Design, Synthesis and Evaluation of A Novel Teoptinib Derivative as an Effective Anti-Hepatocellular Carcinoma Agent.

BACKGROUND & PURPOSE: Hepatocellular Carcinoma (HCC) is a type of liver cancer known for its poor prognosis and high mortality. Teoptinib is a highly selective MET inhibitor that has been used in the treatment of liver cancer. Although good progress has been made in clinical treatment, further improvement is still needed. In this study, a series of novel Teoptinib derivatives were synthesized and evaluated as anti-cancer agents for the treatment of liver cancer, and an oral nanodrug delivery system was also explored. METHODS: A series of novel Teoptinib derivatives were synthesized, and an oral nanodrug delivery system was also explored. HPLC, high-resolution mass spectrometer and NMR were used to determine the structure and molecular formula of the synthesized compounds. Zeta potential assay was used to access the particle size distribution and zeta potential of the nanoparticles. MTT assay, cell colony formation assay, cell apoptosis inhibition assay, cell scratch assay, and the MHCC-97H xenograft model of nude mice assay were used to evaluate the in vitro and in vivo anti-tumor activity of the synthesized compounds. RESULTS: Compound (R)-10 showed the best antitumor activity with 0.010 µM of the IC50 value against MHCC-97H, a human liver cancer cell line with high c-Met expression. The MHCC-97H xenograft model of nude mice assay showed that nano-prodrug of compound (R)-10 exhibited good in vivo activity with 87.67% of the TGI at the dosage of 8 mg/kg. CONCLUSION: We designed and synthesized a series of c-Met inhibitors containing different side chains and chiral centers as anti-liver cancer agents. Among them, compound (R)-10 shows a promising effect as a lead molecule for further study in the treatment of liver cancer. The successful incorporation of (R)-10 into a novel oral nanodrug delivery system highlights the importance of effective drug delivery systems for enhanced therapeutic efficacy.

MicroRNA-298 determines the radio-resistance of colorectal cancer cells by directly targeting human dual-specificity tyrosine(Y)-regulated kinase 1A.

BACKGROUND: Radiotherapy stands as a promising therapeutic modality for colorectal cancer (CRC); yet, the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission. AIM: To elucidate the role played by microRNA-298 (miR-298) in CRC radio-resistance. METHODS: To establish a radio-resistant CRC cell line, HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period. The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR, and protein expression determination was realized through Western blotting. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay. Radio-induced apoptosis was discerned through flow cytometry analysis. RESULTS: We observed a marked upregulation of miR-298 in radio-resistant CRC cells. MiR-298 emerged as a key determinant of cell survival following radiation exposure, as its overexpression led to a notable reduction in radiation-induced apoptosis. Intriguingly, miR-298 expression exhibited a strong correlation with CRC cell viability. Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A (DYRK1A) as miR-298's direct target. CONCLUSION: Taken together, our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation, thereby positioning miR-298 as a promising candidate for mitigating radio-resistance in CRC.

Comprehensive analysis of P2Y family genes expression, immune characteristics, and prognosis in pan-cancer.

BACKGROUND: P2Y receptors are a family of G protein-coupled receptor genes that have an important function in cancer development and metastasis. However, systematic studies have not been conducted on human tumors. This study attempted to explore the role of P2Y family genes (P2Ys) in pan-cancer. METHODS: Gene expression and clinical data were downloaded from The Cancer Genome Alas dataset. Gene differential expression, mutation, prognosis, tumor microenvironment (TME) (containing immune cells infiltration, Estimate/immune/stromal scores, immune checkpoints, immune and molecular subtypes, DNA repair genes and methyltransferase), clinical correlation, protein-protein interaction network and functional enrichment analysis were performed. In addition, experiments such as western blots were performed for validation. RESULTS: Eight P2Ys were differentially expressed in most tumor and normal tissues, and their abnormal expression in a variety of cancers could significantly reduce the survival rate of patients. Expression levels of P2Ys, especially P2Y6, P2Y12, P2Y13, P2Y14, were correlated significantly with immune cells, immune checkpoint genes, immune and molecular subtypes and Estimate/immune/stromal scores in a variety of cancers such as uveal melanoma, liver hepatocellular carcinoma, stomach adenocarcinoma, colorectal cancer (CRC), prostate adenocarcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma (all p < 0.05). P2Ys play an important role in TME and are involved in immune regulation. In addition, enrichment analysis and western blots showed that the levels of P2Y2 and P2Y6 expression regulate the Akt/GSK-3ß/ß-catenin pathway in CRC, thereby affecting epithelial-to-mesenchymal transition. CONCLUSION: P2Ys may be used as potential pan-cancer biomarkers in prognosis and immunology. They may also be new targets for tumor immunotherapy, which has wide clinical implications.

Hematodinium perezi naturally infects Asian brush-clawed crab (Hemigrapsus takanoi).

The parasitic dinoflagellates of the genus Hematodinium have been considered one of the most important emerging pathogens for a broad range of marine crustaceans around the world. In China, frequent outbreaks of Hematodinium infections have caused serious economic losses for local farmers since 2004. Wild crabs were recently indicated to play a vital role in the transmission and spreading of the Hematodinium disease in polyculture pond systems. Based on PCR amplification and histopathological examination, we demonstrated that H. perezi can naturally infect a wild crab species, Hemigrapsus takanoi, which were collected from the waterways located on the coast of Rizhao or Weifang, Shandong Peninsula, China. According to the sequence similarity analysis and phylogenetic analysis, the Hematodinium isolates were identified as H. perezi and belonged to genotype II. The prevalence of H. perezi ranged from 3.3% to 5.7% in H. takanoi originating from Rizhao (n = 165 wild crabs) and from 0.9% to 20.0% in that originating from Weifang (n = 1386 wild crabs), respectively. To our knowledge, H. takanoi is, for the first time, reported as a new host for Hematodinium. Given the wide distribution of H. takanoi on the coasts along the Shandong Peninsula and the relative high prevalence of infection we monitored in our study, we speculate that H. takanoi contributes to the introducing and spreading parasitic Hematodinium between ponds via waterways in a poly-culturing system. Findings in this study broaden the host range of this parasite and expand the scope of our surveillance for Hematodinium disease in China.

Macrophthalmus (Macrophthalmus) abbreviatus Manning & Holthuis, 1981, a new natural host for Hematodinium perezi infection.

Recent reports have shown that wild crabs may be important hosts involved in the transmission and spread of the parasitic Hematodinium in cultured marine crustaceans. Therefore, monitoring the prevalence of Hematodinium infections in wild crabs is necessary to develop effective strategies for the prevention and control of Hematodinium disease. Here we report a wild crab species, Macrophthalmus (Macrophthalmus) abbreviatus Manning & Holthuis, 1981, as a new natural host for Hematodinium sp. infection. It is one of the common wild crab species dwelling in the ponds or waterways connected to the polyculture ponds located on the coast of Rizhao or Weifang, Shandong Peninsula, China. According to the results of PCR detection and phylogenetic analysis targeting the internal transcribed spacer 1 (ITS 1) region, these Hematodinium sp. isolates were identified as H. perezi and fell into the genotype II category within H. perezi. A high monthly prevalence of H. perezi infection was observed during the 2021-2022 field survey, ranging from 33.3% to 90.6% in M. abbreviatus originating from Weifang (n=304 wild crabs) and from 53.6% to 92.9% in those from Rizhao (n=42 wild crabs). Artificial inoculation infection experiments demonstrated that M. abbreviatus could be infected by H. perezi, and massive Hematodinium cells and typical histopathological changes were observed in the hepatopancreas and gill tissues of the infected crabs. To our knowledge, this is the first report of M. abbreviatus as a new natural host for H. perezi infection. Results in the present study extend the known host spectrum for this emerging parasite pathogen, and also provide valuable information for epidemic surveillance of the Hematodinium disease as well.

Prediction and Analysis of Housing Price Based on the Generalized Linear Regression Model.

In order to improve the reliability of housing price prediction and analysis, this article combines the generalized linear regression model to build a real estate price prediction model and analyzes the basic knowledge of data mining. On the basis of this prior knowledge, this article investigates the cluster analysis algorithm and selects the generalized linear regression model as the research focus based on its definition and the characteristics of stock data. Moreover, this article analyzes the estimation methods of the generalized linear regression model and the nonparametric regression model, and then gives the estimation method of a partial linear model. In addition, this article verifies the validity of the model proposed in this article by means of simulation research. Through the simulation and comparison experiments, it can be seen that the housing price prediction system based on the generalized regression model proposed in this article has a high housing price prediction accuracy.

Characterization of a novel shrimp pathogen, Vibrio brasiliensis, isolated from Pacific white shrimp, Penaeus vannamei.

A novel pathogenic strain Vibrio 20190611023 was isolated from the hepatopancreas of moribund cultured Penaeus vannamei suffering from black gill disease. This strain was identified as V. brasiliensis based on the phylogenetic analyses of 16S rDNA gene and five other housekeeping genes (i.e., gapA, ftsZ, mreB, topA and gyrB). Some biochemical features of this strain were determined with an API 20NE system, and its haemolytic activity was determined using a sheep blood agar plate. The pathogenicity of this isolate 20190611023 was confirmed by the experimental challenge tests and histopathological examinations. P. vannamei were challenged via reverse gavage with different doses of bacterial suspensions. The calculated median lethal dose (LD50 ) was (3.16 ± 1.78) × 105  CFU/g (body weight). Moreover, antibiotic susceptibility tests were performed, the results of which showed that the strain 20190611023 was sensitive to chloramphenicol, compound sulphamethoxazole, ciprofloxacin, doxycycline and oxacillin, but resistant to erythromycin, kanamycin, gentamicin, cefoperazone, ceftriaxone, cefamezin and piperacillin. To our knowledge, this is the first report for demonstrating V. brasiliensis as a shrimp pathogen, which expands the host range of V. brasiliensis infection. The present study highlights that more attention should be paid to this novel pathogen in intensive shrimp aquaculture.

A water-stable MOF-AgClO4-abtz as fluorescent sensor for detection of folic acid based on inner filter effect.

Folic acid (FA, Vitamin B9), as a water-soluble chemical compound of the vitamin B groups, plays an important role to human health. Thus, it is of great significance to develop sensitive assays for detection of FA. Herein, we prepared a water-stable metal-organic frameworks {[Ag2(µ2-abtz)(µ3-abtz)(ClO4)]⋅(ClO4)}n (MOF-AgClO4-abtz; abtz = 1-(4-aminobenzyl)-1, 2, 4,-triazole) material, which exhibited a high fluorescent quantum yield of 78.97%, good water dispersibility and excellent chemical stability. Then MOF-AgClO4-abtz was developed as a "turn-off" fluorescent sensor for detection of FA via inner filter effect (IFE). The IFE mechanism was mainly originated from the spectrum overlap between fluorescence emission of MOF-AgClO4-abtz at 350 nm and UV-vis absorption band of FA ranging from 340 to 360 nm, resulting in fluorescence quenching. Furthermore, the proposed method exhibited a good linear response to FA in the concentration range of 0.1-30 µM, and the limit of detection (LOD) was calculated to be 49 nM (S/N = 3). The great reproducibility of the method was checked for three replicate detections of 20 µM FA to find relative standard deviation (RSD) of 3.4%. This method also exhibited excellent long-term stability by detecting 30 µM FA for 7 days, the RSD value was obtained to be 2.8%. Ultimately, this method was employed for sensitive detection of FA in human serum and plasma samples with quantitative spike recoveries ranging from 95.3% to 104.6%.

Assessment of the iodine nutritional status among Chinese school-aged children.

OBJECTIVE: The remarkable success of iodine deficiency disorders (IDD) elimination in China has been achieved through a mandatory universal salt iodization (USI) program. The study aims to estimate the relationship between urinary iodine concentration (UIC) and iodine content in edible salt to assess the current iodine nutritional status of school aged children. METHODS: A total of 5565 students from 26 of 39 districts/counties in Chongqing participated in the study, UIC and iodine content in table salt were measured. Thyroid volumes of 3311 students were examined by ultrasound and goiter prevalence was calculated. RESULTS: The overall median UIC of students was 222 µg/L (IQR: 150-313 µg/L). Median UIC was significantly different among groups with non-iodized salt (iodine content <5 mg/kg), inadequately iodized salt (between 5 and 21 mg/kg), adequately iodized (between 21 and 39 mg/kg) and excessively iodized (>39 mg/kg) salt (P < 0.01). The total goiter rate was 1.9% (60/3111) and 6.0% (186/3111) according to Chinese national and WHO reference values, respectively. Thyroid volume and goiter prevalence were not different within the three iodine nutritional status groups (insufficient, adequate and excessive, P > 0.05). CONCLUSIONS: The efficient implementation of current USI program is able to reduce the goiter prevalence in Chongqing as a low incidence of goiter in school aged children is observed in this study. The widened UIC range of 100-299 µg/L indicating sufficient iodine intake is considered safe with a slim chance of causing goiter or thyroid dysfunction. Further researches were needed to evaluate the applicability of WHO reference in goiter diagnose in Chongqing or identifying more accurate criteria of normal thyroid volume of local students in the future.

Zinc toxicity alters the photosynthetic response of red alga Pyropia yezoensis to ocean acidification.

The globally changing environmental climate, ocean acidification, and heavy metal pollution are of increasing concern. However, studies investigating the combined effects of ocean acidification and zinc (Zn) exposure on macroalgae are very scarce. In this study, the photosynthetic performance of the red alga Pyropia yezoensis was examined under three different concentrations of Zn (control, 25 (medium), and 100 (high) µg L-1) and pCO2 (400 (ambient) and 1000 (high) µatm). The results showed that higher Zn concentrations resulted in increased toxicity for P. yezoensis, while ocean acidification alleviated this negative effect. Ocean acidification increased the relative growth rate of thalli under both medium and high Zn concentrations. The net photosynthetic rate and respiratory rate of thalli also significantly increased in response under ocean acidification, when thalli were cultured under both medium and high Zn concentrations. Malondialdehyde levels decreased under ocean acidification, compared to ambient CO2 conditions and either medium or high Zn concentrations. The activity of superoxide dismutase increased in response to high Zn concentrations, which was particularly apparent at high Zn concentration and ocean acidification. Immunoblotting tests showed that ocean acidification increased D1 removal, with increasing expression levels of the PSII reaction center proteins D2, CP47, and RbcL. These results suggested that ocean acidification could alleviate the damage caused by Zn exposure, thus providing a theoretical basis for a better prediction of the impact of global climate change and heavy metal contamination on marine primary productivity in the form of seaweeds.

Effects of increased CO2 and temperature on the physiological characteristics of the golden tide blooming macroalgae Sargassum horneri in the Yellow Sea, China.

The golden tide, caused by the brown algae Sargassum horneri, exerts severe influences on the Pyropia aquaculture of Jiangsu coast, China. To study the outbreak of the golden tide in response to increasing greenhouse gas emissions, S. horneri was cultured under four conditions: ambient condition (10 °C, 400 µatm), elevated temperature condition (14 °C, 400 µatm), elevated CO2 level (10 °C, 1000 µatm), and potential greenhouse condition (14 °C, 1000 µatm). The growth, photosynthetic performances, and inorganic carbon affinity of S. horneri were studied. The results showed that elevated temperature exerted a more pronounced positive influence on S. horneri growth, photosynthesis, and carbon assimilation than CO2 enrichment. The growth of S. horneri was significantly improved by moderately elevated temperatures, especially under concurrently elevated CO2 levels. This suggests that the greenhouse effect will benefit growth and carbon sequestration of S. horneri, which may enhance the frequency and scale of golden tides.

Designing an "Off-On" Fluorescence Sensor Based on Cluster-Based CaII-Metal-Organic Frameworks for Detection of l-Cysteine in Biological Fluids.

Recently, luminescent metal-organic framework (MOF) materials have attracted considerable attention in fluorescence sensing. In this essay, we prepared a new cluster-based CaII-MOFs {[Ca1.5(µ8-HL1)(DMF)2]·DMF}n (1) with good water dispersibility, excellent photoluminescence properties (FL quantum yield of 20.37%) and great fluorescence stability. Further, it was employed to design as an "off-on" fluorescence sensor for sensitive detection of l-cysteine. This proposed strategy was that fluorescence of CaII-MOFs 1 was quenched for providing a low fluorescence background by the introduction of Pb2+ forming the CaII-MOFs 1/Pb2+ hybrid system. The quenching effect could be ascribed to the static quenching mechanism because of the formation of ground-state complexes and coordination interactions between the free carboxyl of H4L1 ligands of CaII-MOFs 1 and Pb2+. Then, with the addition of l-cysteine into the CaII-MOFs 1/Pb2+ hybrid system, the fluorescence signal was immediately restored. This result was because the Pb2+ was gradually released from the hybrid system by chelation interactions between the -SH groups of l-cysteine and Pb2+. This method received a relative wide linear range varying from 0.05 to 40 µM and a low detection limit of 15 nM for detection of l-cysteine. This proposed strategy was also successfully applied to detect l-cysteine in human serum samples with satisfactory recoveries from 95.9 to 101.5%.

A two-stage model with nitrogen and silicon limitation enhances lipid productivity and biodiesel features of the marine bloom-forming diatom Skeletonema costatum.

To enhance biodiesel production and quality from a bloom-forming diatom Skeletonema costatum, a two-stage model, in which cells were cultured in nutrient replete conditions first and then transferred to nutrient limitation conditions, was explored. Compared to one-stage model, nutrient limitation in the second stage significantly increased lipid content in spite of decreasing growth; consequently, Si-limitation and N-Si-limitation respectively increased lipid productivity by 37.6% and 76.7% for 6 h induction, and 42.8% and 113.7% for 12 induction. Nutrient limitation enhanced the proportions of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) but reduced polyunsaturated fatty acid (PUFA). Therefore, N-Si-limitation reduced iodine value by 33.7% and 45.6% but increased cetane number by 6.4% and 21.6% for 6 and 24 h induction, respectively. These findings indicate that the two-stage model with N-Si-limitation can enhance lipid productivity as well as biodiesel quality from diatoms.

Future CO2-induced seawater acidification mediates the physiological performance of a green alga Ulva linza in different photoperiods.

Photoperiods have an important impact on macroalgae living in the intertidal zone. Ocean acidification also influences the physiology of macroalgae. However, little is known about the interaction between ocean acidification and photoperiod on macroalgae. In this study, a green alga Ulva linza was cultured under three different photoperiods (L: D = 8:16, 12:12, 16:8) and two different CO2 levels (LC, 400 ppm; HC, 1,000 ppm) to investigate their responses. The results showed that relative growth rate of U. linza increased with extended light periods under LC but decreased at HC when exposed to the longest light period of 16 h compared to 12 h. Higher CO2 levels enhanced the relative growth rate at a L: D of 8:16, had no effect at 12:12 but reduced RGR at 16:8. At LC, the L: D of 16:8 significantly stimulated maximum quantum yield (Yield). Higher CO2 levels enhanced Yield at L: D of 12:12 and 8:16, had negative effect at 16:8. Non-photochemical quenching (NPQ) increased with increasing light period. High CO2 levels did not affect respiration rate during shorter light periods but enhanced it at a light period of 16 h. Longer light periods had negative effects on Chl a and Chl b content, and high CO2 level also inhibited the synthesis of these pigments. Our data demonstrate the interactive effects of CO2 and photoperiod on the physiological characteristics of the green tide macroalga Ulva linza and indicate that future ocean acidification may hinder the stimulatory effect of long light periods on growth of Ulva species.

Different Photosynthetic Responses of Pyropia yezoensis to Ultraviolet Radiation Under Changing Temperature and Photosynthetic Active Radiation Regimes.

Macroalgae play a crucial role in coastal marine ecosystems, but they are also subject to multiple challenges due to tidal and seasonal alterations. In this work, we investigated the photosynthetic response of Pyropia yezoensis to ultraviolet radiation (PAR: 400-700 nm; PAB: 280-700 nm) under changing temperatures (5, 10 and 15°C) and light intensities (200, 500 and 800 µmol photons m-2  s-1 ). Under low light intensity (200 µmol photons m-2  s-1 ), P. yezoensis showed the lowest sensitivity to ultraviolet radiation, regardless of temperature. However, higher temperatures inhibited the repair rates (r) and damage rates (k) of photosystem II (PSII) in P. yezoensis. However, under higher light intensities (500 and 800 µmol photons m-2  s-1 ), P. yezoensis showed higher sensitivity to UV radiation. Both r and the ratio of repair rate to damage rate (r:k) were significantly inhibited in P. yezoensis by PAB, regardless of temperature. In addition, higher temperatures significantly decreased the relative UV-inhibition rates, while an increased carbon fixation rate was found. Our study suggested that higher light intensities enhanced the sensitivity to UV radiation, while higher temperatures could relieve the stress caused by high light intensity and UV radiation.

Nitrogen availability modulates the effects of ocean acidification on biomass yield and food quality of a marine crop Pyropia yezoensis.

Pyropia yezoensis is an important marine crop in the world. We cultured it under two levels of partial pressure of carbon dioxide (pCO2) (408 (LC), 998 (HC) µatm) and nitrate (30 (LN) and 500 (HN) µmol L-1) to investigate the effect of ocean acidification on its growth and food quality under changing nitrogen supply. HC decreased growth rate of P. yezoensis under LN but did not affect it under HN. Phycoerythrin and phycocyanin were enhanced by HC, particularly at HN, which contributed to the darker color. HC stimulated the synthesis of sweat amino acids regardless of nitrate condition and umami amino acid only under LN. HN increased the content of umami amino acids regardless of pCO2 condition and sweet amino acids only under HC. Our findings indicate that future ocean acidification may reduce biomass yield of P. yezoensis but increase its color and flavor, which was regulated by nitrate availability.

Physiological acclimation of the green tidal alga Ulva prolifera to a fast-changing environment.

To aid early warning and prevent the outbreak of green tides in the Yellow Sea, both the growth and photosynthetic performance of Ulva prolifera were studied after culture in different temperatures (18, 22, and 26 °C) and light intensities (44, 160, and 280 µmol m-2·s-1). Furthermore, their instantaneous net photosynthetic performance (INPP) was studied to determine the resulting environmental acclimation. The relative growth rates of U. prolifera significantly decreased in response to increasing temperature, while they increased with increasing light intensity. Culture at higher light intensities significantly increased INPP, while higher temperatures decreased the INPP. Culture at lower temperatures lowered INPP, while increased growth temperature increased the effect. These results suggest that high temperatures during the cold season inhibited U. prolifera growth. However, low temperatures during the warm season increase biomass and may cause a large-scale green tide. These results help to understand the correlation between U. prolifera blooms and extreme weather.

Accurate identification of layer number for few-layer WS2 and WSe2 via spectroscopic study.

Transition metal dichalcogenides (TMDs) with a typical layered structure are highly sensitive to their layer number in optical and electronic properties. Seeking a simple and effective method for layer number identification is very important to low-dimensional TMD samples. Herein, a rapid and accurate layer number identification of few-layer WS2 and WSe2 is proposed via locking their photoluminescence (PL) peak-positions. As the layer number of WS2/WSe2 increases, it is found that indirect transition emission is more thickness-sensitive than direct transition emission, and the PL peak-position differences between the indirect and direct transitions can be regarded as fingerprints to identify their layer number. Theoretical calculation confirms that the notable thickness-sensitivity of indirect transition derives from the variations of electron density of states of W atom d-orbitals and chalcogen atom p-orbitals. Besides, the PL peak-position differences between the indirect and direct transitions are almost independent of different insulating substrates. This work not only proposes a new method for layer number identification via PL studies, but also provides a valuable insight into the thickness-dependent optical and electronic properties of W-based TMDs.

Correction to: Relative abundance of ß-thalassemia-related mutations in southern China correlates with geographical coordinates.

Figure 1c. is with numeric error. The error can not result in any change of discussion and conclusion. The proper figures corresponding to Fig 1c are in supplement file, see figure 5 and 6.