Spatial Effects of Air Pollution on the Siting of Enterprises: Evidence from China.

The siting of enterprises is important for enterprises to formulate business objectives and business strategies, both of which are crucial to the development of enterprises in the future. Although there exists an irrefutable fact that the increasingly serious environmental problems are affecting the behaviors of enterprises, how air pollution affects the siting of enterprises has received little academic attention. Therefore, using the dataset of Chinese prefecture-level cities from 2014 to 2020, this paper employs the Spatial Durbin Model to investigate the direct and spatial spillover effects of air pollution on the site selection of enterprises. In addition, this paper also establishes a mediation effect model to explore the impact mechanism of air pollution on the site selection of enterprises. The empirical results show that air pollution exerts a negative impact on both the local and spatially related regions' enterprises' site selection, and the above conclusion is reinforced through a series of robustness checks. The heterogeneity analysis demonstrates that air pollution has a greater inhibitory effect on the siting of low-cleaning enterprises and small-scale enterprises for the local and adjacent regions. The mechanism analysis results indicate that air pollution inhibits the siting of enterprises by reducing the local labor endowment and market scale. Our study enriches the relevant theory of air pollution and enterprises' location nexus, and it also provides an empirical basis for the Chinese government to formulate policies related to air governance and the siting of enterprises.

Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to Immunotherapy.

PURPOSE: Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many "cold" tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy. EXPERIMENTAL DESIGN: Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti-programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo. RESULTS: We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function. CONCLUSIONS: Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti-PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.

A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression.

As a pivotal vesicular trafficking protein, Myoferlin (MYOF) has become an attractive target for cancer therapy. However, the roles of MYOF in colorectal cancer invasion remain enigmatic, and MYOF-targeted therapy in this malignancy has not been explored. In the present study, we provided the first functional evidence that MYOF promoted the cell invasion of colorectal cancer. Furthermore, we identified a novel small molecule inhibitor of MYOF (named YQ456) that showed high binding affinity to MYOF (KD  = 37 nM) and excellent anti-invasion capability (IC50  = 110 nM). YQ456 was reported for the first time to interfere with the interactions between MYOF and Ras-associated binding (Rab) proteins at low nanomolar levels. This interference disrupted several vesicle trafficking processes, including lysosomal degradation, exosome secretion, and mitochondrial dynamics. Further, YQ456 exhibited excellent inhibitory effects on the growth and invasiveness of colorectal cancer. As the first attempt, the anticancer efficacy of YQ456 in the patient-derived xenograft (PDX) mouse model indicated that targeting MYOF may serve as a novel and practical therapeutic approach for colorectal cancer.

Selective sensing of PPi by fluorogenic Al(III)-probe complex in aqueous medium.

A newly designed Schiff base probe JN has been synthesized. It is highly selective and sensitive towards Al3+ in nearly 100% aqueous medium by exhibiting a dramatic "turn-on" fluorescence response at 495 nm (λex = 450 nm). The sensing mechanism of JN towards Al3+ ions was proposed as the combination of PET, ICT, ESIPT, and CHEF processes according to spectra studies and theory calculations. The in situ generated mononuclear Al(III) complex JN-Al3+ could sequentially detect PPi ions by turn-off fluorescence response. The selectivity and sensitivity of the JN-Al3+ complex towards PPi ions are based on demetalization process. Interestingly, the fact that Al3+ can bind with 1, 2, or 3 PPi has been revealed by HRMS study. The probes JN and JN-Al3+ complexes were able to capture Al3+ and PPi ions, respectively, as demonstrated by fluorescence imaging of the adult zebrafish and onion inner epidermal cells samples.

Mechanism of Naringenin Blocking the Protection of LTB4/BLT1 Receptor Against Septic Cardiac Dysfunction.

OBJECTIVE: To investigate the possible role of Naringenin in AMPK signaling pathway in LPS-induced septic cardiac dysfunction in mice and to elucidate the inherent mechanism. METHODS: Male C57 mice were used in the establishment of mouse sepsis model. The effect of Naringenin on septic cardiac dysfunction was observed. Echocardiographic parameters were recorded. Western blot was employed to detect the expressions of BCL-2, BAX, cleaved caspase-3, pNF-kB and IkB-α. Myocardial mitochondria were isolated and extracted. Real-time PCR was applied to detect the expressions of Cox4i, Cox5a mRNA, mt-Nd1, mt-Nd2, mt-Co1 and mt-Co2 mRNA. Western blot was employed to detect the expressions of Complex I, Complex II, and OPA1 to evaluate the effects of Naringenin on myocardial mitochondrial biology and function in septic cardiac dysfunction. RESULTS: The expressions of TNF-α, IL-6, pNF-κB and IκB-α have changed after Naringenin treatment. IκB-α expression was decreased, expressions of TNF-α, IL-6 and pNF-κB were increased. Naringenin has significantly inhibited AMPK and ACC phosphorylation, and decreased PGC1α expression. Moreover, Naringenin reversed the increased expressions of PGC1α and phosphorylation of AMPK and ACC by U75302 treatment, and decreased the expressions of complex I, complex II and OPA1. CONCLUSION: Naringenin inhibits LTB4/BLT1 receptors to attenuate cardiomyocyte inflammation and apoptosis, which may mediate the protective effect of anti-septic cardiac dysfunction by activating AMPK signaling pathway and inhibiting NF-κB signaling and mitochondrial damage.

Regression of castration-resistant prostate cancer by a novel compound QW07 targeting androgen receptor N-terminal domain.

Androgen deprivation therapy (ADT) via surgical or chemical castration frequently fails to halt lethal castration-resistant prostate cancer (CRPC), which is induced by multiple mechanisms involving constitutive androgen receptor (AR) splice variants, AR mutation, and/or de novo androgen synthesis. The AR N-terminal domain (NTD) possesses most transcriptional activity and is proposed as a potential target for CRPC drug development. We constructed a screening system targeting AR-NTD transcription activity to screening a compound library and identified a novel small molecule compound named QW07. The function evaluation and mechanism investigation of QW07 were carried out in vitro and in vivo. QW07 bound to AR-NTD directly, blocked the transactivation of AR-NTD, blocked interactions between co-regulatory proteins and androgen response elements (AREs), inhibited the expression of genes downstream of AR, and inhibited prostate cancer growth in vitro and in vivo. QW07 was demonstrated as an AR-NTD-specific antagonist with the potential to inhibit both canonical and variant-mediated AR signaling to regress the CRPC xenografts and is proposed as a lead compound for a specific antagonist targeting AR-NTD.

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin.

Background: Viral myocarditis (VMC) is a common inflammatory cardiovascular disease with unclear mechanisms, which mainly affects children and adolescents. Apoptosis is the key to CVB3-induced myocarditis, and blocking this process may be beneficial to the therapy of VMC. Hence, this study aimed to explore the protective function of STAT3 on cardiomyocyte apoptosis of VMC and its underlying mechanisms. Methods and Results: In this research, we confirmed that STAT3 was significantly activated in both animal and cell models of VMC. To further clarify what role did STAT3 play in VMC, AG490, an inhibitor of STAT3, was used to suppress p-STAT3. Our results demonstrated that decreased expression of p-STAT3 caused by AG490 significantly aggravated severity of VMC with elevated myocardial inflammation, deteriorative ventricular systolic function and increased mortality. It suggested that STAT3 plays a protective role in VMC. To further identify the anti-apoptosis impact that activated STAT3 made, we constructed lentivirus to regulate the expression of STAT3 in NMCs. We found that up-regulated activated STAT3 attenuated cardiomyocyte apoptosis, but down-regulated one aggravated that, which verified activated STAT3 played an anti-apoptosis role in VMC. Following that, we explored what elements are involved in the anti-apoptotic mechanism of activated STAT3 by using survivin inhibitor YM155. The result showed the anti-apoptotic effect of activated STAT3 does not work in the case of survivin inhibition. Conclusion: Our findings demonstrated STAT3 by targeting survivin alleviated cardiomyocyte apoptosis in CVB3-induced myocarditis.

Older Chinese Americans' Perspectives on Physical Activity: A Mixed Methods Study.

The benefits of physical activity for successful aging are well established. Few interventions however, target older Asian Americans who may have distinct needs for cultural and linguistic tailoring. The heterogeneity among Asian Americans underscores the need to elucidate specific physical activity preferences by ethnic subgroup. To better understand older Chinese Americans' perceptions about physical activity, we conducted a community-engaged, mixed methods study with 60 participants. Through survey and focus groups, four emerging themes characterized perceptions of physical activity: (a) physical activities benefit the body and mind, (b) traditional Chinese culture influences perceptions and preferences for physical activity, (c) physical activity presents opportunities for social engagement, and (d) physical activity facilitates family harmony. Design recommendations includes encouraging mind-body approaches, incorporating culturally specific practices, highlighting opportunities for social engagement, and emphasizing the potential for improved harmony.

An aligned porous electrospun fibrous scaffold with embedded asiatic acid for accelerating diabetic wound healing.

The diabetic non-healing wound is one of the most common complications of diabetics. The long-term stimulus of oxidative stress, inflammation and infection caused by the hyperglycemic microenvironment in the wound site always leads to a delayed healing process of the diabetic wound. To address this issue, in this study, we prepared an asiatic acid (AA)-embedded aligned porous poly(l-lactic acid) (PLLA) electrospun fibrous scaffold (AA-PL) for accelerating diabetic wound healing. The results showed that the electrospun fibers with nanopores on the surfaces were aligned in a single direction, while the AA was well embedded in the fibers and can be continuously released from them. The in vitro results revealed that the AA-PL scaffolds can effectively alleviate the H2O2-induced oxidative stress damage to HaCat cells and downregulate the LPS-induced pro-inflammatory cytokine (IL-1ß, TNF-α, IL6) gene expression in RAW 264.7 macrophage cells. Moreover, the growth of E. coli and S. aureus could be inhibited by the AA-PL scaffolds. The in vivo study further demonstrated that the AA-PL scaffolds can accelerate the re-epithelization, angiogenesis and extracellular matrix formation of a wound by relieving the high oxidative stress, inflammation and infection in the diabetic wound site. This study suggests that the combination of hierarchical structures (nanopores on the aligned fibers) with the controllable release of AA from the scaffolds is an efficient and innovative strategy for the treatment of diabetic non-healing wounds.

Peripheral blood CD4 T-cell and plasmacytoid dendritic cell (pDC) reactivity to herpes simplex virus 2 and pDC number do not correlate with the clinical or virologic severity of recurrent genital herpes.

Leukocytes participate in the immune control of herpes simplex virus (HSV). Data from HIV coinfections, germ line mutations, and case reports suggest involvement of CD4 T cells and plasmacytoid dendritic cells (pDC). We investigated the relationships between these cells and recurrent genital herpes disease severity in the general population. Circulating CD4 T-cell responses to HSV-2 were measured in specimens from 67 immunocompetent individuals with measured genital lesion and HSV shedding rates. Similarly, pDC number and functional responses to HSV-2 were analyzed in 40 persons. CD4 responses and pDC concentrations and responses ranged as much as 100-fold between persons while displaying moderate within-person consistency over time. No correlations were observed between these immune response parameters and genital HSV-2 severity. Cytomegalovirus (CMV) coinfection was not correlated with differences in HSV-2-specific CD4 T-cell responses. The CD4 T-cell response to HSV-2 was much more polyfunctional than was the response to CMV. These data suggest that other immune cell subsets with alternate phenotypes or anatomical locations may be responsible for genital herpes control in chronically infected individuals.