Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor.

Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFRT790M mutation. We designed and synthesized 63 Mobocertinib derivatives by structural modification using the structural similarity strategy and the bioelectronic isoarrangement principle. Then, we evaluated the in vitro antitumor activity of the 63 Mobocertinib derivatives and found that the IC50 of compound H-13 against EGFRL858R/T790M mutated H1975 cells was 3.91 µM, and in further kinase activity evaluation, the IC50 of H-13 against EGFRL858R/T790M kinase was 395.2 nM. In addition, the preferred compound H-13 was able to promote apoptosis of H1975 tumor cells and block the proliferation of H1975 cells in the G0/G1 phase; meanwhile, it was able to significantly inhibit the migratory ability of H1975 tumor cells and inhibit the growth of H1975 cells in a time-concentration-dependent manner. In the in vivo anti-tumor activity study, the preferred compound H-13 had no obvious toxicity to normal mice, and the tumor inhibition effect on H1975 cell-loaded nude mice was close to that of Mobocertinib. Finally, molecular dynamics simulations showed that the binding energy between compound H-13 and 3IKA protein was calculated to be -162.417 ± 14.559 kJ/mol. In summary, the preferred compound H-13 can be a potential third-generation EGFR inhibitor.

Pyrrole-containing hybrids as potential anticancer agents: An insight into current developments and structure-activity relationships.

Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.

Novel markers of MCL1 inhibitor sensitivity in triple negative breast cancer cells.

Triple negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC includes surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.

Integrated micro/nano drug delivery system based on magnetically responsive phase-change droplets for ultrasound theranostics.

Phase-change droplets (PCDs) are intelligent responsive micro and nanomaterials developed based on micro/nano bubbles. Subject to external energy inputs such as temperature and ultrasound, the core substance, perfluorocarbon (PFC), undergoes a phase transition from liquid to gas. This transformation precipitates alterations in the PCDs' structure, size, ultrasound imaging capabilities, drug delivery efficiency, and other pertinent characteristics. This gives them the ability to exhibit "intelligent responses". This study utilized lipids as the membrane shell material and perfluorohexane (PFH) as the core to prepare lipid phase-change droplets. Superparamagnetic nanoparticles (PEG-functionalized Fe3O4 nanoparticles) and the anti-tumor drug curcumin (Cur) were loaded into the membrane shell, forming magnetic drug-loaded phase-change droplets (Fe-Cur-NDs). These nanoscale phase-change droplets exhibited excellent magnetic resonance/ultrasound imaging capabilities and thermal/ultrasound-mediated drug release. The Fe-Cur-NDs showed excellent anti-tumor efficacy for the MCF-7 cells under low-intensity focused ultrasound (LIFU) guidance in vitro. Therefore, Fe-Cur-NDs represent a promising smart responsive theranostic integrated micro/nano drug delivery system.

Relationship between the College Student and the Campus Club: An Evolutionary Game Theory Analysis.

In this paper, we use an evolutionary game theory approach to build a relationship model of students and clubs for the purpose of improving student enthusiasm for participating in club activities. First, the process of the model building is introduced, which mainly includes the basic assumptions and the equilibrium point stability analysis. Based on this analysis, we find that the motivation adjustment of students and clubs is a dynamic process and that unilateral efforts alone cannot achieve an ideal result. Then, we use real data from Yanshan University to evaluate the model, the results of which indicate that the model can analyze the relationship between students and clubs effectively. Finally, we provide relevant suggestions based on the model established in this study, whereby we contribute a theoretical basis and practical guidance for how students can actively participate in clubs, as well as how clubs can better develop themselves.

A probe into the acid deposition mitigation path in China over the last four decades and beyond.

China currently has the highest acid deposition globally, yet research on its status, impacts, causes and controls is lacking. Here, we compiled data and calculated critical loads regarding acid deposition. The results showed that the abatement measures in China have achieved a sharp decline in the emissions of acidifying pollutants and a continuous recovery of precipitation pH, despite the drastic growth in the economy and energy consumption. However, the risk of ecological acidification and eutrophication showed no significant decrease. With similar emission reductions, the decline in areas at risk of acidification in China (7.0%) lags behind those in Europe (20%) or the USA (15%). This was because, unlike Europe and the USA, China's abatement strategies primarily target air quality improvement rather than mitigating ecological impacts. Given that the area with the risk of eutrophication induced by nitrogen deposition remained at 13% of the country even under the scenario of achieving the dual targets of air quality and carbon dioxide mitigation in 2035, we explored an enhanced ammonia abatement pathway. With a further 27% reduction in ammonia by 2035, China could largely eliminate the impacts of acid deposition. This research serves as a valuable reference for China's future acid deposition control and for other nations facing similar challenges.

Molecular basis of A. thaliana KEOPS complex in biosynthesizing tRNA t6A.

In archaea and eukaryotes, the evolutionarily conserved KEOPS is composed of four core subunits-Kae1, Bud32, Cgi121 and Pcc1, and a fifth Gon7/Pcc2 that is found in fungi and metazoa. KEOPS cooperates with Sua5/YRDC to catalyze the biosynthesis of tRNA N6-threonylcarbamoyladenosine (t6A), an essential modification needed for fitness of cellular organisms. Biochemical and structural characterizations of KEOPSs from archaea, yeast and humans have determined a t6A-catalytic role for Kae1 and auxiliary roles for other subunits. However, the precise molecular workings of KEOPSs still remain poorly understood. Here, we investigated the biochemical functions of A. thaliana KEOPS and determined a cryo-EM structure of A. thaliana KEOPS dimer. We show that A. thaliana KEOPS is composed of KAE1, BUD32, CGI121 and PCC1, which adopts a conserved overall arrangement. PCC1 dimerization leads to a KEOPS dimer that is needed for an active t6A-catalytic KEOPS-tRNA assembly. BUD32 participates in direct binding of tRNA to KEOPS and modulates the t6A-catalytic activity of KEOPS via its C-terminal tail and ATP to ADP hydrolysis. CGI121 promotes the binding of tRNA to KEOPS and potentiates the t6A-catalytic activity of KEOPS. These data and findings provide insights into mechanistic understanding of KEOPS machineries.

Rational design and synthesis of 2,4-dichloro-6-methyl pyrimidine derivatives as potential selective EGFRT790M/L858R inhibitors for the treatment of non-small cell lung cancer.

Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today. Based on the previous studies on AZD-9291, we designed and synthesized two series of 2,4-dichloro-6-methylpyrimidine derivatives, 19 compounds in total, as potential inhibitors of the EGFR kinase. The most promising compound, L-18, showed better inhibitory activity (81.9%) and selectivity against EGFRT790M/L858R kinase. In addition, L-18 showed strong antiproliferative activity against H1975 cells with an IC50 value of 0.65 ± 0.06 µM and no toxicity to normal cells (LO-2). L-18 was able to dose-dependently induce the apoptosis of H1975 cells and produced a cell-cycle-blocking effect, and it can also dose-dependently inhibit the migration and invasion of H1975 cells. L-18 also showed in vivo anticancer efficacy in H1975 cells xenograft mice. We also performed a series of in vivo and in vitro toxicological evaluations of compound L-18, which did not cause obvious injury in mice during administration. These results suggest that L-18 may be a promising drug candidate that warrants further investigation.

Assessment of the Relationship Between Genetic Determinants of Obesity, Unhealthy Eating Habits and Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study.

Background: Clinical studies have shown that the onset and exacerbation of chronic obstructive pulmonary disease (COPD) are related to obesity and dietary behaviours, but the genetic relationship between them is not clear.Aims: To investigate the relationship between the genetic determinants of obesity, dietary habits (alcohol consumption, intake of sweets, salt intake) and COPD.Methods: Exposure and outcome datasets were obtained from the IEU Open GWAS project. The exposure dataset includes dietary habits (Salt added to food, Sweets intake, Alcohol consumption), obesity level (represented by body mass index (BMI) and body fat percentage (BFP) data sets.). The outcome dataset includes COPD and acute COPD admissions. The collected data were imported into the RStudio software and conducted Mendelian randomisation analysis. Additionally, heterogeneity and horizontal pleiotropy tests were conducted on the data to ensure the veracity of the results.Results: The results showed that BMI was positively correlated with the risk of acute COPD admission (OR = 1.74, 95% CI 1.39-2.18) and COPD (OR = 1.81, 95%CI 1.41-2.33). In addition, BFP was also a risk factor for COPD (OR = 1.98, 95% CI 1.42-2.77) and acute exacerbation of COPD admission (OR = 1.99, 95%CI 1.43-2.77). The increase of salt, sugar and alcohol consumption will not increase the risk of COPD and the risk of hospitalisation due to COPD.Conclusion: Therefore, we should strengthen the guidance of diet and living habits of obese patients. For patients with heavier weight and higher body fat rate, they should be instructed to lose weight and fat to prevent the occurrence of COPD. For obese patients with COPD, more attention should be paid to prevent the occurrence of acute exacerbation of COPD in advance.

Chromosome-level genome assembly of Oncomelania hupensis: the intermediate snail host of Schistosoma japonicum.

BACKGROUND: Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis, which is a significant cause of morbidity in China, the Philippines and Indonesia. Oncomelania hupensis (Gastropoda: Pomatiopsidae) is the unique intermediate host of S. japonicum. A complete genome sequence of O. hupensis will enable the fundamental understanding of snail biology as well as its co-evolution with the S. japonicum parasite. Assembling a high-quality reference genome of O. hupehensis will provide data for further research on the snail biology and controlling the spread of S. japonicum. METHODS: The draft genome was de novo assembly using the long-read sequencing technology (PacBio Sequel II) and corrected with Illumina sequencing data. Then, using Hi-C sequencing data, the genome was assembled at the chromosomal level. CAFE was used to do analysis of contraction and expansion of the gene family and CodeML module in PAML was used for positive selection analysis in protein coding sequences. RESULTS: A total length of 1.46 Gb high-quality O. hupensis genome with 17 unique full-length chromosomes (2n = 34) of the individual including a contig N50 of 1.35 Mb and a scaffold N50 of 75.08 Mb. Additionally, 95.03% of these contig sequences were anchored in 17 chromosomes. After scanning the assembled genome, a total of 30,604 protein-coding genes were predicted. Among them, 86.67% were functionally annotated. Further phylogenetic analysis revealed that O. hupensis was separated from a common ancestor of Pomacea canaliculata and Bellamya purificata approximately 170 million years ago. Comparing the genome of O. hupensis with its most recent common ancestor, it showed 266 significantly expanded and 58 significantly contracted gene families (P < 0.05). Functional enrichment of the expanded gene families indicated that they were mainly involved with intracellular, DNA-mediated transposition, DNA integration and transposase activity. CONCLUSIONS: Integrated use of multiple sequencing technologies, we have successfully constructed the genome at the chromosomal-level of O. hupensis. These data will not only provide the compressive genomic information, but also benefit future work on population genetics of this snail as well as evolutional studies between S. japonicum and the snail host.

Unveiling the dynamic of nitrogen through migration and transformation patterns in the groundwater level fluctuation zone of a different hyporheic zone sediment.

This study investigates the impact of water levels and soil texture on the migration and transformation of nitrate (NO3--N) and ammonium (NH4+-N) within a soil column. The concentrations of NO3--N gradually decreased from an initial concentration of 34.19 ± 0.86 mg/L to 14.33 ± 0.77 mg/L on day 70, exhibiting fluctuations and migration influenced by water levels and soil texture. Higher water levels were associated with decreased NO3--N concentrations, while lower water levels resulted in increased concentrations. The retention and absorption capacity for NO3--N were highest in fine sand soil, followed by medium sand and coarse sand, highlighting the significance of soil texture in nitrate movement and retention. The analysis of variance (ANOVA) confirmed statistically significant variations in pH, dissolve oxygen and oxidation-reduction potential across the soil columns (p < 0.05). Fluctuating water levels influenced the migration and transformation of NO3--N, with distinct patterns observed in different soil textures. Water level fluctuations also impacted the migration and transformation of NH4+-N, with higher water levels associated with increased concentrations and lower water levels resulting in decreased concentrations. Among the soil types considered, medium sand exhibited the highest absorption capacity for NH4+-N. These findings underscore the significant roles of water levels, soil texture, and soil type in the migration, transformation, and absorption of nitrogen compounds within soil columns. The results contribute to a better understanding of nitrogen dynamics under varying water levels and environmental conditions, providing valuable insights into the patterns of nitrogen migration and transformation in small-scale soil column experiments.

In-sewer stability assessment of 140 pharmaceuticals, personal care products, pesticides and their metabolites: Implications for wastewater-based epidemiology biomarker screening.

The monitoring of pharmaceuticals, personal care products (PCPs), pesticides, and their metabolites through wastewater-based epidemiology (WBE) provides timely information on pharmaceutical consumption patterns, chronic disease treatment rates, antibiotic usage, and exposure to harmful chemicals. However, before applying them for quantitative WBE back-estimation, it is necessary to understand their stability in the sewer system to screen suitable WBE biomarkers thereby reducing research uncertainty. This study investigated the in-sewer stability of 140 typical pharmaceuticals, PCPs, pesticides, and their metabolites across 15 subcategories, using a series of laboratory sewer sediment and biofilm reactors. For the first time, stability results for 89 of these compounds were reported. Among the 140 target compounds, 61 biomarkers demonstrated high stability in all sewer reactors, while 41 biomarkers were significantly removed merely by sediment processes. For biomarkers exhibiting notable attenuation, the influence of sediment processes was generally more pronounced than biofilm, due to its stronger microbial activities and more pronounced diffusion or adsorption processes. Adsorption emerged as the predominant factor causing biomarker removal compared to biodegradation and diffusion. Significantly different organic carbon-water partitioning coefficient (Koc) and distribution coefficient at pH = 7 (logD) values were observed between highly stable and unstable biomarkers, with most hydrophobic substances (Koc > 100 or logD > 2) displaying instability. In light of these findings, we introduced a primary biomarker screening process to efficiently exclude inappropriate candidates, achieving a commendable 77 % accuracy. Overall, this study represents the first comprehensive report on the in-sewer stability of 89 pharmaceuticals, PCPs, pesticides, and their metabolites, and provided crucial reference points for understanding the intricate sewer sediment processes.

Characterization of Firmiana danxiaensis plastomes and comparative analysis of Firmiana: insight into its phylogeny and evolution.

BACKGROUND: Firmiana danxiaensis is a critically endangered and ecologically important tree currently only found in four locations in Danxia or Karst habitats in northern Guangdong Province, China. The specialized habitat preference makes it an ideal model species for study of adaptive evolution. Meanwhile, the phylogenetic relationships of F. danxiaensis in four locations under two landforms are unclear. Therefore, we sequenced its complete chloroplast (cp.) genomes and conducted comprehensive interspecific and intrageneric plastome studies. RESULTS: The F. danxiaensis plastomes in four locations showed a typical quadripartite and circular structure that ranged from 160,832 to 161,206 bp in size, with 112 unique genes encoded. Comparative genomics showed that the plastomes of F. danxiaensis were relatively conserved with high similarity of genome organization, gene number, GC content and SSRs. While the genomes revealed higher biased codon preferences in Karst habitat than those in Danxia habitats. Eighteen and 11 divergent hotpots were identified at interspecific and intrageneric levels for species identification and further phylogenetic studies. Seven genes (clpP, accD, ccsA, ndhH, rpl20, rpoC2, and rps4) were under positive selection and may be related to adaptation. Phylogenetic analysis revealed that F. danxiaensis is sister to F. major and F. simplex. However, the interspecific relationships are not consistent with the habitat types. CONCLUSIONS: The characteristics and interspecific relationship of F. danxiaensis plastomes provide new insights into further integration of geographical factors, environmental factors, and genetic variations on the genomic study of F. danxiaensis. Together, our study will contribute to the study of species identification, population genetics, and conservation biology of F. danxiaensis.

Effect of Ultrasound-Guided Erector Spinae Plane Block on Pain After Laparoscopic Transabdominal Preperitoneal Repair: A Prospective, Double-Blind, Randomized Controlled Study.

Objective: The present study was performed to evaluate the effect of ultrasound-guided erector spinae plane block (ESPB) on pain after laparoscopic transabdominal preperitoneal (TAPP) repair. Therefore, improved postoperative pain management is crucial for enhancing the overall patient experience and recovery. Methods: This prospective, double-blind, randomized controlled trial enrolled 40 male patients with a unilateral inguinal hernia at Xi'an Aerospace General Hospital from November 1, 2020, to February 1, 2021. Participants were assigned through a random number table at a 1:1 ratio to receive either ESPB with 20 ml 0.5% ropivacaine in the experimental group (Group E) or ESPB with 20 ml normal saline in the control group (Group C), with 20 cases in each group. The primary outcome was assessed using visual analogue scale (VAS) scores for exercise pain at 2h, 6h, 12h, 18h, and 24h postoperatively. Secondary outcomes included time lapses before patient-controlled intravenous analgesia (PCIA) use, intraoperative remifentanil usage, additional sufentanil, postoperative nalbuphine consumption, analgesic remedies at 24h postoperatively, and incidence of postoperative adverse events. Results: Group E provided more pain mitigation for patients than Group C, as evidenced by the significantly lower VAS scores during exercise pain at 2h (Group C: 1.95±1.19; Group E:4.00±1.38), 6h (Group C: 2.00±1.12; Group E:3.90±1.37), and 12h (Group C: 2.05±1.05; Group E:3.55±1.36) postoperatively (P < .05), and the pain mitigation for Group C was significant only at 18h and 24h postoperatively compared to at 2h postoperatively (P < .05). Group E resulted in significantly reduced intraoperative use of remifentanil and, additional sufentanil and postoperative nalbuphine consumption versus Group C (P < .05). Group E exhibited a better pain tolerance than Group C, as demonstrated by the longer time lapse before the use of PCIA (RR value=5.709, t=8.446, P < .05). Group C required more analgesic remedies within 24 h after surgery than Group E (P < .05). Group E did not increase the risk of postoperative adverse events, given the absence of statistical significance in the intergroup comparison (P > .05). Conclusion: Ultrasound-guided ESPB demonstrates notable benefits by decreasing intraoperative and postoperative anesthetic drug requirements, enhancing pain management, and elevating postoperative comfort and quality of life for patients. While acknowledging the study's limitations, it is crucial to highlight the potential clinical implications of these findings. The incorporation of ESPB with ropivacaine into postoperative pain management protocols could represent a significant advancement in clinical practice. The observed improvements in pain management and reduced reliance on anesthetic drugs may lead to more tailored and efficient postoperative care, potentially enhancing patient recovery experiences. Further research and practical implementation studies are warranted to fully elucidate the specific impact and optimal integration of ESPB with ropivacaine within broader clinical settings.

KBTBD2 promotes proliferation and migration of gastric cancer via activating EGFR signaling pathway.

BACKGROUND: To explore the role of Kelch repeat and BTB (POZ) domain containing 2 (KBTBD2) in Gastric cancer(GC) via studying the level of KBTBD2 and its impact on GC cells and mice model. METHODS: Expression of KBTBD2 in GC was analyzed by analysis of TCGA data, Western blotting and Real-time quantitative polymerasechain reaction (RT-qPCR). The role of KBTBD2 on GC cells proliferation, viability, invasion, migration and apoptosis in vitro were assessed by using western blotting，RT-qPCR，CCK-8, EDU, Colony Formation Assay, Wound healing assay, Transwell, JC-1 mitochondrial membrane potential and flow cytometry assay, respectively. And levels of Bcl-2, BAX, PARP, E-cadherin, Vimentin, N-cadherin, EGFR, SOS1, NROS, BRAF,ERK1/2 and GAPDH were tested by western blotting. Relation of KBTBD2 and epidermal growth factor receptor (EGFR) was predicted by KEGG analysis. KBTBD2 gene GSEA enrichment was analyzed by using R language. Moreover, CCK-8, western blotting, and wound healing assays were used to verify the correlation of KBTBD2 and EGFR pathway. Finally, tumor growth in mice was also investigated. Cells proliferation, migration and apoptosis were detected by Ki67 staining, Tunnel staining and mouse lung metastasis model. RESULTS: KBTBD2 was highly expressed in GC, and was related to poor prognosis. Moreover, silencing KBTBD2 suppressed GC cell proliferation, migration and invasion, while also inhibited the EMT, but promoted apoptosis. At the same time, KBTBD2 overexpression showed opposite results. In addition, KBTBD2 regulated the EGFR pathway. Further, silencing KBTBD2 inhibited tumor growth, cell proliferation and migration but promoted apoptosis in vivo, and KBTBD2 overexpression showed opposite results. CONCLUSIONS: KBTBD2 was highly expressed in GC. KBTBD2 promotes the progress of GC by activating EGFR signal pathway. KBTBD2 may thus be a novel target for treating GC.

Delayed recovery of surface water chemistry from acidification in subtropical forest region of China.

The three largest acid rain regions of current earth are located in northern and western Europe, eastern North America, and East Asia. Sulfur and nitrate concentrations in headwater streams in Europe and North America decreased as atmospheric sulfur and nitrogen deposition decreased, albeit with a considerable delay. However, how water chemistry responds to the declining sulfur and nitrogen deposition in China is unclear. The regional survey of surface water chemistry during 2010 and 2018 within the Sichuan Basin in southwestern China showed that the recovery of the surface water chemistry was delayed for at least 5 years owing to the release of previously deposited sulfur and nitrogen stored in the soil. After sulfur deposition declined from its peak value, the subregions of purplish soil with low sulfate adsorption capacity still exhibited a net sulfur release in 2010, but this release was no longer evident by 2018. The subregions with the red and yellow soils, which have a high sulfate adsorption capacity, operated as sulfur sinks during 2010 and 2018, indicating a continuous immobilization process through sulfate reduction despite a decrease in sulfur deposition. Additionally, this sulfate reduction countered the release of sulfate caused by sulfur desorption. There was a substantial nitrogen sink within the Sichuan Basin. Nitrogen leaching decreased slowly with the declined nitrogen deposition, except in regions where nitrogen deposition exceeded the critical threshold. Compared to temperate forest regions in Europe, the Sichuan Basin and its surrounding areas have experienced higher decline rates in the leaching of sulfur and nitrogen, highlighting that the subtropical forest region undergoes a faster restoration of surface water chemistry.

Proteomics Sequencing Reveals the Role of TGF-ß Signaling Pathway in the Peripheral Blood of Offspring Rats Exposed to Fluoride.

The underlying mechanism of fluorosis has not been fully elucidated. The purpose of this study was to explore the mechanism of fluorosis induced by sodium fluoride (NaF) using proteomics. Six offspring rats exposed to fluoride without dental fluorosis were defined as group A, 8 offspring rats without fluoride exposure were defined as control group B, and 6 offspring rats exposed to fluoride with dental fluorosis were defined as group C. Total proteins from the peripheral blood were extracted and then separated using liquid chromatography-tandem mass spectrometry. The identified criteria for differentially expressed proteins were fold change > 1.2 or < 0.83 and P < 0.05. Gene Ontology function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the oeCloud tool. The 177 upregulated and 22 downregulated proteins were identified in the A + C vs. B group. KEGG pathway enrichment analysis revealed that transforming growth factor-ß (TGF-ß) signaling pathway significantly enriched. PPI network constructed using Cytoscape confirmed RhoA may play a crucial role. The KEGG results of genes associated with fluoride and genes associated with both fluoride and inflammation in the GeneCards database also showed that TGF-ß signaling pathway was significantly enriched. The immunofluorescence in HPA database showed that the main expression sites of RhoA are plasma membrane and cytosol, while the main expression site of Fbn1 is the Golgi apparatus. In conclusion, long-term NaF intake may cause inflammatory response in the peripheral blood of rats by upregulating TGF-ß signaling pathway, in which RhoA may play a key role.

High-Pressure Synthesis, Crystal Structure, and Physical Properties of a Spinel Compound Co0.7Al2S4.

In this paper, we report on the discovery of a spinel compound, Co0.7Al2S4, which was synthesized at high-pressure. The systematic characterizations were carried out by structural, magnetic, and heat capacity measurements. The compound crystallizes into a cubic structure with the space group Fd3̅m (no. 227) and the lattice constant a = 9.9580(1) Å. Magnetic susceptibility measurements suggest that Co0.7Al2S4 exhibits a spin glass ground state, freezing at Tf ∼ 7.2 K with a Weiss temperature Tθ ∼ -115.9 K, which is verified by ac magnetic susceptibility and heat capacity measurements. The frustration parameter f for Co0.7Al2S4 is calculated to be about 16.6, based on the formula f = | Tθ/Tf |, indicating that Co0.7Al2S4 is a high-frustration magnet. Specific heat data displays a T2 dependence below the freezing temperature, which is different from the linear dependence observed in a common spin glass system. Compared with the similar compound CoAl2O4, it is suggested that the vacancies in the Co sites should be responsible for the occurrence of the spin glass behavior of Co0.7Al2S4.

Implications of uncertainty in technology cost projections for least-cost decarbonized electricity systems.

Plans for decarbonized electricity systems rely on projections of highly uncertain future technology costs. We use a stylized model to investigate the influence of future cost uncertainty, as represented by different projections in the National Renewable Energy Laboratory 2021 Annual Technology Baseline dataset, on technology mixes comprising least-cost decarbonized electricity systems. Our analysis shows that given the level of future cost uncertainty as represented by these projections, it is not possible to predict with confidence which technologies will play a dominant role in future least-cost carbon emission-free energy systems. Successful efforts to reduce costs of individual technologies may or may not lead to system cost reductions and widespread deployments, depending on the success of cost-reduction efforts for competing and complementary technologies. These results suggest a portfolio approach to reducing technology costs. Reliance on uncertain cost breakthroughs risks costly outcomes. Iterative decision-making with learning can help mitigate these risks.