NR0B1 augments sorafenib resistance in hepatocellular carcinoma through promoting autophagy and inhibiting apoptosis.

NR0B1 is frequently activated in hepatocellular carcinoma (HCC). However, the role of NR0B1 is controversial in HCC. In this study, we observed that NR0B1 was an independent poor prognostic factor, negatively correlated with the overall survival of HCC and the relapse-free survival of patients treated with sorafenib. Meanwhile, NR0B1 promoted the proliferation, migration, and invasion of HCC cells, inhibited sorafenib-induced apoptosis, and elevated the IC50 of sorafenib in HCC cells. NR0B1 was further displayed to increase sorafenib-induced autophagic vesicles and activate Beclin1/LC3-II-dependent autophagy pathway. Finally, NR0B1 was revealed to transcriptionally suppress GSK3ß that restrains AMPK/mTOR-driven autophagy and increases BAX-mediated apoptosis. Collectively, our study uncovered that the ectopic expression of NR0B1 augmented sorafenib-resistance in HCC cells by activating autophagy and inhibiting apoptosis. Our findings supported that NR0B1 was a detrimental factor for HCC prognosis.

Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer.

BACKGROUND: BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene. OBJECTIVE: This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC. METHODS: Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line. RESULTS: A novel nonsense variant (c.1114A > T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway. CONCLUSION: The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.

Study of the stereospecificity in the biotransformation of the four isomers of loxoprofen sodium in rats by chiral HPLC.

Loxoprofen sodium is a chiral drug with two chiral centers. In our previous work, we found that the elimination of its four isomers showed stereospecificity in rats, while how the stereospecific behavior occurred in vivo was unclear. To clarify this issue, each single isomer of loxoprofen sodium was prepared by a chiral semi-preparative high-performance liquid chromatography (HPLC) and then administered to rats. By analysis of each isomer in rat plasma utilizing an analytical chiral HPLC, it was discovered that the chiral inversion occurred only to its (2R)-isomers, one from (1'S,2R)- to (1'S,2S)-isomer and the other from (1'R,2R)- to (1'R,2S)-isomer. The reduction of α-substituted cyclopentanone occurred only to its (1'R)-isomers, with (1'R,2R)-isomer reduced to (2'S,1'R,2R)-trans-alcohol and (1'R,2S)- to (2'S,1'R,2S)-trans-alcohol. Interestingly, both the inversion and the reduction reaction occurred to its (1'R,2R)-isomer due to the special stereo-structure with both (2R)- and (1'R)-configuration, and conversely, neither of them occurred to its (1'S,2S)-isomer, which caused the significantly different elimination rate in vivo. These new findings were meaningful for evaluation of the safety and efficacy of chiral drugs.

Plasmonic Probing of Deoxyribonucleic Acid Hybridization at the Single Base Pair Resolution.

Partial DNA duplex formation greatly impacts the quality of DNA hybridization and has been extensively studied due to its significance in many biological processes. However, traditional DNA sensing methods suffer from time-consuming amplification steps and hinder the acquisition of information about single-molecule behavior. In this work, we developed a plasmonic method to probe the hybridization process at a single base pair resolution and study the relationship between the complementarity of DNA analytes and DNA hybridization behaviors. We measured single-molecule hybridization events with Au NP-modified ssDNA probes in real time and found two hybridization adsorption events: stable and transient adsorption. The ratio of these two hybridization adsorption events was correlated with the length of the complementary sequences, distinguishing DNA analytes from different complementary sequences. By using dual incident angle excitation, we recognized different single-base complementary sequences. These results demonstrated that the plasmonic method can be applied to study partial DNA hybridization behavior and has the potential to be incorporated into the identification of similar DNA sequences, providing a sensitive and quantitative tool for DNA analysis.

High-sensitivity optical fiber magnetic field sensor based on multimode optical fiber multi Fabry-Perot interference cavities.

A high-sensitivity optical fiber magnetic field sensor based on a multi-Fabry-Perot interference (F-P) cavity in an etched multimode optical fiber (MMF) was proposed. The MMF was etched along the fiber axis and a hole with the length of about 250 µm formed in the MMF. The multi-F-P cavity in the MMF is a sandwich structure, which is composed of UV glue, magnetic fluid and UV glue. The refractive index and effective cavity length of the magnetic fluid cavity change with the changing of the external magnetic field, which will result in changes of the reflection spectra of the multi-F-P. Thus, the external magnetic field could be detected by the changes of spectra. Experimental results showed that the high magnetic field sensitivity of 299.7 pm/mT and 0.164 dB/mT were obtained in the range of 0∼8 mT weak magnetic induction intensity by using the wavelength and intensity demodulations, respectively. The proposed sensor shows the potential applications in the magnetic field measurement in the weak magnetic environment.

A New Method for Erosion Prediction of 90° Elbow Based on Non-Axisymmetric Ultrasonic-Guided Wave and the PSO-LSSVM Algorithm.

The non-axisymmetric exciting guided wave can detect the thinning section of the elbow, and the time domain energy value of the signal collected at the outer arch position of the receiving end displays a downward trend as the remaining thickness of the erosion area decreases. To address the difficulty in detecting the erosion degree of the elbow with high accuracy, this paper uses the linear frequency modulation (LFM) signal to excite a non-axisymmetric guided wave that propagates in the 90° elbow and collects signals through four PZT receivers. To predict the erosion degree, the corresponding relationship between the energy value of the four signals after fractional Fourier filtering and the degree of elbow erosion is established through the particle swarm optimization (PSO)-least squares support vector machine (LSSVM) algorithm. The results show that the method proposed has an average accuracy rate of 98.1864%, 94.7167%, 99.119%, and 99.9593% for predicting the erosion degree of four elbow samples, and 94.0039%. and 81.2976% for two new erosion degrees, which are higher than the nonlinear regression model, LSSVM algorithm, and BP neural network algorithm. This study has guiding significance for real-time monitoring of elbow erosion.

Chiral Separation, Configuration Confirmation and Bioactivity Determination of the Stereoisomers of Hesperidin and Narirutin in Citrus reticulata Blanco.

Hesperidin and narirutin are a class of flavanone glycosides, which are the main active constituents in Citrus reticulata Blanco. In the present study, a chiral HPLC-UV method with amylose tris(3,5-dimethylphenylcarbamate) as a stationary phase under a normal-phase mode was used to achieve the stereoselective separation of the C-2 diastereomers of hesperidin and narirutin simultaneously. The single epimer was then successfully prepared by applying semi-preparative chromatography, whose absolute configuration (R/S) was characterized by combining the experimental electronic circular dichroism (ECD) detection with time-dependent density functional theory (TDDFT) calculations. The epimer composition of these two chiral flavanone glycosides in Citrus reticulata Blanco was then determined, which was found to be slightly different in the herbs from different production regions. The anti-inflammatory activity of each prepared single epimer was further evaluated, and some differences between one pair of epimers of hesperidin and narirutin were observed, which suggested that the presence of different epimers should be considered in the quality evaluation and control of natural medicine.

A novel missense variant c.71G > T (p.Gly24Val) of the CRYBA4 gene contributes to autosomal-dominant congenital cataract in a Chinese family.

PURPOSE: To investigate the potential genetic defects in a five-generation Chinese family with autosomal dominant congenital cataract (ADCC). METHODS: Whole exome sequencing was performed to search the variants in the candidate genes associated with congenital cataract. Sanger sequencing was used to validate the variants and examine their co-segregation in the patients and their relatives. The potential effect of the variants was analyzed using several bioinformatic methods and further examined through Western blotting and co-immunoprecipitation. RESULTS: A missense variant c. 71 G > T (p. Gly24Val) in the CRYBA4 gene, a known ADCC candidate gene, was identified to be heterozygously present in the patients and co-segregate with cataract in the family. The mutation was absent in all of the searched databases, including our in-house exome sequences of 10,000 Chinese. The alignments of the amino acid sequences of CRYBA4 in a variety of species revealed that the amino acid residue Gly24 was evolutionarily highly conserved, and the in silico analysis predicted that the missense mutation of Gly24Val was damaging for the protein structure and function of CRYBA4. Then, the in vitro expression analysis further revealed that the Gly24Val mutation in CRYBA4 inhibited its binding with CRYBB1. The impaired interaction of ß-crystallin proteins may affect their water-solubility and contribute to the formation of precipitates in lens fiber cells. CONCLUSION: We identified a novel missense variant in the CRYBA4 gene as a pathogenic mutation of ADCC in a Chinese family. Our finding expanded the CRYBA4 variation spectrum associated with congenital cataracts.

Identification of novel single-nucleotide variants altering RNA splicing of PKD1 and PKD2.

The development of sequencing techniques identified numerous genetic variants, and accurate evaluation of the clinical significance of these variants facilitates the diagnosis of Mendelian diseases. In the present study, 549 rare single- nucleotide variants of uncertain significance were extracted from the ADPKD and ClinVar databases. MaxEntScan scoresplice is an in silico splicing prediction tool that was used to analyze rare PKD1 and PKD2 variants of unknown significance. An in vitro minigene splicing assay was used to verify 37 splicing-altering candidates that were located within seven residues of the splice donor sequence excluding canonical GT dinucleotides or within 21 residues of the acceptor sequence excluding canonical AG dinucleotides of PKD1 and PKD2. We demonstrated that eight PKD1 variants alter RNA splicing and were predicted to be pathogenic.

Spatiotemporal self-mode-locked operation in a compact partial multimode Er-doped fiber laser.

We report spatiotemporal self-mode-locked operation at 1.55 µm with a low pump threshold of 32 mW in a compact partial multimode fiber laser system. Spatial filtering and the saturable absorber, both of which originate from the multimode interference (linear or nonlinear) of the single mode-multimode structure in this hybrid configuration, are well suited to the spatiotemporal self-mode-locked operation. Not only stable multimode conventional solitons with different spectral bandwidths but also a multimode soliton molecule complex with different structural bound-state patterns are obtained. It is found that the spatiotemporal evolution of the multimode solitons is dependent on many factors, such as the operating state, the involved frequency component, and the interaction between solitons. Furthermore, an unstable spatiotemporal mode-locked (STML) state where the beam profiles of the solitons change spontaneously is also observed for a specific multimode fiber state and pump power.

Chemical element concentrations in cord whole blood and the risk of preterm birth for pregnant women in Guangdong, China.

Maternal exposure to chemical elements, including essential and non-essential elements, have been found to be associated with preterm births (PTB). However, few studies have measured element concentrations in cord whole blood, which reflects activity at the maternal-fetal interface and may be biologically associated with PTBs. In this study, we determined concentrations of 21 elements in cord whole blood and explored the associations between element concentrations and PTB in a nested case-control study within a birth cohort in Guangdong, China. Finally, 515 preterm infants and 595 full-term infants were included. We performed single-element and multi-element logistic regressions to evaluate linear relationships between element concentrations and PTB. According to the results of single-element models, most essential elements (including K, Ca, Si, Zn, Se, Sr and Fe) were negatively associated with PTB, while Cu, V, Co and Sn were positively associated with PTB. Of the non-essential elements, Sb, Tl, and U were positively associated with PTB, while Pb was negatively associated with PTB. The multi-element model results for most elements were similar, except that the association between Mg and PTB was shown to be significantly positive, and the association for Cu became much larger. A possible explanation is that the effects of Mg and Cu may be influenced by other elements. We performed restricted cubic spline (RCS) regressions and found significantly non-linear exposure-response relationships for Mg, Se, Sr, K and Sb, indicating that the effects of these elements on PTB are not simply detrimental or beneficial. We also examined the joint effect using a Bayesian kernel machine regression (BKMR) model and found the risk of PTB decreased significantly with element mixture concentration when lnC was larger than the median. Bivariate interaction analysis suggested antagonistic effects of Sb on Zn and Sr, which may be attributed to Sb negating the antioxidant capacity of Zn and Sr. This study provides additional evidence for the effect of element exposures on PTB, and will have implications for the prevention of excessive exposures or inappropriate element supplementation during pregnancy.

Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells.

Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples. The acetyl-histone H4 and trimethylated histone H3-lysine 4, two post-translational modifications of histones occupying the TSPY1 promoter, facilitated the TSPY1 expression in PCa cells. In addition, we found that androgen accelerated the TSPY1 transcription on the condition of hypomethylated of TSPY1-CGI and promoted PCa cell proliferation. Moreover, the binding of androgen receptor (AR) to the TSPY1 promoter, enhancing TSPY1 transcription, was detected in PCa cells. Taken together, our findings identified the regulation of DNA methylation, acting as a primary mechanism, on TSPY1 expression in PCa, and revealed that TSPY1 is an androgen-AR axis-regulated oncogene, suggesting a novel and potential target for PCa therapy.

NIR-Activated Multimodal Photothermal/Chemodynamic/Magnetic Resonance Imaging Nanoplatform for Anticancer Therapy by Fe(II) Ions Doped MXenes (Fe-Ti3 C2 ).

2D MXene, Ti3 C2 (TC), has displayed enormous potential in applications in photothermal therapy (PTT), attributing to its biocompatibility and outstanding photothermal conversion capability. However, some tumor ablations are difficult to be realized completely by monotherapy due to the essential defects of monotherapy and intricate tumor microenvironment (TME). In this work, the appropriate doped Fe2+ ions are anchored into the layers of 2D ultrathin TC nanosheets (TC NSs) to synthesize a novel multifunctional nanoshell of Fe(II)-Ti3 C2 (FTC) through interlayer electrostatic adsorption. FTC possesses superior photothermal conversion efficiency (PTCE) than TC NSs, attributing to the enhanced conductivity promoted by interlaminar ferrous ion-channels. Moreover, Fenton reaction based on ferrous ions endows FTC the abilities of reactive oxide species (ROS) releasing and glutathione (GSH) suppression triggered by near-infrared (NIR) laser, featuring splendid biocompatibility and curative effect in hypoxic TME. Meanwhile, magnetic resonance imaging (MRI) responding in FTC reveals the potential as an integrated diagnosis and treatment nanoplatform. FTC could provide new insights into the development of multimoded synergistic nanoplatform for biological applications, especially breaking the shackles of MXenes merely used as a photo-thermal agent (PTA), adopting it to bioimaging sensor and drug loading.

Generation of coherent multicolor noise-like pulse complex in Yb-doped fiber laser mode-locked by GIMF-SA.

We have demonstrated the generation of multicolor noise-like pulse complex in a passively Yb-doped mode-locked fiber laser based on a single mode-graded index multimode-single mode fiber (SMF-GIMF-SMF) device as the saturable absorber (SA). The stimulated Raman scattering (SRS) effect leads to the cascaded generation of the main noise-like pulse (NLP) at 1028.8 nm together with the noise like Raman pulse (RP) at 1076.1 nm. The generated dual wavelength pulses demonstrate the unique properties of mutually synchronization and coherence. The autocorrelation traces show that each of the synchronously mode-locked pulses exhibits a double-scale structure with a narrow peak which consists of a train of quasi-periodic beat pulses with a 35.7 fs pulse width and a pulse separation of about 77.2 fs. The total output power reaches 102.5 mW with 34% of it belonging to the RP. And furthermore, by separating the two pulses with spectral filters, the modulation fringes cannot be observed anymore. These results indicate that the Raman component participates in the mode-locking operation as a 'signal' instead of 'noise'. Such a coherent Raman pulse source provides a novel platform for numerous applications, such as frequency comb spectroscopy and so on.

Raman-scattering-assistant large energy dissipative soliton and multicolor coherent noise-like pulse complex in an Yb-doped fiber laser.

In this Letter, we have demonstrated the generation of dissipative solitons (DSs) or multi-wavelength noise-like pulses (NLPs) directly from a common linear Yb-doped fiber laser in the presence of stimulated Raman scattering (SRS). For the DSs, the pulse energy of the solitons with a pulse width of 74.2 ps reaches 21.2 nJ. For the NLPs, the generation of the main NLP (1032 nm) together with the first-order Raman NLP (1080 nm) is realized. The narrow peak of the double-scale autocorrelation trace is characterized by quasi-periodic beat pulses with a pulse beating of 40.6 fs and a pulse separation of 79 fs, indicating that the generated solitons at dual wavelengths are mutually coherent. Furthermore, a three-color stable NLP complex with a broader spectrum is also obtained. The results contribute to an in-depth understanding of nonlinear dynamics and ultrafast physics.

High-power synchronous multi-wavelength solitons from a multimode mode-locked fiber laser system.

In this Letter, we implement a multimode fiber (MMF) laser system mode-locked by a nonlinear polarization rotation technique for controllable synchronous multi-wavelength soliton generation. The synchronization of the repetition rates for different wavelengths is realized by the special mode transmission in MMF. For dual-wavelength mode-locking at 1566.7 nm and 1617.2 nm, each of the synchronously mode-locked solitons consists of a train of quasi-periodic beat pulses with a pulse width of 84 fs and period of 162 fs. The total output power reaches 532 mW with optimally balanced two-color intensities. Furthermore, switchable dual- and tri-wavelength synchronized femtosecond pulses are also obtained. In contrast to previous reports, this synchronously mode-locked multi-wavelength is output directly from a laser oscillator, which provides a simpler candidate to achieve pulse synchronization.

Enantioselective separation of nonsteroidal anti-inflammatory drugs with amylose tris(3-chloro-5-methylphenylcarbamate) stationary phase in HPLC with a focus on enantiomeric quality control in six pharmaceutical formulations containing racemic mixtures or single stereoisomers.

In the present study, an accurate, rapid, and simple chiral HPLC-UV method with amylose tris(3-chloro-5-methylphenylcarbamate) as stationary phase was developed and applied for enantiomeric determination of six nonsteroidal anti-inflammatory drugs (NSAIDs) in the commercial pharmaceutical formulations, including (R,S)-ibuprofen, S-ibuprofen, (R,S)-ketoprofen, S-ketoprofen, S-naproxen, and (R,S)-loxoprofen sodium. Experiments on the influence of mobile phase composition, proportion of organic modifier, percentage of acid additives, and column temperature on enantioseparation were conducted to obtain the best separation condition. It was indicated that one mobile phase simply composed of acetonitrile-water (0.1% formic acid, v/v) at the proportion of 50:50 (v/v) with a flow rate of 0.6 ml/min at 22°C could simultaneously provide the excellent enantiomeric resolutions for all selected NSAIDs, which made the enantioseparation process more applicable and operable. The newly developed method was then applied for determination of NSAID enantiomers in pharmaceutical formulations containing racemic mixtures or single stereoisomers. Calibration curve of each enantiomer at the concentration of 5.0-100 ug/ml showed good linearity with the correlation coefficient above 0.9996. Satisfactory recovery (96.54-101.54%), good intra-day precision (RSD 0.52-1.46%), and inter-day precision (RSD 0.13-1.09%) were also obtained. The newly developed method was then applied for determination of NSAID enantiomers in pharmaceutical formulations containing racemic mixtures or single stereoisomers. Quantitative results of the commercial capsules and tablets demonstrated that the difference between the declared and measured values did not exceed 1.52%.

Experimental and computational study on the enantioseparation of four chiral fluoroquinolones by capillary electrophoresis with sulfated-ß-cyclodextrin as chiral selector.

In this work, enantioseparation of four chiral fluoroquinolones (FQs), namely, ofloxacin, gemifloxacin, lomefloxacin, and gatifloxacin, was achieved by capillary electrophoresis with sulfated-ß-cyclodextrin (S-ß-CD) as chiral selector. Factors affecting the enantiomeric resolution, such as the concentrations of S-ß-CD, BGE pH conditions, and the buffer types and concentrations, were optimized and discussed. A BGE consisting of 30 g/L S-ß-CD and 30-mM phosphate at pH 4.0 was found fit for enantiomeric resolution of ofloxacin and gemifloxacin, while the same BGE at pH 3.0 was suitable for enantioseparation of lomefloxacin and gatifloxacin. The pH-dependent experiments showed that separation resolutions of four FQs enantiomers were significantly affected by BGE pH, which was thought to be related with the varying electrostatic attraction between the enantiomers and chiral selector. To verify this speculation, molecular docking studies were used for further investigation of the enantiomeric recognition mechanism of S-ß-CD. Molecular model indicated that hydrophobic effect and hydrogen bond were involved in host-guest inclusion, but the electrostatic attraction enhanced the chiral discrimination by increasing the difference in binding energy between individual enantiomers and S-ß-CD. This work provided a further insight into the chiral recognition mechanisms of CD derivatives.

Microfiber sensor probe integrated with a cascaded Fabry-Perot interferometer.

Developing micrometer-nanometer size optical fiber sensors has promising application prospects in microenvironments, such as biological cells, micro robots, and microfluids. We propose a new strategy to fabricate a microfiber sensor probe (MSP). A femtosecond laser was applied to integrate cascaded Fabry-Perot interferometers (FPIs) into a silica microfiber. And a MSP with diameter of ∼8µm, extinction ratio of 15 dB, fitness of 24.6, and Q-factor of 2310 was demonstrated in the experiment. In addition, the MSP was applied for the refractive index and thermal measurement and the sensitivity was observed to be 10 pm/°C and 18.5 nm/RIU. The two-beam approximation model was applied to analyze the spectrum, and simulations were taken to research the refractive index sensitivity influenced by the fiber size.

Magnetic solid-phase extraction based on carbon nanosphere@Fe3 O4 for enantioselective determination of eight triazole fungicides in water samples.

In this work, a carbon nanosphere decorated by Fe3 O4 nanoparticles was prepared, characterized and used as the magnetic adsorbent. Eight commonly used chiral triazole fungicides, including penconazole, uniconazole, paclobutrazol, triazolone, tebuconazole, hexaconazole, triticonazole and epoxiconazole were extracted from two environmental water samples (river water and lake water) by magnetic solid-phase extraction, followed by the enantiomeric analysis on a Chiralpark IC column coupled with a triple quadrupole mass spectrometry to evaluate their possible stereoselective degradation occurring in the water samples. The possible factors affecting the extraction performance, such as amount of used adsorbents, pH and ionic strength of water solution, types and volumes of desorption solvents were systematically investigated. Under the optimum conditions, extraction yields of eight triazole fungicides were above 80% and the concentration factors were as high as 1000. Method detection and quantification limits for the enantiomers of eight triazole fungicides were in the range of 0.56-6.95 ng/L. Satisfactory accuracy (relative recovery 77.8-93.5%), good intraday precision (RSD 4.3-9.8%) and interday precision (RSD 3.1-7.9%) were also obtained. The developed method provided the simplicity of operation, rapidity and high enrichment factor, which can be used to monitor and evaluate the behavior of the individual enantiomer of chiral triazole fungicides.