Background TIGIT and PVRIG, which functions as immune checkpoint inhibitor, are novel targets for immune oncology therapy. They bind to their ligands (PVR/CD155 and PVRL2/CD112 respectively) with high affinity and thus block the interaction of these ligands with the activating receptor CD226. TIGIT and PVRIG are expressed on T cells and NK cells and are upregulated in tumors compared to normal tissues, while their ligands are widely expressed on tumor cells and tumor-associated macrophages, which contributes to local suppression of immune-surveillance. Dual blockage of TIGIT and PVRIG by therapeutic antibodies has synergistic anti-tumor effects in various preclinical studies and showed promising results in early clinical trials. Methods Anti-human TIGIT monoclonal antibodies (mAb) were generated from mouse hybridoma, while anti-human PVRIG Abs were discovered from Alpaca as a single-domain antibody (sdAb). The development of the anti-TIGIT/PVRIG bispecific antibody (bsAb) LAE113 involved using a humanized sequence derived from the lead anti-TIGIT mAb and the anti-PVRIG sdAb. LAE113 was subjected to binding, blocking, and multiple functional assays, along with competitors such as anti-TIGIT mAb (Tiragolumab), anti-PVRIG mAb (COM701), and anti-TIGIT/PVRIG bsAb (SHR-2002), all of which are currently being tested in clinical trials. Additionally, we evaluated the PK profiles of LAE113 in mice and its stability during stress tests. Results LAE113 is a novel humanized IgG4 bsAb against human TIGIT and PVRIG with sub-nanomolar affinity and strong blocking activities at both protein and cellular levels. It also exhibits cross-reactivity to corresponding cynomolgus targets. In NFAT luciferase reporter assays, LAE113 demonstrated approximately 1.5-fold greater potency than Tiragolumab and about 4-fold higher potency than COM701 in rescuing TIGIT or PVRIG-mediated inhibitory signaling, respectively. Moreover, LAE113 demonstrated superior activity in primary CD8+ T cell and NK cell activation assays compared to existing competitors, highlighting its best-in-class potential. LAE113 also exhibited a synergistic effect when combined with anti-PD-L1 mAb in enhancing IFN-γ secretion from CD8+ T cells. Furthermore, it induced potent NK-mediated cytotoxicity against MOLM13 cells better than the combination of anti-TIGIT and anti-PVRIG mAbs. In the single-dose study, LAE113 exhibited stable PK properties, and it maintained structural integrity and purity in stressful conditions. Conclusions LAE113 is an extremely potent TIGIT and PVRIG signaling blocker, outperforming existing competitors (Tiragolumab, COM701, SHR-2002 and SIM0348) in modulating T cell and NK cell functions, and exhibiting a favorable developability profile. It significantly enhanced T cell activity when combined with PD-L1 blockade. These findings suggest that LAE113 holds great promise as a candidate for cancer immunotherapy.

Background GEN-009, a personalized vaccine candidate comprised of ATLAS™-prioritized neoantigens combined with Hiltonol®, is currently being evaluated in a Phase 1/2a clinical trial (NCT03633110). ATLAS™ is a cell-based recall assay that, without predictions, screens each patient's mutanome to identify neoantigens for vaccine inclusion and deleterious Inhibigens™ for exclusion. In the Part A monotherapy cohort, vaccine-specific immune responses were generated in all subjects, against 99% of administered peptides.1 Here we characterize immune responses and their association with reduction in tumors in Part B of the study, in which patients were treated with GEN-009 combined with anti-PD-1-based checkpoint inhibitors (CPI). Methods Fourteen adults with solid tumors were enrolled in the study. During the screening and manufacturing period, patients received standard of care anti-PD-1 CPI. Subsequently, patients were immunized with GEN-009 in combination with anti-PD-1. CPI refractory patients received salvage therapy prior to GEN-009. Peripheral blood mononuclear cells were collected at baseline, pre-vaccination (D1), as well as multiple days post first dose. The magnitude and durability of vaccine-induced immune responses were assessed by quantifying neoantigen-specific responses in fluorospot assays. Proliferation of neoantigen-specific T cells and T cell phenotypes were evaluated by flow cytometry. Circulating tumor DNA (ctDNA) levels were monitored pre- and post-GEN-009 dosing to assess its potential as a predictive biomarker. Results GEN-009 immunization induced neoantigen-specific T cell responses in all evaluable patients, with ex vivo responses emerging as early as 1 month and persisting up to 366 days in some subjects. Comparing RECIST responders (PR, CR) to non-responders (SD, PD), the median breadth of statistically positive responses to vaccine antigens at day 50 was greater in non-responders ex vivo (29 vs. 75%, respectively), however, by IVS assay the proportions inverted (83% vs. 38%). Longitudinal evaluation of neoantigen-specific responses revealed an association between the magnitude and kinetics of cytokine secretion and increased activated and proliferating Ki-67+ T cells and TEM cells in both T cell subsets. Quantification of ctDNA in a subset of patients supported the RECIST readouts in association with the enhanced neoantigen-specific T cell responses. Conclusions Vaccination with GEN-009 combined with anti-PD-1-based therapy induced early, durable, and neoantigen-specific CD4+ and CD8+ T cell responses with pronounced Ki-67+ and TEM cell populations. Overall, a greater breadth of response to vaccine neoantigens was associated with improved clinical benefit, which was further supported by ctDNA levels. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors. References Lam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March; 11(3):696–713. Ethics Approval ETHICS STATEMENT This study was approved by Western Institutional Review Board, approval number 1-1078861-1

In this paper,considering the uncertainty of consumers' demand and inventory,we build a multi-period and multi-objective site location model with the goal of minimizing the total cost and the disutility for residents.By solving this model,the location,the number of each kind of facilities and the logistics flow allocation among facilities are determined.Finally,the results are compared with a static site location model to highlight the advantages of the dynamic site location model and it has strong applied value.

针对逆向物流网络的多目标性和回收废旧产品数量的不确定性,在再制造产品和新产品可相互替代的情形下,建立了随机多目标规划模型.通过求解该模型,可以确定逆向物流网络中设施的位置、数量以及设施间的流量分配.对模型中的机会约束,将其转化为各自的确定性等价类,采用主目标法对多目标问题加以处理.通过Lingo 11.0对模型算例进行求解,并分析了当置信水平和可回收量波动时网络结构和最小成本的变化,进而验证模型的稳定性.

BACKGROUND: Long-term environmental enrichment (EE) stimulation can enhance the transcription of CAMKII and CREB which are very important proteins for neuronal plasticity, learning and memory. OBJECTIVE: To explore the effects of short-term environmental enrichment stimulation on phosphorylation of CAMKII and CREB in Alzheimer's disease mice. METHODS: Either C57/BL6 mice (wild type) or APP/PS1 transgenic mice were used. These laboratorial mice were assigned into three groups: APP/PS1+EE group ( long-term EE stimulations were performed when APP/PS1 transgenic mice, as Alzheimer's disease models, were 6 months old), APP/PS1 control group (APP/PS1 transgenic mice without long-term EE stimulations) and wild-type group (wild type C57/BL6 mice). When the mice of the 3 groups reached to 18 months, each group was randomly divided into two subgroups, baseline subgroup and stimulation subgroup. The mice in every stimulation subgroup were treated with 1 day (short-term) EE stimulation. RESULTS AND CONCLUSION: In the wild type group, the CREB phosphorylation level in the stimulation subgroup was significantly higher than that in the baseline subgroup (P < 0.05), and the CAMKII phosphorylation level had also increased. In the APP/PS1+EE group, the CAMKII phosphorylation level in the stimulation subgroup was slightly higher than that in the baseline subgroup, and there was no distinct difference in the CREB phosphorylation level between the two subgroups. In the APP/PS1 control group, there was no significant difference in CAMKII and CREB phosphorylation levels between the two subgroups. These findings suggest that short-term EE stimulation can induce an increase of CAMKII phosphorylation level in Alzheimer's disease mice only after long-term EE stimulation. However, it can obviously improve the phosphorylation level of CAMKII and CREB in wild type mice.

信息技术与课程整合是信息化社会对教育提出的要求,是教育现代化的必然选择。高等学校是培养跨世纪人才的主要基地,本文分析通过信息技术与高等院校音乐课程的有机整合,给音乐课程带来新的生机和活力,并营造新型教学坏境,实现从教学技术、教学内容、教学方法到教学模式和教育观念等全方位、深层次的教学改革。

Tourism industry is an industry closely linked to geographical space.Studying the formation and evolution of tourism system that is within certain regional space and periodic features displayed in its structure and function,from the perspective of geography science,has an important role in promoting the development of regional tourism industry.Based on the definition of tourism regional system,the paper makes a systematic retrospect of the relevant literature about the evolution of tourism regional system both at home and abroad from the following aspects: spatial distribution of tourist flow and concentration-diffusion effect,space structure,evolutional patterns and mechanism of tourism system.Defects existing in the present studies and study trend are put forward in the hope of providing some useful reference for the study of sustainable development of regional tourism.

奥尔夫教学法是当代世界著名的音乐教育体系之一、它培养全人格发展和创造性能力的宗旨,和生动活泼、丰富多彩的教学形式得到世界各国的高度赞誉和喜爱,在世界广泛流传.幼儿音乐教育是幼儿教育中重要组成部分,音乐是人类的第二语言,节奏是音乐的骨骼,旋律是音乐的灵魂.本文从幼儿节奏教学入手,阐述了对奥尔夫教学法运用的理论实践研究,吸取精华之处,为幼儿音乐课堂增加色彩,使幼儿音乐教学取得显著效果.

《红河谷》是一部历史片,取材于西藏江卡尔孜(简称江孜)1904年反抗英国侵略者的斗争史,更可贵的是作曲家在影片的音乐中加入了大量的西藏民族乐曲,这为影片和影片的音乐都增辉不少。这部电影的音乐旋律动听、配器精良,和声及复调等作曲技术的运用都称得上精湛。本文通过14个音乐与故事交融的场面分析了影片的音乐格调高雅,充满民族风格,因而影片的场面更加壮观。

Based on theoretical analysis,this paper studies the spatial-temporal evolution of regional tourism system of Qingdao from the perspective of spatial structure and system function,by the methods of GIS Spatial Analysis,System Entropy and Ecological Footprint. It got results that,since 1985,regional tourism system of Qingdao has gone through its formative stage,stage of development, and currendy the primary maturity stage,showing good development momentum.The system has initially formed the spatial structure with first tourism center—secondary tourism center—tourism hinterland;its economic function has been growing,and the eco-environmental pressure is still in controllable range with continually increasing ecological footprint efficiency.However,whether it can extend the maturity stage,and smoothly transit from this stage to the update phase of the next high-level circle,it all depends.Therefore,this paper holds that the next key issues of realizing the optimal development of regional tourism system are further exploring the key driving factors and their action mode and intensity as well as analysis on the dynamic mechanism of the system evolution.

电影《失恋33天》改编自鲍鲸鲸的同名人气网络小说,是中国内地首部为光棍节定制的"治愈系"爱情电影。该片由导演滕华涛执导,当红演员文章、白百何主演。故事用亲切又不失幽默的方式讲述女主角黄小仙从遭遇失恋到走出心理阴霾的33天。片中音乐作曲由丁薇和林朝阳担任,二人曾为电影《辛亥革命》担任配乐,对于这部中小成本影片来说,配乐可谓是大手笔了。片中用到了小提琴、大提琴独奏和弦乐四重奏,使整部影片的配乐清新自然、富有朝气,透着浪漫的爱情气息。

Why did seclusion became important in Wang Wei's whole life? There are two reasons.One is that life in seclusion was a fashion in the flourishing Tang Dynasty,which produced many-sided affects and effects for those scholars to go out of or go in the populace society.The other one is that as far as Wang Wei is concerned,so many subjective and decisive factors faced with Wang Wei,such as the political reality,mentality transform,philosophical thoughts played a fatal role,after he became an official,.Therefore,Wang Wei's seclusion had both its popularity of the time and his own peculiarity.As for his seclusion form,it was half official and half solitude.It was a popular way of life in seclusion for scholars which is identical to the philosophical relationship contained in the flourishing Tang Dynasty.Wang Wei's technique of expression,content and creation of scenery for his poems of landscape with hills, streams and gardens and so on have internal relations with his seclusion life form.

Gao Shi and Cen Shen were both poets of frontier poetry,whose creation style is solemn and stirring.However,there are also some differences between their creations.The most important was the writing peaks that appeared in different stage of their lives.And there are various reasons giving rise to the differences,including their values,life attitudes and characters,which also decide the differences between their poetry creating in style,content and expression and the influence of literary heritage and other aspects.

本文首先以李商隐《无题》诗的用意作为切入点,结合其感怀诗、政治诗篇及政治命运,指出《无题》决不是简单的爱情诗,而有更深的思想旨趣,即寄托了作者高远的怀抱与深广的忧愤。其次结合时代背景,阐释作者为何以及如何曲折言志。

Salinity is one of the important limiting factors in plant production worldwide. The objectives of the study were to assess the effect of salt stress on the plant growth and to determine if DNA can be methylated in cotton plants (Gossypium hirsutum) by methylation-sensitive amplified polymorphism (MSAP) technique. The results showed that 100 mmol L-1 NaCl obviously promoted plant height and root length of cotton seedlings, but 200 mmol L-1 NaCl significantly inhibited plant growth; 100–200 mmol L-1 NaCl inhibited the number of lateral root considerably. The analysis of MSAP showed that the level of global DNA methylation decreased from 41.2% to 34.5% as the salt concentrations increased; there was a significantly negative correlation (r=–0.986) between NaCl concentrations and the level of DNA methylation in cotton roots. Under stresses of 100, 150 and 200 mmol L-1 NaCl, methylation and demethylation of DNA were 6.4%, 7.6%, 11.3% and 12.7%, 11.1%, 8.2%, respectively. In addition, the analyses of sequences and RT-PCR showed that expressions of genes homologous to MSAP fragments in roots were different between control and treated plants under salt stress, suggesting that these genes would play an important role in the cotton adaptation of salt stress.

辛弃疾的创作风格多种多样,而在其诸风格中占主导地位的豪放词风也别具一格。辛弃疾继承了苏轼的豪放词风,又以词的当行本色出之,加以发展。在双重审美追求中,创造出一种悲壮苍凉、顿挫沉郁的风格。与之相应,在文本思想上,作者将爱国豪情与抑郁忧思凝注一体。在表现手法上,作者采用了比较曲折的表现手法,比兴用典,借古喻今,营造廓大的词境,备写沉郁顿挫之意。

s:An enterprise's core competence is its capacity for joining forces with other enterprises so as to be able to perform the synthetic function of merging together different resources or talents.Such ability is an important, yet invisible, asset to the enterprise.Knowledge economy has become the mainstream of the world economy.Therefore, information users are in urgent need of a supply of reliable and audited information about the company's core competence.This article intends to analyze the meaning of the company's core competence and its relation with an enterprise's invisible assets.In this paper are put forwards the proposition and some ideas about the research on an enterprise's core competence.

Objective To probe into a new therapy for pain of secondary prolapse of lumbar intervertebral disk. Methods One thousand three hundred and ninety six cases were treated by removing the node with a long round needle, using tendon and muscle symptom differentiation, and searching for focus points of the tendons and muscle node along the foot three yin and three yang tendon and muscle channels. Results Of the 1396 cases, 1145 cases were cured (pain was completely relieved), accounting for 81 7%, 227 cases were effective, accounting for 16 2%, and 29 cases were ineffective, accounting for 2 1%, with a total effective rate of 97 9%. Conclusion The long round needle therapy has a good analgesic effect on secondary prolapse of lumbar intervertebral disc.

Audit risk refers to the possibility of issuing improper audit opinion by registered accountants after auditing when there are major errors and omissions in accounting statements.People in the audit circles have been increasingly aware of audit risk and have placed special emphasis on it.To achieve the goals of avoiding audit risk,improving auditing work and consolidating status of internal auditing bodies,internal auditors have a responsibility to probe into theory of audit risk,fully understand the concept and features of audit risk and causes for its emergence,seek measures to guard against audit risk and apply them in the practice of internal audit to establish a system to control audit risk.

There are many reports about the interactions between grapefruit juice (GJ) and drugs. The finding that GJ can markedly increase oral drug bioavailability was based on an unexpected observation from an interaction study between the felodipine and ethanol, in which GJ was used to mask the taste of ethanol. Subsequent investigations showed that GJ acted by reducing presystemic felodipine metabolism through selective inhibition cytochrome P4503A4 expression in the intestinal wall. The duration of effect of GJ can last 24 h, repeated GJ consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with GJ. Medications with low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by GJ. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of GJ and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a final decision on their importance to the interaction must await results from in vivo testing in humans.