Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation.

Senataxin is an evolutionarily conserved RNA-DNA helicase involved in DNA repair and transcription termination that is associated with human neurodegenerative disorders. Here, we investigated whether Senataxin loss affects protein homeostasis based on previous work showing R-loop-driven accumulation of DNA damage and protein aggregates in human cells. We find that Senataxin loss results in the accumulation of insoluble proteins, including many factors known to be prone to aggregation in neurodegenerative disorders. These aggregates are located primarily in the nucleolus and are promoted by upregulation of non-coding RNAs expressed from the intergenic spacer region of ribosomal DNA. We also map sites of R-loop accumulation in human cells lacking Senataxin and find higher RNA-DNA hybrids within the ribosomal DNA, peri-centromeric regions, and other intergenic sites but not at annotated protein-coding genes. These findings indicate that Senataxin loss affects the solubility of the proteome through the regulation of transcription-dependent lesions in the nucleus and the nucleolus.

A Three-Dimensional Open-Framework Tin(II) Sulfate with Near-Unity Photoluminescence Quantum Yield.

A new open-framework tin(II) sulfate, formulated as C4H12N2·Sn(SO4)2·H2O, was prepared under the structure-directing effect of piperazine. This compound features a 3D structure with 16-ring channels. Under ultraviolet light irradiation, it emits bright yellow luminescence with a near-unity photoluminescence quantum yield. Theoretical calculations were carried out to understand the luminescence mechanism.

Regulation of transcription patterns, poly(ADP-ribose), and RNA-DNA hybrids by the ATM protein kinase.

The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of reactive oxygen species in promoting these lesions. Based on these results, we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.

Synthesis and structure-dependent optical properties of two new organic-inorganic hybrid antimony(III) chlorides.

Two organic-inorganic hybrid antimony(III) chlorides, namely (C9H26N3)2Sb4Cl18 (1) and (C9H26N3)SbCl6 (2), were prepared using a facile solvent evaporation method. They have low-dimensional structures constructed from SbCl6 octahedra and triply protonated N,N,N',N'',N''-pentamethyldiethylenetriamine cations. The organic cations exhibit different conformations in the two compounds. Compound 1 crystallizes in the centrosymmetric space group P1̄, while compound 2 crystallizes in the noncentrosymmetric space group Pca21. Notably, compound 2 exhibits a moderate second harmonic generation (SHG) response of about 1.3 times that of KH2PO4 (KDP) under 1064 nm laser irradiation. Meanwhile, this compound displays green-yellow luminescence under 342 nm ultraviolet light irradiation, indicating its potential as a bifunctional optical material. Theoretical calculations based on density functional theory were also performed to gain insights into the correlation between their structures and optical properties.

Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase.

The ATM protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in Ataxia-telangiectasia patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with expression level and GC content of transcribed genes. In human neuron-like cells in culture we map locations of poly-ADP-ribose and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of ROS in promoting these lesions. Based on these results we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.

Development of an amoxicillin-radix scutellaria extract formulation and evaluation of its pharmacokinetics in pigs.

BACKGROUND: A new antibacterial compound powder of amoxicillin (AMO)/Radix Scutellaria extract (RSE) was developed, and its pharmacokinetics were determined in pigs following oral administration. RESULTS: The MIC ranges of AMO against Escherichia coli, Staphylococcus aureus and Streptococcus were 1-8 µg/mL, 0.5-4 µg/mL and 0.5-64 µg/mL, respectively. The MIC ranges of RSE against E. coli, S. aureus, and Streptococcus were greater than 2.5 mg/mL, 0.156-2.5 mg/mL, and greater than 2.5 mg/mL, respectively. For S. aureus, the combined drug susceptibility test showed that AMO and RSE had an additive or synergistic effect. The results of compatibility test, the excipient screening test and the drug quality control test showed that the formulation had stable quality and uniform properties under the test conditions. Two studies were conducted to investigate the pharmacokinetics of the compound product in pigs. First, the pharmacokinetics of the AMO-RSE powder were compared with those of their respective single products. The results showed no significant change in the main pharmacokinetic parameters when either component was removed from the compound formulation; thus, AMO and RSE have no pharmacokinetic interaction in pigs. Second, pigs were orally administered three different doses of AMO-RSE powder. The Cmax and AUC increased proportionally with increasing p.o. dose; thus, the λz, t1/2λ, MRT, and Tmax were unchanged for the doses of 10, 20, and 30 mg/kg AMO and the doses of 5, 10, and 15 mg/kg BCL, showing that AMO/baicalin in AMO-RSE powder showed linear pharmacokinetic characteristics in pigs. CONCLUSIONS: The combined drug sensitivity test of AMO and RSE against S. aureus showed that the combination was additive or synergistic. Pharmacokinetic studies indicated that AMO and BCL do not interfere with each other in pigs when used in a compound formulation. The pharmacokinetic parameters remained unchanged regardless of the dose for p.o. administration, indicating linear pharmacokinetic properties over the tested dose range. The quality of the AMO-RSE powder was good and stable, providing a foundation for its clinical application in veterinary medicine. Further bioavailability, PK/PD and clinical trials are still needed to determine the final dosage regimen.

Solvent-free synthesis of magnesium phosphite-oxalates that show second-harmonic generation responses.

Two new magnesium phosphite-oxalates were prepared under solvent-free conditions using different amines as structure-directing agents. They feature noncentrosymmetric structures with sql and dia topologies, respectively. The two compounds show moderate second-harmonic generation (SHG) responses under 1064 nm laser irradiation. Theoretical calculations were performed to reveal the origin of their SHG responses.

Host-Guest Symmetry Matching in Two Crystalline Magnesium Sulfate Oxalates Obtained Via a Solvent-Free Route.

The combination of π-conjugated oxalate anion with sulfate group has been explored in the solvent-free synthesis of two new magnesium sulfate oxalates. One of them has a layered structure crystallized in the noncentrosymmetric space group Ia, while the other has a chainlike structure crystallized in the centrosymmetric space group P21/c. The noncentrosymmetric solid has a wide optical bandgap and exhibits a moderate second-harmonic-generation response. Density functional theory calculations were carried out to disclose the origin of its second-order nonlinear-optical response.

A nomogram for predicting residual low back pain after percutaneous kyphoplasty in osteoporotic vertebral compression fractures.

To establish a risk prediction model for residual low back pain after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures. We used retrospective data for model construction and evaluated the model using internal validation and temporal external validation and finally concluded that the model had good predictive performance. INTRODUCTION: The cause of residual low back pain in patients with osteoporotic vertebral compression fractures (OVCFs) after PKP remains highly controversial, and our goal was to investigate the most likely cause and to develop a novel nomogram for the prediction of residual low back pain and to evaluate the predictive performance of the model. METHODS: The clinical data of 281 patients with OVCFs who underwent PKP at our hospital from July 2019 to July 2020 were reviewed. The optimal logistic regression model was determined by lasso regression for multivariate analysis, thus constructing a nomogram. Bootstrap was used to perfomance the internal validation; receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to assess the predictive performance and clinical utility of the model, respectively. Temporal external validation of the model was also performed using retrospective data from 126 patients who underwent PKP at our hospital from January 2021 to October 2021. RESULTS: Lasso regression cross-validation showed that the variables with non-zero coefficients were the number of surgical vertebrae, preoperative bone mineral density (pre-BMD), smoking history, thoracolumbar fascia injury (TLFI), intraoperative facet joint injury (FJI), and postoperative incomplete cementing of the fracture line (ICFL). The above factors were included in the multivariate analysis and showed that the pre-BMD, smoking history, TLFI, FJI, and ICFL were independent risk factors for residual low back pain (P < 0.05). The ROC and calibration curve of the original model and temporal external validation indicated a good predictive power of the model. The DCA curve suggested that the model has good clinical practicability. CONCLUSION: The risk prediction model has good predictive performance and clinical practicability, which can provide a certain basis for clinical decision-making in patients with OVCFs.

DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1.

R loops occur frequently in genomes and contribute to fundamental biological processes at multiple levels. Consequently, understanding the molecular and cellular biology of R loops has become an emerging area of research. Here, it is shown that poly(ADP-ribose) polymerase-1 (PARP-1) can mediate the association of DDX18, a putative RNA helicase, with R loops thereby modulating R-loop homeostasis in endogenous R-loop-prone and DNA lesion regions. DDX18 depletion results in aberrant endogenous R-loop accumulation, which leads to DNA-replication defects. In addition, DDX18 depletion renders cells more sensitive to DNA-damaging agents and reduces RPA32 and RAD51 foci formation in response to irradiation. Notably, DDX18 depletion leads to γH2AX accumulation and genome instability, and RNase H1 overexpression rescues all the DNA-repair defects caused by DDX18 depletion. Taken together, these studies uncover a function of DDX18 in R-loop-mediated events and suggest a role for PARP-1 in mediating the binding of specific DDX-family proteins with R loops in cells.

Complete chloroplast genome sequence of the Tibetan catnip Nepeta hemsleyana Oliver ex Prain (Lamiaceae).

Nepeta hemsleyana Oliver ex Prain (1891) is one of the aromatic Tibetan herbs used to treat convulsions. In this study, the complete chloroplast genome of N. hemsleyana was analyzed and is presented here for the first time. The assembled genome, 152,171 bp in length, contained a large single-copy region (82,214 bp) and a small single-copy region (17,605 bp) separated by a pair of inverted repeats (25,676 bp). A total of 131 genes were identified, including 86 protein-coding genes, 37 transfer RNA genes, and eight ribosomal RNA genes. The phylogenetic analysis also confirmed the early divergence of N. hemsleyana from other species in subtribe Nepetinae.

Preparation, evaluation, and pharmacokinetics in beagle dogs of a taste-masked flunixin meglumine orally disintegrating tablet prepared using hot-melt extrusion technology and D-optimal mixture design.

Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135℃; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.

Preparation and In Vitro/In Vivo Evaluation of Orally Disintegrating/Modified-Release Praziquantel Tablets.

This study was designed to develop orally disintegrating/sustained-release praziquantel (PZQ) tablets using the hot-melt extrusion (HME) technique and direct compression, and subsequently evaluate their release in in vitro and in vivo pharmacokinetics. For the extrusion process, hypromellose acetate succinate (HPMCAS)-LG was the carrier of pure PZQ, with a standard screw configuration used at an extrusion temperature of 140 °C and a screw rotation speed of 100 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and Fourier-transform infrared spectroscopy (FTIR) were performed to characterize the extrudate. Orally disintegrating/sustained-release praziquantel tablets (PZQ ODSRTs) were prepared by direct compression after appropriate excipients were blended with the extrudate. The release amount was 5.10% in pH 1.0 hydrochloric acid at 2 h and over 90% in phosphoric acid buffer at 45 min, indicating the enteric-coating character of PZQ ODSRTs. Compared with the pharmacokinetics of marketed PZQ tablets (Aipuruike®) in dogs, the times to peak (Tmax), elimination half-life (t1/2λ) and mean residence time (MRT) were extended in PZQ ODSRTs, and the relative bioavailability of PZQ ODSRTs was up to 184.48% of that of Aipuruike®. This study suggested that PZQ ODSRTs may have potential for the clinical treatment of parasitosis.

Efficacy of omega-3 polyunsaturated fatty acids on hormones, oxidative stress, and inflammatory parameters among polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: There is a close relationship between hormones, oxidative stress, and inflammatory factors and polycystic ovary syndrome (PCOS). This meta-analysis was conducted to evaluate the changes in hormones, oxidative stress, and inflammatory factors of PCOS patients who were supplemented with omega-3 polyunsaturated fatty acids (n-3 PUFAs). METHODS: The databases of PubMed, Cochrane Library, Embase, and Web of Science were searched from inception to February 2021. We have included all randomized controlled trials (RCTs) that reported the n-3 PUFA treatment in PCOS. Weighted mean differences (WMD) and 95% confidence interval (CI) were calculated, and either the fixed effects model or random effects model was used. RESULTS: 314 studies were initially identified, and 10 RCTs with 610 patients were finally included in the current study. Results suggested that PCOS patients with n-3 PUFAs supplementation may have a reduction in C-reactive protein (CRP; -8.97 mg/dL; 95% CI: -17.66 to -0.28 mg/dL; P=0.04; I2=99%); serum malondialdehyde (MDA; -0.40 mg/dL; 95% CI: -0.56 to -0.25 mg/dL; P<0.00001; I2=42); luteinizing hormone (LH; -1.33 mg/dL; 95% CI: -2.63 to -0.04 mg/dL; P=0.04; I2=0%); serum total testosterone (TT; -0.11 mg/dL; 95% CI: -0.18 to -0.04 mg/dL; P=0.02; I2=73%); and an increase in total antioxidant capacity (TAC; 72.24 mg/dL; 95% CI: 22.32 to 122.16 mg/dL; P=0.005; I2=50%) and serum sex hormone binding globulin (SHBG; 0.68 mg/dL; 95% CI: 0.06 to 1.31 mg/dL; P=0.03; I2=0%).However, no effect on glutathione (GSH; -12.63 mg/dL; 95% CI: -50.34 to 25.07 mg/dL; P=0.51; I2=56%), dehydroepiandrosterone sulfate (DHEAS; -0.01 mg/dL; 95% CI: -1.53 to 1.50 mg/dL; P=0.99; I2=78%), free androgen index (FAI; 0.00 mg/dL; 95% CI: -0.03 to 0.03 mg/dL; P=0.99; I2=0%), or follicle-stimulating hormone (FSH; 0.37 mg/dL; 95% CI: -0.55 to 1.29 mg/dL; P=0.43; I2=61) was found. CONCLUSIONS: This meta-analysis showed that supplementation of n-3 PUFAs in PCOS women can significantly improve CRP, MDA, LH, TT, TAC, and SHBG, but did not affect the concentrations of GSH, DHEAS, FAI, or FSH.

Prognostic impact of eosinophils in peripheral blood and tumor site in patients with esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.

ABSTRACT: To date, no effective biological markers have been identified for predicting the prognosis of esophageal cancer patients. Recent studies have shown that eosinophils are independent prognostic factors in some cancers. This study aimed to identify the prognostic impact of eosinophils in esophageal squamous cell carcinoma patients treated with concurrent chemoradiotherapy (CCRT).This study enrolled 136 patients who received CCRT for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). We evaluated the survival time and clinical pathological characteristics of eosinophils. The Kaplan-Meier method was used to estimate survival data. The log-rank test was used for univariate analysis and the Cox proportional hazards regression model was used to conduct a multivariate analysis.Kaplan-Meier analysis revealed that high eosinophil infiltration correlated with better overall survival (OS) (P = .008) and better progression-free survival (PFS) (P = .015). The increase in absolute eosinophil count after CCRT also enhanced OS (P = .005) and PFS (P = .007). The PFS and OS in patients with high blood eosinophil count before CCRT (>2%) was better than those with low blood eosinophil count(<2%) (P = .006 and P = .001, respectively). Additionally, the multivariate analysis revealed that disease stage and high eosinophil infiltration, increased peripheral blood absolute eosinophil count after CCRT, and high peripheral blood eosinophil count before CCRT were independent prognostic indicators.High eosinophil count of tumor site, increased peripheral blood absolute eosinophil count after CCRT, and high peripheral blood eosinophil count before CCRT are favorable prognostic factors for patients with ESCC treated with CCRT.

The complete mitochondrial genome of the Xinyuan honey bee, Apis mellifera sinisxinyuan (Insecta: Hymenoptera: Apidae).

We analyzed the complete mitochondrial genome of the recently discovered Xinyuan honey bee, Apis mellifera sinisxinyuan using single molecule real-time sequencing. The mitochondrial genome of A. m. sinisxinyuan is a circular molecule of 16,886 bp, comprising 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and a control region rich in A + T. Phylogenetic analysis using 13 protein-coding genes supports a close relationship to another M-lineage honey bee, A. m. mellifera.

Improved light extraction in all-inorganic perovskite light-emitting devices with periodic nanostructures by nanoimprinting lithography.

We report an improved light extraction in all-inorganic perovskite light-emitting devices (PeLEDs) by integrating a periodic corrugated nanostructure at the metallic cathode/organic interface. Nanoimprinting lithography was used to introduce the nanostructures onto the surface of the electron transport layer directly to avoid influencing the morphology and crystallinity of the perovskite film underneath. The trapped energy at the metallic electrode has been successfully outcoupled by the excitation of the surface plasma polariton (SPP) modes induced by the periodic corrugations. The luminance and current efficiency of the periodically corrugated PeLED exhibit enhancements of 42% and 28%, respectively, compared to those of the planar PeLED. The finite-difference time-domain simulation was used to confirm the efficient outcoupling of the SPP modes.

Preparation, characterization, and pharmacokinetics of tilmicosin taste-masked formulation via hot-melt extrusion technology.

Tilmicosin (TMS) is a macrocyclic antibiotic specially used in veterinary clinics, but its extreme bitterness limits its use. This study aimed to obtain a taste-masked formulation of TMS by hot melt extrusion (HME) technology and to investigate the formulation's characterization, stability, and effects in vitro/in vivo. Eudragit® E PO was selected as the carrier, and TMS dissolution in artificial saliva was used as a reference. The HME parameters were optimized via an orthogonal design. The optimized results were as follows: 135 ℃ extrusion temperature, 100 rpm screw speed and 30 % drug load. The masking efficiency of the formulation was evaluated by both simulated oral drug release in vitro and electronic tongue tests. The release of the taste-masked formulation in artificial saliva medium was significantly reduced within 60 s (less than 2%), while the release in 0.1 M HCl buffer was fast (more than 80 %) within 30 min. As suggested by the results of the electronic tongue, the taste-masked formulation had a better taste-masked effect than the commercial premix and the commercial enteric granules. Finally, a pharmacokinetic study was performed. Analysis of variance demonstrated that the pharmacokinetic behavior of the TMS taste-masked formulation was similar to that of the commercial premix, while the absorption effect was better than that of the commercially available enteric granules. This research indicates that the taste-masked formulation has the potential for future commercialization.

Growth-Regulated Hsp70 Phosphorylation Regulates Stress Responses and Prion Maintenance.

Maintenance of protein homeostasis in eukaryotes under normal growth and stress conditions requires the functions of Hsp70 chaperones and associated cochaperones. Here, we investigate an evolutionarily conserved serine phosphorylation that occurs at the site of communication between the nucleotide-binding and substrate-binding domains of Hsp70. Ser151 phosphorylation in yeast Hsp70 (Ssa1) is promoted by cyclin-dependent kinase (Cdk1) during normal growth. Phosphomimetic substitutions at this site (S151D) dramatically downregulate heat shock responses, a result conserved with HSC70 S153 in human cells. Phosphomimetic forms of Ssa1 also fail to relocalize in response to starvation conditions, do not associate in vivo with Hsp40 cochaperones Ydj1 and Sis1, and do not catalyze refolding of denatured proteins in vitro in cooperation with Ydj1 and Hsp104. Despite these negative effects on HSC70/HSP70 function, the S151D phosphomimetic allele promotes survival of heavy metal exposure and suppresses the Sup35-dependent [PSI+ ] prion phenotype, consistent with proposed roles for Ssa1 and Hsp104 in generating self-nucleating seeds of misfolded proteins. Taken together, these results suggest that Cdk1 can downregulate Hsp70 function through phosphorylation of this site, with potential costs to overall chaperone efficiency but also advantages with respect to reduction of metal-induced and prion-dependent protein aggregate production.

Superaerophilic copper nanowires for efficient and switchable CO2 electroreduction.

Copper is one of the most efficient electrocatalysts for switchable carbon dioxide conversion, but the design of an advanced Cu-based catalyst with high selectivity while suppressing hydrogen evolution remains a great challenge. Herein, we use Cu nanowires (Cu NWs) as the starting materials and polytetrafluoroethylene (PTFE) as the surface modifier to make a superaerophilic electrode using a wettability control strategy. This strategy allows tuning of the selectivity of the CO2 reduction reaction (CO2RR) and a decrease of the hydrogen evolution rate simultaneously by facilitating the supply of CO2 reactants and inhibiting the adsorption of water (protons). The transferring point from a pinning to bursting state turned out to be the optimized condition leading to the highest CO2RR faradaic efficiency without significant interference of current density. The optimized superaerophilic Cu NW catalyst showed CO-selectivity with a Faraday efficiency of 71% at -0.4 V vs. RHE and HCOOH-selectivity with a Faraday efficiency of 68% at -0.6 V vs. RHE. Moreover, the accelerated gas and ion diffusion and homogenized reactions also avoided accumulative damage on the surface of the Cu NWs and enhanced the stability of the Cu catalyst. This wettability tuning strategy provides a facile and efficient way to optimize the gas and ion diffusion layers, therefore promoting the performance of the CO2RR. This strategy potentially can be extended to the design of other gas consumption electrocatalysts.