Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.

BackgroundIn multiple sclerosis (MS) and its widely used animal model, experimental autoimmune encephalomyelitis (EAE), autoreactive T cells contribute importantly to central nervous system (CNS) tissue damage and disease progression. Promoting apoptosis of autoreactive T cells may help eliminate cells responsible for inflammation and may delay disease progression and decrease the frequency and severity of relapse. Programmed cell death 5 (PDCD5) is a protein known to accelerate apoptosis in response to various stimuli. However, the effects of recombinant human PDCD5 (rhPDCD5) on encephalitogenic T cell-mediated inflammation remain unknown.MethodsWe examined the effects of intraperitoneal injection of rhPDCD5 (10 mg/kg) on EAE both prophylactically (started on day 0 post-EAE induction) and therapeutically (started on the onset of EAE disease at day 8), with both of the treatment paradigms being given every other day until day 25. Repeated measures two-way analysis of variance was used for statistical analysis.ResultsWe showed that the anti-inflammatory effects of rhPDCD5 were due to a decrease in Th1/Th17 cell frequency, accompanied by a reduction of proinflammatory cytokines, including IFN-γ and IL-17A, and were observed in both prophylactic and therapeutic regimens of rhPDCD5 treatment in EAE mice. Moreover, rhPDCD5-induced apoptosis of myelin-reactive CD4+ T cells, along with the upregulation of Bax and downregulation of Bcl-2, and with activated caspase 3.ConclusionsOur data demonstrate that rhPDCD5 ameliorates the autoimmune CNS disease by inhibiting Th1/Th17 differentiation and inducing apoptosis of predominantly pathogenic T cells. This study provides a novel mechanism to explain the effects of rhPDCD5 on neural inflammation. The work represents a translational demonstration that rhPDCD5 has prophylactic and therapeutic properties in a model of multiple sclerosis

Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells.

Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is characterized by CNS demyelination mediated by autoreactive T cells. Kirenol, a biologically active substance isolated from Herba Siegesbeckiae, has potent anti-inflammatory activities. Here we investigated effects of kirenol on EAE. Kirenol treatment markedly delayed onset of disease and reduced clinical scores in EAE mice. Kirenol treatment reduced expression of IFN-γ and IL-17A in the serum and proportion of Th1 and Th17 cells in draining lymph nodes. Priming of lymphocytes was reduced and apoptosis of MOG-activated CD4+ T cells was increased in kirenol treated EAE mice. Kirenol treatment of healthy animals did not affect the lymphocytes in these non-immunized mice. Further in vitro studies showed that kirenol inhibited viability of MOG-specific lymphocytes and induced apoptosis of MOG-specific CD4+ T cells in a dose- and time-dependent manner. Kirenol treatment upregulated Bax,downregulated Bcl-2,and increased activation of caspase-3 and release of cytochrome c, indicating that a mitochondrial pathway was involved in kirenol induced apoptosis. Moreover, pretreatment with either a pan-caspase inhibitor z-VAD-fmk or a more specific caspase 3 inhibitor Ac-DEVD-CHO in lymphocytes reduced kirenol induced apoptosis. Our findings implicate kirenol as a useful agent for the treatment of MS

Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS

AccidentGPT: Large Multi-Modal Foundation Model for Traffic Accident Analysis

Traffic accident analysis is pivotal for enhancing public safety and developing road regulations. Traditional approaches, although widely used, are often constrained by manual analysis processes, subjective decisions, uni-modal outputs, as well as privacy issues related to sensitive data. This paper introduces the idea of AccidentGPT, a foundation model of traffic accident analysis, which incorporates multi-modal input data to automatically reconstruct the accident process video with dynamics details, and furthermore provide multi-task analysis with multi-modal outputs. The design of the AccidentGPT is empowered with a multi-modality prompt with feedback for task-oriented adaptability, a hybrid training schema to leverage labelled and unlabelled data, and a edge-cloud split configuration for data privacy. To fully realize the functionalities of this model, we proposes several research opportunities. This paper serves as the stepping stone to fill the gaps in traditional approaches of traffic accident analysis and attract the research community attention for automatic, objective, and privacy-preserving traffic accident analysis.Comment: 8 pages, 2 figure

Aging Influence on Fatigue Characteristics of RAC Mixtures Containing Warm Asphalt Additives

Aging is an important factor to affect the long-term performance of asphalt pavement. The fatigue life of a typical warm mix asphalt (WMA) is generally related to various factors of rheological and mechanical properties of the mixture. The study of the fatigue behavior of the specific rubberized WMA is helpful in recycling the scrap tires and saving energy in terms of the conventional laboratory aging process. This study explores the utilization of the conventional fatigue analysis approach in investigating the cumulative dissipated, stiffness, and fatigue life of rubberized asphalt concrete mixtures containing the WMA additive after a long-term aging process. The aged beams were made with one rubber type (−40 mesh ambient crumb rubber), two aggregate sources, two WMA additives (Asphamin and Sasobit), and tested at 5 and 20ºC. A total of 55 aged fatigue beams were tested in this study. The test results indicated that the addition of crumb rubber extends the fatigue resistance of asphalt binder while WMA additive exhibits a negative effect. The study indicated that the WMA additive generally has an important influence on fatigue life. In addition, test temperature and aggregate source play an important role in determining the cumulative dissipated energy, stiffness, and fatigue life of an aged mixture

A TSPO ligand is protective in a mouse model of multiple sclerosis.

Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids

An Explorative Study of the Effectiveness of Mobile Advertising

This study examines factors related to the effectiveness of mobile advertising. Using a large data set with 115, 899 records of ad tap through from a mobile advertising company, we identify that the influencing factors for ad tap through are application type, mobile operators, scrolling frequency, and the regional income level. We use a logit model to analyze how the probability of ad tap through is related to the identified factors. The results show that application type, mobile operators, scrolling frequency, and the regional income level all have significant effects on the likelihood whether users would tap on certain types of advertising. Based on the findings, we propose strategies for mobile advertisers to engage in effective and targeted mobile advertising