CivRealm: A Learning and Reasoning Odyssey in Civilization for Decision-Making Agents

The generalization of decision-making agents encompasses two fundamental elements: learning from past experiences and reasoning in novel contexts. However, the predominant emphasis in most interactive environments is on learning, often at the expense of complexity in reasoning. In this paper, we introduce CivRealm, an environment inspired by the Civilization game. Civilization's profound alignment with human history and society necessitates sophisticated learning, while its ever-changing situations demand strong reasoning to generalize. Particularly, CivRealm sets up an imperfect-information general-sum game with a changing number of players; it presents a plethora of complex features, challenging the agent to deal with open-ended stochastic environments that require diplomacy and negotiation skills. Within CivRealm, we provide interfaces for two typical agent types: tensor-based agents that focus on learning, and language-based agents that emphasize reasoning. To catalyze further research, we present initial results for both paradigms. The canonical RL-based agents exhibit reasonable performance in mini-games, whereas both RL- and LLM-based agents struggle to make substantial progress in the full game. Overall, CivRealm stands as a unique learning and reasoning challenge for decision-making agents. The code is available at https://github.com/bigai-ai/civrealm

Feedback mechanism of front abutment stress on filling rate of backfilling body in coal burst mine

High stress is the main reason for high frequency of rock burst in deep coal mines. Backfilling mining serves as an effective method to control roof strata movement, alleviate the degree of stress concentration, and reduce the failure of surrounding rock and the risk of rock burst. To evaluate the controlling ability of the backfilling on mining stress in the gob area, the 1123 longwall panel of the Gucheng mine is taken as the project background. Theoretical analysis, laboratory test and field measurement are used to study the mining-induced stress distribution in the backfilling longwall face, and to reveal the feedback mechanism between the front abutment stress and bearing capacity of the backfilling body, helping to determine the backfilling rate of coal burst mine. The results show that the backfilling ratio in the early stage is lower than 80%, the subsidence of hard roof is serious, the influence area of front abutment stress is more than 30 m, and the degree of stress concentration reaches 1.5. The influence area and concentration degree of mining-induced stress in the fault affected area increase to 60 m and 1.65, respectively. Surrounding rock instability phenomenon, such as rib spalling and roof fall, happens frequently. The whole dynamic evolution characteristics of bearing stress in the backfilling body is measured. The stress distribution curve is divided into five stages, namely rapid decrease, transient stabilization, rapid increase, slow decrease, and secondary stabilization. The stabilization values of the bearing stress in the upper, middle, and lower regions of the gob area under the condition of low backfilling ratio are 1.5, 5.2 and 2.5 MPa, respectively. The backfilling body in the gob area is divided into non-sufficiently compacted zones and sufficiently compacted zones, and the continuous subsidence model of the hard roof under the support of the backfilling body is constructed, and the “ʅ” type subsidence curve of the hard roof is obtained, and the range of the insufficiently compacted area decreases approximately linearly with the backfilling ratio. The test obtains the evolution curves of elastic modulus and uniaxial compressive strength of the back-filling body with time. By combining with the roof subsidence curve and face advance speed, the distribution curve of mining-induced stress in the whole area of the longwall face is obtained. Negative exponential relationship is established for the backfilling rate and the afront abutment stress, which reveals the reverse feedback mechanism between them. Quantitative assessment on the load reduction and burst prevention effect of backfilling mining is realized. The trinity enhancement measures for improving the backfilling ratio of the gob area are proposed, which raises the backfilling ratio of the 1123 working face to more than 90%. The bearing capacity of the backfilling body is strengthened. The trinity measures reduce the separation space under the hard roof to 50 mm. The stress concentration coefficient decreases to 1.3. Correspondingly, the controlling effect of the surrounding rock of the longwall panel is significantly improved

TAGAP expression influences CD4+ T cell differentiation, immune infiltration, and cytotoxicity in LUAD through the STAT pathway: implications for immunotherapy

BackgroundT-cell Activation GTPase Activating Protein (TAGAP) plays a role in immune cell regulation. This study aimed to investigate TAGAP’s expression and its potential impact on CD4+ T cell function and prognosis in lung adenocarcinoma (LUAD).MethodsWe analyzed TAGAP expression and its correlation with immune infiltration and clinical data in LUAD patients using multiple datasets, including The Cancer Genome Atlas (TCGA-LUAD), Gene Expression Omnibus (GEO), and scRNA-seq datasets. In vitro and in vivo experiments were conducted to explore the role of TAGAP in CD4+ T cell function, chemotaxis, and cytotoxicity.ResultsTAGAP expression was significantly lower in LUAD tissues compared to normal tissues, and high TAGAP expression correlated with better prognosis in LUAD patients. TAGAP was positively correlated with immune/stromal/ESTIMATE scores and immune cell infiltration in LUAD. Single-cell RNA sequencing revealed that TAGAP was primarily distributed in CD4+/CD8+ T cells. In vitro experiments showed that TAGAP overexpression enhanced CD4+ T cell cytotoxicity, proliferation, and chemotaxis. Gene Set Enrichment Analysis (GSEA) indicated that TAGAP was enriched in the JAK-STAT signaling pathway. In vivo experiments in a xenograft tumor model demonstrated that TAGAP overexpression suppressed tumor growth and promoted CD4+ T cell cytotoxicity.ConclusionsTAGAP influences CD4+ T cell differentiation and function in LUAD through the STAT pathway, promoting immune infiltration and cytotoxicity. This study provides a scientific basis for developing novel LUAD immunotherapy strategies and exploring new therapeutic targets

Expert consensus on digital intraoral scanning technology

Digital intraoral scanning is a hot topic in the field of oral digital technology. In recent years, digital intraoral scanning has gradually become the mainstream technology in orthodontics, prosthodontics, and implant dentistry. The precision of digital intraoral scanning and the accuracy and stitching of data collection are the keys to the success of the impression. However, the operators are less familiar with the intraoral scanning characteristics, imaging processing, operator scanning method, oral tissue specificity of the scanned object, and restoration design. Thus far, no unified standard and consensus on digital intraoral scanning technology has been achieved at home or abroad. To deal with the problems encountered in oral scanning and improve the quality of digital scanning, we collected common expert opinions and sought to expound the causes of scanning errors and countermeasures by summarizing the existing evidence. We also describe the scanning strategies under different oral impression requirements. The expert consensus is that due to various factors affecting the accuracy of digital intraoral scanning and the reproducibility of scanned images, adopting the correct scanning trajectory can shorten clinical operation time and improve scanning accuracy. The scanning trajectories mainly include the E-shaped, segmented, and S-shaped methods. When performing fixed denture restoration, it is recommended to first scan the abutment and adjacent teeth. When performing fixed denture restoration, it is recommended to scan the abutment and adjacent teeth first. Then the cavity in the abutment area is excavated. Lastly, the cavity gap was scanned after completing the abutment preparation. This method not only meets clinical needs but also achieves the most reliable accuracy. When performing full denture restoration in edentulous jaws, setting markers on the mucosal tissue at the bottom of the alveolar ridge, simultaneously capturing images of the vestibular area, using different types of scanning paths such as Z-shaped, S-shaped, buccal-palatal and palatal-buccal pathways, segmented scanning of dental arches, and other strategies can reduce scanning errors and improve image stitching and overlap. For implant restoration, when a single crown restoration is supported by implants and a small span upper structure restoration, it is recommended to first pre-scan the required dental arch. Then the cavity in the abutment area is excavated. Lastly, scanning the cavity gap after installing the implant scanning rod. When repairing a bone level implant crown, an improved indirect scanning method can be used. The scanning process includes three steps: First, the temporary restoration, adjacent teeth, and gingival tissue in the mouth are scanned; second, the entire dental arch is scanned after installing a standard scanning rod on the implant; and third, the temporary restoration outside the mouth is scanned to obtain the three-dimensional shape of the gingival contour of the implant neck, thereby increasing the stability of soft tissue scanning around the implant and improving scanning restoration. For dental implant fixed bridge repair with missing teeth, the mobility of the mucosa increases the difficulty of scanning, making it difficult for scanners to distinguish scanning rods of the same shape and size, which can easily cause image stacking errors. Higher accuracy of digital implant impressions can be achieved by changing the geometric shape of the scanning rods to change the optical curvature radius. The consensus confirms that as the range of scanned dental arches and the number of data concatenations increases, the scanning accuracy decreases accordingly, especially when performing full mouth implant restoration impressions. The difficulty of image stitching processing can easily be increased by the presence of unstable and uneven mucosal morphology inside the mouth and the lack of relatively obvious and fixed reference objects, which results in insufficient accuracy. When designing restorations of this type, it is advisable to carefully choose digital intraoral scanning methods to obtain model data. It is not recommended to use digital impressions when there are more than five missing teeth

Ivermectin induces apoptosis of esophageal squamous cell carcinoma via mitochondrial pathway

Background: Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. Methods: The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. Results: Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. Conclusions: These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers.Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay.Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day).Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260)