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The myodural bridge (MDB) complex are fibrous bridges that functionally connect the spinal dura mater to the suboccipital musculature. Previously, we described the maturational sequence of the MDB within the posterior atlanto-occipital interspace of the rat. The present paper describes the morphology and developmental maturation of the MDB within the posterior atlanto-axial interspace of the rat. In the present study, E18 embryonic rats, newborn rats, and adult rats were selected to evaluate the development and growth of the MDB. Within the posterior atlanto-axial interspace of the rat, the fibers of the MDB and its associated muscles, in the embryonic rat, were observed to be scarce and lightly stained. In contrast, these same structures observed in the postnatal rat were quite apparent and robustly stained. After birth, it was observed that MDB originated from the rectus capitis dorsal major muscle, extended forward and downward, and finally merged with the posterior atlanto-axial membrane. As the rats developed and matured, the observed MDB fibers passing through the posterior atlanto-axial interspace appeared denser and more organized. This study evidenced that the MDB fibers within the posterior atlanto-axial interspace were primarily composed of type I collagen fibers in the postnatal rat. By observing the suboccipital region, we are able to hypothesize that the MDB complex plays a key role in maintaining the subdural space located within the upper cervical segment during growth and development. This study provides a morphological basis for future research on the function of the MDB complex.

Extracellular vesicles (EVs) are implicated as promising therapeutics and drug delivery vehicles in various diseases. However, successful clinical translation will depend on development of scalable biomanufacturing approaches, especially due to the documented low levels of intrinsic EV-associated cargo that may necessitate repeated doses to achieve clinical benefit in certain applications. Thus, here we assessed effects of a 3D-printed scaffold-perfusion bioreactor system on the production and bioactivity of EVs secreted from bone marrow-derived mesenchymal stem cells (MSCs), a cell type heavily implicated in generating EVs with therapeutic potential. Our results indicate that perfusion bioreactor culture results in an ~40-80-fold increase, depending on measurement method, in MSC EV production compared to conventional cell culture. Additionally, we demonstrated that MSC EVs generated using the bioreactor system significantly improved wound healing in a diabetic mouse model, with increased CD31+ staining in wound bed tissue compared to animals treated with flask cell culture-generated MSC EVs. Overall, this study establishes a promising solution to major EV translational issues (i.e., scalability and low potency) with potential for adaptation to various EV-based therapeutics and capacity for improvement alongside the continuous advancements in 3D-printing technologies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.

Five-membered N-heterocycles play an important role in organic synthesis and material chemistry, as they are widespread through pharmaceutical molecules and natural products. Chemists have developed many synthetic strategies for constructing five-membered N-heterocycles from N-centered radicals, but the availability of mild and green methods for these transformations is still limited. The cyclization of visible-light-generated N-centered radicals with alkenes has emerged as a powerful tool to enable these chemical transformations in recent years. Through chosen representative examples, the significant developments in this promising field were outlined, including the selection of catalysts, substrate scope, mechanistic understanding (especially density functional theory calculations), and applications. The contents of this Minireview are categorized by intramolecular cyclization and intermolecular N-centered radical addition/cyclization reactions.

BACKGROUND Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear. AIM To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics. RESULTS Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P

Growth differentiation factor 1 (GDF1) is a member of the transforming growth factor-β (TGF-β) superfamily and a protective mediator against the development of post-infarction cardiac remodeling by negatively regulating MEK-ERK1/2 and Smad signaling pathways in the heart. The TGF-β/SMAD pathway has been shown to play a key role in the development of hepatic fibrosis. In addition, fatty liver disease has been associated with reduced MEK/ERK1/2 signaling. However, no previous study has investigated the association between GDF1 and liver fibrosis. Therefore, the aim of this study was to investigate the association between plasma GDF1 and liver fibrosis in patients with stable angina.We included 327 consecutive patients with stable angina. ELISA was used to measure circulating levels of GDF1, and the fibrosis-4 index was used to assess liver fibrosis.The advanced liver fibrosis group had lower median plasma GDF1 levels than those with minimal liver fibrosis. There was a significant negative association between GDF1 plasma level and fibrosis-4 index (r = -0.135, p = 0.019). A lower concentration of GDF1 was significantly and independently associated with an increased risk of liver fibrosis when concentration was analyzed as a continuous variable and by tertile. In addition, fibrosis-4 index, aspartate aminotransferase (AST)-to-platelet ratio index, and AST/alanine aminotransferase ratio were significantly associated with GDF1 concentration.Our results indicated an association between low plasma GDF1 and liver fibrosis in the enrolled patients. Further investigations into the role of plasma GDF1 in the pathogenesis of liver fibrosis are warranted.

AIM Emerging evidence has suggested that metformin may be protective against the development of human-papillomavirus-related cancers. Anal intraepithelial neoplasia (AIN) is highly associated with human papillomavirus infection and a precancerous status of anal cancer. The aim of this study was to investigate the relationship between metformin usage and the development of AIN in a large national sample. METHODOLOGY The IBM MarketScan dataset was used to design a nested case-control study from 2010 to 2017. Patients aged 18-65 years with type 2 diabetes mellitus (DM) were evaluated, and cases of AIN were identified. Four controls were randomly selected in the risk set of each case by using incidence density sampling. The association between metformin usage and AIN was assessed using multivariate logistic regression modelling. RESULTS A total of 258 patients with type 2 DM were diagnosed with AIN during the study interval, and these were matched to 1032 control patients without a diagnosis of AIN. Patients who developed AIN had 38% lower odds of prior metformin use compared to those without a history of AIN (P

Thoracic sympathectomy to treat palmar hyperhidrosis (PH) has widely been performed. Many patients regret the surgery due to compensatory hyperhidrosis (CH), gustatory hyperhidrosis, arrhythmia, hypertension, gastrointestinal disturbances, and emotional distress. Robotic applications in microsurgery are very limited. We report the technique and long-term patient-reported outcomes of bilateral robot-assisted microsurgical sympathetic trunk reconstruction with a sural nerve graft in an interdisciplinary setting. A 59-year-old female suffered from severe adverse effects after endoscopic thoracic sympathectomy (ETS) for PH 25 years ago. She reported CH over the whole trunk, gustatory hyperhidrosis, excessive dry hands, and emotional distress. An interdisciplinary surgical team performed a bilateral sympathetic trunk reversal reconstruction with an interpositional sural nerve graft per side by a da Vinci® Robot. The nerve graft was microsurgically coapted using 9-0 sutures end-to-end to the sympathetic trunk stumps and side-to-end to the intercostal nerves T2-T4. At 24, 33 and 42 months, palmar dryness and emotional distress were strongly reduced. A highly specialized interdisciplinary setting may provide a precise, safe, and efficient treatment for ETS sequelae. A clinical study is initiated to validate this new therapy.