Beyond conventional care : developing novel therapeutic approaches to combat arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder without a definitive cure. Although RA is driven by systemic autoimmunity, its most pronounced manifestation is organspecific inflammation, particularly synovitis in joints. Persistent synovitis results in progressive joint damage and deformity, ultimately compromising joint function. The etiology of RA is multifaceted, intricately intertwining genetic, environmental, and immunological elements. While autoreactive agents have traditionally been viewed as pathogenic contributors to the development of arthritis, our research, utilizing multiple experimental arthritis models, has pinpointed several pivotal autoreactive mediators, which are surprisingly regulatory. In study I, we established a cartilage antibody induced arthritis (CAIA) model. The deficiency of Fc gamma receptor (FCGR) 2B enables swift onset of CAIA within a 12-hour time frame, and overrides the resistance arising from complement C5 deficiency. Notably, our results highlight that FCGR3 is essential and sufficient for CAIA development. The role of FCGR4 remains to be further elucidated. In Study II, we engineered a range of recombinant antibodies targeting the F4 epitope on type-II collagen (COL2). One of these antibodies, denoted R69-4, not only prevented the onset of CAIA, but also effectively suppressed the established disease. Further screening revealed that R69-4 binds to numerous targets in the synovial fluid (SF), including the complement C1q. As a result, R69-4 markedly dampens FCGR3 signaling in SF neutrophils, thereby interrupting neutrophil self-orchestrated recruitment. Given this efficacy, R69-4 emerges as a promising therapeutic candidate for RA, particularly during its acute stage. In study III, we introduced mutations to the immunodominant T cell epitope of COL2. A mutation resulting in higher affinity to major histocompatibility complex class II (MHC II) confers resistance to collagen-induced arthritis (CIA). However, the absence of either FCGR2B or neutrophil cytosolic factor 1 (NCF1) disrupts this tolerance. In particular, the deficiency of NCF1 leads to a reduction of regulatory T cells (Tregs), and a decrease of autoimmune regulator (AIRE) expression in medullary thymic epithelial cells (mTECs). In Study IV, we identified a subset of autoreactive B cells that are ubiquitously present across species. These B cells target the C1 epitope on COL2. Transferring these C1 B cells effectively suppressed arthritis of recipient mice in an antigen-specific manner. We further discerned that the suppressive efficacy of C1 B cells stems from the activation of Tregs and the functional integrity of CD72. In RA patients, we noted a reduced frequency of C1 B cells, possibly attributed to their differentiation into plasma cells. Interventions that can reverse this transition may contribute to preventing the onset of RA

MM-NeRF: Multimodal-Guided 3D Multi-Style Transfer of Neural Radiance Field

3D style transfer aims to render stylized novel views of 3D scenes with the specified style, which requires high-quality rendering and keeping multi-view consistency. Benefiting from the ability of 3D representation from Neural Radiance Field (NeRF), existing methods learn the stylized NeRF by giving a reference style from an image. However, they suffer the challenges of high-quality stylization with texture details for multi-style transfer and stylization with multimodal guidance. In this paper, we reveal that the same objects in 3D scenes show various states (color tone, details, etc.) from different views after stylization since previous methods optimized by single-view image-based style loss functions, leading NeRF to tend to smooth texture details, further resulting in low-quality rendering. To tackle these problems, we propose a novel Multimodal-guided 3D Multi-style transfer of NeRF, termed MM-NeRF, which achieves high-quality 3D multi-style rendering with texture details and can be driven by multimodal-style guidance. First, MM-NeRF adopts a unified framework to project multimodal guidance into CLIP space and extracts multimodal style features to guide the multi-style stylization. To relieve the problem of lacking details, we propose a novel Multi-Head Learning Scheme (MLS), in which each style head predicts the parameters of the color head of NeRF. MLS decomposes the learning difficulty caused by the inconsistency of multi-style transfer and improves the quality of stylization. In addition, the MLS can generalize pre-trained MM-NeRF to any new styles by adding heads with small training costs (a few minutes). Extensive experiments on three real-world 3D scene datasets show that MM-NeRF achieves high-quality 3D multi-style stylization with multimodal guidance, keeps multi-view consistency, and keeps semantic consistency of multimodal style guidance. Codes will be released later

Selenium intake help prevent age-related cataract formation: Evidence from NHANES 2001–2008

IntroductionCataract is one of the leading causes of blindness and visual impairment, about 16 million people around the world. Trace elements play an important role in a variety of the processes in human body. This study aimed to investigate the association between daily dietary intake of trace elements and age-related cataract incidence based on data from the National Health and Nutrition Examination Survey (NHANES) 2001–2008.MethodsIron, zinc, copper, and selenium were conducted in this study among subjects aged 50 years and older for African Americans and 55 and older in US adults. Multivariate logistic regression analysis was used in different models to investigate the association of trace elements intake and cataract.ResultsAfter screening, 7,525 subjects were ultimately included in this study. A significant negative association was found between selenium intake and cataract incidence in adjusted models using multivariate logistic regression analysis (model 1: OR = 0.998, 95% CI = 0.997–1.000; model 2: OR = 0.997, 95% CI = 0.995–1.000; and model 3: OR = 0.998, 95% CI = 0.995–1.000). After dividing selenium intake into quintiles, significant negative associations between selenium intake and cataract were observed in the first quintile of model 3, the fourth and fifth quintiles of all models. In subgroup analyses adjusted for age and sex, a significant negative association was observed only in women aged 65–74 years.DiscussionOur study points out that maintaining daily dietary selenium intake at higher levels is helpful for cataract prevention, and that increasing daily dietary selenium intake in American women aged 65–74 years may contribute to the prevention of age-related cataract. The intakes of iron, zinc, copper may not be associated with age-related cataract

Synergizing Human-AI Agency: A Guide of 23 Heuristics for Service Co-Creation with LLM-Based Agents

This empirical study serves as a primer for interested service providers to determine if and how Large Language Models (LLMs) technology will be integrated for their practitioners and the broader community. We investigate the mutual learning journey of non-AI experts and AI through CoAGent, a service co-creation tool with LLM-based agents. Engaging in a three-stage participatory design processes, we work with with 23 domain experts from public libraries across the U.S., uncovering their fundamental challenges of integrating AI into human workflows. Our findings provide 23 actionable "heuristics for service co-creation with AI", highlighting the nuanced shared responsibilities between humans and AI. We further exemplar 9 foundational agency aspects for AI, emphasizing essentials like ownership, fair treatment, and freedom of expression. Our innovative approach enriches the participatory design model by incorporating AI as crucial stakeholders and utilizing AI-AI interaction to identify blind spots. Collectively, these insights pave the way for synergistic and ethical human-AI co-creation in service contexts, preparing for workforce ecosystems where AI coexists.Comment: V1.0 on Oct 25th, 202

Systematically Detecting Packet Validation Vulnerabilities in Embedded Network Stacks

Embedded Network Stacks (ENS) enable low-resource devices to communicate with the outside world, facilitating the development of the Internet of Things and Cyber-Physical Systems. Some defects in ENS are thus high-severity cybersecurity vulnerabilities: they are remotely triggerable and can impact the physical world. While prior research has shed light on the characteristics of defects in many classes of software systems, no study has described the properties of ENS defects nor identified a systematic technique to expose them. The most common automated approach to detecting ENS defects is feedback-driven randomized dynamic analysis ("fuzzing"), a costly and unpredictable technique. This paper provides the first systematic characterization of cybersecurity vulnerabilities in ENS. We analyzed 61 vulnerabilities across 6 open-source ENS. Most of these ENS defects are concentrated in the transport and network layers of the network stack, require reaching different states in the network protocol, and can be triggered by only 1-2 modifications to a single packet. We therefore propose a novel systematic testing framework that focuses on the transport and network layers, uses seeds that cover a network protocol's states, and systematically modifies packet fields. We evaluated this framework on 4 ENS and replicated 12 of the 14 reported IP/TCP/UDP vulnerabilities. On recent versions of these ENSs, it discovered 7 novel defects (6 assigned CVES) during a bounded systematic test that covered all protocol states and made up to 3 modifications per packet. We found defects in 3 of the 4 ENS we tested that had not been found by prior fuzzing research. Our results suggest that fuzzing should be deferred until after systematic testing is employed.Comment: 12 pages, 3 figures, to be published in the 38th IEEE/ACM International Conference on Automated Software Engineering (ASE 2023

Relationship between high dose intake of vitamin B12 and glaucoma: Evidence from NHANES 2005–2008 among United States adults

ObjectiveGlaucoma has currently become the second leading cause of blindness in the world. Serum vitamin B12 level has been found to be involved in the development and progression of glaucoma. We performed the present study to confirm this association.MethodsThis cross-sectional study included 594 participants aged 40 years and older in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008. Retinal imaging was performed using the Ophthalmic Digital Imaging system (Retinography) to assess the retina for the presence of features of glaucomatous lesions. Logistic regression models were used to assess the association between dietary vitamin intake and glaucoma.ResultsAfter screening, 594 subjects were finally included. Among all vitamin intakes, we observed significant differences between the two groups for vitamin B12 intake (5.93 vs. 4.77 mg, p = 0.033). According to the logistic regression results, the intake of vitamin B12 was significantly positively associated with glaucoma (model 1: OR = 1.078, 95% CI = 1.019–1.141; model 2: OR = 1.092, 95% CI = 1.031–1.158; model 3: OR = 1.092, 95% CI = 1.029–1.158). After performing a quantile regression, we observed a significant positive association between vitamin B12 intake and incident glaucoma in the fourth quartile (model 1: OR = 1.133, 95% CI = 1.060–1.210; model 2: OR = 1.141, 95% CI = 1.072–1.215; model 3: OR = 1.146, 95% CI = 1.071–1.226).ConclusionsTherefore, the above results, high-dose intake of vitamin B12 may promote the development of glaucoma