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China has the world’s largest reserves of rare earth elements. Rare earth permanent magnet material has always been one of the popular industries in the investment market. CAPM is the basic asset-pricing model in financial economics. There are a number of studies conducted to examine the applicability of CAPM to stock markets in different industries and to investigate the modification method to improve the model’s prediction accuracy. In this study, seven leading enterprises in China’s rare earth permanent magnet material industry listed on the A-share market were selected as the research subjects. Based on CAPM, regression analysis was conducted on the monthly data from March 2016 to February 2022. The results demonstrated that using the ? coefficient to explain the risk of China’s rare earth permanent magnet industry is ineffective. The ultimate benefit was less affected by market indexes but mainly by non-systematic risks. CAPM has low applicability to China’s rare earth permanent magnet material industry and requires further improvement. Nevertheless, CAPM still has some guiding significance in making enterprise comparisons and investment decisions.

Background: Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Pathogenic T cells, such as Th1 and Th17, infiltrate the CNS, resulting in neuroinflammation, demyelination and axonal damage. Th1 activates microglia (MG) in the CNS and Th17 acts as a chemokine to recruit immune cells into the CNS. MG is a resident immune cell in the CNS and its activation is associated with destruction of myelin and secretion of inflammatory cytokines such as IL-12, IL-23 and IL-1β. IL-12 and IL-23 are important for Th1 and Th17 differentiation and reactivation, respectively. IL-1β is a key mediator of the inflammatory response. Benzoylacetonitrile (BTN) has been shown to reduce disease severity in mouse model of MS and reduce Th1 and Th17 differentiation in vitro. However, the effects of BTN on MG are unknown, and this study was aimed to investigate the effects of BTN on MG activation in vitro. We hypothesize that BTN can suppress MG activation and decrease the production of inflammatory cytokines. Methods: Primary MG were pretreated with BTN at concentration of 200μM or 300μM for 2 hours or with DMSO (vehicle), followed by lipopolysaccharide (LPS) 100ng/ml stimulation for 1.5 or 3 hours. RNA was isolated from MG and mRNA expression levels of IL-12, IL-23, IL-1β were measured using Q-PCR. Results: Our results showed that BTN suppressed MG activation and reduced inflammatory cytokine production. The mRNA expression levels of IL-12, IL-23, and IL-1β in LPS and BTN-treated MG were significantly lower than LPS-treated MG.Conclusion: This study demonstrated that BTN was able to suppress MG expression of inflammatory cytokines in vitro, suggesting that BTN exhibits immunomodulatory effects on MG activation in vitro. BTN has a potential to attenuate neuroinflammation in MS through the reduction of inflammatory cytokines. Conclusion: This study demonstrated that BTN was able to suppress MG expression of inflammatory cytokines in vitro, suggesting that BTN exhibits immunomodulatory effects on MG activation in vitro. BTN has a potential to attenuate neuroinflammation in MS through the reduction of inflammatory cytokines.

In recent years, wildfires have ravaged the landscape in many Western American states, especially California. But will these horrific wildfire experiences increase public support for wildfire adaptation measures? We conducted an individual-level survey in California in 2019. Combining survey data with geocoded information about a respondent’s proximity to wildfire events and exposure to wildfire smoke, we assess whether respondents’ experiences increased support for several wildfire adaptation policies. We also control for party affiliation. We find that Californians generally oppose restrictive resilience policies and view the decision to take adaptive steps as a matter of personal choice. Republicans are generally more opposed than Democrats to spending public funds to incentivize resilience measures, but proximity to wildfires lessens their opposition to using public funds to encourage homeowners to upgrade their properties for increased protection from wildfires and encourage relocation to safer places. Although exposure to wildfire smoke is extensive and harmful to health, we found that its main impact on policy preferences was statistically insignificant.

Hydrogen peroxide (H2O2) plays essential roles in redox signaling and oxidative stress, and its dynamic concentration is critical to human health and diseases. Here we report the design, syntheses, and biological applications of HKPerox-Red and HKPerox-Ratio for quantitative measurement of H2O2. Both probes were successfully applied to detect endogenous H2O2 fluxes in living cells or zebrafish, and biological effects of multiple stress inducers including rotenone, arsenic trioxide, and starvation were investigated. As H2O2 is a common by-product for oxidase oxidation, a general assay was developed for ultrasensitive detection of various metabolites (glucose, uric acid, and sarcosine). Moreover, cellular H2O2 measurements were achieved for the first time by combining flow cytometry with live cell calibration. This study provides a pair of unique molecular tools for advanced H2O2 bio-imaging and assay development.

Hydrogen peroxide (H2O2) plays essential roles in redox signaling and oxidative stress, and its dynamic concentration is critical to human health and diseases. Here we report the design, syntheses, and biological applications of HKPerox-Red and HKPerox-Ratio for quantitative measurement of H2O2. Both probes were successfully applied to detect endogenous H2O2 fluxes in living cells or zebrafish, and biological effects of multiple stress inducers including rotenone, arsenic trioxide, and starvation were investigated. As H2O2 is a common by-product for oxidase oxidation, a general assay was developed for ultrasensitive detection of various metabolites (glucose, uric acid, and sarcosine). Moreover, cellular H2O2 measurements were achieved for the first time by combining flow cytometry with live cell calibration. This study provides a pair of unique molecular tools for advanced H2O2 bio-imaging and assay development., New class of H2O2 probes, HKPerox-Red and HKPerox-Ratio, were developed for quantitative measurement of H2O2 generated in multiple disease models using bio-imaging, flow cytometry, and in vitro assays in an ultra-sensitive and selective manner.

The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction. In the current study, we sought to assess the mechanism(s) through which the PXR regulates barrier function during inflammation. In Caco-2 intestinal epithelial cell monolayers, tumor necrosis factor-α/interferon-γ exposure disrupted the barrier and triggered zonula occludens-1 relocalization, increased expression of myosin light-chain kinase (MLCK), and activation of c-Jun N-terminal kinase 1/2 (JNK1/2). Activation of the PXR [rifaximin and [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester (SR12813); 10 μM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16α-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr-/-, mice. Furthermore, PCN treatment protected the barrier in the dextran-sulfate sodium model of experimental colitis, an effect that was associated with reduced expression of mucosal MLCK and phosphorylated JNK1/2. Together, our data suggest that the PXR regulates the intestinal epithelial barrier during inflammation by modulating cytokine-induced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammation-associated barrier disruption in the context of IBD.

Introduction For patients (pts) with relapsed or refractory follicular lymphoma (r/r FL) beyond front-line therapy, there is no well-defined standard of care (SOC) treatment, especially in the third-line or later (3L+) setting. Treatment decisions for symptomatic patients depend on comorbidities, extent of disease, lines of prior therapy and duration of response to initial anti-CD20 containing treatment. Treatment options for 3L+ may include similar options to the ones in earlier lines, with a preference for non-cross-resistant schemes. Recently, a plethora of new compounds are being studied in clinical trials. A systematic literature review (SLR) was conducted to identify relevant evidence on clinical outcomes in pts with r/r FL, including conventional treatments and emerging compounds, within the 3L+ setting. Methods We performed a SLR on March 17, 2020. Clinical trials and observational studies were searched through Embase, PubMed, and Cochrane Central Register of Controlled Clinical Trials from 1998 to 2020, followed by relevant conference proceedings and regulatory documents. Evidence assessing any intervention as 3L+ FL and published in English language was included. If a study included broader indolent non-Hodgkin's lymphoma (iNHL) pts, only FL data was reported; if a study included pts with fewer than 3L+, 3L+ data was included, with mixed line results excluded. Conventional treatments, defined as approved or clinical guideline recommended treatments, included anti-CD20 monoclonal antibody (mAb)-containing regimen, mAb alone, chemotherapy alone, phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib), lenalidomide + rituximab (R2), radio-immunotherapy (RIT) with yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, autologous and allogeneic stem cell transplantation (auto- and allo-SCT). Emerging compounds included new treatments that are not approved but were tested in the context of clinical trials (bruton tyrosine kinase inhibitors, bortezomib, polatuzumab vedotin, daratumumab, inotuzumab, bi-specific T-cell engaging CD19 mAb, anti-CD19 chimeric antigen receptor T-cell [CAR-T] therapy). Results Of the 3747 publications identified, 74 studies assessing 26 treatment regimens, including conventional ones like rituximab (R)-containing immunochemotherapy to emerging compounds such as CAR-T therapies, were selected. Across the conventional regimens, 7 studies reported clinical trial data with relatively large 3L+ FL populations (Table 1). With R monotherapy, PI3K inhibitors and tazemetostat, the reported complete response (CR) rates and overall response rates (ORR) ranged from 1-20% and 34-77%, while median duration of response (mDOR) ranged between 7.9-16.3 months. Three clinical trials with PI3K inhibitors reported proportions of pts achieving a response of at least 6 months in duration ranging from 18-30%; median progression-free survival (mPFS) ranging from 8.3-11.2 months. For tazemetostat, mPFS was 11.0 months in EZH2 mutant vs 5.7 months in wild-type FL. With allo-SCT, 2-yr PFS rate was 88% and 57% for pts with CR and PR, respectively. Overall survival (OS) data varied: median overall survival (mOS) was 28-38 months for PI3K inhibitors while mOS was up to 85 months after allo-SCT, despite high non-relapse mortality (NRM) rates with most common causes of death being graft-versus-host disease (GvHD) and infections. Safety profiles were also different across treatments, with most common side effects being hepatotoxicity, diarrhea and infections (PI3K inhibitors) to GvHD (allo-SCT). Three trials presented patient-reported outcomes (PRO) data, all using the Functional Assessment of Cancer Therapy (FACT) questionnaire. Two studies with PI3K inhibitors demonstrated favorable or clinically significant improvement on pts quality of life (QoL), but 1 allo-SCT trial did not show a significant difference between baseline and 2 years post-transplant scores. Conclusion To our knowledge, this is the first SLR focusing on 3L+ treatments of FL. Heterogeneity in study design, patient population, safety profile and reported outcomes make it challenging to identify an optimal treatment regimen for FL in the 3L+ setting. More PRO data are needed considering the important role pt QoL plays in treatment selection. Disclosures Ma: Novartis:Current Employment.Kaur:Novartis:Current Employment.Zhao:Novartis:Current Employment.Zhang:Novartis:Current Employment.Ramos:Novartis:Current Employment.Kumar:Novartis:Current Employment.John:Novartis:Current Employment.Bubuteishvili Pacaud:Novartis:Current Employment.Forcina:Novartis:Current Employment.

SUMMARYMutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10–15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b- and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

Mutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b- and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.