Abstract Research Question/Issue In this paper, we examine the effects of share lending or recall on proxy voting, with a particular focus on the role of index funds. Research Findings/Insights Our ...study reveals that higher index ownership in a firm is associated with an increased likelihood of share recall, particularly in the presence of higher institutional ownership, lower past return performance, smaller firm size, and when more shares are held by younger fund families with higher turnover ratios or higher management fees. Using the Russell 1000/2000 Index reconstitution as an exogenous shock, we establish a causal relationship between index ownership and share recall through instrumental variable (IV) analysis. Furthermore, we find a positive correlation between index ownership and share recall for proxy voting proposals related to compensation, director election, and those sponsored by management. In subsequent proxy votes, shareholder‐sponsored proposals and environmental, social, and governance (ESG) proposals receive more support in firms with higher index ownership, especially when share recall is more prevalent. Our analysis does not provide evidence to support the conjecture that firms with higher index ownership are more vulnerable to empty voting issues. Theoretical/Academic Implications Our study enhances the understanding of how index funds recall shares during proxy voting and the impact of index ownership on voting outcomes. The findings support the practice of index funds recalling shares to actively engage in proxy voting, effectively addressing the conflict between short‐term profit‐seeking through securities lending and long‐term governance responsibilities. Practitioner/Policy Implications We contribute to a better understanding of the role of index funds in corporate governance and shed light on the consequences of securities lending in proxy votes. These findings have important implications for investors, policymakers, and market participants in managing the potential conflicts arising from securities lending activities and promoting effective corporate governance practices.
(1) Background: Clarify the coordinated development level of production, living, and ecological spaces in the underdeveloped areas of China and their relationship with the intensity of human ...activity. Explore and address the problems that are likely to be faced when developing these areas and improve the quality of China’s new urbanization development. Promote the coordinated and sustainable development of the economy, society and ecology in underdeveloped areas. Guizhou Province is located in southwest China; the landform is broken and complex. Its economic development level is low. It is one of the representatives of underdeveloped areas in China. Therefore, Guizhou Province of China was selected as the study area. (2) Methods: This paper constructs the evaluation index system of the production–living–ecological space (PLES) functional system in China’s underdeveloped areas, and uses the coupling coordination degree model to measure the development coordination level of the study area. The human activity intensity model was used to calculate the human activity intensity in the study area. Response index is introduced to analyze the relationship between the spatial function coupling coordination degree and the intensity of human activities. (3) Results: Before 2015, the level of functional coupling coordination degree of production–living–ecological space (PLES) in the study area fluctuated, and after 2015, it showed a stable and coordinated development trend. The intensity of human activity continues to increase, and the interaction between human activity and local production–living–ecological space (PLES) function coupling coordination is intense. (4) Conclusions: human activity is a significant factor affecting regional, coordinated and sustainable development. In less developed areas, the impact of human activity is more obvious. Human activity, in combination with the theory of the human–land relationship and the moderate intensity of human activity, are important ways to improve the coordinated and sustainable development of underdeveloped regions.
Although previous studies have reported an association between thyroid function and anti-Müllerian hormone (AMH) levels, which is considered a reliable marker of ovarian reserve, the causal ...relationship between them remains uncertain. This study aims to investigate whether thyrotropin (TSH), free thyroxine (fT4), hypo- and hyperthyroidism are causally linked to AMH levels.
We obtained summary statistics from three sources: the ThyroidOmics Consortium (N = 54,288), HUNT + MGI + ThyroidOmics meta-analysis (N = 119,715), and the most recent AMH genome-wide association meta-analysis (N = 7,049). Two-sample MR analyses were conducted using instrumental variables representing TSH and fT4 levels within the normal range. Additionally, we conducted secondary analyses to explore the effects of hypo- and hyperthyroidism. Subgroup analyses for TSH were also performed.
MR analyses did not show any causality relationship between thyroid function and AMH levels, using normal range TSH, normal range fT4, subclinical hypothyroidism, subclinical hyperthyroidism and overt hypothyroidism as exposure, respectively. In addition, neither full range TSH nor TSH with individuals <50 years old was causally associated with AMH levels. MR sensitivity analyses guaranteed the robustness of all MR results, except for the association between fT4 and AMH in the no-
+
group.
Our findings suggest that there was no causal association between genetically predicted thyroid function and AMH levels in the European population.
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•The magnolol-containing polymeric prodrug micelles rapidly released magnolol taking advantage of the mildly acidic tumor microenvironment.•The micelles exhibited superior demonstrate ...excellent tumor targeting ability compared to magnolol.•The micelles had a longer half-life and extended duration of action in vivo.
Magnolol shows promise as an effective anti-tumor therapeutic agent. Nevertheless, the clinical application of this agent is constrained by its inherent water insolubility and diminished stability. In the present investigation, we have developed a new approach to address these limitations by creating an acid-responsive amphiphilic polymeric prodrug (PMag) that contains acetal bonds and magnolol, and can self-assemble into polymeric micelles (PMag-Ms) in aqueous solutions. We conducted in vitro release studies and observed that the micelles rapidly released magnolol at an acidic pH of 5.0, but only released minimal amounts of magnolol at a neutral pH of 7.4. In vitro investigations performed on gastric cancer cells elucidated that PMag-Ms selectively induced cell apoptosis and G1 phase cell cycle arrest, exhibiting higher efficacy than magnolol alone. Furthermore, in vivo studies confirmed that PMag-Ms exhibited superior inhibition of tumor growth, favorable biocompatibility with organs, increased accumulation in tumor tissues, and enhanced targeting efficiency compared to magnolol. Pharmacokinetic analysis also revealed that PMag-Ms had a longer half-life and extended duration of action in vivo. These results highlight the potential of the synthesized acid-degradable PMag-Ms as a promising therapeutic option for gastric cancer.
Poly ADP-ribose polymerase (PARP) inhibitor monotherapies are selectively effective in patients with pancreatic, breast, prostate, and ovarian cancers with
mutations. Cancer patients with more ...frequent wild-type
show poor responses to PARP inhibitors. Moreover, patients who are initially sensitive to these inhibitors eventually respond poorly to drugs. In the present study, we discover that abrogation of Kruppel-like factor 5 (KLF5) significantly inhibits homologous recombination, which is the main mechanism for DNA double-stranded repair. Furthermore, the downregulation of KLF5 expression promotes the DNA damage induced by olaparib and significantly reduces the IC
of the RARP inhibitor in pancreatic cancer cells. Overexpression of BRCA1 reverses the above effects caused by silencing of
. Olaparib combined with a KLF5 inhibitor has an enhanced cytotoxic effect. Mechanistically, we identify
as a KLF5 target gene. BRCA1 is positively correlated with KLF5 in PDAC tissue. Our results indicate that inhibition of KLF5 may induce BRCAness in a larger pancreatic cancer subset with proficient BRCA. The combination of KLF5 inhibitors and PARP inhibitors provides a novel treatment strategy to enhance the sensitivity of BRCA1-proficient pancreatic cancer to PARP inhibitors.
Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody–drug conjugates (ADCs), and many examples are currently in clinical development. In order to ...further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
This study was based on the use of whole-genome DNA methylation sequencing technology to identify DNA methylation biomarkers in tumor tissue that can predict the prognosis of patients with pancreatic ...cancer (PCa). TCGA database was used to download PCa-related DNA methylation and transcriptome atlas data. Methylation driver genes (MDGs) were obtained using the MethylMix package. Candidate genes in the MDGs were screened for prognostic relevance to PCa patients by univariate Cox analysis, and a prognostic risk score model was constructed based on the key MDGs. ROC curve analysis was performed to assess the accuracy of the prognostic risk score model. The effects of PIK3C2B knockdown on malignant phenotypes of PCa cells were investigated in vitro. A total of 2737 differentially expressed genes were identified, with 649 upregulated and 2088 downregulated, using 178 PCa samples and 171 normal samples. MethylMix was employed to identify 71 methylation-driven genes (47 hypermethylated and 24 hypomethylated) from 185 TCGA PCa samples. Cox regression analyses identified eight key MDGs (LEF1, ZIC3, VAV3, TBC1D4, FABP4, MAP3K5, PIK3C2B, IGF1R) associated with prognosis in PCa. Seven of them were hypermethylated, while PIK3C2B was hypomethylated. A prognostic risk prediction model was constructed based on the eight key MDGs, which was found to accurately predict the prognosis of PCa patients. In addition, the malignant phenotypes of PANC-1 cells were decreased after the knockdown of PIK3C2B. Therefore, the prognostic risk prediction model based on the eight key MDGs could accurately predict the prognosis of PCa patients.
Vaccine hesitancy was found in couples seeking artificial reproductive technology (ART) services. As the main vaccine used in China, investigations into the influence of inactivated coronavirus ...disease 2019 (COVID-19) vaccines on human fertility is needed.
This retrospective cohort study included data on COVID-19 vaccination, clinical characteristics, and reproductive outcome of 1,000 intrauterine insemination (IUI) cycles in 653 couples from March 2021 to March 2022 in a single university hospital-based center for reproductive medicine. The IUI cycles were divided into two categories based on sperm source, including 725 cycles in 492 women undergoing artificial insemination with their husband's sperm (AIH) and 275 cycles in 161 women undergoing artificial insemination with donor sperm (AID). Women were then divided into two groups. The vaccine exposed group included women vaccinated prior to insemination and the unexposed group included women who were not vaccinated or vaccinated after insemination. Reproductive outcomes including ongoing pregnancy rate, clinical pregnancy rate, and miscarriage rate were assessed.
Inactivated COVID-19 vaccinated women prior to intrauterine insemination in AIH cycles have comparable ongoing pregnancy rate (11.1 vs. 10.3%,
= 0.73), clinical pregnancy rate (12.5 vs. 11.3%,
= 0.60) as compared with unvaccinated counterparts. Similarly, there were no significant differences in ongoing pregnancy rate (20.9 vs. 28.1%,
= 0.17), clinical pregnancy rate (21.7 vs. 28.8%,
= 0.19) between vaccine exposed and unexposed groups in AID cycles. Multivariable logistic regression analyses showed that inactivated COVID-19 vaccination status cannot independently influence the reproductive outcomes of AIH and AID cycles. Subgroup analysis of vaccine exposed cycles showed that doses of vaccination and Interval between the last dose of vaccination and insemination have no influence on the reproductive outcomes of AIH cycles.
No negative effects were found on female fertility in IUI cycles following exposure to the inactivated COVID-19 vaccine. These findings indirectly reflect the safety of inactivated COVID-19 vaccine toward reproductive health and help to mitigate vaccine hesitancy among people planning to conceive.
Background:
Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the ...beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear.
Purpose:
This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests.
Methods:
Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD.
Results:
A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2.
Conclusion:
This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.
Crocus sativus L. is commonly used as functional food and medicinal herb in traditional Chinese medicine. In this study, the spectrum–effect relationship was established between HPLC fingerprints and ...in vitro antioxidant activity of saffron to improve the quality evaluation method of saffron. The fingerprints of 21 batches of saffron collected from different regions were assessed, and the data were further analyzed by chemometric methods, including similarity analysis, hierarchical clustering analysis, principal component analysis, and orthogonal partial least squares discriminant analysis. The spectrum–effect relationship between fingerprints and antioxidant effect of saffron was analyzed by grey relational analysis and partial least square methods to figure out the antioxidant component of saffron. Thirteen common peaks of 21 batches of saffron were included in the analysis, and peak 3 (picrocrocin), peak 7 (crocin I), and peak 10 (crocin II) were identified as the main active components responsible for antioxidant efficacy. Besides, a multi-index quality control method was developed for simultaneous determination of these three antioxidant components in saffron. Taken together, this study provided new strategies for the quality control and the development of new bioactive products of saffron in the future.
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