Dental caries, one of the most prevalent infectious diseases worldwide, affects approximately 80% of children and the majority of adults. Dental caries may result in endodontic disease, leading to ...dental pulp necrosis, periapical inflammation and bone resorption, severe pain, and tooth loss. Periapical inflammation may also increase inflammation in other parts of the body. Although many studies have attempted to develop therapies for this disease, there is still an urgent need for effective treatments. In this study, we applied a novel gene therapeutic approach using recombinant adeno-associated virus (AAV)-mediated RNAi knockdown of Cathepsin K (Ctsk) gene expression, to target osteoclasts and periapical bone resorption in a mouse model. We found that AAV-sh-Cathepsin K (AAV-sh-Ctsk) impaired osteoclast function in vivo and furthermore reduced bacterial infection-stimulated bone resorption by 88%. Reduced periapical lesion size was accompanied by decreases in mononuclear leukocyte infiltration and inflammatory cytokine expression. Our study shows that AAV-RNAi silencing of Cathepsin K in periapical tissues can significantly reduce endodontic disease development, bone destruction, and inflammation in the periapical lesion. This is the first demonstration that AAV-mediated RNAi knockdown gene therapy may significantly reduce the severity of endodontic disease.
This study aims to clarify the potential function of ATAD2 (ATPase family, AAA domain containing 2) in regulating proliferative and apoptotic abilities of colorectal carcinoma (CRC).
ATAD2 levels in ...CRC specimens and cell lines were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Overall survival in CRC patients with high or low level of ATAD2 was assessed by Kaplan-Meier method. The correlation between ATAD2 level and clinical characteristics of CRC patients was analyzed by χ2 test. Univariable and multivariable Cox regression models were generated to illustrate potential risk factors for the overall survival of CRC. After knockdown of ATAD2 in SW620 cells, relative levels of Cyclin D1, ppRb, pRb, E2F1, Cyclin E and cleaved Caspase 3 were detected by Western blot. Regulatory effects of ATAD2 on viability, clonality, cell cycle distribution, and apoptosis in SW620 and HCT15 cells were examined by a series of functional experiments.
Upregulated ATAD2 in CRC was correlated to tumor size, tumor node metastasis (TNM) staging, and histological classification of CRC. High level of ATAD2 predicted poor prognosis in CRC patients. Cox regression test suggested that ATAD2 level, tumor size, TNM staging and histological classification were independent factors influencing overall survival in CRC. Knockdown of ATAD2 reduced viability and clonality in SW620 and HCT15 cells. In addition, cell cycle was arrested in G1 phase and apoptosis was stimulated in CRC cells with ATAD2 knockdown. In SW620 cells transfected with ATAD2 shRNA, protein levels of Cyclin D1, ppRb, E2F1 and Cyclin E were downregulated, and cleaved Caspase 3 was upregulated.
ATAD2 is upregulated in CRC tissues and correlated to poor prognosis of CRC patients. It exerts an anti-proliferation role in CRC by arresting cell cycle in G1/S phase and triggering apoptosis via the Rb-E2F1 signaling.
Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious ...small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.
In drug delivery systems, pH‐sensitive polymers are commonly used as drug carriers, and significant efforts have been devoted to the aspects of controlled delivery and release of drugs. However, few ...studies address the possible autophagic effects on cells. Here, for the first time, using a fluorescent autophagy‐reporting cell line, this study evaluates the autophagy‐induced capabilities of four types of pH‐sensitive polymeric nanoparticles (NPs) with different physical properties, including size, surface modification, and pH‐sensitivity. Based on experimental results, this study concludes that pH‐sensitivity is one of the most important factors in autophagy induction. In addition, this study finds that variation of concentration of NPs could cause different autophagic effect, i.e., low concentration of NPs induces autophagy in an mTOR‐dependent manner, but high dose of NPs leads to autophagic cell death. Identification of this tunable autophagic effect offers a novel strategy for enhancing therapeutic effect in cancer therapy through modulation of autophagy.
Using a fluorescent autophagy‐reporting cell, the autophagy‐induced capabilities of four types of pH‐sensitive nanoparticles with variable physiochemical parameters, such as size, surface modification, and pH‐sensitivity are systematically evaluated. The results exhibit that pH‐sensitivity is one of the most important factors in autophagy induction, and that the variation of pH‐sensitivity/concentration of nanoparticles could cause two distinctly different autophagic effects.
Omics sciences enable a systems-level perspective in characterizing cardiovascular biology. Integration of diverse proteomics data via a computational strategy will catalyze the assembly of ...contextualized knowledge, foster discoveries through multidisciplinary investigations, and minimize unnecessary redundancy in research efforts.
The goal of this project is to develop a consolidated cardiac proteome knowledgebase with novel bioinformatics pipeline and Web portals, thereby serving as a new resource to advance cardiovascular biology and medicine.
We created Cardiac Organellar Protein Atlas Knowledgebase (COPaKB; www.HeartProteome.org), a centralized platform of high-quality cardiac proteomic data, bioinformatics tools, and relevant cardiovascular phenotypes. Currently, COPaKB features 8 organellar modules, comprising 4203 LC-MS/MS experiments from human, mouse, drosophila, and Caenorhabditis elegans, as well as expression images of 10,924 proteins in human myocardium. In addition, the Java-coded bioinformatics tools provided by COPaKB enable cardiovascular investigators in all disciplines to retrieve and analyze pertinent organellar protein properties of interest.
COPaKB provides an innovative and interactive resource that connects research interests with the new biological discoveries in protein sciences. With an array of intuitive tools in this unified Web server, nonproteomics investigators can conveniently collaborate with proteomics specialists to dissect the molecular signatures of cardiovascular phenotypes.
Identifying the polymorphism of the spermatozoon ultrastructure of squamates is vital for improving the accuracy of phylogenic analyses. Multiple studies have been conducted to distinguish the ...similarities and differences among the sperms of squamates, but these studies have mainly focused on lizards. Thus, there is a need to update the database of the ultrastructure of snake spermatozoa. Myrrophis chinensis is a protected snake in China because of its economic and scientific value. In this study, we examined the ultrastructure of the M. chinensis epididymal spermatozoon. The ultrastructure of the M. chinensis spermatozoon was found to have the following characteristics: dense collar, multilaminar membranes, extracellular microtubules and extraordinary elongation of the midpiece, all of which are typical sperm characteristics of the synapomorphies of Serpentes. Although no unique trait was identified, the current findings could still provide valuable data for phylogenetic analysis.
The 16Cr–5Al oxide dispersion strengthened (ODS) ferritic steel was fabricated by sol–gel method in combination with hydrogen reduction, mechanical alloying (MA) and spark plasma sintering (SPS) ...techniques. The phase characterization, microstructure and oxidation resistance of the 16Cr–5Al–ODS steel were investigated in comparison with the Al free 16Cr–ODS steel. X-ray diffraction (XRD) patterns showed that the Al free and Al added 16Cr–ODS steels exhibited typical ferritic characteristic structure. The microstructure analysis investigated by transmission electron microscopy (TEM) and energy dispersive spectrometry (EDS) revealed that Y–Ti–O complexes with particle size of 10–30nm were formed in the Al free matrix and Y–Al–O complexes with particle size of 20–100nm were formed in the Al contained high-Cr ODS steel matrix. These complexes are homogeneously distributed in the matrices. The fabricated 16Cr–5Al–ODS steel exhibited superior oxidation resistance compared with the Al free 16Cr–ODS steel and the commercial 304 stainless steel owing to the formation of continuous and dense Al2O3 film on the surface.
In this study, we describe the epidemiological investigation of the first African swine fever (ASF) outbreak in a local domestic pig farm in the New Territories of Hong Kong in 2021. In the outbreak ...farm, several affected pigs presented clinical and pathological signs consistent with ASF, while the remaining pigs showed nonspecific clinical signs or did not exhibit any clinical signs. The relative low morbidity and mortality of ASF on this farm resulted in delayed detection and implementation of the control response. Despite this delay, no further spread of the disease from this farm to other farms or wild boars was observed. The clinical presentation of ASF in terms of morbidity and mortality on this farm indicated that it is essential for effective surveillance aimed at early detection for farmers, veterinarians, and pathologists to be educated about the different ways ASF can express itself in domestic pig populations. Epidemiological investigations consisted of field inspection, interviews with farm personnel to assess the management and biosecurity practices within the farm, and laboratory testing of animal and environmental samples. In addition, the complete genome of ASFV was obtained directly from the tissues of an infected pig to facilitate the epidemiological investigation. The genetic relationship at the whole genome level indicated that the isolate shared the highest level of similarity with genotype II ASFVs, including a 2019 isolate from Guangdong province, China (GD2019). Overall, the information presented here from the on-farm investigation with that from diagnostic testing and molecular analyses provides a basis for informed actions to prevent future incidents in farms with similar characteristics. Furthermore, this study highlighted the need to increase current knowledge about the molecular diversity amongst circulating viruses and potentially trace the source of infection.
Background and purpose
Huntington's disease is due to a CAG triplet repeat elongation in the huntingtin gene. Boundaries in CAG numbers have been found between healthy people with and without risk to ...pass the disorder to the next generation, and between people without, with a mild, or with a fully penetrant phenotype. These data have been generated in western populations and it is not clear whether they are also valid amongst Chinese.
Methods
In order to establish normative data in the huntingtin gene for Chinese people, 966 chromosomes from normal controls were tested. Further, the range of CAG repeats was examined in a cohort from six centres and a total of 368 patients with the disease were included.
Results
The CAG triplet repeat range in normal controls was between 9 and 35 (mean 18.9, SD 2.57). Triplets in the range between 26 and 35 were found in 2.5%. In the patient cohort, triplet repeats in the shorter allele were between 8 and 37 (mean 17.7, SD 1.6). In the longer allele, a range between 36 and 120 was found. There was a negative correlation (−0.65, r = 0.42) between age at onset and the number of triplet repeats in the larger allele. The mean age at onset was 38 years, with a range between 2 and 70 years. In 23 patients (6%) a childhood or juvenile onset was noted.
Conclusion
These data show comparable ranges of huntingtin gene CAG triplet repeats in normal people and in patients with Huntington's disease as in western populations.
Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation-induced ...injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll-like receptor (TLR) and Interleukin-1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR-activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast-stimulating lipopeptide (FSL-1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88-dependent function. FSL-1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis-stimulating factors. The ability of FSL-1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL-1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent.
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