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Haohua Yuan,1 Huan Gui,1 Shuanghui Chen,1 Lan Zhu,1 Chenglv Wang,1 Qianyu Jing,2 Hang Lv,1 Quan Wan,2 Shuyi Wang,1 Shengwen Zhou,1 Xiaodong Ren,1 Yingjie Nie,1,3 Linzhao Li1 1Medical College, Guizhou University, Guizhou Province, 550025, People’s Republic of China; 2School of Preclinical Medicine of Zunyi Medical University, Zunyi, Guizhou Province, 563000, People’s Republic of China; 3NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, 550002, People’s Republic of ChinaCorrespondence: Yingjie Nie; Linzhao Li, Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, People’s Republic of China, Tel +86-085188274013; +86-085188274016, Email nienyj@hotmail.com; lzli@gzu.edu.cnPurpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD).Methods: R848-loaded PLGA nanoparticles modified with 2-HP-β-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo.Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-β-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an effi

Data protection legislation like the European Union's General Data Protection Regulation (GDPR) establishes the \textit{right to be forgotten}: a user (client) can request contributions made using their data to be removed from learned models. In this paper, we study how to remove the contributions made by a client participating in a Federated Online Learning to Rank (FOLTR) system. In a FOLTR system, a ranker is learned by aggregating local updates to the global ranking model. Local updates are learned in an online manner at a client-level using queries and implicit interactions that have occurred within that specific client. By doing so, each client's local data is not shared with other clients or with a centralised search service, while at the same time clients can benefit from an effective global ranking model learned from contributions of each client in the federation. In this paper, we study an effective and efficient unlearning method that can remove a client's contribution without compromising the overall ranker effectiveness and without needing to retrain the global ranker from scratch. A key challenge is how to measure whether the model has unlearned the contributions from the client $c^*$ that has requested removal. For this, we instruct $c^*$ to perform a poisoning attack (add noise to this client updates) and then we measure whether the impact of the attack is lessened when the unlearning process has taken place. Through experiments on four datasets, we demonstrate the effectiveness and efficiency of the unlearning strategy under different combinations of parameter settings., Comment: Accepted in ECIR 2024

Nos referimos a un proyecto ApS como una práctica académica que combina procesos de aprendizaje y servicio a la comunidad con el fin de ayudar al alumnado a implicarse en los proyectos y actividades de su entorno. La aplicación en la que se centra el desarrollo del presente TFG se ideó en el TFG de la UNED de Lozano [9] y la elección de las principales tecnologías usadas en la aplicación actual se hizo en el marco del TFG de la UNED de Alonso [11]. Casar una oferta con una demanda de ApS era un proceso costoso, y por eso los profesores concurrieron con la necesidad de tener un soporte informático para facilitar este proceso. Esta necesidad se convirtió en una propuesta que acabó siendo el TFG a día de hoy, un proyecto web que busca cumplir las necesidades de las dos partes. Partiendo de las versiones de los TFG anteriores, nuestro objetivo es terminar las funcionalidades pendientes relativas a los procesos previos a la creación de un proyecto ApS, tener terminado el objetivo principal del proyecto, la de poder crear un partenariado a partir de las ofertas y las demandas existentes. Otro objetivo consiste en implementar un sistema de notificaciones que notifique a los distintos usuarios implicados sobre los cambios de estado relevantes en los procesos, además de un estudio de experiencia de usuario tras desplegar la aplicación. Sobre las tecnologías utilizadas, en este TFG hemos continuado con las tecnologías utilizadas en las versiones anteriores: Angular, Express.js, Node.js, JavaScript y MySQL., We refer to an ApS project as an academic practice that combines learning processes and community service in order to help students get involved in projects and activities in their environment. The application on which the development of this TFG is focused was devised in the TFG of the UNED of Lozano [9] and the choice of the main technologies used in the current application was made within the framework of the TFG of the UNED of Alonso [ eleven]. Matching an offer with an ApS demand was an expensive process, and for this reason the teachers agreed with the need to have computer support to facilitate this process. This need became a proposal that ended up being the TFG today, a web project that seeks to meet the needs of both parties. Based on the versions of the previous TFG, our objective is to finish the pending functionalities related to the processes prior to the creation of an ApS project, to have finished the main objective of the project, that of being able to create a partnership based on the offers and the existing demands. Another objective is to implement a notification system that notifies the different users involved about relevant status changes in the processes, as well as a user experience study after deploying the application. Regarding the technologies used, in this TFG we have continued with the technologies used in previous versions: Angular, Express.js, Node.js, JavaScript and MySQL.

Federated online learning to rank (FOLTR) aims to preserve user privacy by not sharing their searchable data and search interactions, while guaranteeing high search effectiveness, especially in contexts where individual users have scarce training data and interactions. For this, FOLTR trains learning to rank models in an online manner -- i.e. by exploiting users' interactions with the search systems (queries, clicks), rather than labels -- and federatively -- i.e. by not aggregating interaction data in a central server for training purposes, but by training instances of a model on each user device on their own private data, and then sharing the model updates, not the data, across a set of users that have formed the federation. Existing FOLTR methods build upon advances in federated learning. While federated learning methods have been shown effective at training machine learning models in a distributed way without the need of data sharing, they can be susceptible to attacks that target either the system's security or its overall effectiveness. In this paper, we consider attacks on FOLTR systems that aim to compromise their search effectiveness. Within this scope, we experiment with and analyse data and model poisoning attack methods to showcase their impact on FOLTR search effectiveness. We also explore the effectiveness of defense methods designed to counteract attacks on FOLTR systems. We contribute an understanding of the effect of attack and defense methods for FOLTR systems, as well as identifying the key factors influencing their effectiveness.

A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically-related, antibody sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody sensitive viruses is a promising approach to induce potent bNAbs in humans.

In this perspective paper we study the effect of non independent and identically distributed (non-IID) data on federated online learning to rank (FOLTR) and chart directions for future work in this new and largely unexplored research area of Information Retrieval. In the FOLTR process, clients participate in a federation to jointly create an effective ranker from the implicit click signal originating in each client, without the need to share data (documents, queries, clicks). A well-known factor that affects the performance of federated learning systems, and that poses serious challenges to these approaches, is that there may be some type of bias in the way data is distributed across clients. While FOLTR systems are on their own rights a type of federated learning system, the presence and effect of non-IID data in FOLTR has not been studied. To this aim, we first enumerate possible data distribution settings that may showcase data bias across clients and thus give rise to the non-IID problem. Then, we study the impact of each setting on the performance of the current state-of-the-art FOLTR approach, the Federated Pairwise Differentiable Gradient Descent (FPDGD), and we highlight which data distributions may pose a problem for FOLTR methods. We also explore how common approaches proposed in the federated learning literature address non-IID issues in FOLTR. This allows us to unveil new research gaps that, we argue, future research in FOLTR should consider. This is an important contribution to the current state of FOLTR field because, for FOLTR systems to be deployed, the factors affecting their performance, including the impact of non-IID data, need to be thoroughly understood., Comment: 10 pages full paper, accepted at SIGIR2022

Paraphrase generation is a fundamental and long-standing task in natural language processing. In this paper, we concentrate on two contributions to the task: (1) we propose Retrieval Augmented Prompt Tuning (RAPT) as a parameter-efficient method to adapt large pre-trained language models for paraphrase generation; (2) we propose Novelty Conditioned RAPT (NC-RAPT) as a simple model-agnostic method of using specialized prompt tokens for controlled paraphrase generation with varying levels of lexical novelty. By conducting extensive experiments on four datasets, we demonstrate the effectiveness of the proposed approaches for retaining the semantic content of the original text while inducing lexical novelty in the generation., Comment: Accepted by AAAI 2022 (Oral)

In the context of carbon peak and carbon neutral policies, low-carbon construction has been the focus of most countries worldwide. As one of the most effective ways to achieve green construction, many countries have launched low-carbon policies to promote the development of prefabrication. However, the effectiveness and influencing factors of low-carbon policies on prefabrication need to be further verified under the dynamic game between the government and the construction enterprise. Therefore, this study considered subsidy and carbon tax policies and developed an evolutionary game model to promote the development of the prefabricated construction market. The evolutionary stable strategy of the government and construction enterprise under different scenarios was obtained. Subsequently, a numerical analysis was conducted to further investigate the impact of the key factors on the stable strategy. The results showed that an appropriate hybrid policy of subsidies and taxes could positively promote the prefabrication implementation of the construction enterprise. The government should adopt an appropriate policy intensity according to the maturity of the market. This study can provide effective guidance and practical enlightenment for the government to achieve low-carbon, green, and sustainable construction., Integral Design & Management

Determining structures of protein complexes is crucial for understanding cellular functions. Here, we describe an integrative structure determination approach that relies on in vivo measurements of genetic interactions. We construct phenotypic profiles for point mutations crossed against gene deletions or exposed to environmental perturbations, followed by converting similarities between two profiles into an upper bound on the distance between the mutated residues. We determine the structure of the yeast histone H3-H4 complex based on ~500,000 genetic interactions of 350 mutants. We then apply the method to subunits Rpb1-Rpb2 of yeast RNA polymerase II and subunits RpoB-RpoC of bacterial RNA polymerase. The accuracy is comparable to that based on chemical cross-links; using restraints from both genetic interactions and cross-links further improves model accuracy and precision. The approach provides an efficient means to augment integrative structure determination with in vivo observations.

Chen Wei,1–4* Chaogang Yang,1–4* Shuyi Wang,1–4 Dongdong Shi,1–4 Chunxiao Zhang,1–4 Xiaobin Lin,1–4 Bin Xiong1–41Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, People’s Republic of China; 2Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, People’s Republic of China; 3Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, People’s Republic of China; 4Hubei Cancer Clinical Study Center, Wuhan 430071, People’s Republic of China *These authors contributed equally to this work Background: M2 macrophages are crucial components of tumor microenvironment that frequently associated with the resistance of therapeutic treatments in human cancers, but their role in the chemosensitivity of colorectal cancer (CRC) to 5-fluorouracil (5-FU) is still obscure.Methods: In our study, we clarified the biological functions of M2 macrophages and their mechanism on the chemosensitivity of CRC cells to 5-FU. Then, we analyzed the correlation between CCL22 and CD68+, and CD163+, tumor-associated macrophages (TAMs), and further elucidated the prognostic value of CCL22 and CD163+, M2 macrophages in clinical CRC samples.Results: M2 macrophages decreased the inhibitory effect of 5-FU on CRC cells migration and invasion by secreting CCL22, and declined the apoptosis induced by 5-FU. Treated with a neutralizing anti-CCL22 antibody destroyed these effects. We further illuminated that M2 macrophages regulated 5-FU resistance of CRC cells through epithelial-mesenchymal transition (EMT) program, PI3K/AKT pathway, and caspase-mediated apoptosis. Clinically, CCL22 was found to have elevated expression in CRC tissue samples, and was positively associated with CD163+, TAMs. Furthermore, the patients with higher CD163+, M2 macrophages and higher expression of CCL22 i

Chun-Xiao Zhang,* Shu-Yi Wang,* Shuang-Qian Chen, Shuai-Long Yang, Lu Wan, Bin Xiong Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Background: Glasgow prognostic score (GPS) is widely known as a systemic inflammatory-based marker. The relationship between pretreatment GPS and gastric cancer (GC) survival and clinicopathological features remains controversial. The aim of the study was to conduct a meta-analysis of published studies to evaluate the association between pretreatment GPS and survival and clinicopathological features in GC patients. Methods: We searched PubMed, Embase, MEDLINE, and BioMed databases for relevant studies. Combined analyses were used to assess the association between pretreatment GPS and overall survival, disease-free survival, and clinicopathological parameters by Stata Version 12.0. Results: A total of 14 studies were included in this meta-analysis, including 5,579 GC patients. The results indicated that pretreatment high GPS (HGPS) predicted poor overall survival (hazard ratio =1.51, 95% CI: 1.37–1.66, P<0.01) and disease-free survival (hazard ratio =1.45, 95% CI: 1.26–1.68, P<0.01) in GC patients. Pretreatment HGPS was also significantly associated with advanced tumor–node–metastasis stage (odds ratio [OR] =3.09, 95% CI: 2.11–4.53, P<0.01), lymph node metastasis (OR =4.60, 95% CI: 3.23–6.56, P<0.01), lymphatic invasion (OR =3.04, 95% CI: 2.00–4.62, P<0.01), and venous invasion (OR =3.56, 95% CI: 1.81–6.99, P<0.01). Conclusion: Our meta-analysis indicated that pretreatment HGPS could be a predicative factor of poor survival outcome and clinicopathological features for GC patients. Keywords: Glasgow

Jie Wang,1,* Shengzi Wang,1 Xinmao Song,1,* Wenjiao Zeng,2 Shuyi Wang,3 Fu Chen,1 Hao Ding1 1Department of Radiation Oncology, Eye, Ear, Nose, and Throat Hospital, Fudan University, 2Department of Pathology, Shanghai Medical School, Fudan University, 3Department of Pathology, Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Cancer-related systemic inflammation has been demonstrated to be associated with poor outcome in multiple types of cancers. Meanwhile, the local inflammation, which is characterized by dense intratumoral immune infiltrate, is a favorable predictor of survival outcome. Purpose: To evaluate the role of systemic and local inflammation in predicting outcome in patients with laryngeal squamous cell carcinoma. Patients and methods: In this retrospective study, 120 patients who had undergone postoperative radiotherapy were enrolled. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as calculated from pretreatment whole blood counts, were used to indicate systemic inflammation. The optimal cutoff values of NLR and PLR were determined using receiver operating characteristic curve analysis. Tumor infiltrating lymphocytes (TILs) density, as assessed by pathologist review of hematoxylin and eosin-stained slides, was used to represent local inflammation. Overall survival (OS) and recurrence-free survival (RFS) were assessed using the Kaplan–Meier method and multivariate Cox regression analysis. Results: The best cutoff was 2.79 for NLR and 112 for PLR. Kaplan–Meier analysis revealed that high NLR, high PLR, and low TILs density were significantly correlated with inferior OS and RFS, respectively (all P<0.05). The Cox proportional multivariate hazard model showed that a high pretreatment PLR and a low TILs density were both independently correlated with poor OS and RFS, respectively (all P&lt

Genetic interaction (GI) maps, comprising pairwise measures of how strongly the function of one gene depends on the presence of a second, have enabled the systematic exploration of gene function in microorganisms. Here, we present a two-stage strategy to construct high-density GI maps in mammalian cells. First, we use ultracomplex pooled shRNA libraries (25 shRNAs/gene) to identify high-confidence hit genes for a given phenotype and effective shRNAs. We then construct double-shRNA libraries from these to systematically measure GIs between hits. A GI map focused on ricin susceptibility broadly recapitulates known pathways and provides many unexpected insights. These include a noncanonical role for COPI, a previously uncharacterized protein complex affecting toxin clearance, a specialized role for the ribosomal protein RPS25, and functionally distinct mammalian TRAPP complexes. The ability to rapidly generate mammalian GI maps provides a potentially transformative tool for defining gene function and designing combination therapies based on synergistic pairs.

RNA polymerase II (RNAPII) lies at the core of dynamic control of gene expression. Using 53 RNAPII point mutants, we generated a point mutant epistatic miniarray profile (pE-MAP) comprising ∼60,000 quantitative genetic interactions in Saccharomyces cerevisiae. This analysis enabled functional assignment of RNAPII subdomains and uncovered connections between individual regions and other protein complexes. Using splicing microarrays and mutants that alter elongation rates in vitro, we found an inverse relationship between RNAPII speed and in vivo splicing efficiency. Furthermore, the pE-MAP classified fast and slow mutants that favor upstream and downstream start site selection, respectively. The striking coordination of polymerization rate with transcription initiation and splicing suggests that transcription rate is tuned to regulate multiple gene expression steps. The pE-MAP approach provides a powerful strategy to understand other multifunctional machines at amino acid resolution.

To protect the genome, cells have evolved a diverse set of pathways designed to sense, signal, and repair multiple types of DNA damage. To assess the degree of coordination and crosstalk among these pathways, we systematically mapped changes in the cell's genetic network across a panel of different DNA-damaging agents, resulting in ~1,800,000 differential measurements. Each agent was associated with a distinct interaction pattern, which, unlike single-mutant phenotypes or gene expression data, has high statistical power to pinpoint the specific repair mechanisms at work. The agent-specific networks revealed roles for the histone acetyltranferase Rtt109 in the mutagenic bypass of DNA lesions and the neddylation machinery in cell-cycle regulation and genome stability, while the network induced by multiple agents implicates Irc21, an uncharacterized protein, in checkpoint control and DNA repair. Our multiconditional genetic interaction map provides a unique resource that identifies agent-specific and general DNA damage response pathways.

it is generally assumed that polymeric micelles, upon administration into the blood stream, carry drug molecules until they are taken up into cells followed by intracellular release. The current work revisits this conventional wisdom. The study using dual-labeled micelles containing fluorescently labeled copolymers and hydrophobic fluorescent probes entrapped in the polymeric micelle core showed that cellular uptake of hydrophobic probes was much faster than that of labeled copolymers. This result implies that the hydrophobic probes in the core are released from micelles in the extracellular space. Forster resonance energy transfer (FRET) imaging and spectroscopy were used to monitor this process in real time. A FRET pair, DiIC(18(3)) and DiOC(18(3)), was loaded into monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) micelles. By monitoring the FRET efficiency, release of the core-loaded probes to model membranes was demonstrated. During administration of polymeric micelles to tumor cells, a decrease of FRET was observed both on the cell membrane and inside of cells, indicating the release of core-loaded probes to the cell membrane before internalization. The decrease of FRET on the plasma membrane was also observed during administration of paclitaxel-loaded micelles. Taken together, our results suggest a membrane-mediated pathway for cellular uptake of hydrophobic molecules preloaded in polymeric micelles. The plasma membrane provides a temporal residence for micelle-released hydrophobic molecules before their delivery to target intracellular destinations. A putative role of the PEG shell in the molecular transport from micelle to membrane is discussed.

論文(哲學碩士)--香港中文大學硏究院敎育學部,1994., 參考文獻: leaves 243-252, 王淑儀., 鳴謝 --- p.iv, 圖表 --- p.iii, 撮要 --- p.v, Chapter 第一章 --- 問題說明 --- p.1, Chapter 第二章 --- 文獻評述 --- p.6, Chapter (一） --- 「國家」本質的討論 --- p.6, Chapter (二） --- 「國家」理論的探討 --- p.8, Chapter (三） --- 教育政策與國家理論 --- p.27, Chapter 第三章 --- 研究架構、問題與研究方法 --- p.34, Chapter (一） --- 研究架構 --- p.34, Chapter (二） --- 研究問題 --- p.41, Chapter (三） --- 硏究方法 --- p.44, Chapter 第四章 --- 英文教育政策的轉變與確立 --- p.47, Chapter (I) --- 英文教育政策的轉變 --- p.47, Chapter (II) --- 英文教育政策的確立 --- p.52, Chapter (III) --- 1878年英文教育政策的轉變原因 --- p.55, Chapter (IV) --- 英文教育政策的確立-- 香港大學在1912年成立的原因 --- p.87, Chapter (V) --- 總结 --- p.99, Chapter 第五章 --- 中文教育政策的轉變（I) -- 1913年教育條例 --- p.104, Chapter (I) --- 1913年前中文學校的情況 --- p.104, Chapter (II) --- 1913年教育條例的內容 --- p.104, Chapter (III) --- 1913年教育條例出現的原因 --- p.111, Chapter (IV --- )總结 --- p.130, Chapter 第六章 --- 中文教育政策的轉變（II) -- 殖民地政府分別於1926年成立官立漢文中學 及1927年於香港大學設立中文糸 --- p.136, Chapter (I) --- 官立漢文中學及港大中文糸成立的經過 --- p.136, Chapter (II) --- 官立漢文中學及港大中文糸成立的原因 --- p.141, Chapter (III) --- 總结, Chapter 第七章 --- 中文教育政策的轉變（III) - - 1935年公佈《賓尼報告書》 --- p.170, Chapter (I) --- 1935殖民地政府公佈《賓尼報告書》-- 強調初等教育 --- p.178, Chapter (II) --- 1935殖民地政府公佈《賓尼報告書》-- 強調初等教育的原因 --- p.182, Chapter (III) --- 總结 --- p.199, Chapter 第八章 --- 總结, Chapter (一） --- 中英教育政策的轉變 --- p.203, Chapter (二） --- 研究意義 --- p.207, Chapter (三） --- 研究限制 --- p.212, 註釋 --- p.215, 中文參考書目及論文 --- p.243, 英文參考書目及論文 --- p.246, http://library.cuhk.edu.hk/record=b5888126, Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)