RaidEnv: Exploring New Challenges in Automated Content Balancing for Boss Raid Games

The balance of game content significantly impacts the gaming experience. Unbalanced game content diminishes engagement or increases frustration because of repetitive failure. Although game designers intend to adjust the difficulty of game content, this is a repetitive, labor-intensive, and challenging process, especially for commercial-level games with extensive content. To address this issue, the game research community has explored automated game balancing using artificial intelligence (AI) techniques. However, previous studies have focused on limited game content and did not consider the importance of the generalization ability of playtesting agents when encountering content changes. In this study, we propose RaidEnv, a new game simulator that includes diverse and customizable content for the boss raid scenario in MMORPG games. Additionally, we design two benchmarks for the boss raid scenario that can aid in the practical application of game AI. These benchmarks address two open problems in automatic content balancing, and we introduce two evaluation metrics to provide guidance for AI in automatic content balancing. This novel game research platform expands the frontiers of automatic game balancing problems and offers a framework within a realistic game production pipeline.Comment: 14 pages, 6 figures, 6 tables, 2 algorithm

An integrative approach for exploring the nature of fibroepithelial neoplasms.

BACKGROUND: Malignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT. METHODS: We collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT. RESULTS: MPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects. CONCLUSIONS: This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT

Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents

On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoacyclovir (<b>2a</b>) and selenoganciclovir (<b>2b</b>) were designed based on bioisoteric rationale and synthesized via the diselenide <b>7</b> as the key intermediate. Compound <b>2a</b> exhibited potent anti-HSV-1 and -2 activities while <b>2b</b> exerted moderate anti-HCMV activity, indicating that these nucleosides can serve as a novel template for the development of new antiviral agents

Polypharmacology of <i>N</i>⁶‑(3-Iodobenzyl)­adenosine-5′‑<i>N</i>‑methyluronamide (IB-MECA) and Related A₃ Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential

A₃ adenosine receptor (AR) ligands including A₃ AR agonist, <i>N</i>⁶-(3-iodobenzyl)­adenosine-5′-<i>N</i>-methyl­uronamide (<b>1a</b>, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, <b>1a</b> significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A₃ AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A₃ AR pathway may not be directly involved in the adiponectin promoting activity. In a target deconvolution study, their adiponectin-promoting activity was significantly correlated to their binding activity to both peroxisome proliferator activated receptor (PPAR) γ and PPARδ. They functioned as both PPARγ partial agonists and PPARδ antagonists. In the diabetic mouse model, <b>1a</b> and its structural analogues A₃ AR antagonists significantly decreased the serum levels of glucose and triglyceride, supporting their antidiabetic potential. These findings indicate that the polypharmacophore of these compounds may provide therapeutic insight into their multipotent efficacy against various human diseases

Discovery and Structure-Activity Relationships of Novel Template, Truncated 1 &apos;-Homologated Adenosine Derivatives as Pure Dual PPAR gamma/delta Modulators

Following our report that A(3) adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)gamma/delta, we discovered a new template, 1&apos;-homologated adenosine analogues 4a-4t, as dual PPARy/delta modulators without AR binding. Removal of binding affinity to A(3)AR was achieved by 1&apos;-homologation, and PPAR gamma/delta dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPAR gamma/delta but lacked PPAR alpha binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPAR gamma/delta, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPAR delta-binding affinity but preserved PPAR gamma affinity, indicating that the C2 position defines a pharmacophore for selective PPAR gamma ligand designs. PPAR gamma/delta dual modulators functioning as both PPAR gamma partial agonists and PPAR delta antagonists promoted adiponectin production, potential against hypoadiponectinemia-associated cancer and metabolic diseases.N

<i>N</i>⁶‑Substituted 5′‑<i>N</i>‑Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A₃ Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Potent and selective A₃ adenosine receptor (AR) agonists were identified by the replacement of 4′-oxo- or 4′-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4′-seleno analogues preferred a glycosidic <i>syn</i> conformation and South sugar puckering, as shown in the X-ray crystal structure of 5′-<i>N</i>-methylcarbamoyl derivative <b>3p</b>. Among the compounds tested, <i>N</i>⁶-3-iodobenzyl analogue <b>3d</b> was found to be the most potent A₃AR full agonist (<i>K</i>_i = 0.57 nM), which was ≥800- and 1900-fold selective for A₁AR and A_2AAR, respectively. In the <i>N</i>⁶-cycloalkyl series, 2-Cl analogues generally exhibited better hA₃AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the <i>N</i>⁶-3-halobenzyl series. <i>N</i>⁷ isomers <b>3t</b> and <b>3u</b> were much weaker in binding than corresponding <i>N</i>⁹ isomers, but compound <b>3t</b> lacked A₃AR activation, appearing to be a weak antagonist. 2-Cl-<i>N</i>⁶-3-iodobenzyl analogue <b>3p</b> inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4′-selenonucleoside A₃AR agonists as novel antistroke agents