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This Viewpoint responds to the analysis of 2D IR spectra of vibration cavity polariton in the study reported in The Journal of Physical Chemistry Letters (Duan, et al. 2021, 12, 11406). That report analyzed 2D IR spectra of strongly coupled molecules, such as W(CO)6 and nitroprusside anion, based on subtracting a background signal generated by polariton filtered free space signals. They assigned the resulting response as being due to excited polaritons. We point out in this Viewpoint that virtually all of the response can be properly reproduced using the physics of transmission through an etalon containing a material modeled with a complex dielectric function describing the ground and excited state absorber populations. Furthermore, such a coupled system cannot be described as a scaled sum of the bare molecular and cavity responses.

NASH is associated with high levels of cholesterol and triglyceride (TG) in the liver; however, there is still no approved pharmacological therapy. Synthesis of cholesterol and TG is controlled by sterol regulatory element-binding protein (SREBP), which is found to be abnormally activated in NASH patients. We aim to discover small molecules for treating NASH by inhibiting the SREBP pathway.Here, we identify a potent SREBP inhibitor, 25-hydroxylanosterol (25-HL). 25-HL binds to insulin-induced gene (INSIG) proteins, stimulates the interaction between INSIG and SCAP, and retains them in the endoplasmic reticulum, thereby suppressing SREBP activation and inhibiting lipogenesis. In NASH mouse models, 25-HL lowers levels of cholesterol and TG in serum and the liver, enhances energy expenditure to prevent obesity, and improves insulin sensitivity. 25-HL dramatically ameliorates hepatic steatosis, inflammation, ballooning, and fibrosis through down-regulating the expression of lipogenic genes. Furthermore, 25-HL exhibits both prophylactic and therapeutic efficacies of alleviating NASH and atherosclerosis in amylin liver NASH model diet-treated LdlrThis study provides the proof of concept that inhibiting SREBP activation by targeting INSIG to lower lipids could be a promising strategy for treating NASH. It suggests the translational potential of 25-HL in human NASH and demonstrates the critical role of SREBP-controlled lipogenesis in the progression of NASH by pharmacological inhibition.

Workplace violence against psychiatric professionals is a growing problem, yet nationally representative data in China are lacking. This study examines workplace violence against psychiatrists and psychiatric nurses in China as well as its association with workforce stability and well-being .Data came from a 2019 national survey of 14,264 participants (including 4,520 psychiatrists and 9,744 nurses) from 41 psychiatric hospitals across China. The occurrence of physical and verbal assaults among psychiatrists and psychiatric nurses was reported. Logistic regression models were constructed to examine the participants' characteristics associated with encountering workplace violence and the association of encountering violence with self-reported quality of life, health status, turnover intention, and career satisfaction. Analyses were performed during 2020.In 2019, among 14,264 psychiatrists and psychiatric nurses in China, 81% reported encountering workplace violence during the past year. Psychiatrists were 0.68 (95% CI=0.55, 0.83) times less likely to report an encounter of violence than nurses. Male and younger nurses were 2.20 (95% CI=1.72, 2.81) and 1.21 (95% CI=1.01, 1.45) times more likely to report violence. Psychiatrists who had a higher educational degree or a higher professional rank were more vulnerable to violence. Encountering violence was significantly associated with poor quality of life, less satisfaction with health status, greater intention to leave the current job, and career dissatisfaction.Workplace violence against psychiatrists and psychiatric nurses are common in China, indicating that China's psychiatric professionals are facing a significant threat to occupational safety. To maintain psychiatric workforce stability, actions are needed to reduce the prevalence of workplace violence at the system, institutional, and individual levels.

Qi Tan,* Limin Duan,* Qi Huang,* Wenjuan Chen,* Zimo Yang, Jiangbin Chen, Yang Jin Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang JinDepartment of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People’s Republic of ChinaTel +86-135-5436-1146Fax +86-27-85755457Email whuhjy@126.comBackground: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1β has been widely studied. In this study, we focused on the effect of IL-1β on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms.Methods: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1β in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1β. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1β and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1β.Results: Our results showed that IL1β was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1β. In vivo, IL-1β increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1β.Conclusion: IL-1β promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1β links inflammation to glycolysis in LUAD, and targeting IL-1β and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.Keywords: interleukin 1β, glycolysis, lung adenocarcinoma, p38 signaling

In this study, the “particle in a box” idea, which was broadly developed in semiconductor quantum dot research, was extended into mid-infrared (IR) cavity modes by applying lateral confinement in an optical cavity. The discrete cavity modes hybridized with molecular vibrational modes, resulting in a quartet of polariton states that can support multiple coherence states in the IR regime. We applied tailored pump pulse sequences to selectively prepare these coherences and verified the multi-coherence existence. The simulation based on Lindblad equation showed that because the quartet of polariton states resided in the same cavity, they were specifically robust toward decoherence caused by fluctuations in space. The multiple robust coherences paved the way for entangled states and coherent interactions between cavity polaritons, which would be critical for advancing polariton-based quantum information technology.

Vibrational strong coupling (VSC) between molecular vibrations and microcavity photons yields a few polaritons (light-matter modes) and many dark modes (with negligible photonic character). Although VSC is reported to alter thermally activated chemical reactions, its mechanisms remain opaque. To elucidate this problem, we followed ultrafast dynamics of a simple unimolecular vibrational energy exchange in iron pentacarbonyl [Fe(CO)5] under VSC, which showed two competing channels: pseudorotation and intramolecular vibrational-energy redistribution (IVR). We found that under polariton excitation, energy exchange was overall accelerated, with IVR becoming faster and pseudorotation being slowed down. However, dark-mode excitation revealed unchanged dynamics compared with those outside of the cavity, with pseudorotation dominating. Thus, despite controversies around thermally activated VSC modified chemistry, our work shows that VSC can indeed alter chemistry through a nonequilibrium preparation of polaritons.

Extracellular vesicles (EVs) can contain DNA, RNA, proteins and metabolic molecules from primary origins; they are coated with a phospholipid bilayer membrane and released by cells into the extracellular matrix. EVs can be obtained from various body liquids, including the blood, saliva, cerebrospinal fluid, and urine. As has been proved, EVs-mediated transfer of biologically active molecules is crucial for various physiological and pathological processes. Extensive investigations have already begun to explore the diagnosis and prognosis potentials for EVs. Furthermore, research has continued to recognize the critical role of nucleic acids and proteins in EVs. However, our understanding of the comprehensive effects of metabolites in these nanoparticles is currently limited and in its infancy. Therefore, we have attempted to summarize the recent research into the metabolomics of EVs in relation to potential clinical applications and discuss the problems and challenges that have occurred, to provide more guidance for the future development in this field.

Molecular vibrational polaritons, hybrid quasi-particles formed by molecular vibrations and cavity photons through strong light–matter coupling, have attracted much attention due to their potential...

KRAS is the most frequently mutated oncogene in cancer and is particularly common in lung, pancreatic and colorectal cancers. While KRAS has been undruggable, covalent KRAS G12C inhibitors, sotorasib and adagrasib, that bind preferentially to GDP-bound KRAS and prevent exchange for GTP and interaction with downstream effectors, have been approved for use in NSCLC. While these reagents show promising efficacy and are well-tolerated by patients, acquired drug resistance rapidly develops. The drug resistance landscape of G12C inhibitors is complex, with several mechanisms of resistance already described, ranging from reactivation of mutated RAS or other RAS isoforms, acquisition of new KRAS mutations, and genetic alterations of pro-growth signaling pathways. Thus, an ideal approach to overcoming drug resistance will need to target multiple different mechanisms. We exposed NSCLC and pancreatic cell lines (NCI-H358, NCI-H1373 and MIA PaCa-2, respectively) to increasing doses of sotorasib or adagrasib until the resulting cells grow normally in the presence of 10 µM of each inhibitor. Sotorasib-resistant cells, designated as S-R, remarkably remain sensitive to adagrasib, suggesting that the resistant cells continue to be dependent on mutant KRAS for survival. In contrast, adagrasib-resistant cells, designated as A-R, are resistant to both inhibitors. Treatment of innate and acquired adagrasib-resistant cells with 500 nM adagrasib attenuated RAS activity; however, this is compensated for by increased KRAS, HRAS and NRAS mRNA and restored p-ERK levels, a surrogate marker of RAS activity. Moreover, analysis of RTK activation in drug-resistant cells reveals that adagrasib treatment induces the activity of specific RTKs in a cell-line specific manner. Interestingly, during the acquisition of adagrasib resistance, several RTKs are strongly induced to escape drug inhibition. These results indicate the need to simultaneously reduce both KRAS G12C and compensating RTK activity to effectively treat KRAS G12C NSCLC. The majority of oncogenic RTKs are known to be dependent on the molecular chaperone HSP90 for their proper folding and stability. Therefore, a heterobifunctional chaperone-mediated protein degrader (CHAMP), RNK07421, was designed to specifically target both KRAS G12C and HSP90. RNK07421 induces an artificial ternary complex with KRAS G12C and HSP90, while also inhibiting the activity of both proteins and promoting proteasomal degradation of KRAS G12C via HSP90-associated E3-ligases. Treatment of adagrasib-resistant NSCLC cells and PDOs with RNK07421 resulted in decreased levels of KRAS G12C, p-ERK and RTKs. Furthermore, in vivo treatment with RNK07421 demonstrated dramatic tumor growth inhibition as compared to adagrasib treatment alone. Together, these observations indicate that the novel mechanisms of action of RNK07421 may provide several advantages over G12C inhibitors and possibly other targeted protein degradation agents to effectively treat KRAS G12C-dependent NSCLC. Citation Format: Ines Pulido Endrino, Qiyue Luan, Jennifer Graeber, Brianna Borger, Chenghao Ying, Jinhua Li, Zimo Yang, Zhiyong Wang, Yaya Wang, Yuetong Sun, Yan Dai, Ian Papautsky, Thomas L. Prince, Guoqiang Wang, Kevin P. Foley, Weiwen Ying, Takeshi Shimamura. Overcoming KRAS G12C inhibitor resistance with a chaperone-mediated protein degrader (CHAMP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB231.

Covalent KRAS(G12C) inhibitors have recently shown promising efficacy in the clinic. However, the rapid development of drug resistance compromises their long-term benefits, indicating the need for additional approaches to treat KRAS-mutated cancers. Targeted protein degradation represents one such potential approach. We have therefore explored applying Chaperone-mediated Protein Degradation (CHAMP) technology to degrade KRAS(G12C) protein. CHAMPs are heterobifunctional small molecules that mediate protein degradation by inducing proximity between a target protein and the HSP90 chaperone complex, resulting in target ubiquitination and degradation by the proteasome. Due HSP90 being highly activated in cancer cells, CHAMPs also preferentially accumulate in tumors relative to normal tissues, resulting in an improved therapeutic index relative to typical inhibitors. In order to chemically induce KRAS(G12C) degradation, CHAMP compounds were synthesized by covalently coupling KRAS(G12C)- and HSP90-binding moieties through a short linker. CHAMP treatment of KRAS(G12C)-mutated cell lines resulted in formation of a KRAS(G12C)-CHAMP-HSP90 ternary complex and subsequent proteasome-dependent KRAS(G12C) degradation and inhibition of cell proliferation. In contrast, combination treatment with KRAS(G12C) and HSP90 inhibitors did not result in substantial KRAS(G12C) degradation. Importantly, CHAMPs retained potency in cell line models of resistance to covalent KRAS(G12C) inhibitors. Further, in mouse xenograft models, CHAMPs displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues and strongly inhibited tumor growth at tolerated doses. Based on these findings, KRAS(G12C)-degrading CHAMPs represents a promising approach to the treatment of KRAS(G12C)-mutated cancers. Citation Format: Kevin P. Foley, Chenghao Ying, Yaya Wang, Yan Dai, Zhiyong Wang, Jinhua Li, Zimo Yang, Yuetong Sun, Hao Xin Zhou, Thomas L. Prince, Guoqiang Wang, Weiwen Ying. Chemically induced chaperone-mediated protein degradation (CHAMP) of KRAS(G12C) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1649.

Flatfoot is common among children. Symptomatic flexible flatfoot is one of the various types which needs treatment. Wearing insoles is considered one of the conservative therapies, but its effects are still uncertain. This study aims to provide evidence for the efficacy of insoles treatment among school-aged children with symptomatic flexible flatfoot.Patient who were Children who were diagnosed with symptomatic flexible flatfoot and received insoles treatment in authors' institute were retrospectively included. Their ages, body mass index, pain positions, pain frequency, valgus angle, arch index and visual analogue scale (VAS) score were collected before and after insole treatment.A total of 32 children were included in this study. The results showed that wearing insoles for 2 years caused a significant improvement in pain frequency, valgus angle, arch index and VAS score.This study indicated that pediatric symptomatic flexible flatfoot could be relieved by wearing insoles for 2 years. Insole treatment might be a workable option for pediatric symptomatic flexible flatfoot in children older than 6 years old.

Background Interleukin(IL)-1β is a promising target for many diseases such as atherosclerosis, rheumatoid arthritis and cancer because it has been found to involve in the development of diseases. Anakinra, Canakinumab and Rilonacept were three Food and Drug Administration (FDA)-approved drugs and used for inhibiting IL-1β. Our study aims to access the trends and development for IL-1β inhibitors using bibliometric analysis. Methods All publication records were obtained from databases Web of Science and Pubmed. Publishing characteristics including organization, author, journals and co-authorship, Keywords, co-occurrence network, related journals network were analyzed by VOSviewer 1.6.16 (by Leiden University) and Bibliometric package in R(4.0.5). Graph prism 8 was used to performed descriptive analysis of all data. Results 274 publications were enrolled in our study. Of the three drugs, anakinra has been extensively studied, with 130 publications related to it between 1997 and 2021. Clinical studies on IL-1β antagonists mainly focused on rheumatoid arthritis. Non-inflammatory diseases such as cardiovascular disease and cancer were also found in the related clinical research. The United States published the most articles in clinical research on IL-1β inhibitor and it was the country that participated in the most collaborations. Conclusion Targeting IL-1β was still a hot spot for clinical research in inflammatory diseases. As progresses are made in the field, Canakinumab and Rilonocept as two novel inhibitors, will increase in a similar trend to that of Anakinra. The number of studies about the inhibitors targeting IL-1β in inflammatory diseases will emerge more in the future. Cancer therapy might be the trend in the clinical studies of antagonizing IL-1β.

Atypical vibrational interactions Vibrational energy transfer (VET) between solute molecules is generally unfavorable in liquids because of weak intermolecular forces. Xiang et al. measured the two-dimensional infrared spectrum of a molecular mixture, W(CO) 6 and W( 13 CO) 6 , with saturated concentrations in a binary solvent embedded in an optical microcavity. This experiment showed that the VET between the asymmetric stretch vibrations of two solute molecules is enhanced via polaritonic intermediate states formed by a strong coupling with the cavity mode. The efficiency is modulated by the cavity lifetime, which provides an opportunity to control the VET process in the liquid phase. This could lead to various practical implementations. Science , this issue p. 665

Photoredox-catalyzed aminoarylation and thioamination of unactivated alkenes have been developed, providing novel synthetic routes to access synthetically challenging quaternary carbon-centered ben...

Against the background of economic globalization, the strategies for constructing college students' entrepreneurial value judgment are explored, providing college graduates with more employment options and thereby keeping up with the trend of the times. The documentary analysis and questionnaire survey methods are adopted to investigate contemporary college students' entrepreneurial value judgments, and the investigation results are organized. According to documentary materials, the discovered problems are analyzed to put forward strategies for constructing college students' entrepreneurial value judgments based on educational psychology. Results show that only 14.1% of college graduates choose to start a business; 48.7% do not understand or recognize the entrepreneurial values; 14.8% believe teaching activities on constructing entrepreneurial value judgments are insufficient, and the entrepreneurial atmosphere is lacking. Regarding the above investigation results, strategies for constructing college students' entrepreneurial value judgments are proposed, involving the construction environment, construction system, construction method, and construction mechanism. Hence, considering contemporary college students' entrepreneurial values, the proposed strategies for constructing college students' entrepreneurial judgments are suitable and valuable, providing a practical reference for enriching and perfecting the college innovation and entrepreneurship education systems.

Strong coupling enables delocalized intercavity nonlinearity by combining the photon delocalization and molecular anharmonicity., Realizing nonlinear interactions between spatially separated particles can advance molecular science and technology, including remote catalysis of chemical reactions, ultrafast processing of information in infrared (IR) photonic circuitry, and advanced platforms for quantum simulations with increased complexity. Here, we achieved nonlinear interactions at ultrafast time scale between polaritons contained in spatially adjacent cavities in the mid-IR regime, altering polaritons in one cavity by pumping polaritons in an adjacent one. This was done by strong coupling molecular vibrational modes with photon modes, a process that combines characteristics of both photon delocalization and molecular nonlinearity. The dual photon/molecule character of polaritons enables delocalized nonlinearity—a property that neither molecular nor cavity mode would have alone.

Objectives This was the first study to systematically landscape and examine China’s nationwide standardized residency training in radiology. Methods In this retrospective cross-sectional study, we used data from the 2019 national survey of the first two cohorts of 3679 radiology residents who completed training in 2017 and 2018 across all 31 provinces in China. A total of 1163 (32%) residents participated in the survey. Multivariable logistic regression was used to examine the implementation frequency of 24 identified training tasks (categorized into six competencies) by region, demographics, and other residency information. Results Among the 1163 respondents, 592 (51%) were trained in the more developed eastern region. Of the 24 identified training tasks, 15 were implemented significantly differently across regions, while the frequency of the most frequently conducted tasks (e.g., CT, MR, and radiograph interpretation and reporting) was consistent. The top 10 tasks all fell into the patient care and medical knowledge competency domains, while other competencies tended to be neglected. We found region and marital status were the most influential factors of training task implementation frequencies. Respondents trained in the northeast and the west were more likely to report, for instance, radiological examination recommendation (OR = 1.91, 95%CI = 1.27–2.88), as “very frequent.” Married respondents were more likely to report first-line night shift as “very frequent” (OR = 1.71, 95%CI = 1.29–2.26). Conclusions Despite the fast-win achievements of developing a national radiology residency training program, there is a gap to train quality and homogeneous radiologists across regions. Future improvement should be more tailored to residents’ personal characteristics and emphasize some “soft” competencies (e.g., communication skills).