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Nonsense-mediated mRNA decay (NMD) and its regulation play an important role in eliminating faulty transcripts and controlling gene expression. However, measuring NMD activity and characterizing its targets remain challenging. In this study, we set out to establish Nanopore direct RNA sequencing in combination with quantitative real-time PCR (qPCR) as a method for analyzing NMD activity and its targets in cultured cell lines and clinical tissue samples. Nanopore RNA sequencing could detect more isoforms than short-read sequencing, especially in identifying novel isoforms and predicting isoforms annotated with premature termination codon (PTC). Changes in transcriptional isoforms of five genes (PRS, RPL12, SRSF2, PPIA, and TMEM208) could faithfully reflect NMD activity in the three cell lines and prostate cancer (PCA) samples. NMD activity in PCA samples varied, but some patients showed an increased trend. Together, Nanopore sequencing was superior in identifying NMD targets and evaluating NMD activity compared with short-read sequencing, and the NMD markers we screened may be used for measuring NMD activity in clinical patients. • Nanopore sequencing predicted transcripts with PTC and detected novel isoforms. • A set of NMD markers were screened based on Nanopore sequencing at transcriptional level. • Verification experiment by qPCR confirmed the NMD marker could faithfully reflect NMD activity. [ABSTRACT FROM AUTHOR]

Primary processing treatments are crucial to the flavor profile of coffee beans, which create the flavor precursors basis in coffee husks and diffuse into the beans, with satisfying outcomes. In this study, eleven coffee husks of Coffea arabica with different primary processing treatments (sun exposure, washing and honey treatment) from three latitudes of Yunnan were investigated by the combination of HS-SPME-GC-MS and PTR-TOF-MS. A total of 114 volatile organic compounds (VOCs) and 77 masses were identified. The characteristic compounds octanoic acid (S1) and methyl linoleate (S11) in sun-exposed, phenethyl alcohol (F4), methyl salicylate (F7), 3,5-dimethylbenzaldehyde (F9) and phytone (T9) in washed and n -hexadecanoic acid (S9) of honey-treated husks were recognized by the ions at m/z 33.032, m/z 68.049, m/z 83.049, m/z 67.054, m/z 57.034, m/z 41.030 and m/z 49.010, respectively. This study demonstrated the feasibility and complementarity of HS-SPME-GC-MS and PTR-TOF-MS in the rapid identification of VOCs in coffee husks. Meanwhile, the antioxidant capacities of the 11 husks were evaluated in vitro , and the sun-exposed samples exhibited most promising potency, in which methyl salicylate (F7), methyl linoleate (S11), methyl linolenate (S13), ethyl linoleate (S14), ethyl linolenate (S16), linalool (T1), citronellol (T2) and caffeine (J3) contributed mainly to the antioxidant capacities. • The volatile profiles of 3 primary processed coffee husks were recognized firstly. • HS-SPME-GC-MS and PTR-TOF-MS were first introduced to rapid analysis of coffee husks. • Sun-exposed coffee husks were potential antioxidants in future application. [ABSTRACT FROM AUTHOR]

The GABA A receptor (GABA A R) is the main inhibitory receptor in the adult mammalian brain. GABA A R function is dependent on its expression, distribution, and the chloride (Cl−) transmembrane gradient, which is determined by the potassium-chloride cotransporter 2 (KCC2) in the adult brain. KCC2 and GABA A R are downregulated in an activity-dependent manner during seizure induction. Functionally, KCC2 and GABA A R are closely related membrane proteins which modulate GABAergic inhibition. However, it remains unclear how their downregulation during seizure induction is coordinated. This study aimed to assess this interaction. Our results revealed that KCC2 and GABA A R were simultaneously downregulated in both in vivo and in vitro seizure models induced by the convulsant cyclothazide (CTZ), which was at least partly due to structural coupling in hippocampal neuronal membranes. Immunohistochemistry revealed colocalization of gephyrin with KCC2 and co-immunoprecipitation exhibited a direct coupling between GABA A R α1-subunit and KCC2 protein in hippocampal cell membranes. KCC2 specific short hairpin RNA (KCC2-shRNA) was employed to specifically reduce the expression of KCC2 in cultured hippocampal neurons. This resulted in a significant reduction in KCC2-independent GABAergic miniature inhibitory post-synaptic current (mIPSC) amplitude in shKCC2-transfected neurons. Further, pre-treatment with furosemide, a KCC2 inhibitor, during CTZ stimulation followed by washout significantly prevented convulsant stimulation-induced membrane KCC2 downregulation and significantly attenuated GABA A R downregulation concomitant with recovery of suppressed KCC2-independent GABAergic mIPSC amplitude. Our results suggest that the coordinated downregulation of KCC2 and GABA A R during seizure induction exerts a strong functional impact on GABA A R, highlighting an important regulatory mechanism in epilepsy. • KCC2 knockdown reduced KCC2-independent GABAergic mIPSC amplitude. • Membrane KCC2 and GABA A receptor co-localized to coordinate membrane expression in hippocampal neurons. • Membrane KCC2 co-localized with GABA A R to regulate GABA A receptor inhibitory function in hippocampal neurons. • Downregulation of mKCC2 simultaneously causes downregulation of GABA A receptor. [ABSTRACT FROM AUTHOR]

Mesenchymal cells in the liver provide the microenvironment for hepatoblasts expansion and differentiation. We have previously demonstrated that myofibroblasts (MFs) promoted hepatoblasts differentiation into cholangiocytes, whereas its role in controlling the proliferation of hepatoblasts and their differentiated cholangiocytes remains elusive. Here, we investigated the role of MFs in regulating the proliferation of hepatoblasts and their differentiated cholangiocytes using an indirect coculture system. When cocultured with hepatoblasts, MFs promoted hepatoblasts differentiation into cholangiocytes and inhibited the proliferation and stemness of hepatoblasts. However, when hepatoblasts already differentiated into cholangiocytes, MFs promoted the differentiated cholangiocytes proliferation. In addition, hepatoblast proliferation genes such as hepatocyte growth factor (HGF), insulin-like growth factor-1 and 2 (IGF-1 and 2), midkine 1 (Mdk1), and pleiotrophin (Ptn) expression in MFs were down-regulated compared with their levels in fibroblasts. Our findings uncover the role of MFs in controlling the proliferation of hepatoblasts and their differentiated cholangiocytes, potentially providing a novel therapeutic strategy for cholangiocyte regeneration. Image 1 • Myofibroblasts (MFs) inhibited the proliferation and stemness of hepatoblasts. • MFs promoted the differentiated cholangiocytes proliferation. • MFs expressed less growth factors for hepatoblasts. [ABSTRACT FROM AUTHOR]

[Display omitted] • 9-methyl-9 H -purine and thieno[3,2- d ]pyrimidine derivatives were designed as mTOR inhibitors. • 15i was a potent and selective mTOR inhibitor. • 15i inhibited the proliferation of cancer cells by inducing cell cycle arrest at the G0/G1 phase. • 15i could induce autophagy by activating autophagic flux. The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9 H -purine and thieno[3, 2- d ]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i , which display nanomolar to low micromolar IC 50 s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug. [ABSTRACT FROM AUTHOR]

Linalool and geraniol are the primary components of rose oil, palmarosa oil, and citronella oil and many other essential oils, and two important compounds used in the flavour and fragrance, cosmetic or pharmaceutical industries. Phase equilibria (LLE, VLE, solubility, etc. ) and related thermodynamic properties of a mixture are essential in the processes design and control of mass transfer process. In this work, experimental (liquid + liquid) equilibria data of the systems (water + 1-propanl + linalool) and (water + 1-propanl + geraniol) are presented. The (liquid + liquid) equilibria of both systems were determined with a tie-line method at T = (283.15, 298.15 and 313.15) K under atmospheric pressure. The well-known Hand, Bachman and Othmer–Tobias equations were used to test the reliability of the experimental values. The influence of the temperature on the (liquid + liquid) phase equilibria of the mixtures, the binodal curves and distribution ratios of 1-propanl are shown and discussed. Moreover, the NRTL and UNIQUAC models were applied to fit the data for both ternary systems. The interaction parameters obtained from both models successfully correlated the equilibrium compositions. Furthermore, the ternary systems could be represented using the binary parameters of the thermodynamic model with a function of temperature. [ABSTRACT FROM AUTHOR]

As an eco-friendly compound and good solvent, cineole (1,8-cineole, eucalyptol) has been evaluated for the extraction property of phenols (phenol or p-cresol) from aqueous solutions. This paper presents experimental (liquid + liquid) equilibrium (LLE) data for the ternary (water + phenol + cineole) and (water + p-cresol + cineole) mixtures from high concentration to low concentration of phenols-water solution. The mutual solubility of the binary (water + cineole) and (water + phenol or p-cresol) systems, and the LLE results for the ternary systems were determined with a tie-line method at T = (283.15, 298.15, and 313.15) K under atmospheric pressure. The experiment LLE results showed that cineole as a good extractant exhibited high extraction ability for phenol or p-cresol from aqueous solutions. The influence of temperature on the (liquid + liquid) phase equilibria was studied. The well-known Hand and Bachman equations were used to test the reliability of the experimental values. Moreover, the experimental LLE results were satisfactorily correlated by the NRTL and UNIQUAC models. [ABSTRACT FROM AUTHOR]

Mesoporous TiO 2 has several potential applications due to its unique electronic and optical properties, although its structures and morphologies are typically difficult to tune because of its uncontrollable and fast sol-gel reaction. In this study we have coupled the template-directed-sol-gel-chemistry with the low-cost, scalable, and environmentally benign aerosol (spray-drying) one-pot preparation technique for the fabrication of hierarchically mesoporous TiO 2 microspheres and Fe 3 O 4 @mesoporous TiO 2− x microspheres in a large scale. Parameters during the pre-hydrolysis and spray-drying treatment were varied to successfully control the bead diameter, morphology, monodispersity, surface area and pore size for improving their effectiveness for better application. Unlike to the previous aerosol synthetic approaches, where mainly quite a high temperature gradient with the strict control of spray-drying precursor concentration is implied, our strategy is lying on comparatively low drying temperature with an additional post-ultrasonication (further hydrolysis and condensation) route of the pre-calcined TiO 2 samples. As-synthesized mesoporous microspheres have a size distribution from 500 nm to 5 μm, specific surface areas ranging from 150 to 162 m 2 g −1 and mean pore sizes of several nanometers (4–6 nm). Further Fe 3 O 4 @mesoporous TiO 2− x microspheres were observed to show remarkable selective phosphopeptide-enrichment activity which might have significant importance in disease diagnosis and other biomedical applications. [ABSTRACT FROM AUTHOR]

Abstract: This article deals with averaging principle for stochastic FitzHugh–Nagumo system with different time-scales. Under suitable conditions, the existence of an averaging equation eliminating the fast variable for this coupled system is proved, and as a consequence, the system can be reduced to a single stochastic ordinary equation with a modified coefficient. Moreover, the rate of convergence for the slow component towards the solution of the averaging equation is of order 1/2. [Copyright &y& Elsevier]

Dried blood spots (DBS) collected from infants shortly after birth for the newborn screening program (NSP) in the United States are valuable resources for the assessment of exposure to environmental chemicals in newborns. The NSP was debuted as a public health program in the United States in the 1960s; and the DBS samples collected over a period of time can be used in tracking temporal trends in exposure to environmental chemicals by newborns. In this study, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were measured in DBS samples collected from newborns in Upstate New York from 1997 to 2011 by gas chromatography–high resolution mass spectrometry (GC–HRMS). Twelve PCBs and two OCPs were found in DBS samples at a detection rate above 50% ( n =51). The mean whole blood concentration of ΣPCBs (sum of 12 congeners) over the 15-year period was 1.06 ng/mL, followed by p , p′ -DDE (0.421 ng/mL) and HCB (0.065 ng/mL). The measured concentrations of PCBs and p , p′ -DDE in infants׳ blood were comparable to those reported in cord blood, suggesting maternal/trans-placental transfer of these compounds from mothers to fetuses. The concentrations of ΣPCBs and p , p′ -DDE in blood samples of infants decreased significantly between 1997 and 2001, and no significant reduction was found thereafter. This observation is consistent with the trends reported for these chemicals in other human tissues in the United States. [ABSTRACT FROM AUTHOR]

Central post-stroke pain (CPSP) is chronic neuropathic pain due to a lesion or dysfunction of the central nervous system following cerebrovascular insult. This syndrome is characterized by chronic somatosensory abnormalities including spontaneous pain, hyperalgesia and allodynia, which localize to body areas corresponding to the injured brain region. However, despite its potential to impair activities of daily life and cause mood disorders after stroke, it is probably the least recognized complication of stroke. All currently approved treatments for CPSP have limited efficacy but troublesome side effects. The detailed mechanism underlying CPSP is still under investigation; however, its diverse clinical features indicate excessive central neuronal excitability, which is attributed to loss of inhibition and excessive neuroinflammation. Recently, exogenous epoxyeicosatrienoic acids (EETs) have been used to attenuate the mechanical allodynia in CPSP rats and proven to provide a quicker onset and superior pain relief compared to the current first line drug gabapentin. This anti-nociceptive effect is mediated by reserving the normal thalamic inhibition state through neurosteroid-GABA signaling. Moreover, mounting evidence has revealed that EETs exert anti-inflammatory effects by inhibiting the expression of vascular adhesion molecules, activating NFκB, inflammatory cytokines secretion and COX-2 gene induction. The present review focuses on the extensive evidence supporting the potential of EETs to be a multi-functional therapeutic approach for CPSP. Additionally, the role of EETs in the crosstalk between anti-CPSP and the comorbid mood disorder is reviewed herein. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (MTB) is a severe causing agent of tuberculosis (TB). Although H37Rv, the type strain of M. tuberculosis was sequenced in 1998, annotation errors of encoding genes have been frequently reported in hundreds of papers. This phenomenon is particularly severe at the 5′ end of the genes. Here, we applied a TMPP [(N -Succinimidyloxycarbonylmethyl) tris (2,4,6-trimethoxyphenyl) phosphonium bromide] labeling combined with StageTip separating strategy on M. tuberculosis H37Rv to characterize the N-terminal start sites of its annotated encoding genes. Totally, 1047 proteins were identified with 2058 TMPP labeled N-terminal peptides from all the 2625 mass spectrometer (MS) sequenced proteins. Comparative genomics analysis allowed the re-annotation of 43 proteins' N-termini in H37Rv and 762 proteins in Mycobacteriaceae. All revised N-termini start sites were distributed in 5'-UTR of annotated genes due to over-annotation of previous N-terminal initiation codon, especially the ATG. In addition, we identified and verified a novel gene Rv1078A in +3 frame different from the annotated gene Rv1078 in +2 frame. Altogether, our findings contribute to the better understanding of N-terminal of H37Rv and other species from Mycobacteriaceae that can assist future studies on biological study. • TMPP labeling combined with StageTip separating strategy can extensively correct annotated encoding genes. • 43 proteins' N-termini in H37Rv and 762 proteins in Mycobacteriaceae are wrongly annotated. • Over-prediction of initiation codon with ATG is one of the main reasons for genome mis-annotation. • A novel gene Rv1078A can be added in H37Rv annotation. [ABSTRACT FROM AUTHOR]

• A KOH-doped PBI membrane was applied in DHFC for the first time. • The influence of anolyte, membrane thickness and oxygen humidity was investigated. • A peak power density of 0.708 W cm−2 was achieved. Alkaline direct hydrazine (N 2 H 4) fuel cells (DHFCs) are considered one of the most promising liquid-fed fuel cells because of their high energy density, high theoretical voltage, and zero carbon dioxide (CO 2) emissions. However, the lack of a suitable electrolyte membrane impedes the further development of alkaline DHFC. Herein, a potassium hydroxide (KOH)-doped polybenzimidazole (PBI) membrane is applied in alkaline DHFCs, and the detailed operating conditions are investigated for the first time. With optimal KOH and N 2 H 4 concentrations in the anolyte, membrane thickness, and cathode gas humidity, the DHFC gives a peak power density of 0.708 W cm−2. The results of this study demonstrate the promising application of PBI membranes in DHFC and provide a platform to evaluate the performance of catalysts synthesized for DHFC. [ABSTRACT FROM AUTHOR]

Prion diseases, such as Creutzfeldt–Jakob disease and bovine spongiform encephalopathy, are fatal neurodegenerative diseases that affect many mammals including humans and are caused by the misfolding of prion protein (PrP). A naturally occurring protective polymorphism G127V in human PrP has recently been found to significantly attenuate prion diseases, but the mechanism has remained elusive. We herein report that the hydrophobic chain introduced in G127V significantly inhibits amyloid fibril formation by human PrP, highlighting the protective effect of the G127V polymorphism. We further introduce an amino acid with a different hydrophobic chain (Ile) at the same position and find that G127I has similar protective effects as G127V. Moreover, we show that these two neutralizing mutations, G127V and G127I, significantly decrease the human PrP cytotoxicity resulting from PrP fibril formation, mitochondrial damage, and elevated reactive oxygen species production enhanced by a strong prion-prone peptide PrP 106-126. These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases. Image 1 • Neutralizing mutations modulate the liquid-liquid phase separation of the normal cellular prion proteinPrP. • Neutralizing mutations significantly inhibit the fibrillization of prion protein (PrP). • Neutralizing mutations protect against mitochondrial damage in cells. • Neutralizing mutations decrease reactive oxygen species production and cytotoxicity of PrP. [ABSTRACT FROM AUTHOR]

• K ATP channel opening could relief chronic pain. • K ATP channel opening activates the Gas6/Axl/SOCS3 axis to induce inflammatory tolerance. • K ATP channels could be a target for attenuating chronic pain. Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that K ATP channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that K ATP channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest–specific 6 (Gas6)−/− and Axl−/− mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The K ATP channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening K ATP channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the K ATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relieve chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia. [ABSTRACT FROM AUTHOR]

As an eco-friendly compound from essential oils, 1,8-cineole (cineole, eucalyptol) has the potential to replace the ozone depleting industrial solvents. This paper presents experimental (liquid + liquid) equilibrium (LLE) data for four alcohol–water systems containing 1,8-cineole. To evaluate the phase equilibrium properties of 1,8-cineole in aqueous alcohol mixtures, LLE values for the ternary systems (water + methanol or ethanol or 1-propanol or 1-butanol + 1,8-cineole) were determined with a tie-line method at T = 298.15 K under atmospheric pressure. The well-known Hand, Bachman and Othmer–Tobias equations were used to test the reliability of the experimental results. The binodal curves and distribution ratios of alcohol in the mixtures are shown and discussed. The experimental LLE values were satisfactorily correlated by the NRTL and UNIQUAC models. [ABSTRACT FROM AUTHOR]

Environmentally persistent free radicals (EPFRs) can pose exposure risks by inducing the generation of reactive oxygen species. As a new class of pollutants, EPFRs have been frequently detected in atmospheric particulate matters. In this study, the seasonal variations and sources of EPFRs in a severe cold region in Northeastern China were comprehensively investigated, especially for the high pollution events. The geomean concentration of EPFRs in the total suspended particle was 6.58 × 1013 spins/m3 and the mean level in winter was one order of magnitude higher than summer and autumn. The correlation network analysis showed that EPFRs had significantly positive correlation with carbon component, K+ and PAHs, indicating that EPFRs were primarily emitted from combustion and pyrolysis process. The source appointment by the Positive Matrix Factorization (PMF) model indicated that the dominant sources in the heating season were coal combustion (48.4%), vehicle emission (23.1%) and biomass burning (19.4%), while the top three sources in the non-heating season were others (41.4%), coal combustion (23.7%) and vehicle emissions (21.2%). It was found that the high EPFRs in cold season can be ascribed to the extensive use of fossil fuel for heating demand; while the high EPFRs occurred in early spring were caused by the large-scale opening combustion of biomass. In summary, this study provided important basic information for better understanding the pollution characteristics of EPFRs, which suggested that the implementation of energy transformation and straw utilization was benefit for the control of EPFRs in severe cold region. [Display omitted] • EPFRs in winter was one order of magnitude higher than other seasons. • EPFRs showed significantly positive correlation with carbon components and PAHs. • EPFRs in heating season were mainly from coal combustion. • High EPFRs in spring was directly influenced by large-scale opening biomass burning. • Energy transformation and straw utilization was benefit for EPFRs control. [ABSTRACT FROM AUTHOR]

Pharmaceutical compounds (PhCs) pose a growing concern with potential environmental impacts, commonly introduced into the environment via wastewater treatment plants (WWTPs). The occurrence, removal, and season variations of 60 different classes of PhCs were investigated in the baffled bioreactor (BBR) wastewater treatment process during summer and winter. The concentrations of 60 PhCs were 3400 ± 1600 ng/L in the influent, 2700 ± 930 ng/L in the effluent, and 2400 ± 120 ng/g dw in sludge. Valsartan (Val, 1800 ng/L) was the main contaminant found in the influent, declining to 520 ng/L in the effluent. The grit chamber and BBR tank were substantially conducive to the removal of VAL. Nonetheless, the BBR process showcased variable removal efficiencies across different PhC classes. Sulfadimidine had the highest removal efficiency of 87 ± 17% in the final effluent (water plus solid phase). Contrasting seasonal patterns were observed among PhC classes within BBR process units. The concentrations of many PhCs were higher in summer than in winter, while some macrolide antibiotics exhibited opposing seasonal fluctuations. A thorough mass balance analysis revealed quinolone and sulfonamide antibiotics were primarily eliminated through degradation and transformation in the BBR process. Conversely, 40.2 g/d of macrolide antibiotics was released to the natural aquatic environment via effluent discharge. Gastric acid and anticoagulants, as well as cardiovascular PhCs, primarily experienced removal through sludge adsorption. This study provides valuable insights into the intricate dynamics of PhCs in wastewater treatment, emphasizing the need for tailored strategies to effectively mitigate their release and potential environmental risks. [Display omitted] • PhC dynamics in wastewater exhibit different seasonal patterns. • BBR wastewater treatment displays variable removal efficiencies. • Diverse elimination mechanisms identified for pharmaceutical compounds. • High stability and hydrophilicity render certain PhCs prevalent in effluent. [ABSTRACT FROM AUTHOR]

• WNY1613 was a potent and selective PI3Kδ inhibitor with piperazinone-containing purine scaffold. • WNY1613 could induce cancer cell apoptosis and inhibit the phosphorylation of PI3K downstream components in NHL cell lines. • WNY1613 exhibited anti-NHL activity in vitro and in vivo. PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1 H -benzo d imidazol-1-yl)-9-methyl-6-morpholino-9 H -purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation. [ABSTRACT FROM AUTHOR]

• A novel strategy to prepare Fe, N and S tri-doped graphene (Fe-N-S-GR) is reported. • The codoping of Fe, N and S is essential for the formation of Pt nanodendrites (NDs). • The Pt NDs/Fe-N-S-GR catalyst exhibits much higher MOR electrocatalytic properties. • DFT studies reveal the mechanism of Pt NDs/Fe-N-S-GR for enhanced MOR properties. Multiatom-doped carbon nanomaterials have emerged as very promising electrocatalysts for fuel cell applications because of the synergistic electron effect that occurs between the hetero-dopants. However, their electrochemical properties strongly depend on the structural design of the doped heteroatoms, and a fundamental understanding of their electrocatalytic mechanism is still a challenge. Herein, a novel and effective sulfonated iron phthalocyanine pyrolysis strategy to synthesize Fe, N, and S tri-doped graphene nanohybrids is reported, and this hybrid is utilized as the catalyst support for highly efficient Pt nanodendrites. In this strategy, the incorporation of S atoms is rationally engineered by the sulfonate groups in the phthalocyanine molecules, and it leads to the uniform distribution of an active FeN x -S 2 configuration in the graphene structure, along with the Fe and N atoms. The Pt nanodendrites assembled on Fe, N, and S tri-doped graphene exhibit a much higher electrocatalytic activity and long-term electrochemical durability for methanol oxidation. Both controlled experiments and density functional theory calculations reveal that the co-doping of Fe, N, and S atoms is beneficial for the formation of dendritic Pt nanoparticles and the electrochemical performance enhancement of Pt nanodendrites. The density functional theory calculations indicate that the co-doping of Fe, N, and S atoms not only increases the ability to adsorb Pt and the catalyst durability, but also enhances the CO tolerance ability and prevents the poisoning effect during methanol oxidation. This study demonstrates a new method for the controllable synthesis of multi-doped graphene-based electrocatalysts with optimized surface structures and electrochemical performances. [ABSTRACT FROM AUTHOR]

Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT 1 R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT 1 R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis. [ABSTRACT FROM AUTHOR]

ABX 3 -type organic lead halide perovskites have gained increasing attention as light harvester for solar cells due to their high power conversion efficiency (PCE). Recently, it has become a trend to avoid the use of expensive hole-transport materials (HTMs) and precious metals, such as Au, to be competitive in future commercial development. In this study, we fabricated mixed-cation perovskite-based solar cells through one-step spin-coating using methylammonium (CH 3 NH 3 + ) and formamidinium (HN = CHNH 3 + ) cations to extend the optical absorption range into the red region and enhance the utilization of solar light. The synthesized hole-conductor-free cells with carbon electrode and mixed cations exhibited increased short-circuit current, outperforming the cells prepared with pure methylammonium, and PCE of 10.55%. This paper proposes an efficient approach for fabricating high-performance and low-cost perovskite solar cells. [ABSTRACT FROM AUTHOR]

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment (TME) through limiting immune cell infiltration into tumors. The defective vascular perfusion in tumors also impairs the delivery and efficacy of chemotherapeutic agents. Targeting abnormal tumor blood vessels has emerged as an effective therapeutic strategy to improve the outcome of chemotherapy and immunotherapy. In this study, we demonstrated that Salvianolic acid B (SalB), one of the major ingredients of Salvia miltiorriza elicited vascular normalization in the mouse models of breast cancer, contributing to improved delivery and response of chemotherapeutic agent cisplatin as well as attenuated metastasis. Moreover, SalB in combination with anti-PD-L1 blockade retarded tumor growth, which was mainly due to elevated infiltration of immune effector cells and boosted delivery of anti-PD-L1 into tumors. Mechanistically, tumor cell enhancer of zeste homolog 2 (Ezh2)-driven cytokines disrupted the endothelial junctions with diminished VE-cadherin expression, which could be rescued in the presence of SalB. The restored vascular integrity by SalB via modulating the interactions between tumor cells and endothelial cells (ECs) offered a principal route for achieving vascular normalization. Taken together, our data elucidated that SalB enhanced sensitivity of tumor cells to chemotherapy and immunotherapy through triggering tumor vascular normalization, providing a potential therapeutic strategy of combining SalB and chemotherapy or immunotherapy for patients with breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro , and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo . Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis. [ABSTRACT FROM AUTHOR]

Here we reported that co-administration of docetaxel and a cell-permeable short-chain ceramide (C6) resulted in a striking increase in growth inhibition and apoptosis in primary and transformed breast cells (MCF-7 and MDA-231), which were associated with mitochondrial permeability transition pore (mPTP) opening, a significant reactive oxygen species (ROS) production and the pro-apoptotic AMP-Protein Kinase (AMPK) as well as c-Jun N-terminal kinases (JNK) activations. Contrarily, the mPTP blocker sanglifehrin A (SfA) or the ROS scavenger N-acetyl- l -cysteine (NAC) largely inhibited co-administration-induced cytotoxicity. Further, cyclosporin A (CsA), the inhibitor of cyclophilin-D (Cyp-D, the key mPTP component), as well as Cyp-D RNA silencing also suppressed breast cancer cell death by the co-treatment, while cells overexpressing Cyp-D showed hypersensitivity to docetaxel. Meanwhile, JNK and AMPK inhibition alleviated cell death induced by the co-administration in cultured breast cancer cells. Significantly, C6 ceramide plus docetaxel caused dramatic human epidermal growth factor receptor (HER)-1/-2 degradation and downstream Akt/Erk inhibition in HER-2 expressing MDA-231 cells. These in vitro findings provide confidence in support of further development of C6 ceramide as an adjunct of docetaxel for the treatment of the metastatic breast cancer. [ABSTRACT FROM AUTHOR]

• A novel method was developed to simultaneously record SCE and EEG signals. • The method's validity was evaluated using a classical resting-state study design. • Spectral characteristics in resting state were delineated for SCE and EEG signals. • Spectral power of delta and alpha oscillations was able to predict EC/EO behaviors. • Top-down regulation from the brain to spinal cord was found in delta oscillations. The brain and the spinal cord together make up the central nervous system (CNS). The functions of the human brain have been the focus of neuroscience research for a long time. However, the spinal cord is largely ignored, and the functional interaction of these two parts of the CNS is only partly understood. This study developed a novel method to simultaneously record spinal cord electrophysiology (SCE) and electroencephalography (EEG) signals and validated its performance using a classical resting-state study design with two experimental conditions: eyes-closed (EC) and eyes-open (EO). We recruited nine postherpetic neuralgia patients implanted with a spinal cord stimulator, which was modified to record SCE signals simultaneously with EEG signals. For both EEG and SCE, similar differences were found in delta- and alpha-band oscillations between the EC and EO conditions, and the spectral power of these frequency bands was able to predict EC/EO behaviors. Moreover, causal connectivity analysis suggested a top-down regulation in delta-band oscillations from the brain to the spinal cord. Altogether, this study demonstrates the validity of simultaneous SCE-EEG recording and shows that the novel method is a valuable tool to investigate the brain-spinal interaction. With this method, we can better unite knowledge about the brain and the spinal cord for a deeper understanding of the functions of the whole CNS. [ABSTRACT FROM AUTHOR]

[Display omitted] • Six C-3′-C-6″ type of biflavonoids were isolated from S. trichoclada. • RF-A showed the strongest activity against MCF-7 cells among all isolated compounds. • RF-A induced the accumulation of ROS and Lipid peroxidation in MCF-7 cells. • RF-A induced ferroptosis in MCF-7 cells via the upregulation of VDAC2 protein. Breast cancer is one of the major malignant tumors in females, and currently, recurrence and metastasis are the main obstacles preventing effective breast cancer treatment. Biflavonoids of secondary metabolites from plants are excellent anticancer agents to fight sensitive and resistant breast cancer cell lines. In this study, six C-3′-C-6″ biflavonoids, including one new robustaflavone A (1 , RF-A) and five known robustaflavone derivatives (2 – 6) , were isolated from Selaginella trichoclada for the first time. We aimed to evaluate the inhibitory effects of compounds 1 – 6 against human breast cancer MCF-7 cells. Among the six compounds, RF-A showed the strongest activity, decreasing cell viability with an IC 50 value of 11.89 μΜ. Furthermore, RF-A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways. [ABSTRACT FROM AUTHOR]

Epilepsy in pregnancy can lead to substantial maternal and neonatal morbidity and mortality. Early intervention in pregnant women with epilepsy (WWE), accurate assessment of the severity of their condition, and effective treatment are required to improve maternal and neonatal prognosis. Many obstetricians lack experience in monitoring and treating pregnant WWE. The aim of this study was to describe the demographic and clinical characteristics of pregnant WWE and examine maternal and neonatal outcomes. Medical records of 75 pregnant women with a history of epilepsy who delivered at Beijing Tiantan Hospital, China between January 2006 and December 2019 were retrospectively reviewed. Pregnant women with a history of epilepsy were matched 1:2 with a control group of 150 pregnant women without epilepsy who delivered at Beijing Tiantan Hospital during the same time period. Information including type and frequency of epilepsy and seizures, maternal complications, medication, delivery mode, newborn weight, and newborn Apgar score were recorded. In subgroup analyses, pregnant WWE were stratified according to presence or absence of seizures during pregnancy and generalized seizure vs. nongeneralized seizure. The incidence of anemia, hypertensive disorder of pregnancy, premature rupture of membranes (PROM), cesarean section, and postpartum hemorrhage was significantly higher (p < 0.05), and mean newborn weight and newborn Apgar score were significantly lower (p < 0.05) in pregnant WWE compared with pregnant women without epilepsy. The incidence of premature delivery was significantly higher (p < 0.05), and mean newborn weight was significantly lower (p < 0.05) in pregnant WWE with seizures vs. without seizures. Mean newborn weight was significantly lower (p = 0.01) in pregnant WWE with nongeneralized seizures vs. generalized seizures. Pregnant WWE are at high risk of anemia, gestational hypertension, PROM, cesarean section, postpartum hemorrhage, and low newborn weight and Apgar score. Women with epilepsy who experience seizures during pregnancy are at high risk of preterm birth and having low birth weight infants. Pregnant WWE who experience nongeneralized seizures are at high risk of having low birth weight infants. These data emphasize the need to routinely monitor fetal weight on ultrasound and offer appropriate intervention. These findings highlight the need for healthcare providers to take a multidisciplinary approach to the management of pregnant WWE. Pregnant WWE are at high risk of obstetric complications. Women with epilepsy who experience seizures during pregnancy are at high risk of preterm birth and having low birth weight infants. Pregnant WWE who experience nongeneralized seizures are at high risk of having low birth weight infants. These data highlight the need for healthcare providers to take a multidisciplinary approach to the management of pregnant WWE. • Pregnant women with epilepsy (WWE) are at high risk of maternal and neonatal complications. • WWE who experience seizures during pregnancy are at high risk of preterm birth and having low birth weight infants. • Pregnant WWE who experience non-generalized seizures are at high risk of having low birth weight infants. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrosing interstitial lung disease with limited therapeutic options and a median survival of 3 years after diagnosis. Dysregulated epithelial regeneration is key event involved in initiating and sustaining IPF. The type II alveolar epithelial cells (AECIIs) play a crucial role for epithelial regeneration and stabilisation of alveoli. Loss of cell apical-basal polarity contributes to fibrosis. AECII has apical-basal polarity, but it is poorly understood whether AECII apical-basal polarity loss is involved in fibrosis. Bleomycin is a traditional inducer of pulmonary fibrosis. Here firstly we observed that bleomycin induced apical-basal polarity loss in cultured AECIIs. Next, cell polarity proteins lethal (2) giant larvae 1 (Lgl1), PAR-3A, aPKC and PAR-6B were investigated. We found bleomycin induced increases of Lgl1 protein and decreases of PAR-3A protein, and bleomycin-induced PAR-3A depression was mediated by increased-Lgl1. Then Lgl1 siRNA was transfected into AECIIs. Lgl1 siRNA prevented apical-basal polarity loss in bleomycin-treated AECIIs. At last, Lgl1 -conditional knockout mice were applied in making animal models. Bleomycin induced pulmonary fibrosis, but this was attenuated in Lgl1 -conditional knockout mice. Together, these data indicated that bleomycin mediated AECII apical-basal polarity loss which contributed to experimental pulmonary fibrosis. Inhibition of Lgl1 should be a potential therapeutic strategy for the disease. • Bleomycin induced type II alveolar epithelial cell (AECII) apical-basal polarity loss. • Increased lethal (2) giant larvae 1 (Lgl1) mediated AECII apical-basal polarity loss. • Lgl1 siRNA prevented bleomycin-induced AECII apical-basal polarity loss in vitro. • Inhibition of Lgl1 by Lgl1 -knockout attenuated experimental pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Pum2 is a ribonucleic acid binding protein that controls target mRNA turnover. It has been reported to be potentially associated with cardiac fibrosis. However, little is known about the role of Pum2 in cardiac disease. In this study, we found that Pum2 was upregulated in the rat heart tissue subjected to ischemia/reperfusion procedure and cultured neonatal rat ventricular cardiomyocytes (NRVMs) with hypoxia/reoxygenation (H/R) treatment. Further, knockdown of Pum2 showed a beneficial effect on H/R treated NRVMs through decreasing caspase 3-associated apoptosis, whereas overexpression of Pum2 increased H/R-induced NRVMs apoptosis. Moreover, our results demonstrated that Sirt1 was identified as the target of Pum2-mediated mRNA decay in cardiomyocytes, and two Pum2 binding elements were found in the 3′-untranslated region of Sirt1 mRNA. Additionally, overexpression of Pum2 prompted the acetylation of LKB1 by decreasing Sirt1's mRNA level, which in turn repressed the activity of AMPK pathway in both normoxic and H/R-treated NRVMs. Finally, our data indicated that the pro-apoptotic effect of Pum2 was dependent on Sirt1 and AMPK. Collectively, our results provide the evidence that Pum2-mediated Sirt1 mRNA decay plays a detrimental role in H/R-induced cardiomyocytes injury. • Pum2 can be induced by ischemia/reperfusion in vivo or hypoxia/reoxygenation in vitro. • Knockdown of Pum2 showed a beneficial effect against H/R-induced cardiomyocytes apoptosis. • Sirt1 is found as the target of Pum2-mediated mRNA decay. • Pum2 can suppress AMPK's activation via prompting acetylation of LKB1. [ABSTRACT FROM AUTHOR]

In this study, 20 P. aeruginosa strains were isolated from 112 farmed mink exhibiting hemorrhagic pneumonia in mideastern Shandong province, China. Serotype G (18/20) was the dominant serotype among the isolates with prevalence in mink, followed by serotype B (1/20), serotype C (1/20). The 9 virulence-associated genes of P. aeruginosa were tested using PCR. The prevalence of the virulence genes for the isolates were algD 95% (19/20), plcH 85% (17/20), exoY 80% (16/20), aprA 75% (15/20), lasB 70% (14/20), exoS 65% (13/20), exoT 60% (12/20) and toxA 60% (12/20), respectively. The 20 isolates were negative for exoU gene. The isolates exhibited multidrug resistance and cross resistance, using antimicrobial disc susceptibility assays. The animal experiments demonstrated that LD50% of the P.aeruginosa–CS–2 in the intratracheally challenged mink was 2.2 × 107.0 CFU, and 6.8 × 104.0 CFU in the intraperitoneally challenged mink. It implied that both the inoculation doses and the routes of inoculation could have influences on the pathogenicity of P. aeruginosa in mink. Therefore, the evolutionary and epidemiological surveillance of P. aeruginosa in mink should be further strengthened for public health. • P. aeruginosa serotype G was prevalent in mink in Shandong Province, China. • Different serotypes of P. aeruginosa can co-circulate in the same farm. • The infection routes affect the pathogenicity of P. aeruginosa to mink. [ABSTRACT FROM AUTHOR]