A fast radio burst source at a complex magnetized site in a barred galaxy.

Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.

LncRNA-mediated regulation of cell signaling in cancer.

To date, a large number of long non-coding RNAs (lncRNAs) have been recently discovered through functional genomics studies. Importantly, lncRNAs have been shown, in many cases, to function as master regulators for gene expression and thus, they can play a critical role in various biological functions and disease processes including cancer. Although the lncRNA-mediated gene expression involves various mechanisms, such as regulation of transcription, translation, protein modification, and the formation of RNA-protein or protein-protein complexes, in this review, we discuss the latest developments primarily in important cell signaling pathways regulated by lncRNAs in cancer.

Egr-1 regulates irradiation-induced autophagy through Atg4B to promote radioresistance in hepatocellular carcinoma cells.

Although hepatocellular carcinoma (HCC) is usually response to radiation therapy, radioresistance is still the major obstacle that limits the efficacy of radiotherapy for HCC patients. Therefore, further investigation of underlying mechanisms in radioresistant HCC cells is warranted. In this study, we determined the effect of early growth response factor (Egr-1) on irradiation-induced autophagy and radioresistance in HCC cell lines SMMC-7721 and HepG2. We showed that autophagy-related gene 4B (Atg4B) is induced by Egr-1 upon ionizing radiation (IR) in HCC cells. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) revealed that Egr-1 binds to the Atg4B promoter to upregulate its expression in HCC cells. Suppression of Egr-1 function by dominant-negative Egr-1 dampens IR-induced autophagy, cell migration, and increases cell sensitivity to radiotherapy. Together, these results suggest that Egr-1 contributes to HCC radioresistance through directly upregulating target gene Atg4B, which may serve as a protective mechanism by preferential activation of the autophagy.

Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis.

BC200 is a long non-coding RNA (lncRNA) that has been implicated in the regulation of protein synthesis, yet whether dysregulation of BC200 contributes to the pathogenesis of human diseases remains elusive. In this study, we show that BC200 is upregulated in breast cancer; among breast tumor specimens there is a higher level of BC200 in estrogen receptor (ER) positive than in ER-negative tumors. Further experiments show that activation of estrogen signaling induces expression of BC200. To determine the significance of ER-regulated BC200 expression, we knockout (KO) BC200 by CRISPR/Cas9. BC200 KO suppresses tumor cell growth in vitro and in vivo by expression of the pro-apoptotic Bcl-xS isoform. Mechanistically, BC200 contains a 17-nucleotide sequence complementary to Bcl-x pre-mRNA, which may facilitate its binding to Bcl-x pre-mRNA and recruitment of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a known splicing factor. Consequently, hnRNP A2/B1 interferes with association of Bcl-x pre-mRNA with the Bcl-xS-promoting factor Sam68, leading to a blockade of Bcl-xS expression. Together, these results suggest that BC200 plays an oncogenic role in breast cancer. Thus, BC200 may serve as a prognostic marker and possible target for attenuating deregulated cell proliferation in estrogen-dependent breast cancer.

1,25-Dihydroxyvitamin D3 regulates expression of LRP1 and RAGE in vitro and in vivo, enhancing Aß1-40 brain-to-blood efflux and peripheral uptake transport.

Alzheimer's disease (AD) is characterized by the accumulation and deposition of plaques of amyloid-ß (Aß) peptide in the brain. Growing epidemiological and experimental studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts neuroprotection against AD. However, the underlying mechanisms of the action remain unclear. Since Aß clearance plays a crucial role in Aß balance in the brain, the aim of the present study was to investigate potential effects of 1,25(OH)2D3 on Aß1-40, the major soluble oligomeric form of Aß, clearance via transport across blood-brain barrier (BBB) mediated by low-density lipoprotein receptor-related protein 1 (LRP1) (efflux) and receptor for advanced glycation end products (RAGE) (influx) and peripheral uptake by liver mediated by LRP1. We identified colocalization of LRP1 and RAGE at BBB of mice, established an in vitro BBB model by culturing monolayer mouse brain microvascular endothelial cell line (bEnd.3) cells under hypoxia and observed that 1,25(OH)2D3 treatment enhanced Aß1-40 efflux across the BBB model and uptake by HepG2 cells. After 1,25(OH)2D3 exposure, LRP1 expression was increased significantly both in vivo and in vitro, and RAGE expression was reduced in the in vitro BBB model but not in microvascular endothelial cells of mice hippocampus. Additionally, we explored the correlation between the corresponding effects of 1,25(OH)2D3 and its nuclear hormone receptor vitamin D receptor (VDR) level. We found that VDR expression was upregulated after 1,25(OH)2D3 treatment both in vivo and in vitro. Collectively, our finding that 1,25(OH)2D3 reduces cerebral Aß1-40 level by increasing Aß1-40 brain-to-blood efflux and peripheral uptake through regulating LRP1 and RAGE could shed light on the mechanism of 1,25(OH)2D3 neuroprotection against AD. And the action of 1,25(OH)2D3 might be associated with the VDR pathway.

The effects of food on the pharmacokinetics of mitiglinide tablets in healthy volunteers and a novel mass-spectrometric (UPLC-MS/MS) method for such studies.

WHAT IS KNOWN AND OBJECTIVE: Mitiglinide (MGN) is a new insulinotropic agent of the glinide class with rapid onset. The effects of food intake on the pharmacokinetic (PK) profile of mitiglinide tablets after single oral administration have not yet been reported in healthy adults. We aimed to assess the effects of food intake on the PK properties of mitiglinide (MGN) tablets, using a novel analytical method, after single escalating oral doses in healthy Chinese volunteers. METHODS: In this open-label, randomized, single-dose (three distinct doses), two-way crossover PK study, three doses of MGN 5, 10 or 20 mg were administered to healthy adult volunteers after an overnight fast (fasted condition) or low-fat breakfast (fed condition) (period 1). After 7 days, the participants received the same dose under the opposite fed/fasted condition (period 2). Serial blood samples were obtained before and through 8 h after study drug administration. Concentrations of MGN in plasma were determined using UPLC-MS/MS. Adverse events (AEs) were monitored and recorded on each in-clinic day. RESULTS AND DISCUSSION: Twenty-four Chinese volunteers (eight [four men, four women] volunteers per group) were enrolled in the study. The extent of absorption of MGN was similar in both fed and fasted conditions at single doses in the range 5-20 mg. Food intake was associated with decreases in C(max) by 60·4% to 65·2% in the three dose groups and greatly delayed T(max) [0·36(Standard deviation 0·16) vs. 1·75(0·92) hours with 5 mg, 0·29(0·19) vs. 1·97(0·81) hours with 10 mg and 0·30(0·10) vs. 1·18(0·68) hours with 20 mg; all, P < 0·05]. t(1/2) , CL/F and V/F (P > 0·05) were unaffected. MRT(0-8) at the 5 and 10-mg doses, but not at the 20-mg dose, were markedly lower in fasted volunteers than fed volunteers (P < 0·05). WHAT IS NEW AND CONCLUSIONS: Using a novel UPLC-MS/MS method, we showed that food intake affected the rate but not the extent of absorption of MGN within the 5- to 20-mg dose range. Gender did not appear to affect the PK properties of MGN in either fasted or fed states. MGN should be preferably taken before food.

Validated LC-MS/MS assay for the quantitative determination of nalbuphine in human plasma and its application to a pharmacokinetic study.

A solid-phase extraction-liquid chromatographic-tandem mass spectrometry method for the determination of nalbuphine concentrations in human plasma has been developed. Samples (1 mL) were extracted using a Strata™-X solid phase extraction cartridges. Chromatographic separation of nalbuphine and naloxone (internal standard) was achieved on a Phenomenex Kinetex PFP (2.6 µm, 100 A, 100 × 2.1 mm) column using a mobile phase consisting of 0.1% formic acid, 15 mM ammonium acetate in deionized water and acetonitrile (60:40, v/v). The flow rate was 0.3 mL/min and the total run time was 2 min. Detection of the analytes was achieved using positive ion electrospray ionization via multiple reactions monitoring mode. The mass transitions were m/z 358 → 340 for nalbuphine and m/z 328 → 310 for naloxone. The assay was linear over the concentration range 0.50-500.00 ng/mL, with correlation coefficients ≥0.995. The lower limit of quantitation was set at 0.5 ng/mL plasma based on an average signal-to-noise ratio of 44.79. The intra- and inter-day precision was less than 8.07% in terms of relative standard deviation and accuracy ranged from 94.97 to 106.29% at all quality control levels. The method was applied successfully to determine nalbuphine concentrations in human plasma samples obtained from subjects receiving intravenous administration of nalbuphine. The method is rapid, sensitive, selective and directly applicable to human pharmacokinetic studies involving nalbuphine.

Identifying high-risk areas of schistosomiasis and associated risk factors in the Poyang Lake region, China.

The epidemiology of schistosomiasis japonicum over small areas remains poorly understood, and this is particularly true in China. We aimed to identify high-risk areas for schistosomiasis and associated risk factors in the Poyang Lake region, China. A cross-sectional study was conducted and 60 of 920 persons (6.5%) were found to be infected with Schistosoma japonicum. Locations of households and snail habitats were determined using a hand-held global positioning system. We mapped the data in a geographical information system and used spatial scan statistics to explore clustering of infection, logistic regression and Bayesian geostatistical models to identify risk factors for each individual's infection status and multinomial logistic regression to identify risk factors for living in a cluster area. The risk of schistosomiasis was spatially clustered and higher in fishermen and males, not in persons who lived in close proximity to snail habitats and infected water sources. This study has demonstrated significant spatial variation in the prevalence of schistosomiasis at a small spatial scale. The results suggest that demographic factors (gender, occupation) rather than the distance to infected water are driving human transmission at small-scale spatial levels. Such information can be used to plan locally targeted interventions based on anthelminthic drug administration, snail control and sanitation improvement.

Location of active transmission sites of Schistosoma japonicum in lake and marshland regions in China.

Schistosomiasis control in China has, in general, been very successful during the past several decades. However, the rebounding of the epidemic situation in some areas in recent years raises concerns about a sustainable control strategy of which locating active transmission sites (ATS) is a necessary first step. This study presents a systematic approach for locating schistosomiasis ATS by combining the approaches of identifying high risk regions for schisotosmiasis and extracting snail habitats. Environmental, topographical, and human behavioural factors were included in the model. Four significant high-risk regions were detected and 6 ATS were located. We used the normalized difference water index (NDWI) combined with the normalized difference vegetation index (NDVI) to extract snail habitats, and the pointwise 'P-value surface' approach to test statistical significance of predicted disease risk. We found complicated non-linear relationships between predictors and schistosomiasis risk, which might result in serious biases if data were not properly treated. We also found that the associations were related to spatial scales, indicating that a well-designed series of studies were needed to relate the disease risk with predictors across various study scales. Our approach provides a useful tool, especially in the field of vector-borne or environment-related diseases.

Generalized negative binomial distribution: a promising statistical distribution for Oncomelania hupensis in the lake- and marsh-land regions of China.

A new generalization of the negative binomial distribution (GNBD) is introduced and fitted to counts of Oncomelania hupensis, the intermediate host of Schistosoma japonicum, made, in areas of Chinese lakeland and marshland, early in the winter of 2005 and late in the spring of 2006. The GNBD was found to fit the snail data better than the standard negative binomial distribution (NBD) that has previously been widely used to model the distribution of O. hupensis. With two more parameters than the NBD, the GNBD can integrate many discrete distributions and is more flexible than the NBD in modelling O. hupensis. It also provides a better theoretical distribution for the quantitative study of O. hupensis, especially in building an accurate prediction model of snail density. The justification for adopting the GNBD is discussed. The GNBD allows researchers to broaden the field in the quantitative study not only of O. hupensis and schistosomiasis japonica but also of other environment-related helminthiases and family-clustered diseases that have, traditionally, been modelled using the NBD.

Localization and activity of calmodulin is involved in cell-cell adhesion of tumor cells and endothelial cells in response to hypoxic stress.

Adhesion of tumor cells to endothelial cells is known to be involved in the hematogenous metastasis of cancer, which is regulated by hypoxia. Hypoxia is able to induce a significant increase in free intracellular Ca2+ levels in both tumor cells and endothelial cells. Here, we investigate the regulatory effects of calmodulin (CaM), an intracellular calcium mediator, on tumor cell-endothelial cell adhesion under hypoxic conditions. Hypoxia facilitates HeLa cell-ECV304 endothelial cell adhesion, and results in actin cytoskeleton rearrangement in both endothelial cells and tumor cells. Suppression of CaM activation by CaM inhibitor W-7 disrupts actin cytoskeleton organization and CaM distribution in the cell-cell contact region, and thus inhibits cell-cell adhesion. CaM inhibitor also downregulates hypoxia-induced HIF-1-dependent gene expression. These results suggest that the Ca2+ -CaM signaling pathway might be involved in tumor cell-endothelial cell adhesion, and that co-localization of CaM and actin at cell-cell contact regions might be essential for this process under hypoxic stress.

Loss of phospholipids asymmetry in red blood cells contributes to anemia in uremic patients.

Anemia is common in dialysis patients. Change in phospholipids asymmetry in red blood cells (RBCs) may affect the removal of RBCs from the circulation and thus shorten the lifespan of RBCs. In the present study, we investigated phospholipids asymmetry in RBCs in uremic patients and its relationship with anemia. We studied 34 continuous ambulatory peritoneal dialysis (CAPD) patients (age: 51 +/- 15 years), 73 hemodialysis (HD) patients (age: 48 +/- 12 years), 8 pre-dialysis renal-failure patients (age: 42 +/- 21 years), and 16 healthy controls (age: 32 +/- 9 years). All patients were clinically stable. Phospholipids asymmetry as measured by phosphatidylserine exposure was determined by a flow-cytometric annexin V-binding assay. Hemoglobin levels were 93 +/- 20 g/L, 83 +/- 17 g/L, 78 +/- 21 g/L, and 145.8 +/- 12.5 g/L for CAPD patients, pre-dialysis patients, HD patients, and healthy controls respectively. Phosphatidylserine exposure in RBCs was significantly higher in uremic patients as compared with healthy controls, especially in HD patients--whose values were significantly higher than values seen in CAPD patients and pre-dialysis patients. No significant difference was seen in RBC phosphatidylserine exposure between pre-dialysis patients and CAPD patients. Cells positive for annexin V binding were 1.58%, 1.40%, 2.11%, and 0.71% for CAPD patients, pre-dialysis patients, HD patients, and healthy controls respectively. Significant reverse correlations were seen between annexin V and hemoglobin (r = -0.381, p < 0.001), and between annexin V and hematocrit (r = -0.355, p < 0.001). Our results suggest that (1) anemia is common in our uremic patients, especially in HD patients; and (2) anemia in uremic patients may be partly related to the loss of phospholipids asymmetry in RBCs.

Hyaluronan preserves peritoneal membrane transport properties.

BACKGROUND: We have shown that intraperitoneal (i.p.) addition of hyaluronan (HA) in a single dwell study in rat could increase peritoneal fluid removal by decreasing the peritoneal fluid absorption rate. In this study, we investigated the impact of repeated use of HA on peritoneal membrane transport characteristics. METHODS: Twelve male Sprague-Dawley rats received a once-daily i.p. injection of 25 mL 4.25% glucose dialysis solution without (HP group, n = 6) or with 0.025% HA (HA group, n = 6) for 1 week. Forty-eight hours after the last injection, a 4-hour dwell using 25 mL 4.25% glucose dialysis solution with i.p. volume marker and frequent dialysate and blood samplings was performed in each rat as well as in rats that did not receive any injection (control group, n = 8). RESULTS: Although the i.p. volumes were significantly lower in the HP and HA groups compared to the control group, i.p. volume in the HA group was significantly higher than in the HP group. Net ultrafiltration at 4 hours was 5.6 +/- 1.3 mL, 10.2 +/- 1.8 mL, and 13.2 +/- 0.6 mL for the HP, HA, and control group, respectively. The peritoneal fluid absorption rate decreased by 45% in the HA group compared to the HP group. There was no significant difference in peritoneal fluid absorption rate between the HA and the control group. No difference was found in the direct lymphatic absorption rate between the HP and HA groups [0.010 +/- 0.003 mL/minute in the HP group and 0.011 +/- 0.004 mL/min in the HA group] although they were both higher than that of the control group (0.004 +/- 0.001 mL/min). The solute transport rates were in general significantly higher in the HP group compared to the HA and control groups, and there was no significant difference between the latter two groups, except that protein transport rate was significantly lower in the HA group compared to the control group. CONCLUSIONS: The present study suggests that (1) repeated exposure to hypertonic glucose-based dialysis solution results in increased peritoneal solute transport rates, as well as increased peritoneal fluid absorption rates; and (2) these changes, reflecting a highly permeable peritoneal membrane, were ameliorated by repeated i.p. addition of hyaluronan. The similar changes in the direct lymphatic absorption rate in rats that received daily i.p. injection of dialysis solution suggest that direct peritoneal lymphatic absorption was not influenced by hyaluronan.

Increased peritoneal membrane permeability is associated with abnormal peritoneal surface layer.

OBJECTIVES: We recently showed that the peritoneal surface layer may be an important barrier in modulating peritoneal membrane permeability. In the present study, we investigated the relationship between an increased peritoneal transport rate and the peritoneal surface layer. METHODS: Male Sprague-Dawley rats (n = 8) received intraperitoneal injections of 4.25% glucose dialysate daily for 1 week. Forty-eight hours after the last injection, a 4-hour dwell study using 25 mL 4.25% glucose dialysate was performed in each rat. The results were compared with those from control rats that received no intraperitoneal injections (n = 8). The peritoneal fluid and small-solute transport characteristics were evaluated. The peritoneal surface layer was studied using an electron microscope. The phospholipids content of the dialysate was also evaluated. RESULTS: Peritoneal fluid removal was significantly reduced in the daily injection group (30.6 +/- 1.3 mL) as compared with the control group (38.2 +/- 0.6 mL). The peritoneal fluid absorption rate and small-solute transport rate were also significantly higher in the daily injection group as compared with the control group. The amounts of phospholipids in the dialysate were significantly lower in the daily injection group--especially the quantity of phosphatidylcholine. However, lysophosphatidylcholine increased significantly in the daily injection group. Electron microscopy showed that the peritoneal surface layer was almost completely gone in the daily injection group, but that a dense and thick (average 4 microm) peritoneal surface layer was present on the top of the mesothelial cells in the control group. CONCLUSIONS: Our results suggest that daily injection of hypertonic glucose dialysate significantly increased the peritoneal transport rate. The increased peritoneal transport rate was associated with a significant reduction in the peritoneal surface layer and the phospholipids content of the dialysis effluent.

Comparison of three chronic dialysis models.

The chronic peritoneal dialysis model is important for understanding the pathophysiology of peritoneal transport and for studying biocompatibility of peritoneal dialysis solutions. In this study, we compared three different chronic peritoneal dialysis models. A peritoneal catheter was placed in 23 male Sprague-Dawley rats, 12 of which had an intact omentum (model 1) and 11 of which received an omentectomy (model 2). Seven other rats, without a catheter, received a daily intraperitoneal injection (model 3). Each rat received a daily infusion of 25 mL of 3.86% glucose dialysis solution either through the catheter (models 1 and 2) or through injection (model 3) for 4 weeks. Then, a 4-hour dwell study using 3.86% glucose solution with an intraperitoneal volume marker and frequent dialysate and blood sampling was performed in each rat. The intraperitoneal volume was significantly lower in all the dialysis groups as compared to a control group (n = 6) in which the rats had no chronic dialysate exposure. The peritoneal fluid absorption rate, as well as the direct lymphatic absorption rate, was significantly higher in the three dialysis groups as compared to the control group. In general, no significant differences were seen in any of the parameters among the three dialysis models. Owing to catheter obstruction, three rats in model 1 and four rats in model 2 were lost during dialysis. Histological examination showed no significant differences among the three dialysis groups. Our results suggest that omentectomy may not be necessary in the chronic peritoneal dialysis model when using dialysate infusion and no drainage. Based on the present study, we think that perhaps model 1 may be the method of choice to test new peritoneal dialysis solutions. However, owing to its simplicity, model 3 could also be used if great care is taken to avoid puncturing the intestine or injecting into the abdominal wall.

Urban air pollution monitoring: laser-based procedure for the detection of carbon monoxide gas.

Urban air quality is of considerable importance in many cities throughout Europe and the USA. In particular, current EU legislation has driven an expansion of monitoring of more pollutants at more sites. At present in the UK, real time readings are now available for benzene, buta-1,3-diene and other volatile organic compounds, airborne fine dust (PM10), CO, 03, SO2, and NOX. Carbon monoxide is produced to varying degrees in all combustion processes but more than 90% is caused by emissions from petrol vehicle exhausts. The World Health Ogranisation guidelines for exposure to the gas is < 10 ppm for 8 h and 85 ppm for periods not exceeding 15 min. All the pollutants mentioned above are monitored by different detection techniques and it has been the authors' philosophy to develop instrumentation which can monitor all the different pollutants using a single detector. To this end, a multiphoton laser based procedure, using simple ionization chambers, has been developed to detect the different pollutants with different wavelengths. For CO, a 2 + 1 resonance enhanced multiphoton ionization (REMPI) scheme at 230 nm can be used with detection limits of about 1 ppm.

[Determination of sinomenine HCl in serum and urine by HPLC and its pharmacokinetics in normal volunteers].

A RP-HPLC method was developed to determine the concentrations of sinomenine HCl in serum and urine and its pharmacokinetics was studied in healthy volunteers. C18H37 column was eluted with the mobile phase of acetonitrile--0.01 mol.L-1 sodium phosphate monobasic--N, N, N', N'-tetramethylenediamine (46:54:0.22 v/v, pH 6.9) and the ultraviolet absorbance was monitored at 263 nm. Triazolan was used as internal standard. The calibration curves were linear in the range of 6-480 ng.ml-1 in serum and 0.06-3 micrograms.ml-1 in urine, with mean recoveries of 75.46% and 91.38% respectively. The lowest detectable limits were 4 ng.ml-1 in serum and 40 ng.ml-1 in urine and the RSD for the intra-day and inter-day were less than 5%. A single oral dose of 80 mg sinomenine HCl tablet was given to 8 healthy male volunteers. The concentrations of sinomenine HCl in serum and urine were determined. The serum concentration--time curve was found to fit a two-compartment open model with first order elimination. The pharmacokinetic parameters were: T1/2 alpha 0.791 +/- 0.491 h, T1/2 beta 9.397 +/- 2.425 h, Tmax 1.040 +/- 0.274 h, Cmax 246.604 +/- 71.165 ng.ml-1, AUC 2651.158 +/- 1039.050 ng.h.ml-1, CL 0.033 +/- 0.010 ng.ml-1.