Extracellular matrix (ECM) remodeling is necessary for the development and self-healing of tissue, and the process is tissue specific. Matrix metalloproteinases (MMPs) play a role in ECM remodeling ...by unwinding and cleaving ECM. We hypothesized that ECM remodeling by MMPs is involved in the differentiation of stem cells into specific lineages during self-healing. To prove the hypothesis, we investigated which MMPs are involved in the osteogenic differentiation of human mesenchymal stem cells (hMSCs) grown on a type I collagen (Col I) matrix, and we found that specifically high expression of MMP13 in hMSCs grown on a Col I matirx during osteogenic differentiation. Moreover, knocking down of MMP13 decreased the osteogenic differentiation of hMSCs grown on a Col I matrix. In addition, pre-treatment of recombinant human MMP13 lead to remodeling of Col I matrix and increased the osteogenic differentiation of hMSCs and in vivo bone formation following the upregulation of the expression of runt-related transcription factor 2 (RUNX2), integrin α3 (ITGA3), and focal adhesion kinase. Furthermore, the transcription factor RUNX2 bound to the MMP13 promoter. These results suggest that growth on a remodeled Col I matrix by MMP13 stimulates osteogenic differentiation of hMSCs and self-healing of bone tissue via an MMP13/ITGA3/RUNX2 positive feedback loop.
Self-healing of tissue could be the key to treating diseases that cannot be overcome by present technology. We investigated the mechanism underlying the self-healing of tissue and we found that the osteogenic differentiation was increased in hMSCs grown on a remodeled Col I matrix by the optimized concentration of MMP13 not in hMSCs grown on a Col I fragments cleaved by a high concentration of MMP13. In addition, we found the remodeled Col I matrix by MMP13 increased the osteogenic capacity through a MMP13/integrin α3/RUNX2 positive feedback loop. This result would be able to not only provide a strategy for bone tissue-specific functional materials following strong evidence about the self-healing mechanism of bone through the interaction between stem cells and the ECM matrix. As such, we strongly believe our finding will be of interest to researchers studying biomaterials, stem cell biology and matrix interaction for regenerative medicine and therapy.
Display omitted
Although cesarean delivery and prenatal exposure to antibiotics are likely to affect the gut microbiome in infancy, their effect on the development of atopic dermatitis (AD) in infancy is unclear. ...The influence of individual genotypes on these relationships is also unclear. To evaluate with a prospective birth cohort study whether cesarean section, prenatal exposure to antibiotics, and susceptible genotypes act additively to promote the development of AD in infancy.
The Cohort for Childhood of Asthma and Allergic Diseases (COCOA) was selected from the general Korean population. A pediatric allergist assessed 412 infants for the presence of AD at 1 year of age. Their cord blood DNA was subjected to interleukin (IL)-13 (rs20541) and cluster-of-differentiation (CD)14 (rs2569190) genotype analysis.
The combination of cesarean delivery and prenatal exposure to antibiotics associated significantly and positively with AD (adjusted odds ratio, 5.70; 95% CI, 1.19-27.3). The association between cesarean delivery and AD was significantly modified by parental history of allergic diseases or risk-associated IL-13 (rs20541) and CD14 (rs2569190) genotypes. There was a trend of interaction between IL-13 (rs20541) and delivery mode with respect to the subsequent risk of AD. (P for interaction = 0.039) Infants who were exposed prenatally to antibiotics and were born by cesarean delivery had a lower total microbiota diversity in stool samples at 6 months of age than the control group. As the number of these risk factors increased, the AD risk rose (trend p<0.05).
Cesarean delivery and prenatal antibiotic exposure may affect the gut microbiota, which may in turn influence the risk of AD in infants. These relationships may be shaped by the genetic predisposition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the ...proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.
Extracellular vesicles (EVs) are nano-sized carriers that reflect the parent cell's information and are known to mediate cell-cell communication. In order to overcome the disadvantages of mesenchymal ...stem cells (MSCs) in cell therapy, such as unexpected differentiation leading to tumorization, immune rejection, and other side effects, EVs derived from MSCs (MSC-EVs) with the tissue regenerative function have been studied as new cell-free therapeutics. However, therapeutic applications of EVs require overcoming several challenges. First, the production efficiency of MSC-EVs should be increased at least as much as the quantity of them are required to their clinical application; second, MSC-EVs needs to show various functionality further, thereby increasing tissue regeneration efficiency. In this study, we treated tauroursodeoxycholic acid (TUDCA), a biological derivative known to regulate cholesterol, to MSCs and investigated whether TUDCA treatment would be able to increase EV production efficiency and tissue regenerative capacity of EVs. Indeed, it appears that TUDCA priming to MSC increases the yield of MSC-EVs >2 times by reducing the cellular cholesterol level in MSCs and increasing the exocytosis-related CAV1 expression. Interestingly, it was found that the EVs derived from TUDCA-primed MSCs (T-EV) contained higher amounts of anti-inflammatory cytokines (IL1RN, IL6, IL10, and IL11) and osteogenic proteins (ALP, RUNX2, BMP2, BMPR1, and BMPR2) than those in control MSC-EVs (C-EV). Besides, it was shown that T-EV not only regulated M1/M2 macrophages differentiation of monocytes, also effectively increased the osteogenic differentiation of MSCs as well as bone tissue regeneration in a bone defect rat model. Based on these results, it is concluded that TUDCA treatment to MSC as a new approach endows EV with high-yield production and functionality. Thus, we strongly believe T-EV would be a powerful therapeutic material for bone tissue regeneration and potentially could be expanded to other types of tissue regeneration for clinical applications.
Display omitted
•A strategy priming MSCs with TUDCA for improving bone regenerative capacities of MSC-EVs was successfully developed.•The yield of T-EV significantly increased compared with original MSC-EVs.•T-EV contained much more abundant anti-inflammatory cytokines and osteogenic factors compared with original MSC-EVs.•T-EV showed remarkable anti-inflammatory and osteogenic activity.
Tomato yellow leaf curl virus (TYLCV) is one of the most well-known tomato-infecting begomoviruses and transmitted by Bemisia tabaci. Seed transmission has previously been reported for some RNA ...viruses, but TYLCV has not previously been described as a seed-borne virus. In 2013 and 2014, without whitefly-mediated transmission, TYLCV was detected in young tomato plants germinated from fallen fruits produced from TYLCV-infected tomato plants in the previous cultivation season. In addition, TYLCV-Israel (TYLCV-IL) was also detected in seeds and their seedlings of TYLCV-infected tomato plants that were infected by both viruliferous whitefly-mediated transmission and agro-inoculation. The seed infectivity was 20-100%, respectively, and the average transmission rate to seedlings was also 84.62% and 80.77%, respectively. TYLCV-tolerant tomatoes also produced TYLCV-infected seeds, but the amount of viral genome was less than seen in TYLCV-susceptible tomato plants. When tomato plants germinated from TYLCV-infected seeds, non-viruliferous whiteflies and healthy tomato plants were placed in an insect cage together, TYLCV was detected from whiteflies as well as receiver tomato plants six weeks later. Taken together, TYLCV-IL can be transmitted via seeds, and tomato plants germinated from TYLCV-infected seeds can be an inoculum source of TYLCV. This is the first report about TYLCV seed transmission in tomato.
Sepsis is a life-threatening condition with a high mortality rate. Early prediction and treatment are the most effective strategies for increasing survival rates. This paper proposes a neural ...architecture search (NAS) model to predict the onset of sepsis with a low computational cost and high search performance by applying a genetic algorithm (GA). The proposed model shares the weights of all possible connection nodes internally within the neural network. Externally, the search cost is reduced through the weight-sharing effect between the genotypes of the GA. A predictive analysis was performed using the Medical Information Mart for Intensive Care III (MIMIC-III), a medical time-series dataset, with the primary objective of predicting sepsis onset 3 h before occurrence. In addition, experiments were conducted under various prediction times (0-12 h) for comparison. The proposed model exhibited an area under the receiver operating characteristic curve (AUROC) score of 0.94 (95% CI: 0.92-0.96) for 3 h, which is 0.31-0.26 higher than the scores obtained using the Sequential Organ Failure Assessment (SOFA), quick SOFA (qSOFA), and Simplified Acute Physiology Score (SAPS) II scoring systems. Furthermore, the proposed model exhibited a 12% improvement in the AUROC value over a simple model based on the long short-term memory neural network. Additionally, it is not only optimally searchable for sepsis onset prediction, but also outperforms conventional models that use similar predictive purposes and datasets. Notably, it is sufficiently robust to shape changes in the input data and has less structural dependence.
Human skin is made up of multiple layers and is designed to protect the human body. The stratum corneum (SC), specifically, is a keratinized layer of skin through which molecules heavier than 500 Da ...cannot penetrate. Traditional methods of transdermal drug delivery through the SC, such as hypodermic needles, are less than ideal because their size and appearance can cause fear and pain, creating hesitation, limiting self-administration, and preventing their use in some patients altogether. A new technology has been developed to address these limitations, in which an array of needles, each microns in diameter and length, called microneedles, are able to pierce the skin’s SC to deliver therapeutic agents without stimulating the proprioceptive pain nerves. These needles provide a strong advantage because they are capable of being incorporated into patches that can be conveniently self-administered by patients, while also offering the same bioabsorption and bioavailability currently provided by hypodermic needles. There have been many advancements in microneedle fabrication, and there are currently many variations of microneedle technology. Therefore, the purpose of this review is to provide a broad, introductory summary of current microneedle technology.
Display omitted
Artificial scaffolds made up of various synthetic biodegradable polymers have been reported to have many advantages including cheap manufacturing, easy scale up, high mechanical ...strength, convenient manipulation, and molding into an unlimited variety of shapes. However, the synthetic biodegradable polymers still have the insufficiency for cartilage regeneration owing to their acidic degradation products. To reduce acidification by degradation of synthetic polymers, we incorporated magnesium hydroxide (MH) nanoparticles into porous polymer scaffold not only to effectively neutralize the acidic hydrolysate but also to minimize the structural disturbance of scaffolds. The neutralization effect of poly(D,L-lactic-co-glycolic acid; PLGA)/MH scaffold was confirmed with the maintenance of neutral pH, contrary to a PLGA scaffold with low pH. Further, the scaffolds were applied to evaluate the chondrogenic differentiation of the human bone marrow mesenchymal stem cells. In in vitro study, the PLGA/MH scaffold enhanced the chondrogenesis markers and reduced the calcification, compared to the PLGA scaffold. Additionally, the PLGA/MH scaffold reduced the release of inflammatory cytokines, compared to the PLGA scaffold, as the cell death decreased. Moreover, the addition of MH reduced necrotic cell death at the early stage of chondrogenic differentiation. Further, the necrotic cell death by the PLGA scaffold was mediated by cleavage of caspase-1, the so-called interleukin 1-converting enzyme, and MH alleviated it as well as nuclear factor kappa B expression. Furthermore, the PLGA/MH scaffold highly supported chondrogenic healing of rat osteochondral defect sites in in vivo study. Therefore, it was suggested that a synthetic polymer scaffold containing MH could be a novel healing tool to support cartilage regeneration and further treatment of orthopedic patients.
Synthetic polymer scaffolds have been widely utilized for tissue regeneration. However, they have a disadvantage of releasing acidic products through degradation. This paper demonstrated a novel type of synthetic polymer scaffold with pH-neutralizing ceramic nanoparticles composed of magnesium hydroxide for cartilage regeneration. This polymer showed pH-neutralization property during polymer degradation and significant enhancement of chondrogenic differentiation of mesenchymal stem cells. It reduced not only chondrogenic calcification but also release of proinflammatory cytokines. Moreover, it has an inhibitory effect on necrotic cell death, particularly caspase-1-mediated necrotic cell death (pyroptosis). In in vivo study, it showed higher healing rate of the damaged cartilage in a rat osteochondral defect model. We expected that this novel type of scaffold can be effectively applied to support cartilage regeneration and further treatment of orthopedic patients.
Abstract
Background
Open reduction and plate fixation are the preferred treatment options for most distal humerus fractures in adults. However, it is often challenging for orthopedic surgeons because ...of the complex anatomy and the difficulty in achieving stable fixation. This multicenter study aimed to analyze the complication types and rates of patients with distal humerus fractures treated with open reduction and plate fixation, and compare the results with those found in the literature. In addition, we describe the clinical outcomes.
Methods
This retrospective multicenter study was conducted between September 2001 and March 2021 and included data from four hospitals. In total, 349 elbows underwent surgical treatment at these hospitals during the study period. Patients > 17 years of age who were treated by plate fixation were included, and patients who were treated by other fixation methods were excluded. A total of 170 patients were included in the study. The following types of complications were investigated: (1) nerve related; (2) fixation and instrument related; (3) osteosynthesis related; (4) infection; and (5) others.
Results
The following complications were found: (1) 26 (15.3%) cases of postoperative ulnar nerve symptoms; 4 (2.4%) of postoperative radial nerve symptoms; (2) one (0.6%) case of screw joint penetration and screw loosening; and eight (4.7%) cases of hardware removal due to instrument skin irritation; (3) seven (4.1%) cases of nonunion; (4) two (1.2%) and four (2.2%) cases of superficial and deep infection, respectively, and seven (3.9%) cases of wound complication; and (5) 37 (21.8%) cases of heterotrophic ossification, 79 (46.5%) cases of elbow stiffness (did not achieve functional range of motion ROM), and 41 (24.1%) cases of osteoarthritis over Broberg and Morrey Grade I.
Paradoxically, the postoperative ulnar nerve symptoms were more frequent in the prophylactic ulnar nerve anterior transposition group. However, this difference was not statistically significant (
p
= 0.086). The mean ROM was 123.5° flexion to 9.5° extension. The average Disabilities of the Arm, Shoulder and Hand (DASH) score was 14.5 ± 15.6.
Conclusions
Open reduction and plate fixation for distal humeral fractures is a reasonable treatment option with acceptable complication rates and favorable clinical outcomes. Surgeons must be vigilant about ulnar nerve complications.
Level of Evidence
Therapeutic Level III.
The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier ...disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD.
This retrospective, 1∶3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire.
The median age of the affected children (43.8% male) was 26 months (18.25-36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41-5.90, P = 0.00) were independently associated with an increased risk.
This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
