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.
Understanding the drivers of market concentration in the generic pharmaceutical industry is essential to guaranteeing the availability of low-cost generics. In this paper, we develop a structural ...model to capture the multiple determinants governing manufacturers’ entry decisions; in particular, we focus on how manufacturing complexity and the regulatory environment for generics approval affect concentration in drug markets. We estimate the model using data collated from six disparate sources. We find that manufacturing complexity, as reflected in the number of active ingredients, for example, significantly reduces the likelihood of generics entry. Moreover, the delay in the review process for the generics applications significantly affects the number of firms entering a market. Our policy simulations suggest that a shortened drug approval review time significantly increases the average number of entrants per market and reduces the fraction of markets with no generics entry; however, a notable portion of markets would still lack any generic competition.
This paper was accepted by Jayashankar Swaminathan, operations management.
Supplemental Material:
The online appendix is available at
https://doi.org/10.1287/mnsc.2022.4423
.
High-density human activities have rapidly changed the pattern of urban land use/land cover (LULC), affecting the supply of urban ecosystem services (ESs). This poses a challenge to the balance of ...urban development and ecological protection, which may be more serious in ecologically fragile regions. This study identified key LULC change (LULCC) impacts on ESs in Ordos, an ecologically fragile region in Northwest China. The urbanization process of Ordos will continue in 2030 under the business-as-usual scenario due to its strategic positioning in the National Energy Base of China. The future LULC simulation results showed that developed land in eastern Ordos will continue to expand in 2030, and more forest and grassland will appear in western Ordos as a result of ecological restoration. The results of the InVEST model in calculating four important ESs showed that the ES supply in the densely populated areas (eastern Ordos) has declined, and more attention must be given to natural vegetation protection in the urbanization process. Although carbon storage in the western region has increased due to afforestation, this also reduces the water yield supply, which may exacerbate the water shortage in Ordos. Supported by this framework, more sustainable urban land use management can be undertaken to balance the conflict between ecological protection and urbanization. This will contribute to regional ecological health and sustainable urban development.
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•Ecosystem services (ESs) need specific attention in ecologically fragile regions.•Urbanization will continue in 2030 under the business-as-usual scenario in Ordos.•Beneficial ESs declined due to transfer from natural vegetation to developed land.•Ecological protection is particularly important in densely populated eastern counties.•Afforestation may reduce water yield which is challenging for water-scarce cities.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•3D PANI/PDI organic heterojunction was successfully constructed.•Excellent photocatalytic performance and stability for TC degradation.•Larger delocalized π-conjugated system and ...energy-matched heterojunction structure.•Possible pathways and mechanism of photocatalytic degradation of TC.
Polyaniline/Perylene diimide organic heterojunction photocatalyst with three-dimensional structure (3D PANI/PDI) has been successfully prepared via an in-situ growth process. 3D PANI/PDIexhibited efficient performance in the degradation of tetracycline (TC) under visible light irradiation. The degradation rate of TC by 3D 20%-PANI/PDIis 15.3 times and 17.0 times that of pure PDI and PANI in static system, respectively. Moreover, 3D PDI/PANI showed outstanding stability and could continuously degrade TC for up to 75 h in a dynamic system. The enhanced photocatalytic performance and stability of 3D PANI/PDI mainly comes from the following three aspects: (i) The introduction of PANI polymer backbone reinforced the strength of the PDI hydrogel, thereby improved the catalytic stability of the system; (ii) The three-dimensional network structure provided more reactive sites and medium transport channels; (iii) Larger delocalized π-electron conjugated system and energy-matched heterojunction structure were established through π-π interactions between PANI and PDI, which improved the efficiency of the migration and separation of photo-generated carriers. Finally, the mechanism and mineralization pathways of TC were systematically studied. Superoxide radical (O2−), hydrogen peroxide (H2O2) and hole (h+) were the main reactive species (RSs) for the degradation of TC. Under the attack of RSs, the TC under hydroxylation, dealkylation, aromatization, and ring-opening processes, eventually leading to complete mineralization. This work provides a new promising approach for improving the photocatalytic performance of organic catalysts and indicates that 3D PANI/PDI organic heterojunction photocatalyst can be efficiently applied for the water environmental remediation.
Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitinproteasome system, have the potential to revolutionize the ...healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the
in vivo
performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the
in vivo
degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.
This tutorial review discusses the convergence of drug delivery systems and PROTACs, surveys the burgeoning PROTAC delivery strategies, summarizes their design principles, clarifies their challenges, and outlooks future translational opportunities.
The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population
. Although recent reports reveal that the Omicron variant robustly escapes ...vaccine-associated and therapeutic neutralization antibodies
, 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.
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.
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.
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
. 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
values, this region was considered as the candidate sex determination region (SDR) in A. japonicus.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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