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Development (Cambridge, England) Jul 2024Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by...
Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach utilizing both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7bp substitution mutation results in massive perturbation of the Tinman regulatory network orchestrating dorsal musculature, manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation.
PubMed: 38958007
DOI: 10.1242/dev.202355 -
Arteriosclerosis, Thrombosis, and... Jul 2024Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender... (Review)
Review
Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women's Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.
PubMed: 38957985
DOI: 10.1161/ATVBAHA.124.320910 -
Regenerative Medicine Jul 2024Adjunctive pharmacological treatment may improve nerve regeneration. We investigated nerve regeneration processes of PXL01 - a lactoferrin-derived peptide - after...
Adjunctive pharmacological treatment may improve nerve regeneration. We investigated nerve regeneration processes of PXL01 - a lactoferrin-derived peptide - after repair of the sciatic nerve in healthy Wistar rats. PXL01, sodium hyaluronate (carrier) or sodium chloride was administered around the repair. After 6 days axonal outgrowth, Schwann cell response, pan- (CD68) and pro-healing (CD206) macrophages in sciatic nerve, sensory neuronal response in dorsal root ganglia (DRG) and expression of heat shock protein 27 (HSP27) in sciatic nerves and DRGs were analyzed. Despite a lower number of pan-macrophages, other investigated variables in sciatic nerves or DRGs did not differ between the treatment groups. PLX01 applied locally inhibits inflammation through pan-macrophages in repaired sciatic nerves without any impact on nerve regeneration or pro-healing macrophages.
PubMed: 38957920
DOI: 10.1080/17460751.2024.2361515 -
Burns & Trauma 2024Burns are an underestimated serious injury negatively impacting survivors physically, psychologically and economically, and thus are a considerable public health burden.... (Review)
Review
Burns are an underestimated serious injury negatively impacting survivors physically, psychologically and economically, and thus are a considerable public health burden. Despite significant advancements in burn treatment, many burns still do not heal or develop serious complications/sequelae. The nucleotide-binding oligomerization domain-like receptors (NLRs) family pyrin domain-containing 3 (NLRP3) inflammasome is a critical regulator of wound healing, including burn wound healing. A better understanding of the pathophysiological mechanism underlying the healing of burn wounds may help find optimal therapeutic targets to promote the healing of burn wounds, reduce complications/sequelae following burn, and maximize the restoration of structure and function of burn skin. This review aimed to summarize current understanding of the roles and regulatory mechanisms of the NLRP3 inflammasome in burn wound healing, as well as the preclinical studies of the involvement of NLRP3 inhibitors in burn treatment, highlighting the potential application of NLRP3-targeted therapy in burn wounds.
PubMed: 38957662
DOI: 10.1093/burnst/tkae020 -
Burns & Trauma 2024The unique ability of piezoelectric materials to generate electricity spontaneously has attracted widespread interest in the medical field. In addition to the ability to... (Review)
Review
The unique ability of piezoelectric materials to generate electricity spontaneously has attracted widespread interest in the medical field. In addition to the ability to convert mechanical stress into electrical energy, piezoelectric materials offer the advantages of high sensitivity, stability, accuracy and low power consumption. Because of these characteristics, they are widely applied in devices such as sensors, controllers and actuators. However, piezoelectric materials also show great potential for the medical manufacturing of artificial organs and for tissue regeneration and repair applications. For example, the use of piezoelectric materials in cochlear implants, cardiac pacemakers and other equipment may help to restore body function. Moreover, recent studies have shown that electrical signals play key roles in promoting tissue regeneration. In this context, the application of electrical signals generated by piezoelectric materials in processes such as bone healing, nerve regeneration and skin repair has become a prospective strategy. By mimicking the natural bioelectrical environment, piezoelectric materials can stimulate cell proliferation, differentiation and connection, thereby accelerating the process of self-repair in the body. However, many challenges remain to be overcome before these concepts can be applied in clinical practice, including material selection, biocompatibility and equipment design. On the basis of the principle of electrical signal regulation, this article reviews the definition, mechanism of action, classification, preparation and current biomedical applications of piezoelectric materials and discusses opportunities and challenges for their future clinical translation.
PubMed: 38957661
DOI: 10.1093/burnst/tkae013 -
Microbiota and Host 2023The epithelial lining of the small intestine mediates its absorptive and secretory function and thus is a critical component of human health. Regeneration and renewal of...
The epithelial lining of the small intestine mediates its absorptive and secretory function and thus is a critical component of human health. Regeneration and renewal of the epithelium is the result of proliferation of intestinal stem cells (ISCs). Many cell types and molecular factors are known to regulate the ability of ISCs to proliferate, including adjacent neighboring epithelial cells and the underlying, supportive stromal cells. The microbiome resides in the lumen of the small intestine and is in close contact with the epithelium. Due to its proximity to ISCs, it has been hypothesized that species within the microbiome have the capacity to regulate ISC proliferation and differentiation. This review highlights research that probes interactions between ISCs and the microbiome in the small intestine to detail the current understanding of microbial regulation of ISCs. Results from these studies provide important knowledge that can be exploited to identify therapeutic targets or develop novel preventative treatments to treat intestinal diseases.
PubMed: 38957594
DOI: 10.1530/mah-23-0012 -
Frontiers in Immunology 2024Endocytosis represents a category of regulated active transport mechanisms. These encompass clathrin-dependent and -independent mechanisms, as well as fluid phase... (Review)
Review
Endocytosis represents a category of regulated active transport mechanisms. These encompass clathrin-dependent and -independent mechanisms, as well as fluid phase micropinocytosis and macropinocytosis, each demonstrating varying degrees of specificity and capacity. Collectively, these mechanisms facilitate the internalization of cargo into cellular vesicles. Pregnancy is one such physiological state during which endocytosis may play critical roles. A successful pregnancy necessitates ongoing communication between maternal and fetal cells at the maternal-fetal interface to ensure immunologic tolerance for the semi-allogenic fetus whilst providing adequate protection against infection from pathogens, such as viruses and bacteria. It also requires transport of nutrients across the maternal-fetal interface, but restriction of potentially harmful chemicals and drugs to allow fetal development. In this context, trogocytosis, a specific form of endocytosis, plays a crucial role in immunological tolerance and infection prevention. Endocytosis is also thought to play a significant role in nutrient and toxin handling at the maternal-fetal interface, though its mechanisms remain less understood. A comprehensive understanding of endocytosis and its mechanisms not only enhances our knowledge of maternal-fetal interactions but is also essential for identifying the pathogenesis of pregnancy pathologies and providing new avenues for therapeutic intervention.
Topics: Humans; Pregnancy; Endocytosis; Female; Maternal-Fetal Exchange; Animals; Biological Transport; Nutrients; Immune Tolerance; Placenta
PubMed: 38957469
DOI: 10.3389/fimmu.2024.1415794 -
Frontiers in Immunology 2024
Topics: Humans; Artificial Intelligence; Inflammation; Phenotype; Animals
PubMed: 38957459
DOI: 10.3389/fimmu.2024.1443534 -
Journal of Orthopaedic Translation Jul 2024The deployment of bone grafts (BGs) is critical to the success of scaffold-guided bone regeneration (SGBR) of large bone defects. It is thus critical to provide...
BACKGROUND
The deployment of bone grafts (BGs) is critical to the success of scaffold-guided bone regeneration (SGBR) of large bone defects. It is thus critical to provide harvesting devices that maximize osteogenic capacity of the autograft while also minimizing graft damage during collection. As an alternative to the Reamer-Irrigator-Aspirator 2 (RIA 2) system - the gold standard for large-volume graft harvesting used in orthopaedic clinics today - a novel intramedullary BG harvesting concept has been preclinically introduced and referred to as the ARA (aspirator + reaming-aspiration) concept. The ARA concept uses aspiration of the intramedullary content, followed by medullary reaming-aspiration of the endosteal bone. This concept allows greater customization of BG harvesting conditions vis-à-vis the RIA 2 system. Following its successful validation, we hypothesized that an ARA concept-collected BG would have comparable osteogenic capacity compared to the RIA 2 system-collected BG.
METHODS
We used 3D-printed, medical-grade polycaprolactone-hydroxyapatite (mPCL-HA, wt 96 %:4 %) scaffolds with a Voronoi design, loaded with or without different sheep-harvested BGs and tested them in an ectopic bone formation rat model for up to 8 weeks.
RESULTS
Active bone regeneration was observed throughout the scaffold-BG constructs, particularly on the surface of the bone chips with endochondral bone formation, and highly vascularized tissue formed within the fully interconnected pore architecture. There were no differences between the BGs derived from the RIA 2 system and the ARA concept in new bone volume formation and in compression tests (Young's modulus, = 0.74; yield strength, = 0.50). These results highlight that the osteogenic capacities of the mPCL-HA Voronoi scaffold loaded with BGs from the ARA concept and the RIA 2 system are equivalent.
CONCLUSION
In conclusion, the ARA concept offers a promising alternative to the RIA 2 system for harvesting BGs to be clinically integrated into SGBR strategies.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
Our results show that biodegradable composite scaffolds loaded with BGs from the novel intramedullary harvesting concept and the RIA 2 system have equivalent osteogenic capacity. Thus, the innovative, highly intuitive intramedullary harvesting concept offers a promising alternative to the RIA 2 system for harvesting bone grafts, which are an important component for the routine translation of SGBR concepts into clinical practice.
PubMed: 38957270
DOI: 10.1016/j.jot.2024.05.002 -
International Journal of Nanomedicine 2024Salidroside (SAL) is the most effective component of , a traditional Chinese medicine. Cryptotanshinone (CT) is the main fat-soluble extract of , exhibiting considerable...
BACKGROUND
Salidroside (SAL) is the most effective component of , a traditional Chinese medicine. Cryptotanshinone (CT) is the main fat-soluble extract of , exhibiting considerable potential for application in osteogenesis. Herein, a polycaprolactone/gelatin nanofiber membrane loaded with CT and SAL (PSGC membrane) was successfully fabricated via coaxial electrospinning and characterized.
METHODS AND RESULTS
This membrane capable of sustained and controlled drug release was employed in this study. Co-culturing the membrane with bone marrow mesenchymal stem cells and human umbilical vein endothelial cells revealed excellent biocompatibility and demonstrated osteogenic and angiogenic capabilities. Furthermore, drug release from the PSGC membrane activated the Wnt/β-catenin signaling pathway and promoted osteogenic differentiation and vascularization. Evaluation of the membrane's vascularization and osteogenic capacities involved transplantation onto a rat's subcutaneous area and assessing rat cranium defects for bone regeneration, respectively. Microcomputed tomography, histological tests, immunohistochemistry, and immunofluorescence staining confirmed the membrane's outstanding angiogenic capacity two weeks post-operation, with a higher incidence of osteogenesis observed in rat cranial defects eight weeks post-surgery.
CONCLUSION
Overall, the SAL- and CT-loaded coaxial electrospun nanofiber membrane synergistically enhances bone repair and regeneration.
Topics: Osteogenesis; Animals; Nanofibers; Gelatin; Polyesters; Glucosides; Phenols; Phenanthrenes; Humans; Neovascularization, Physiologic; Human Umbilical Vein Endothelial Cells; Mesenchymal Stem Cells; Rats, Sprague-Dawley; Rats; Male; Bone Regeneration; Membranes, Artificial; Coculture Techniques; Drug Liberation; Cell Differentiation
PubMed: 38957181
DOI: 10.2147/IJN.S461141