Abnormal proliferation and/or persistence of synoviocytes and inflammatory cells has long been described in inflammatory arthritis conditions, but only relatively recently has substantial attention ...been drawn to the relevance of abnormal apoptotic processes in disease pathogenesis and treatment. This review summarizes a current understanding of the Fas (CD95)–Fas ligand (CD178) apoptotic system, which has most predominantly been examined in rheumatoid arthritis. There, synovial inflammation is often characterized by a unique resistance to Fas-related apoptosis, and agonistic therapeutic interventions upon Fas have consistently been found beneficial in both animal and human disease models. Therefore, modulation of the Fas pathway will hopefully be of both pathogenic and therapeutic interest in the study of inflammatory arthritis conditions in general.
Objective
To identify the clinical and pathological predictors of central lymph node metastasis (CLNM) in patients with clinically lymph node-negative papillary thyroid microcarcinoma (PTMC).
...Materials and methods
Data pertaining to 541 clinically lymph node-negative PTMC patients who underwent thyroid surgery at the Shanghai General Hospital between January 2010 and December 2013 were retrospectively analyzed. According to histopathological evidence of central lymph node involvement, patients were divided into central lymph node metastasis (CLNM)-positive and CLNM-negative groups; risk factors for CLNM were identified statistically.
Results
LNM was found in 148 (27.4%) patients. Gender (
P
= 0.002), age (
P
< 0.001), tumor size (
P
< 0.001), multifocality (
P
< 0.001), and extrathyroidal extension (
P
< 0.001) were significantly different between CLNM-positive and CLNM-negative groups. On multivariate analyses, male sex (odds ratio OR = 2.656), age <45 years (OR = 4.184), tumor size >0.575 cm (OR = 2.105), gross extrathyroidal extension (OR = 14.605) and multifocality (OR = 2.084) were independent risk factors for CLNM. Among patients who did not have any of these five risk factors, only 3.9% were found to have CLNM.
Conclusions
A relatively high prevalence of CLNM was observed in patients with clinically lymph node-negative PTMC. CLNM was associated with male sex, younger age, larger tumor size, extrathyroidal extension and multifocal PTMC.
A numerical model including 29 reactions and 11 species is developed to investigate the spatial-temporal distributions of species and electric field in oxygen parallel-plate positive pulsed ...dielectric barrier discharge for ozone generation. Electron energy conservation equation is coupled to electron continuity equation, heavy species continuity equation and Poisson's equation. The spatial-temporal distributions of species and electric field are obtained at electron avalanche and during streamer propagation. The results show the dominant positive ion, negative ion and excited species are O2+, O3− and O2(∑g+1), respectively. The average streamer propagation velocity is about 5.56 × 104 m/s. Overall electron density almost increases exponentially but with a violent oscillation in the vicinity of anode at electron avalanche. Electron density increases at first and then declines in the vicinity of anode and streamer channel during streamer propagation, and increases gradually in streamer head with the development of streamer, as well as reduces sharply to almost zero near cathode. Electron density almost remains constant in whole streamer channel at any one moment. Other species have a similar spatial-temporal distribution.
•A plasma fluid and chemical model coupling electron energy conservation is developed.•Spatial-temporal distribution of species and electric field were obtained in oxygen pulsed DBD.•Obvious oscillations present near anode and the streamer propagation velocity is about 5.56 × 104 m/s.
Acinetobacter baumannii can cause severe nosocomial and community-acquired pneumonia. To study the pathogenesis of A. baumannii and to develop new treatments, appropriate mouse models are needed. ...Most reported mouse models of pulmonary A. baumannii infection are non-lethal or require mouse immunosuppression to enhance infection. These models are not suitable for studying host immune responses or evaluating immunotherapies.
The virulence of 30 clinical isolates was assessed in mice. The most virulent isolate, SJZ24, was selected to develop a pneumonia model in immunocompetent mice. The cytokine mRNA expression in the lung was assessed with real-time PCR. The cell infiltration in bronchoalveolar lavage fluid (BALF) after SJZ24 infection was determined by flow cytometry. Vaccine efficacy was assessed using this model.
Intratracheal inoculation of SJZ24 (5 × 107 CFU) resulted in death in 100% of the mice (5/5). SJZ24-infected mice showed high bacterial burdens in blood and organs as well as severe lung-tissue damage. Infection with SJZ24 induced increased inflammatory cytokine expression in the lung and increased neutrophil infiltration in BALF. Immunization with inactivated whole cells of SJZ24 showed 100% protection (5/5) against A. baumanni infection in this model.
We established a lethal pneumonia model in immunocompetent mice with hypervirulent A. baumannii isolate SJZ24. This model can be used to study the immune response to A. baumannii infection and to evaluate vaccine efficacy.
The T helper lymphocyte is responsible for orchestrating the appropriate
immune response to a wide variety of pathogens. The recognition of the
polarized T helper cell subsets Th1 and Th2 has led to ...an understanding of the
role of these cells in coordinating a variety of immune responses, both in
responses to pathogens and in autoimmune and allergic disease. Here, we discuss
the mechanisms that control lineage commitment to the Th1 phenotype. What has
recently emerged is a rich understanding of the cytokines, receptors, signal
transduction pathways, and transcription factors involved in Th1
differentiation. Although the picture is still incomplete, the basic pathways
leading to Th1 differentiation can now be understood in in vitro and a number
of infection and disease models.
Corneal endothelium-associated corneal blindness is the most common indication for corneal transplantation. Restorative corneal transplant surgery is the only option to reverse the blindness, but a ...global shortage of donor material remains an issue. There are immense clinical interests in the development of alternative treatment strategies to alleviate current reliance on donor materials. For such endeavors, ex vivo propagation of human corneal endothelial cells (hCECs) is required, but current methodology lacks consistency, with expanded hCECs losing cellular morphology to a mesenchymal-like transformation. In this study, we describe a novel dual media culture approach for the in vitro expansion of primary hCECs. Initial characterization included analysis of growth dynamics of hCECs grown in either proliferative (M4) or maintenance (M5) medium. Subsequent comparisons were performed on isolated hCECs cultured in M4 alone against cells expanded using the dual media approach. Further characterizations were performed using immunocytochemistry, quantitative real-time PCR, and gene expression microarray. At the third passage, results showed that hCECs propagated using the dual media approach were homogeneous in appearance, retained their unique polygonal cellular morphology, and expressed higher levels of corneal endothelium-associated markers in comparison to hCECs cultured in M4 alone, which were heterogeneous and fibroblastic in appearance. Finally, for hCECs cultured using the dual media approach, global gene expression and pathway analysis between confluent hCECs before and after 7-day exposure to M5 exhibited differential gene expression associated predominately with cell proliferation and wound healing. These findings showed that the propagation of primary hCECs using the novel dual media approach presented in this study is a consistent method to obtain bona fide hCECs. This, in turn, will elicit greater confidence in facilitating downstream development of alternative corneal endothelium replacement using tissue-engineered graft materials or cell injection therapy.
To clarify the effect of C addition on shape memory effect (SME) in Fe-Mn-Si-based alloys, the SME and microstructures of two Fe-Mn-Si-Cr-Ni alloys with different C contents had been studied after ...deformed between 293K and 77K. The results showed that the SME in the Fe-Mn-Si-based alloys can be significantly enhanced by the addition of more C when deformed at a proper temperature. A comparable recovery strain of 4.2% to that in the Fe-Mn-Si-based alloys subjected to special treatments was obtained in a solution treated Fe-16.99Mn-5.59Si-9.28Cr-5.67Ni-0.12C alloy when deformed at 77K. This significant improvement can be ascribed to the remarkably increased difference between the critical stress for the permanent slip and that for the stress-induced ε martensitic transformation due to the addition of more C.
In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such ...as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-α and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.
The genome-editing Cas9 protein uses multiple amino-acid residues to bind the target DNA. Considering only the residues in proximity to the target DNA as potential sites to optimise Cas9's activity, ...the number of combinatorial variants to screen through is too massive for a wet-lab experiment. Here we generate and cross-validate ten in silico and experimental datasets of multi-domain combinatorial mutagenesis libraries for Cas9 engineering, and demonstrate that a machine learning-coupled engineering approach reduces the experimental screening burden by as high as 95% while enriching top-performing variants by ∼7.5-fold in comparison to the null model. Using this approach and followed by structure-guided engineering, we identify the N888R/A889Q variant conferring increased editing activity on the protospacer adjacent motif-relaxed KKH variant of Cas9 nuclease from Staphylococcus aureus (KKH-SaCas9) and its derived base editor in human cells. Our work validates a readily applicable workflow to enable resource-efficient high-throughput engineering of genome editor's activity.
Forkhead (Fox) transcription factors play key roles in immunoregulation. Members of the Foxo subfamily have been implicated in the regulation of the cell cycle and/or apoptosis, but their specific ...immunological contexts remain largely undefined. We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis. Foxo3a deficiency leads to spontaneous lymphoproliferation, associated with inflammation of several organs, in the absence of overt apoptotic defects. These findings correlated with the presence of hyperactivated helper T cells, which proliferated more vigorously and produced more Th1 and Th2 cytokines than their wild-type counterparts. Foxo3a inhibits NF-κB activation, whose overactivity was responsible for T cell hyperactivity in Foxo3a-deficient mice. Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-κB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities.
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