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Using a multitier mapping of supply-chain relationships constructed from granular global, firm-to-firm supplier–customer linkages data, we quantify the degree of financial risk propagation from the supply network beyond firms’ direct supply-chain connections and isolate structural network properties serving as significant moderators of risk propagation. We first document a baseline fact: a significant proportion of tier-2 suppliers are shared by tier-1 suppliers. We then construct two simple metrics to capture the degree of tier-2 sharing and disentangle its effect from tier-2 suppliers’ own risks. We show that the focal firms’ risk levels are significantly related to the proportion of shared tier-2 suppliers in their supply network, and the effect becomes monotonically stronger as their tier-2 suppliers become more highly shared. Finally, we uncover causal relationships behind these associations using a new source of exogenous, idiosyncratic risk events in an event study setting. We show that, as tier-2 suppliers are impacted by these events, focal firms experience negative abnormal returns, the magnitude of which is significantly larger when the impacted tier-2 suppliers are more heavily shared. Overall, our study uncovers the subtier network structure as an important risk source for the focal firm, with the degree of tier-2 sharing as the main moderator. Our results also provide the microfoundation for a common structure in idiosyncratic risks and suggest the importance of incorporating the effect of subtier supply network structure in the portfolio-optimization process. This paper was accepted by Vishal Gaur, operations management.

Immunotherapy strategies that use cell‐based delivery systems have sparked much interest in the treatment of malignancies, owing to their high biocompatibility, excellent tumor targeting capability, and unique biofunctionalities in the tumor growth process. A variety of design principles for cell‐based immunotherapy, including cell surface decoration, cell membrane coating, cell encapsulation, genetically engineered cell, and cell‐derived exosomes, give cancer immunotherapy great potential to improve therapeutic efficacy and reduce adverse effects. However, the treatment efficacy of cell‐based delivery methods for immunotherapy is still limited, and practical uses are hampered due to complex physiological and immunological obstacles, such as physical barriers to immune infiltration, immunosuppressive tumor microenvironment, upregulation of immunosuppressive pathways, and metabolic restriction. In this review, we present an overview of the design principles of cell‐based delivery systems in cancer immunotherapy to maximize the therapeutic impact, along with anatomical, metabolic, and immunological impediments in using cell‐based immunotherapy to treat cancer. Following that, a summary of novel delivery strategies that have been created to overcome these obstacles to cell‐based immunotherapeutic delivery systems is provided. Also, the obstacles and prospects of next‐step development of cell‐based delivery systems for cancer immunotherapy are concluded in the end. This review covers the design of cell‐based delivery systems for cancer immunotherapy, as well as the significant challenges limiting the efficacy of cell‐based immunotherapy and summarizes recent advances in overcoming those barriers to improve cancer treatment outcomes.

Manipulating the reversible redox chemistry of transition metal dichalcogenides for energy storage often faces great challenges as it is difficult to regulate the discharged products directly. Herein we report that tensile-strained MoSe 2 (TS-MoSe 2 ) can act as a host to transfer its strain to corresponding discharged product Mo, thus contributing to the regulation of Gibbs free energy change (Δ G ) and enabling a reversible sodium storage mechanism. The inherited strain results in lattice distortion of Mo, which adjusts the d-band center upshifted closer to the Fermi level to enhance the adsorbability of Na 2 Se, thereby leading to a decreased Δ G of the redox chemistry between Mo/Na 2 Se and MoSe 2 . Ex situ and in situ experiments revealed that, unlike the unstrained MoSe 2 , TS-MoSe 2 shows a highly reversible sodium storage, along with an evidently improved reaction kinetics. This work sheds light on the study on electrochemical energy storage mechanism of other electrode materials. Manipulating the redox chemistry of transition metal dichalcogenides still faces challenges. Here the authors report that tensile-strained MoSe2 can pass on the strain to its sodiated product Mo, and thus regulate the Gibbs free energy in the charging process to enable the reversible sodium storage.

Background Sex determination mechanisms are complicated and diverse across taxonomic categories. Sea cucumber Apostichopus japonicus is a benthic echinoderm, which is the closest group of invertebrates to chordate, and important economic and ecologically aquaculture species in China. A. japonicus is dioecious, and no phenotypic differences between males and females can be detected before sexual maturation. Identification of sex determination locus will broaden knowledge about sex-determination mechanism in echinoderms, which allows for the identification of sex-linked markers and increases the efficiency of sea cucumber breeding industry. Results Here, we integrated assembly of a novel chromosome-level genome and resequencing of female and male populations to investigate the sex determination mechanisms of A. japonicus . We built a chromosome-level genome assembly AJH1.0 using Hi-C technology. The assembly AJH1.0 consists of 23 chromosomes ranging from 22.4 to 60.4 Mb. To identify the sex-determination locus of A. japonicus , we conducted genome-wide association study (GWAS) and analyses of distribution characteristics of sex-specific SNPs and fixation index F ST . The GWAS analysis showed that multiple sex-associated loci were located on several chromosomes, including chromosome 4 (24.8%), followed by chromosome 9 (10.7%), chromosome 17 (10.4%), and chromosome 18 (14.1%). Furthermore, analyzing the homozygous and heterozygous genotypes of plenty of sex-specific SNPs in females and males confirmed that A. japonicus might have a XX/XY sex determination system. As a physical region of 10 Mb on chromosome 4 included the highest number of sex-specific SNPs and higher F ST values, this region was considered as the candidate sex determination region (SDR) in A. japonicus . Conclusions In the present study, we integrated genome-wide association study and analyses of sex-specific variations to investigate sex determination mechanisms. This will bring novel insights into gene regulation during primitive gonadogenesis and differentiation and identification of master sex determination gene in sea cucumber. In the sea cucumber industry, investigation of molecular mechanisms of sex determination will be helpful for artificial fertilization and precise breeding.

In task-based second language (L2) writing research, genre effects on linguistic features are usually explained by either task complexity hypothesis or differences in communicative demands. The basic distinction between the two explanations is determined by whether cognitive factors are at work. To date, the actual causes for L2 learners’ different linguistic features in different genres are still unclear. Aiming at providing empirical evidence for explaining the mechanism of genre effects, this investigation uses dependency-grammar-based measures to examine the role of cognitive factors in L2 argumentative, narrative, and descriptive writings. A total of 540 compositions from three different proficiency groups of English as a foreign language learners were collected, and their mean dependency distances and their distributions of dependency distance were calculated. It was found that in all proficiency groups of compositions, dependency distance distributions of five types showed significant differences between genres. Since dependency distance reflects cognitive load, those five dependency types were able to show that cognitive factors are at play in the writing process. Among the five types, the phrasal dependency relation types could reveal genre effects regardless of learners’ language proficiency, and clausal dependency relation types might pinpoint learners’ threshold of perceiving task complexity. The findings suggest that genre effects on linguistic features in L2 writings may result from different cognitive demand imposed by writing tasks with different genres, and genre effect may exhibit variation among different proficiency groups.

Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir. Increased density of tumor associated macrophages has been correlated with tumor recurrence following surgery. Here the authors design an alginate-based hydrogel encapsulating anti-PD-1-conjugated platelets and nanoparticles loaded with the macrophage-depleting CSF-1R inhibitor pexidartinib, showing inhibition of post-surgery tumor recurrence in preclinical models.

Pore-forming Gasdermin protein-induced pyroptosis in tumor cells promotes anti-tumor immune response through the release of pro-inflammatory cytokines and immunogenic substances after cell rupture. However, endosomal sorting complexes required for transport (ESCRT) III-mediated cell membrane repair significantly diminishes the tumor cell pyroptosis by repairing and subsequently removing gasdermin pores. Here, we show that blocking calcium influx-triggered ESCRT III-dependent membrane repair through a biodegradable nanoparticle-mediated sustained release of calcium chelator (EI-NP) strongly enhances the intracellularly delivered GSDMD-induced tumor pyroptosis via a bacteria-based delivery system (VNP-GD). An injectable hydrogel and a lyophilized hydrogel-based cell patch are developed for peritumoral administration for treating primary and metastatic tumors, and implantation for treating inoperable tumors respectively. The hydrogels, functioning as the local therapeutic reservoirs, can sustainedly release VNP-GD to effectively trigger tumor pyroptosis and EI-NP to prevent the ESCRT III-induced plasma membrane repair to boost the pyroptosis effects, working synergistically to augment the anti-tumor immune response. Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.

Purpose: Avoiding difficulties in career decision-making has long been recognized as an important lifelong pursuit for individuals. Parental influence is an important environmental factor in college students' career decision-making. In recent years it has been shown that overparenting can be a risk factor that hinders college students' career development. Participants and Method: This study was conducted with third-year students from four universities in Northeast China, and 743 valid questionnaires were received. With SPSS 24.0 and PROCESS plug-in, we built a moderated mediation model to examine the mediation effects of career expectation pressure and career decision self-efficacy between overparenting and career indecision and parent-adolescent expectation congruence's moderating role in this relationship. Results: The results of this study indicate that overparenting is positively associated with college students' career indecision. Career expectation pressure and career decision self-efficacy mediate the relationship between overparenting and career indecision. In addition, parent-adolescent expectation congruence moderated the adverse relationship of overparenting on career expectation pressure and career indecision. Conclusion: This study builds on previous research to explore the potential mechanisms of overparenting on adolescent career indecision. The results of this study may have implications for interventions in adolescent career decision-making to reduce the negative impact of overparenting on adolescent career development by providing feasible and effective interventions for overparenting families. Limitation: Other factors (eg, proactive personality) may also have played a positive role in this relationship in this study. We hope future studies will explore the moderating effects of different personality traits. Keywords: career decision self-efficacy, career expectation pressure, career indecision, college students, expectation congruence, overparenting

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population 1 . Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies 2 – 10 , the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants. The replication and pathogenicity of the Omicron variant of SARS-CoV-2 is attenuated compared with the original strain and other variants.

Inkjet printing technology is expected to enhance printed display mass production technology in the future. Nozzle-array printheads form the basis for printed display mass production applications. However, jet instability caused by air bubble entrapment and nozzle wettability changes during the printing process is a major challenge in the application of this technology. To adapt to possible nozzle abnormalities, a high-adaptability nozzle-array printing system based on a set covering printing planning (SCPP) model for printed display manufacturing is designed in this study. The study consists of two parts. First, a printing system based on multistep visual inspection and closed-loop feedback is proposed to accurately detect and screen abnormal nozzle positions. Notably, the inkjet printing system can identify nozzles with abnormal ejection characteristics and ensure that the remaining nozzles work accurately and stably. Then, an SCPP model is established for display pixel printing planning by using the remaining normal nozzles on the nozzle-array printhead. This model can output the most efficient printing path and nozzle printing action and can adapt to any pixel pattern, nozzle type, and abnormal nozzle distribution. The system and technology are highly adaptable and scalable for fabricating large-area printed display devices.