Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

FOXF2 and FOXQ1, forkhead box transcription factor superfamily members, are encoded by neighboring genes located on human chromosome 6p25.3 and play opposite roles in epithelial-mesenchymal transition (EMT) and metastasis in basal-like breast cancer (BLBC). However, the relationship between FOXF2 and FOXQ1 in cancer remains unknown. Here, we found mutual transcriptional repression between FOXF2 and FOXQ1, and the reciprocal negative feedback loop controlled EMT, aggressiveness, and chemoresistance in BLBC cells. We further demonstrated that FOXF2 recruited nuclear receptor corepressor 1 and histone deacetylase 3 to the FOXQ1 promoter to inhibit its transcription in BLBC cells, but FOXQ1 did not exert such an effect on FOXF2. Our findings reveal novel mechanisms underlying the determination of BLBC aggressiveness and the transrepressive function of FOXF2 in a basal-like cell subtype-specific manner. Therefore, blocking the vicious cycle of the abnormal reciprocal feedback loop between FOXF2 and FOXQ1 to induce cell differentiation and restore tissue homeostasis is a promising strategy for the treatment of aggressive BLBC.-Kang, L.-J., Yu, Z.-H., Cai, J., He, R., Lu, J.-T., Hou, C., Wang, Q.-S., Li, X.-Q., Zhang, R., Feng, Y.-M. Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

[Spatial Differences and Influencing Factors of Denitrification and ANAMMOX Rates in Spring and Summer in Lake Taihu].

Denitrification and ANAMMOX are the main nitrogen removal processes in lakes, which are of great significance for maintaining the nitrogen balance. Lake Taihu is a large, shallow lake. There are great spatial and temporal differences in the nutrient levels and algal blooms, which will affect the rates of denitrification and ANAMMOX. In order to understand the spatial and temporal variations in the denitrification and ANAMMOX rates and their influencing factors in Lake Taihu, undisturbed sediment cores were collected from Meiliang Bay, Gonghu Bay, Zhushan Bay, Dapukou Bay, Xukou Bay, and the center of Lake Taihu in the spring and summer of 2020. The results showed that the spatial distribution of the denitrification and ANAMMOX rates varied greatly in different areas of Lake Taihu in spring. The denitrification and ANAMMOX rates were (27.74±8.45)-(142.43±35.54) µmol·(m2·h)-1 and (2.35±1.06)-(17.95±8.66) µmol·(m2·h)-1, respectively. The contribution of ANAMMOX to nitrogen removal was relatively low, ranging from (7.82±1.71)% to (11.20±1.53)%. In summer, the denitrification and ANAMMOX rates were (165.68±62.14) µmol·(m2·h)-1 and (33.56±10.66) µmol·(m2·h)-1, respectively. The nitrogen removal rates were relatively low in other areas where the denitrification and ANAMMOX rates were (25.47±10.46)-(42.50±16.46) µmol·(m2·h)-1 and (2.65±0.94)-(5.95±2.65) µmol·(m2·h)-1, respectively. The contribution of ANAMMOX to nitrogen removal was (13.62±1.95)%-(7.24±1.78)%. The denitrification rate in summer was generally lower than that in spring, while the ANAMMOX rate did not decrease significantly compared with that in spring. The statistical analysis showed that the denitrification and ANAMMOX rates were significantly correlated with the substrate nitrogen concentration (P<0.01), which indicated that the nitrogen concentration was the main factor causing the difference in the nitrogen removal rates in different lake regions. In addition, there was a significant positive correlation between the contribution rate of ANAMMOX and the concentration of chlorophyll-a (P<0.05), thereby indicating that cyanobacteria blooms have a great influence on the change in the contribution of ANAMMOX to nitrogen removal.

[Effects of Land Use on Nutrient Concentrations in the Inflow River of Lake Taihu, China].

Land use is an important factor affecting non-point nutrient loading. Here, the Wuxi River basin was selected to analyze the influence of sub-basin land use on nutrient concentrations using remotely sensed land use data and monthly river water quality variables from October 2019 to September 2020. The results showed that the water quality of the river was closely related to land-use type. Specifically, dryland farmland, villages, and building land have a strong promoting influence on nitrogen, phosphorus, organic carbon, and phytoplankton chlorophyll a. The proportion of orchard land was also positively correlated with river nutrient concentrations. A negative correlation was observed between the proportion of forest land and nutrient concentrations. Moreover, the proportion of the water area in rivers and reservoirs was negatively correlated with the total dissolved nitrogen and nitrate concentrations in the river, and the proportion of the water area in natural pits and fishponds was negatively correlated with river nitrate and ammonia concentrations. Furthermore, the proportion of river and fishpond areas was positively correlated with the concentration of dissolved total phosphorus, dissolved organic carbon, and the permanganate index, while the proportion of the natural pond area was positively correlated with the concentration of particulate phosphorus and phytoplankton chlorophyll a. The influence of land-use types on water quality was also affected by distance from the river. This research indicates that the appropriate utilization of land and wetlands is key to controlling non-point nutrient loading in the river network, including Lake Taihu. Specifically, the self-purification capacity of wetland waters should be incorporated into nutrient control schemes, and special attention should be paid to the reduction of non-point source pollution in the drylands along the downstream riverbanks and urbanized areas.

[Influence of Nutrient Pulse Input on Nitrogen and Phosphorus Concentrations and Algal Growth in the Sediment-Water System of Lake Taihu].

Lake sediments not only act as a reservoir of nutrients, but are also a source of secondary pollution of nutrients for overlying water, which can buffer the variations in nutrients in overlying water and affect nutrient bioavailability and algal growth. In the current study, a simulation experiment was conducted using sediment cores collected in Meiliang Bay. Our aim was to elucidate the effect of nitrogen (N) and phosphorus (P) pulse input on variations in the water nutrient level and algal growth. We also clarified the migration and redistribution process of N and P between the sediment overlying water and algae. The results showed that the concentration of N in overlying water of the treatment group (with sediment) was much lower than that in controls (no sediment) when N was input at a pulse rate of 0.30 mg·(L·d)-1. The loss rate of N in the overlying water of the treatment group ranged from 0.144 mg·(L·d)-1 to 0.156 mg·(L·d)-1 and that in the control ranged from 0.021 mg·(L·d)-1to 0.039 mg·(L·d)-1. On the contrary, the denitrification rate of overlying water in the treatment group ranged from 40.793 mg·(m2·d)-1 to 44.193 mg·(m2·d)-1, accounting to 48%-52% of the external N loading. In contrast, the denitrification rate of overlying water in controls was from 0.021 mg·(L·d)-1to 0.039 mg·(L·d)-1, only accounting for 7%-13% of the external N loading. These results indicated that the sediment-water interface is the main site of denitrification in shallow lakes and plays an essential role in reducing N pollution in lakes. With respect to the pulse input of P at a rate of 0.015 mg·(L·d)-1, the majority of P (about 52%-58%) was imported into the sediment at a rate from 2.210 mg·(m2·d)-1to 2.422 mg·(m2·d)-1, and only a small proportion, approximately 23%-26%, was utilized by algae. The remaining P existed in overlying water in a dissolved state. These results implied that the sediment can buffer the external P input as an obvious "sink" effect of nutrients. Our results also showed that the sediment acts as a "source" of P when no external P was added. The release rate of P from the sediment to overlying water was from 0.310 mg·(m2·d)-1 to 0.468 mg·(m2·d)-1. In situ high-resolution analysis of ZrO-Chelex DGT showed that the DGT-P concentration in the interstitial water was much higher than that in the overlying water, and the concentration of DGT-P was significantly correlated with the concentration of DGT-Fe in interstitial water. These results indicate that changes in the redox potential may cause considerable release of internal phosphorus. In summary, our study showed that internal P in sediments can be released into the overlying water and support the growth of algae when the external nutrients are controlled. As a result, a delayed response was observed in the nutrient concentration in overlying water to external P reduction. Therefore, the dual control of N and P may have a better practical application to mitigate cyanobacteria blooms in shallow lakes.

[Spatial-temporal Variations and Driving of Nitrogen and Phosphorus Ratios in Lakes in the Middle and Lower Reaches of Yangtze River].

In spring and summer of 2018, 26 lakes in the middle and lower reaches of the Yangtze River were studied to determine the temporal and spatial characteristics of nitrogen and phosphorus ratios (TN/TP) and their influencing factors. The differences in nitrogen and phosphorus ratios in different types of lakes (including water-psaaing lakes, deep reservoirs and eutrophic lakes) and in different seasons were analyzed in terms of the sources of the lakes, lake depth, suspended particulate matter concentrations, and phytoplankton levels. The average TN/TP was 21.52±14.28 in spring and 21.73±23.78 in summer. The TN/TP varied significantly in different types of lakes. The TN/TP ratios in water-passing lakes, deep reservoirs and eutrophic lakes were 20.41±9.25, 40.97±33.37, and 14.38±7.40 during spring, and were 22.62±6.48, 96.38±45.91, and 10.91±4.44 during summer, respectively. The TN/TP of the water-passing lakes and deep reservoirs increased significantly in summer, while that of the eutrophic lakes decreased significantly, which indicates that TN/TP changes and lake nutritional status are closely related. The source of nutrients in lakes and reservoirs affects the TN/TP. The TN/TP of lakes and reservoirs had a significant correlation with the lake depth in both spring and summer, indicating that lake depth is a key factor affecting the ratio of nitrogen and phosphorus. In addition, in eutrophic lakes with higher absolute nutrient concentrations, TN/TP has less effect on phytoplankton, while in deep-water lakes with lower absolute nutrient concentrations, TN/TP can determine the growth of phytoplankton limited by phosphorus. Therefore, the governance strategy of lakes in the middle and lower reaches of the Yangtze River should prioritize phosphorus control. Local digging, controlling non-point source pollution, sediment dredging, and changing fishery production methods can be applied to improve the ecological quality of the eutrophic lakes.

[Influence of Potamogeton crispus on Lake Water Environment and Phytoplankton Community Structure].

The decomposition of submerged macrophytes is generally associated with dramatic changes in the water environment, such as the large release of nutrients (e.g., nitrogen and phosphorus) and organic carbon to the surrounding waters, which may result in significant changes in phytoplankton community structure. In this study, Potamogeton crispus, physicochemical variables, and phytoplankton samples were collected in 14 shallow lakes in the middle and lower Jianghuai Plain in spring (growing period of P. crispus) and summer (decomposition phase of P. crispus) of 2018. The effects of the decline of P. crispus on water quality and phytoplankton community structure were quantified. The results showed that water transparency increased significantly in spring because the growth of P. crispus inhibits sediment resuspension and macrophytes can transport the nutrients from the water column to the sediment. The values of dissolved oxygen and pH also increased significantly due the photosynthesis by macrophytes. In contrast, the decomposition of P. crispus during summer months caused a significant increase in water turbidity and organic matter. There were considerable differences in phytoplankton biomass and cyanobacterial biomass in the sites with or without P. crispus, and the corresponding ratios of cyanobacterial biomass to the total algal biomass were 18.96% and 34.05%, respectively. Higher values of cyanobacterial biomass were observed with the decomposition of P. crispus than its counterpart in summer because ① the decomposition of macrophytes provided sufficient organic matter and nutrient (nitrogen and phosphorus) resources for cyanobacterial growth; ② P. crispus decline in summer significantly increased water turbidity, which makes cyanobacteria occupy a better ecological niche and more efficiently utilize nitrogen and phosphorus.

Effects of Butyphthalide Combined with Idebenone on Inflammatory Cytokines and Vascular Endothelial Functions of Patients with Vascular Dementia.

OBJECTIVE: To determinate the clinical effect of butyphthalide combined with idebenone in the treatment of vascular dementia (VD) and the influence on inflammatory cytokines and vascular endothelial functions. STUDY DESIGN: Clinical comparative study. PLACE AND DURATION OF STUDY: Department of Neurology, Baoding First Central Hospital, from June 2017 to June 2018. METHODOLOGY: Eighty-eight VD patients were divided into observation group (44 cases) and control group (44 cases) at random. Idebenone was given to the control group, and butyphthalide combined with idebenone was given to the observation group for 12 weeks. C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were detected before and after the treatment to evaluate the level of serum inflammatory factors. Peripheral blood endothelial microparticles (EMPs), endothelin (ET-1), and vascular endothelial growth factor (VEGF) were detected to evaluate vascular endothelial functions. Mini-mental state examination (MMSE), clinical dementia scale (CDR), and ability of daily life (ADL), were used to evaluate cognitive function, dementia degree, and self-care ability in daily life. The occurrences of adverse reactions were recorded. RESULTS: Before the treatment, the comparison differences in the indexes of both groups had no statistical significance (p>0.05). After the treatment, the scores of CD62E+, VEGF, and MMSE of observation group rose obviously, compared with those before the treatment, and were significantly higher than those of control group (p <0.05). After the treatment, the scores of IL-6, CRP, TNF-α, IL-1ß, CD31+, CDl44+, ET-1, CDR and ADL of observation group significantly lowered, compared with those before the treatment, and were significantly lower than those of control group (p <0.05). The differences in the adverse reactions of both groups had no statistical significance (p >0.05). CONCLUSION: Butyphthalide combined with idebenone can effectively reduce serum inflammatory factor level of VD patients, regulate vascular endothelial functions, relieve dementia degree, and improve cognitive function and daily activity ability.

FOXF2 reprograms breast cancer cells into bone metastasis seeds.

Bone metastases occur in most advanced breast cancer patients and cause serious skeletal-related complications. The mechanisms by which bone metastasis seeds develop in primary tumors and specifically colonize the bone remain to be elucidated. Here, we show that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. The epithelial-to-osteomimicry transition regulated by FOXF2 confers a tendency on cancer cells to metastasize to bone which leads to osteolytic bone lesions. The BMP antagonist Noggin significantly inhibits FOXF2-driven osteolytic bone metastasis of breast cancer cells. Thus, targeting the FOXF2-BMP/SMAD axis might be a promising therapeutic strategy to manage bone metastasis. The role of FOXF2 in transactivating bone-related genes implies a biological function of FOXF2 in regulating bone development and remodeling.

FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway.

Lymphatic metastasis is the main route of breast cancer metastasis. It is known that lymphangiogenesis facilitates lymphatic metastasis through vascular endothelial growth factor-C (VEGF-C)/VEGF receptor 3 (VEGFR3) pathway-linked interactions between the tumor and its microenvironment. Here, we report a novel mechanism of lymphatic metastasis by which aggressive basal-like breast cancer (BLBC) cells form lymphatic vessel-like structures that are identified by the positive expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin, and VEGFR3, and termed as lymphangiogenic mimicry (LM), for the first time. Our clinical evidence and experimental data in vivo and in vitro revealed that forkhead box F2 (FOXF2) deficiency promotes the lymphatic metastasis of BLBC by conferring a lymphangiogenic mimetic feature upon cancer cells through directly activating VEGFR3 transcription. The fact that FOXF2 controls the activation of the VEGF-C/VEGFR3 signaling pathway in BLBC cells provides potential molecular diagnostic and therapeutic strategies for lymphatic metastasis in BLBC patients.

Genotyping of nucleocapsid protein gene of HCV in HIVHCV co-infected patients in Kunming in 2019 / 中国热带医学

@#Abstract: Objective　To investigate the distribution characteristics of HCV genotypes and subtypes in patients with HIV (human immunodeficiency virus, HIV)/HCV co-infection in Kunming based on the nucleocapsid protein gene sequence of HCV (hepatitis C virus). Methods　Serum was collected from HIV/HCV co-infected patients with household registration in 14 county-level cities, districts and counties under the jurisdiction of Kunming, who admitted to Yunnan Provincial Infectious Disease Hospital from March to August 2019. The viral RNA was extracted from the serum, reverse transcribed to synthesize cDNA, and the HCV nucleocapsid protein gene-specific primers were used for nested PCR amplification. The positive amplification products were sequenced, bioinformatics software such as DNAstar and MEGAX were used for sequence analysis. Results　A total of 64 samples from co-infected patients with clinical diagnosis of suspected HIV/HCV were collected and amplified by HCV nucleocapsid protein gene-specific primers, of which 17 samples were amplified positively. The results of sequence analysis showed that the sequences of 9 cases were located in the same evolutionary branch as the HCV 3b subtype sequence, and the nucleotide homology was 93.3%-95.2%; the sequences of 5 cases were located in the same evolutionary branch as the HCV 1b subtype sequence, and the nucleotide homology was 96.8%-97.6%; the sequence of one case and the subtype sequence of HCV 3a gene were located in the same evolutionary branch, and the nucleotide homology was 95.2%; the sequence of one case and HCV 6n gene subtype sequence were located in the same evolutionary branch, and the nucleotide homology was 97.9%; One case was located in the same evolutionary branch as the HCV 6u gene subtype sequence, and the nucleotide homology was 98.4%. Conclusions　HCV 1b, HCV 3a, HCV 3b, HCV 6n and HCV 6u genotypes or subtypes of HCV are prevalent in Kunming, and HCV 3b is the most prevalent genotype.

Synergism in mixtures of cymoxanil and mancozeb on Phytophthora infestans in vivo.

The preventive activity of 1:8 mixture of cymoxanil and mancozeb against Phytophthora infestans was higher than that of either the two single ingredients or the other nine mixtures. The synergistic interaction existed (synergy ratio 2.01) between the two at the mixing ratio of 1:8, whereas additive interaction (synergy ratios ranged from 0.73 to 1.34) existed at the mixing ratios ranging from 1:1 to 1:7, from 1:9 to 1:10, 1:8 was the optimal ratio. The preventive activity of 1:8 mixture was higher than the curative and the eradicative. In addition, the eradicative synergism of inhibiting sporangia production on lesions was stronger than the eradicative synergism of inhibiting lesion extension and suppressing infection of sporangia, and than the curative synergism of inhibiting lesion sporulation on detached potato leaflets.