CEMSSL: A Unified Framework for Multi-Solution Inverse Kinematic Model Learning of Robot Arms with High-Precision Manipulation

Multiple solutions mainly originate from the existence of redundant degrees of freedom in the robot arm, which may cause difficulties in inverse model learning but they can also bring many benefits, such as higher flexibility and robustness. Current multi-solution inverse model learning methods rely on conditional deep generative models, yet they often fail to achieve sufficient precision when learning multiple solutions. In this paper, we propose Conditional Embodied Self-Supervised Learning (CEMSSL) for robot arm multi-solution inverse model learning, and present a unified framework for high-precision multi-solution inverse model learning that is applicable to other conditional deep generative models. Our experimental results demonstrate that our framework can achieve a significant improvement in precision (up to 2 orders of magnitude) while preserving the properties of the original method. The related code will be available soon

In Vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

This study was supported by a Wellcome Trust-NIH PhD Studentship to SB, WDF and NV. Grant number 098252/Z/12/Z. SB, CHC and WDF are supported by the Intramural Research Program, NCI, NIH. NHG and WL are supported by the Intramural Research Program, NIA, NIH.Peer reviewedPublisher PD

Thalidomide Analogues Suppress Lipopolysaccharide-Induced Synthesis of TNF-α and Nitrite, an Intermediate of Nitric Oxide, in a Cellular Model of Inflammation

An unregulated neuroinflammation accompanies numerous chronic and acute neurodegenerative disorders and it is postulated that such a neuroinflammatory component likely exacerbates disease progression. A key player in brain inflammation is the microglial cell; a vital soluble factor synthesized by activated microglial cells is the key cytokine, tumor necrosis factor–alpha (TNF-α). Additionally, microglial cells release IL-1α/β, reactive oxygen species (ROS), such as superoxide (O2-) and reactive nitrogen species (RNS) like nitric oxide (NO). Nitric oxide reactive oxygen species can undergo various forms of interactions in cells whereby the synthesis of RNS / ROS intermediates are generated that can damage cell membranes. The presence of oxidative damaged cells is implicated with the abnormal cellular activity in brain or in the spinal cord, and is a classical feature of neurodegenerative disorders. To aid characterize this process, a quantitative analysis of nitrite generation was undertaken on agents developed to lower TNF-α levels in cell culture. Nitrite is a stable end product of nitric oxide metabolism and, thereby, acts as a surrogate measure of the highly unstable nitric oxide. Utilizing a RAW 264.7 cellular model of lipopolysaccharide-induced inflammation that induces high levels of TNF-α protein accompanied by a robust generation of nitrite, the properties of a series of thalidomide-based TNF-α synthesis inhibitors were evaluated to reduce the levels of both. Specific analogues of thalidomide effectively suppressed the generation of both TNF-α and nitrite at well-tolerated doses

TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

Abstract Background Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. Methods Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. Results Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. Conclusion Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases

Design, synthesis and biological assessment of N-adamantyl, substituted adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and angiogenesis inhibitory activities

Acknowledgements SB, NV, WDF funded by a Wellcome Trust-NIH PhD Scholarship (Grant number: 098252/Z/12/Z).Peer reviewedPostprin

Linking young men who have sex with men (YMSM) to STI physicians: a nationwide cross-sectional survey in China.

BACKGROUND: Many young men who have sex with men (YMSM) are reluctant to seek health services and trust local physicians. Online information seeking may encourage YMSM to identify and see trustworthy physicians, obtain sexual health services, and obtain testing for sexually transmitted infections (STIs). This study examined online STI information seeking behaviors among Chinese YMSM and its association with offline physician visits. METHODS: We conducted a nationwide online survey among YMSM through WeChat, the largest social media platform in China. We collected information on individual demographics, sexual behaviors, online STI information seeking, offline STI testing, and STI physician visits. We examined the most commonly used platforms (search engines, governmental websites, counseling websites, generic social media, gay mobile apps, and mobile medical apps) and their trustworthiness. We assessed interest and willingness to use an MSM-friendly physician finder function embedded within a gay mobile app. Logistic regression models were used to examine the correlation between online STI information searching and offline physician visits. RESULTS: A total of 503 men completed the survey. Most men (425/503, 84.5%) searched for STI information online. The most commonly used platform to obtain STI information were search engines (402/425, 94.5%), followed by gay mobile apps (201/425, 47.3%). Men reported high trustworthiness of information received from gay mobile apps. Men also reported high interest (465/503, 92.4%) and willingness (463/503, 92.0%) to use a MSM-friendly physician finder function within such apps. Both using general social media (aOR =1.14, 95%CI: 1.04-1.26) and mobile medical apps (aOR =1.16, 95%CI: 1.01-1.34) for online information seeking were associated with visiting a physician. CONCLUSION: Online STI information seeking is common and correlated with visiting a physician among YMSM. Cultivating partnerships with the emerging mobile medical apps may be useful for disseminating STI information and providing better physician services to YMSM

Heuristic Search for Planning with Different Forced Goal-Ordering Constraints

Planning with forced goal-ordering (FGO) constraints has been proposed many times over the years, but there are still major difficulties in realizing these FGOs in plan generation. In certain planning domains, all the FGOs exist in the initial state. No matter which approach is adopted to achieve a subgoal, all the subgoals should be achieved in a given sequence from the initial state. Otherwise, the planning may arrive at a deadlock. For some other planning domains, there is no FGO in the initial state. However, FGO may occur during the planning process if certain subgoal is achieved by an inappropriate approach. This paper contributes to illustrate that it is the excludable constraints among the goal achievement operations (GAO) of different subgoals that introduce the FGOs into the planning problem, and planning with FGO is still a challenge for the heuristic search based planners. Then, a novel multistep forward search algorithm is proposed which can solve the planning problem with different FGOs efficiently

Activation of the DDR Pathway Leads to the Down-Regulation of the TGFβ Pathway and a Better Response to ICIs in Patients With Metastatic Urothelial Carcinoma

Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of metastatic urothelial carcinoma (mUC), a dominant type of bladder cancer (BC). Previous studies have shown an association between gene mutations in the DNA damage response (DDR) pathway and the immunotherapy response in mUC but have neglected the effect of the activation level of the DDR pathway on the ICI response in mUC. A published immunotherapy cohort with genome, transcriptome and survival data for 348 mUC patients was used. An external cohort (The Cancer Genome Atlas Bladder Cancer) and the GSE78220 cohort were used for validation. The activation level of the DDR pathway was quantified using single-sample gene set enrichment analysis (ssGSEA). Further analysis on the genome, immunogenicity, and the immune microenvironment was conducted using the DDR ssGSEA enrichment score-high (DSSH) group and the DDR ssGSEA enrichment score-low (DSSL) group. In the mUC cohorts, the DSSH group was associated with longer overall survival times (P=0.026; Hazard ratio=0.67; 95%CI: 0.46−0.95). The DSSH group was also associated with higher tumor mutation burden, neoantigen load, immune-activated cell patterns, and immune-related gene expression levels. The GSEA results indicated an immune activation state in DSSH group, which correlated with a down-regulation in the transforming growth factor β receptor signaling pathway. Our study suggests that the activation level of the DDR pathway may be a novel predictive marker for immunotherapy efficacy in patients with mUC