Zirconium-Catalyzed Synthesis of 6-(Trifluoromethyl)-2H-pyran-2-ones via C-C Bond Cleavage.

A strategy for the annulation reaction of alkynones with ethyl 4,4,4-trifluoro-3-oxobutanoate through C-C bond cleavage is described. The zirconium-catalyzed transformation provides access to a wide range of structurally diverse 6-(trifluoromethyl)-2H-pyran-2-ones in moderate to good yields, utilizing Na2CO3 as a base. Further transformations into trifluoromethylated arene derivatives have been demonstrated as well. Furthermore, plausible reaction pathways are proposed by conducting various control experiments and isolating a ß-diketone intermediate (X-ray) containing an intramolecular hydrogen bond.

One-Pot Assembly of 2-Trifluoromethyl Benzothiazole and Benzoselenazole via Copper-Mediated Three-Component Cascade Reaction.

A domino one-pot synthesis of 2-(trifluoromethyl) benzothiazole via copper-mediated three-component cascade reaction starting from the easily accessible starting materials such as o-iodoanilines, methyl trifluoropyruvate, and elemental sulfur is reported. The present strategy displayed a comprehensive substrate scope and good functional group tolerance and enabled access to a variety of substituted 2-(trifluoromethyl) benzothiazoles. A 2-(trifluoromethyl) benzoselenazole has also been synthesized utilizing this reaction methodology.

Research on factors influencing the academic entrepreneurial ability of teachers in the digital age: Evidence from China.

In the contemporary digital economy, economic development increasingly relies on the innovation and dissemination of knowledge. Academic entrepreneurship, as a direct channel for knowledge dissemination into the marketplace, is significantly influenced by digital technology. Consequently, how to improve academic entrepreneurial ability has become a hot research topic. This study is grounded in the theory of reciprocal determinism within the context of the digital economy. We use the "2019 China Digital Economy Development Index White Paper" and collect data from 1843 survey questionnaires in China to conduct empirical research with a ridge regression model. It primarily focuses on the following individual factors and social environmental factors on academic entrepreneurial ability of teachers (AEAT): digital economy (DE), organizational support (OS), policy environment (PE), and personal learning growth (PLG). First, the findings show that the DE, OS, PE, and PLG have a significant positive impact on improving AEAT. Second, the results also indicate that social environmental factors relative to personal factors will have a greater impact. Finally, this study not only presents the first attempt to establish a connection between DE and AEAT but also holds significant managerial implications for enhancing AEAT within the context of the DE. Despite the increasing body of literature on academic entrepreneurship, the research domain pertaining specifically to AEAT remains fragmented and lacks comprehensive theoretical development. There is a pressing need for more systematic and thorough investigations to unveil the black box of factors influencing AEAT in the context of the DE.

Silicon Distribution-Induced Actuation Film with Bidirectional Bending Deformation and Versatile Bionic Applications.

As an important branch of intelligent materials, the research and development of stimulus-responsive flexible intelligent actuation materials is of great significance to promote the industrialization of intelligent materials. In this study, the asymmetric PVA-co-PE/silicon nanoparticle (PPSN) composite films and PVA-co-PE/silicon sol (PPSS) composite film with different silicon distributions were prepared by a simple spraying method. The silicon nanoparticle layer in the PPSN composite film was similar to the sand-like water-absorbing layer, which can quickly absorb water and permeate it into the interior region, leading to the hygroscopic expansion behavior on one side of the nanofiber film. Then, the PPSN composite film would quickly bend and deform to the silicon nanoparticle side. However, in the PPSS composite film, due to the excellent hygroscopicity and swelling characteristics of the silica sol layer, the composite film can be rapidly deformed to the PVA-co-PE nanofiber film side under moisture stimulation. The above results subvert the traditional asymmetric actuation film, which mainly depends on the hydrophilicity difference to determine the hygroscopic responsiveness and deformation direction, and ignore that the swelling degree is the main factor determining the bending direction of actuator. In addition, both the composite films can quickly respond to moisture stimulation (<1 s) and produce large-scale bending deformation (180°). Furthermore, due to the excellent interface adhesion formed by the continuity structure in the PPSS composite film, it has better actuation stability than the PPSN composite film. The excellent actuation characteristics and different bending directions of the PPSN and PPSS composite films make it a great application prospect in the field of bionics in the future.

Regioselective synthesis of 3-trifluoromethyl 1,2,4-triazoles via photocycloaddition of sydnone with CF3CN.

A general and regioselective synthesis of 3-trifluoromethyl 1,2,4-triazoles has been achieved through photocycloaddition of sydnone with trifluoroacetonitrile. This method employed trifluoroacetaldehyde O-(aryl)oxime as the CF3CN precursor and tolerated various functional groups to furnish 3-trifluoromethyl 1,2,4-triazole products in moderate to good yields. Mechanistic experiments revealed an energy transfer from photocatalyst 4-CzIPN to the sydnone substrates.

Synthesis of 2-trifluoromethyl thiazoles via [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates with CF3CN.

2,2,2-Trifluoroacetaldehyde O-(aryl)oxime was employed for the [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates for the synthesis of 2-trifluoromethyl 4,5-disubstituted thiazoles. The reaction works well with various substituted pyridinium 1,4-zwitterionic thiolates in moderate to good yields. The synthetic potential of the obtained 2-trifluoromethyl 4,5-disubstituted thiazoles was demonstrated.

Relationship Between Entrepreneurship Education Curriculum and Agricultural Students' Satisfaction in China.

Developing agriculture is an important way to get rid of poverty and boost economic development. Entrepreneurship, especially entrepreneurship education, is considered to be an important contributor to the realization of the above objectives. Entrepreneurship education has received more and more attention. Improving the entrepreneurial willingness and skills of agricultural students is of great significance to the economic and social development of developing countries. In order to explore the relationship between entrepreneurship education curricula and satisfaction, especially the agricultural students, we conducted a questionnaire survey in 35 universities across the country between 2018 and 2019 to evaluate the entrepreneurship education of agricultural students in Chinese universities. And 1223 valid questionnaires with 7 interviews were obtained. Furthermore, we used the structural equation model to empirically analyze the questionnaire data and found that entrepreneurship practice plays a part in the mediating effect between entrepreneurship curriculum and satisfaction with entrepreneurship education. This paper expands literature on entrepreneurship education and has certain reference significance for training a large number of agricultural entrepreneurial talents the practice of entrepreneurship education in other developing countries.

2,2,2-Trifluoroacetaldehyde O-(Aryl)oxime: A Precursor of Trifluoroacetonitrile.

The preparation of 2,2,2-trifluoroacetaldehyde O-(aryl)oxime, a previously inaccessible precursor of trifluoroacetonitrile, via reaction of hydroxylamine and trifluoroacetaldehyde hydrate is reported. This precursor released CF3CN in quantitative yield under mildly basic conditions. The precursor was successfully used in the synthesis of trifluoromethylated oxadiazoles. The facile, cost-effective, scalable, and recyclable procedure makes these trifluoroacetonitrile precursors generally applicable.

The Impact of Entrepreneurship Competitions on Entrepreneurial Competence of Chinese College Students.

Entrepreneurship competitions are an important way to implement entrepreneurship education in universities and the main way for many students improve their entrepreneurial competence. To clarify the mechanism of the role of entrepreneurship competition on the entrepreneurial competence of university students, based on data from a sample of 170,764 university students from 31 provinces in China, this study constructs a moderated mediation model that focuses on the mediating role of entrepreneurial spirit (ES) in entrepreneurial competition (ECompetition) and entrepreneurial competence (ECompetence) and the moderating role of entrepreneurial practice (EP). The results showed that ECompetition found to have a significant positive predictive effect on ECompetence. ES plays a mediating role in the relationship between ECompetition and competence. The direct predictive effect of ECompetition on ECompetence and the mediating effect of ES on their relationship is moderated by EP. The results provide a new perspective on the impact of entrepreneurship competition on college students' entrepreneurial competence and expands the experiential learning theory in entrepreneurship education.

An aerobic copper-mediated domino process for the synthesis of 3-(trifluoromethylseleno)indoles.

An aerobic copper-mediated domino reaction for the synthesis of 3-(trifluoromethylseleno)indoles by trifluoromethylselenolation of N-Ts 2-alkynylaniline with [(bpy)CuSeCF3]2 is reported. This reaction proceeds through sequential oxidation, alkyne coordination, and deprotonation followed by reductive elimination. This mild and robust method is highly functional group tolerant and provides straightforward access to 3-(trifluoromethylseleno)indoles in moderate to good yields.

Synthesis of 2,3-Bis(trifluoromethylseleno) Indoles through an Oxidative Copper-Mediated Domino Reaction.

An oxidative copper-mediated double trifluoromethylselenolation of terminal 2-alkynylanilines using [(bpy)CuSeCF3]2 is reported, providing a moderately efficient and convenient approach to 2,3-bis(trifluoromethylseleno)indoles. Mechanistic studies show that a cascade sequence of oxidation, trifluoromethylselenolation, 5-endo-dig cyclization, and elimination is involved in this transformation.

In Vivo Profiling with 18F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions.

Demonstrating target engagement in vivo is an important milestone in drug development, both to establish on target, on tissue interactions but also to identify potentially undesirable off tissue binding. The glucocorticoid receptor (GR) is a long-studied yet vexing drug target that has recently re-emerged as a potential druggable driver of many solid tumor types including breast and prostate cancer, and several antagonists are currently in early phase clinical trials. Since GR is also ubiquitously expressed in normal tissues, understanding antagonist/GR interactions in normal tissues and tumor is crucial to defining a therapeutic index. Herein, we demonstrate that the GR radioligand 18F-YJH08 can map drug/GR engagement in vivo. Profiling target engagement in vivo showed that the GR antagonists RU486 (mifepristone) and CORT125281 engaged GR in fewer normal tissues compared to ORIC-101 or the agonist dexamethasone. Furthermore, 18F-YJH08 detected GR in human prostate cancer tumor models and measured receptor binding by RU486. In summary, these data show for the first time that antagonist/GR interactions can be measured in vivo with 18F-YJH08, a finding with clinical relevance as GR antagonists and 11C-YJH08 are currently in clinical trials.

How to Improve Entrepreneurship Education in "Double High-Level Plan" Higher Vocational Colleges in China.

Entrepreneurship education complements vocational education in helping students develop their career prospects. This empirical study comprehensively analyzed sample data of 13,885 students from 40 "Double High-level Plan" higher vocational colleges in China using robust standard error regression analysis and other methods. The results showed that Entrepreneurship Practice (EP), Entrepreneurship Curriculum (EC), and Integration of Entrepreneurship Education and Professional Education (IEEPE) have a significant positive effect on Entrepreneurship Education Performance (EEP), with EP being the most important factor. Furthermore, ascribed factors (gender, household registration, only child or not, whether parents have entrepreneurial experience) and self-achieved factors (double high-level type, school area, subject major, whether to accept social entrepreneurship education) were found to affect students' perception of investment in entrepreneurship education. The study summarizes the existing problems of entrepreneurship education in "Double High-level Plan" higher vocational colleges and proposes four suggestions: pursue the integrated development of entrepreneurship education and "Double High-level" construction, advance both theoretical education and practical education, promote digital reform of the "three teaches" (teachers, teaching materials, and teaching methods), and develop entrepreneurship education in a comprehensive and balanced manner. This has certain theoretical and practical significance for the improvement of entrepreneurship education in other developing countries.

Entrepreneurship Education, Psychological Cognition, and Entrepreneurship Activities: An Analysis Based on a Fuzzy-Set Qualitative Comparative Analysis.

At present, research in the field of college students' entrepreneurship has proliferated, but these studies tend to analyze the net benefits of various factors on entrepreneurial activities, which are affected by the configuration effects of multiple factors; hence, it remains unclear whether entrepreneurial education can make graduates more efficient to started their own companies. To fill this gap in the literature, drawing on general systems theory and using fuzzy-set qualitative comparative analysis (fsQCA), we take 1,87,914 undergraduate and junior college students from 1,231 colleges and universities in China as a sample to explore the relationships among the five conditions in the entrepreneurship education environment and cognitive level (i.e., the quality of staff, subject curriculum, entrepreneurial competition, intentions, and opportunity identifications) and entrepreneurial activities. The fsQCA results show that none of these factors are sufficient for entrepreneurial activity. In contrast, three combinations of the five conditions (i.e., co-creation type, competition-oriented environment, and entrepreneurship education that fits under the guidance of entrepreneurial intention) can produce high entrepreneurial activity, as well as substitution and complementarity among the various elements within the configuration. These results show that the combined effect of the five conditions is more conducive to the entrepreneurial activities of college students. Finally, after a discussion of the study's findings, theoretical, and practical contributions are analyzed with regard to the field of entrepreneurship in Chinese colleges, and alternative options indicate that college students are more likely to become entrepreneurs in the future.

In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET.

The biology of human granzymes remains enigmatic in part due to our inability to probe their functions outside of in vitro assays or animal models with divergent granzyme species. We hypothesize that the biology of human granzymes could be better elaborated with a translational imaging technology to reveal the contexts in which granzymes are secreted and biochemically active in vivo. Here, we advance toward this goal by engineering a Granzyme targeting Restricted Interaction Peptide specific to family member B (GRIP B) to measure secreted granzyme B (GZMB) biochemistry with positron emission tomography. A proteolytic cleavage of 64Cu-labeled GRIP B liberates a radiolabeled form of Temporin L, which sequesters the radioisotope by binding to adjacent phospholipid bilayers. Thus, at extended time points postinjection (i.e., hours, not seconds), tissue biodistribution of the radioisotope in vivo reflects relative units of the GZMB activity. As a proof of concept, we show in three syngeneic mouse cancer models that 64Cu-GRIP B detects GZMB from T cells activated with immune checkpoint inhibitors (CPI). Remarkably, the radiotracer detects the proteolysis within tumors but also in lymphoid tissue, where immune cells are activated by a systemic CPI. Control experiments with an uncleavable analogue of 64Cu-GRIP B and tumor imaging studies in germline GZMB knockout mice were applied to show that 64Cu-GRIP B is specific for GZMB proteolysis. Furthermore, we explored a potential noncytotoxic function for GZMB by applying 64Cu-GRIP B to a model of pulmonary inflammation. In summary, we demonstrate that granzyme biochemistry can be assessed in vivo using an imaging modality that can be scaled vertically into human subjects.

How Entrepreneurship Education at Universities Influences Entrepreneurial Intention: Mediating Effect Based on Entrepreneurial Competence.

Research shows that entrepreneurial activities significantly promote economic development, which enhances the importance of the innovative entrepreneurial potential of college students. This study analyzes the effect of entrepreneurship education on entrepreneurial intention from the perspective of planned behavior theory. By examining the significant role of entrepreneurship education at colleges and universities on economic and social development, we established a conceptual model. To understand the relationship between entrepreneurship education and entrepreneurial intention, the hypotheses propose the intermediary role of entrepreneurial ability, and the study provides evidence from China the relationship between entrepreneurship education and entrepreneurial intention. Improving entrepreneurial intention and encouraging college students to establish businesses through entrepreneurship education in universities is crucial. This study proposes a hypothetical model of the relationship between entrepreneurial competence and entrepreneurial intention in entrepreneurship education at universities. Using a questionnaire survey of college students with practical experience in the Yangtze River Delta of China, the bootstrap method in the SPSS macro program process software verifies the hypotheses. The results show that entrepreneurial teaching, business plan competition, and entrepreneurial practice support positively affect entrepreneurial competence. In addition, entrepreneurial competence plays an intermediary role in the relationship between entrepreneurial teaching, business plan competition, entrepreneurship practice support, and entrepreneurial intention. Entrepreneurship education improves the ability to establish a business in the present and in entrepreneurial activities in the future. Entrepreneurial competence obtained through entrepreneurship education continuously affects entrepreneurial intention.

The Role of Entrepreneurship Policy in College Students' Entrepreneurial Intention: The Intermediary Role of Entrepreneurial Practice and Entrepreneurial Spirit.

Entrepreneurship is a sustainable development tool that supports the alleviation of poverty and unemployment. Focusing on the promotion of entrepreneurial intention (EI) under the background of entrepreneurship education (EE), this study used a structural equation model to examine the role of entrepreneurship policy (EPo), entrepreneurial practice (EPr), and entrepreneurial spirit (ES) on the EI of 384 college students from 22 universities in Guangdong Province. The test results show that there are significant positive correlations between EPo and EI; EPo and EPr; EPo and ES; and EPr and EI. They also support the hypothesis that EPr enhances the positive effect that EPo has on EI. This study puts forth measures to improve EI and makes contributions to future research on EE.

The Synthesis and Structural Requirements for Measuring Glucocorticoid Receptor Expression In Vivo with (±)-11C-YJH08 PET.

Noninvasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to elaborate the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)-11C-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]-quinoline ((±)-11C-YJH08), a radioligand for PET that engages the ligand binding domain on GR. Methods: (±)-11C-YJH08 was synthesized by reacting the phenol precursor with 11C-methyl iodide. The biodistribution was studied in vivo. Specific binding was tested in vivo with adrenalectomy and ligand competition. A library of analogs was synthesized and studied in vitro and in vivo to understand the (±)-11C-YJH08 structure-activity relationship. Rodent dosimetry studies were performed to estimate the human-equivalent doses of (±)-11C-YJH08. Results: (±)-11C-YJH08 was synthesized by reaction of the phenolic precursor with 11C-methyl iodide, giving a radiochemical yield of 51.7% ± 4.7% (decay-corrected to starting 11C-methyl iodide). Specific binding was observed in many tissues, including the brain. An analysis of the (±)-YJH08 structure-activity relationship showed that (R)- and (S)-enantiomers are equally avid for GR by occupying discrete binding modes. A focused chemical screen revealed that the aryl fluoride motif on YJH08 is essential for high-affinity GR binding in vitro, high tissue uptake in vivo, and efficient passage across the blood-brain barrier. Lastly, we performed dosimetry studies on rodents, from which we estimated the human-equivalent doses of (±)-11C-YJH08 to be commensurate with the widely used 11C and 18F tracers. Conclusion: These studies reveal the molecular determinants of a high-affinity and high-selectivity ligand-receptor interaction and support the use of (±)-11C-YJH08 PET to make the first measurements of GR expression in human subjects.

Ferronostics: Measuring Tumoral Ferrous Iron with PET to Predict Sensitivity to Iron-Targeted Cancer Therapies.

Although cancer has been known for decades to harbor an insatiable appetite for iron, only recently has the chemistry emerged to exploit this altered state therapeutically, by targeting the expanded cytosolic labile iron pool (LIP) of the cancer cell. The state of the art includes therapies that react with the LIP to produce cytotoxic radical species (in some cases also releasing drug payloads) and molecules that exacerbate LIP-induced oxidative stress to trigger ferroptosis. Effectively implementing LIP-targeted therapies in patients will require biomarkers to identify those tumors with the most elevated LIP and thus most likely to succumb to LIP-targeted interventions. Toward this goal, we tested whether tumor uptake of the novel LIP-sensing radiotracer 18F-TRX aligns with tumor sensitivity to LIP-targeted therapies. Methods:18F-TRX uptake was assessed in vivo among 10 subcutaneous and orthotopic human xenograft models. Glioma and renal cell carcinoma were prioritized because these tumors have the highest relative expression levels of STEAP3, the oxidoreductase that reduces ferric iron to the ferrous oxidation state, in the Broad Institute Cancer Cell Line Encyclopedia. The antitumor effects of the LIP-activated prodrug TRX-CBI, which releases the DNA alkylator CBI, were compared in mice bearing U251 or PC3 xenografts, tumors with high and intermediate levels of 18F-TRX uptake, respectively. Results:18F-TRX showed a wide range of tumor accumulation. An antitumor assessment study showed that the growth of U251 xenografts, the model with the highest 18F-TRX uptake, was potently inhibited by TRX-CBI. Moreover, the antitumor effects against U251 were significantly greater than those observed for PC3 tumors, consistent with the relative 18F-TRX-determined LIP levels in tumors before therapy. Lastly, a dosimetry study showed that the estimated effective human doses for adult male and female mice were comparable to those of other 18F-based imaging probes. Conclusion: We report the first evidence-to our knowledge-that tumor sensitivity to an LIP-targeted therapy can be predicted with a molecular imaging tool. More generally, these data bring a new dimension to the nuclear theranostic model by showing a requirement for imaging to quantify, in situ, the concentration of a metastable bioanalyte toward predicting tumor drug sensitivity.

Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET.

PURPOSE: We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models. EXPERIMENTAL DESIGN: [89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR-, CD46+, prostate-specific membrane antigen-negative (PSMA-)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545. RESULTS: [89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection). CONCLUSIONS: [89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.