary molars, where root resorption and decreased cementoblast mineralization were also observed. Furthermore, when we injected the exosomes from M0 and M1- and M2-polarized macrophages into mice, it was observed that the cementoblast mineralization was attenuated in the group injected with M1-polarized macrophage exosomes, while it was augmented in the group injected with M2-polarized macrophage exosomes.

A Novel Tension Machine Promotes Bone Marrow Mesenchymal Stem Cell Osteoblastic and Fibroblastic Differentiation by Applying Cyclic Tension.

Bone marrow mesenchymal stem cells (BMSCs) are intraosseous stem cells, and the effects of tensile strain on BMSC differentiation mediate several bone-related treatments. To study the response of BMSCs under tension, we designed and developed a small cellular tension instrument, iStrain. When iStrain applied tension on BMSCs, these cells exhibited convergence in the alignment direction and lengthening of the cell processes and cell body. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting demonstrated that iStrain-mediated cyclic tension promotes the differentiation of BMSCs toward osteogenesis and fibrogenesis. And the mRNA and protein expression of differentiation-related genes changes with the extension of tension time.

Hip Fracture Management Using External Fixation-A Systematic Review.

INTRODUCTION: Patients with significant comorbidities have high general anaesthetic risks and are often thought to be undesirable candidates for general anaesthesia and, therefore, surgery. External fixation uses local or regional anaesthesia, and allows patients with significant comorbidities to avoid the risks of general anaesthesia. It has been described to be successful in the management of high-risk patients with intertrochanteric fractures. However, published data have been derived from small case series, and no published literature has attempted to analyse them in totality. This review aims to pool together these case series, and to evaluate the outcomes and complications of external fixation when performed in high-risk patients with intertrochanteric fractures. MATERIALS AND METHODS: The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) guidelines. All studies that reported the outcomes of external fixation for intertrochanteric fractures of high-risk patients were included. RESULTS: A total of 13 publications, involving 687 patients, were included in the review. All the studies reported postoperative radiological reduction and complete fracture healing with reduction of limb length discrepancy. One study using parallel placement of proximal fixation screws showed shorter operative duration as compared to convergent placement. Another study mentioned that there was no significant difference in mortality rates between patients with stable fractures and those with unstable fractures who underwent external fixation. All the studies reported a decrease in postoperative immobility, reduction in pain and improvement in clinical outcome hip scores. CONCLUSION: External fixation is promising and useful especially in the management of high-risk patients with intertrochanteric fractures. The procedure can help with radiological reduction of the fracture, reduction of limb length discrepancy, reduction of operative duration, decrease in postoperative immobility, reduction in pain and improvement in clinical outcome hip scores. The procedure is versatile and seems to be able to accommodate both stable and unstable fractures. However, unstable fractures may be associated with greater postoperative morbidity, and it may be worthwhile to prognosticate based on the stability of the patients' fracture for better risk-benefit analysis preoperatively. Shorter operative times can also be achieved through parallel proximal pin placement, without impact on mortality or morbidity.

Impact of Knowledge and Attitudes on Lifestyle Practices in Preventing Type 2 Diabetes Mellitus.

INTRODUCTION: Diabetes mellitus is a major public health issue in Singapore. To shape healthcare policies for the primary prevention of diabetes, it is crucial to understand Singaporeans' knowledge, attitudes and practices related to diabetes and its prevention. This study aimed to assess the knowledge, attitudes and lifestyles of individuals without diabetes. MATERIALS AND METHODS: A cross-sectional household survey was performed between 31 January to 3 February 2019 to examine knowledge, attitudes and practices related to diabetes. Inclusion criteria of the participants included: 1) Singaporeans/permanent residents, 2) between 30 to 64 years old, and 3) who did not have a diagnosis of diabetes. Logistic and linear regression models were used to analyse the association of knowledge and attitudes with physical activity and diet habits, respectively. RESULTS: Among 806 participants, 72.2% did not meet the Health Promotion Board's physical activity recommendation. Physical activity was associated with better diabetes knowledge (odds ratio [OR] 5.38, 95% confidence interval [CI] = 1.65-17.53, P = 0.049), stronger beliefs in diabetes prevention (OR 3.36, 95% CI = 1.02-11.12, P = 0.047) and lower levels of worry about diabetes (OR 0.41, 95% CI 0.17-1.00, P = 0.049). Neither knowledge nor beliefs or worries about diabetes was associated with diet. CONCLUSION: There is a need to reinforce the importance of physical activity and healthy diet in preventing diabetes. Although improving the knowledge level of diabetes may increase physical activity of the population, it is unlikely to improve dietary choices without effective behavior change interventions.

Flagellin-deficient outer membrane vesicles as adjuvant induce cross-protection of Salmonella Typhimurium outer membrane proteins against infection by heterologous Salmonella serotypes.

Salmonella enteric serovar infections result in high morbidity and mortality worldwide. Cross-protective vaccines are an effective strategy in controlling salmonellosis caused by multiple serotypes. In our previous study, outer membrane vesicles (OMVs) derived from flagellin-deficient Salmonella Typhimurium (S. Typhimurium) were proven effective in mediating cross-protection against infection by multiple Salmonella serotypes; OMVs also exhibit potent adjuvant effects. In this study, we further investigated the adjuvant capacities of flagellin-deficient S. Typhimurium OMVs. Our finding showed that outer membrane proteins (OMPs) in combination with flagellin-deficient S. Typhimurium OMVs could function as adjuvants and invoke stronger humoral, cellular, mucosal, and cross-protective immune responses compared to conventional aluminum (alum). Furthermore, as an adjuvant, OMVs could induce significantly higher cellular immune responses and display enhanced cross-protection for OMPs against wild-type virulent Salmonella Choleraesuis and Salmonella Enteritidis challenge. In summary, OMVs function as a potent adjuvant with the capability of conferring greater cross-protection against infection by multiple Salmonella serotypes, and may be of great value as an effective vaccine adjuvant in enteric diseases.

Outer Membrane Vesicles: Current Status and Future Direction of These Novel Vaccine Adjuvants.

Adjuvants have been of great interest to vaccine formulation as immune-stimulators. Prior to the recent research in the field of immune stimulation, conventional adjuvants utilized for aluminum-based vaccinations dominated the adjuvant market. However, these conventional adjuvants have demonstrated obvious defects, including poor protective efficiency and potential side effects, which hindered their widespread circulation. Outer membrane vesicles (OMVs) naturally exist in gram-negative bacteria and are capable of engaging innate and adaptive immunity and possess intrinsic adjuvant capacity. They have shown tremendous potential for adjuvant application and have recently been successfully applied in various vaccine platforms. Adjuvants could be highly effective with the introduction of OMVs, providing complete immunity and with the benefits of low toxicity; further, OMVs might also be designed as an advanced mucosal delivery vehicle for use as a vaccine carrier. In this review, we discuss adjuvant development, and provide an overview of novel OMV adjuvants and delivery vehicles. We also suggest future directions for adjuvant research. Overall, we believe that OMV adjuvants would find high value in vaccine formulation in the future.

Pericecal hernia of the inferior ileocecal recess: CT findings.

Internal abdominal herniations are rare. A 34-year-old healthy man was seen in the emergency room because of severe lower abdominal pain and episodic vomiting. Pericecal internal herniation of the inferior ileocecal recess was suspected by abdominal CT study and confirmed by exploratory laparotomy. Finally, the herniated ileal loops were reduced, and the redundant peritoneum was resected. In the present case, CT demonstrates the precise anatomic diagnosis and shows acute complications that should be recommended preoperatively. Urgent surgical intervention is necessary to prevent strangulation, which is responsible for high mortality. Early diagnosis and treatment had a good outcome.

Rapid creation of a temporary isolation ward for patients with severe acute respiratory syndrome in Taiwan.

OBJECTIVES: To rapidly establish a temporary isolation ward to handle an unexpected sudden outbreak of severe acute respiratory syndrome (SARS) and to evaluate the implementation of exposure control measures by healthcare workers (HCWs) for SARS patients. DESIGN: Rapid creation of 60 relatively negative pressure isolation rooms for 196 suspected SARS patients transferred from 19 hospitals and daily temperature recordings of 180 volunteer HCWs from 6 medical centers. SETTING: A military hospital. RESULTS: Of the 196 patients, 34 (17.3%) met the World Health Organization criteria for probable SARS with positive results of serologic testing for SARS-associated coronavirus (SARS-CoV), reverse transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal or throat swabs for SARS-CoV, or both. Seventy-four patients had suspected SARS based on unprotected exposure to SARS patients; three of them had positive results on RT-PCR but negative serologic results. The remaining 88 patients did not meet the criteria for a probable or suspected SARS diagnosis. Of the 34 patients with probable SARS, 13 were transferred to medical centers to receive mechanical ventilation due to rapid deterioration of chest x-ray results, and three patients died of SARS despite intensive therapy in medical centers. During the study period, one nurse developed probable SARS due to violation of infection control measures, but there was no evidence of cross-transmission to other HCWs. CONCLUSIONS: Despite the use of full personal protection equipment, the facility failed to totally prevent exposures of HCWs to SARS but minimized the risk of nosocomial transmission. Better training and improvements in infection control infrastructure may limit the impact of SARS.

Interaction of hydrogen with metal nitrides and imides.

The pursuit of a clean and healthy environment has stimulated much effort in the development of technologies for the utilization of hydrogen-based energy. A critical issue is the need for practical systems for hydrogen storage, a problem that remains unresolved after several decades of exploration. In this context, the possibility of storing hydrogen in advanced carbon materials has generated considerable interest. But confirmation and a mechanistic understanding of the hydrogen-storage capabilities of these materials still require much work. Our previously published work on hydrogen uptake by alkali-doped carbon nanotubes cannot be reproduced by others. It was realized by us and also demonstrated by Pinkerton et al. that most of the weight gain was due to moisture, which the alkali oxide picked up from the atmosphere. Here we describe a different material system, lithium nitride, which shows potential as a hydrogen storage medium. Lithium nitride is usually employed as an electrode, or as a starting material for the synthesis of binary or ternary nitrides. Using a variety of techniques, we demonstrate that this compound can also reversibly take up large amounts of hydrogen. Although the temperature required to release the hydrogen at usable pressures is too high for practical application of the present material, we suggest that more investigations are needed, as the metal-N-H system could prove to be a promising route to reversible hydrogen storage.