Imaging surface structure and premelting of ice Ih with atomic resolution.

Ice surfaces are closely relevant to many physical and chemical properties, such as melting, freezing, friction, gas uptake and atmospheric reaction1-8. Despite extensive experimental and theoretical investigations9-17, the exact atomic structures of ice interfaces remain elusive owing to the vulnerable hydrogen-bonding network and the complicated premelting process. Here we realize atomic-resolution imaging of the basal (0001) surface structure of hexagonal water ice (ice Ih) by using qPlus-based cryogenic atomic force microscopy with a carbon monoxide-functionalized tip. We find that the crystalline ice-Ih surface consists of mixed Ih- and cubic (Ic)-stacking nanodomains, forming 19 × 19 periodic superstructures. Density functional theory reveals that this reconstructed surface is stabilized over the ideal ice surface mainly by minimizing the electrostatic repulsion between dangling OH bonds. Moreover, we observe that the ice surface gradually becomes disordered with increasing temperature (above 120 Kelvin), indicating the onset of the premelting process. The surface premelting occurs from the defective boundaries between the Ih and Ic domains and can be promoted by the formation of a planar local structure. These results put an end to the longstanding debate on ice surface structures and shed light on the molecular origin of ice premelting, which may lead to a paradigm shift in the understanding of ice physics and chemistry.

Cynarin alleviates intervertebral disc degeneration via protecting nucleus pulposus cells from ferroptosis.

Intervertebral disc degeneration (IVDD) leads to a series of degenerative spine diseases. Clinical treatment of IVDD is mainly surgery, lacking effective drugs to alleviate intervertebral disc degeneration. In this study, we analysed the mRNA sequencing dataset of human degenerative intervertebral disc tissues and revealed the participation of ferroptosis in IVDD. Furthermore, we confirmed that TNF-α, an important cytokine in IVDD, induces ferroptosis in nucleus pulposus cells. Subsequently, a ferroptosis inhibitors screening strategy using multiple ferroptosis indicators was developed. Through the screen of various natural compounds, cynarin, a natural product enriched in Artichoke, was discovered to inhibit ferroptosis of nucleus pulposus cells. Cynarin can dose-dependently inhibit the catabolism of nucleus pulposus cells, increase the expression of key ferroptosis-inhibiting genes (GPX4 and NRF2), inhibit the increment of cellular Fe2+, lipid peroxides, and reactive oxygen species. It can also prevent mitochondria shrinkage, reduce mitochondria cristae density in ferroptosis, and prevent IVDD in the rat model. In conclusion, cynarin is a potential candidate for the drug development for IVDD.

HXPY: A High-Performance Data Processing Package for Financial Time-Series Data.

A tremendous amount of data has been generated by global financial markets everyday, and such time-series data needs to be analyzed in real time to explore its potential value. In recent years, we have witnessed the successful adoption of machine learning models on financial data, where the importance of accuracy and timeliness demands highly effective computing frameworks. However, traditional financial time-series data processing frameworks have shown performance degradation and adaptation issues, such as the outlier handling with stock suspension in Pandas and TA-Lib. In this paper, we propose HXPY, a high-performance data processing package with a C++/Python interface for financial time-series data. HXPY supports miscellaneous acceleration techniques such as the streaming algorithm, the vectorization instruction set, and memory optimization, together with various functions such as time window functions, group operations, down-sampling operations, cross-section operations, row-wise or column-wise operations, shape transformations, and alignment functions. The results of benchmark and incremental analysis demonstrate the superior performance of HXPY compared with its counterparts. From MiBs to GiBs data, HXPY significantly outperforms other in-memory dataframe computing rivals even up to hundreds of times. Supplementary Information: The online version contains supplementary material available at 10.1007/s11390-023-2879-5.

Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration Via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression.

Intervertebral disc degeneration (IVDD)-induced lower back pain (LBP) is a common problem worldwide. The underlying mechanism is partially accredited to ferroptosis, based on sequencing analyses of IVDD patients from the gene expression omnibus (GEO) databases. In this study, it is shown that polydopamine nanoparticles (PDA NPs) inhibit oxidative stress-induced ferroptosis in nucleus pulposus (NP) cells in vitro. PDA NPs scavenge reactive oxygen species (ROS), chelate Fe2+ to mitigate iron overload, and regulate the expression of iron storage proteins such as ferritin heavy chain (FHC), ferritin, and transferrin receptor (TFR). More importantly, PDA NPs co-localize with glutathione peroxidase 4 (GPX4) around the mitochondria and suppress ubiquitin-mediated degradation, which in turn exerts a protective function via the transformation and clearance of phospholipid hydroperoxides. PDA NPs further down-regulate malondialdehyde (MDA) and lipid peroxide (LPO) production; thus, antagonizing ferroptosis in NP cells. Moreover, PDA NPs effectively rescue puncture-induced degeneration in vivo by targeting ferroptosis and inhibiting GPX4 ubiquitination, resulting in the upregulation of antioxidant pathways. The findings offer a new tool to explore the underlying mechanisms and a novel treatment strategy for IVDD-induced LBP.

DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.

Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain-containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin-proteasome-mediated degradation of NRF2 via competitive binding to the Kelch-like ECH-associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS.

Direct N-H Activation to Generate Nitrogen Radical for Arylamine Synthesis via Quantum Dots Photocatalysis.

Represented herein is the first example of N-radical generation direct from N-H bond activation under mild and redox-neutral conditions. The in situ generated N-radical intercepts a reduced heteroarylnitrile/aryl halide for C-N bond formation under visible-light irradiation of quantum dots (QDs). A series of aryl and alkylamines with heteroarylnitriles/aryl halides exhibit high efficiency, site-selectivity and good functional-group tolerance. Moreover, consecutive C-C and C-N bond formation using benzylamines as substrates is also achieved, producing N-aryl-1,2-diamines with H2 evolution. The redox-neutral conditions, broad substrate scope, and efficiency of N-radical formation are advantageous for organic synthesis.

Biomimetic multifunctional hybrid sponge via enzymatic cross-linking to accelerate infected burn wound healing.

Preparing sponge dressings with stable wet adhesion remains difficult in wound repair, especially in burn wounds with bleeding and large amounts of exudate. In this work, a multifunctional hybrid sponge dressing (DHGT+PHMB+TiO2NPs) with good wet adhesion was developed by combining biomimetic and enzymatic cross-linking reactions. The sponge dressing matrix (DHGT) was prepared by tyrosinase-catalyzed cross-linking of dopamine-modified hyaluronic acid (DOPA-HA) and gelatin. The multifunctional hybrid sponge dressing was obtained by loading polyhexamethylene biguanide (PHMB) and titanium dioxide nanoparticles (TiO2NPs) onto the DHGT matrix. The newly developed sponge dressing exhibited high mechanical properties, good wet adhesion, antibacterial activity, reactive oxygen species (ROS) scavenging, biocompatibility, and excellent hemostasis ability. In vivo studies showed that the multifunctional hybrid sponge dressing could significantly accelerate the healing of infected full-thickness burn wounds by inhibiting bacterial growth, accelerating skin tissue reepithelialization, collagen deposition, and angiogenesis, as well as regulating the expression of inflammatory factors and cytokines.

Direct Excitation of Aldehyde to Activate the C(sp2 )-H Bond by Cobaloxime Catalysis toward Fluorenones Synthesis with Hydrogen Evolution.

A new way to form fluorenones via the direct excitation of substrates instead of photocatalyst to activate the C(sp2 )-H bond under redox-neutral condition is reported. Our design relies on the photoexcited aromatic aldehyde intermediates that can be intercepted by cobaloxime catalyst through single electron transfer for following ß-H elimination. The generation of acyl radical and successful interception by a metal catalyst cobaloxime avoid the use of a photocatalyst and stoichiometric external oxidants, affording a series of highly substituted fluorenones, including six-membered ketones, such as xanthone and thioxanthone derivatives in good to excellent yields, and with hydrogen as the only byproduct. This catalytic system features a readily available metal catalyst, mild reaction conditions and broad substrate scope, in which sunlight reaction and scale-up experiments by continuous-flow approach make the new methodology sustainable and amenable for potentially operational procedures.

BNTA alleviates inflammatory osteolysis by the SOD mediated anti-oxidation and anti-inflammation effect on inhibiting osteoclastogenesis.

Abnormal activation and overproliferation of osteoclast in inflammatory bone diseases lead to osteolysis and bone mass loss. Although current pharmacological treatments have made extensive advances, limitations still exist. N-[2-bromo-4-(phenylsulfonyl)-3-thienyl]-2-chlorobenzamide (BNTA) is an artificially synthesized molecule compound that has antioxidant and anti-inflammatory properties. In this study, we presented that BNTA can suppress intracellular ROS levels through increasing ROS scavenging enzymes SOD1 and SOD2, subsequently attenuating the MARK signaling pathway and the transcription of NFATc1, leading to the inhibition of osteoclast formation and osteolytic resorption. Moreover, the results also showed an obvious restrained effect of BNTA on RANKL-stimulated proinflammatory cytokines, which indirectly mediated osteoclastogenesis. In line with the in vitro results, BNTA protected LPS-induced severe bone loss in vivo by enhancing scavenging enzymes, reducing proinflammatory cytokines, and decreasing osteoclast formation. Taken together, all of the results demonstrate that BNTA effectively represses oxidation, regulates inflammatory activity, and inhibits osteolytic bone resorption, and it may be a potential and exploitable drug to prevent inflammatory osteolytic bone diseases.

Engeletin Alleviates the Inflammation and Apoptosis in Intervertebral Disc Degeneration via Inhibiting the NF-κB and MAPK Pathways.

Purpose: Low back pain (LBP) induced by intervertebral disc degeneration (IDD) brings progressively painful status and impairs the normal daily living. Engeletin is a plant-derived medicine with anti-inflammation and antioxidant functions. Therefore, we aim to confirm its protective effects against the intervertebral disc degeneration in vivo and in vitro. Methods: The cytotoxicity of engeletin was validated by CCK-8 tests. Using the TNF-α to simulate the inflammation status in vitro, the expression of inflammatory mediators and MMP families were determined by qPCR, Western blotting and confocal microscopy. Cell apoptosis was analyzed by flow cytometry and TUNEL assay. The expression of apoptosis-related proteins was tested by Western blotting. The activation of NF-κB and MAPK pathways was evaluated by Western blotting and confocal microscopy. In vivo, percutaneous needle puncture was used to establish the IDD model in rat, and engeletin was administrated via intradiscal injection. The therapeutic effects of engeletin were detected through imaging and histology analysis. Results: Cell viability tests demonstrated there was little cytotoxicity of engeletin toward NP cells. Pretreatment with engeletin effectively ameliorate the TNF-α-induced up-regulation of inflammatory mediators and MMP families, promoting the anabolism of ECM meanwhile. Cell apoptosis was also attenuated with the addition of engeletin. We found that the activation of MAPK and NF-κB signaling pathways and the nuclear translocation of phosphorylated p65 and p38 were inhibited prominently with the treatment of engeletin which may be the potential molecular mechanism for its anti-inflammation effects. Finally, the IDD induced by percutaneous needle puncture was partially alleviated with the injection of engeletin in vivo. Conclusion: As a natural compound with little cytotoxicity, engeletin possesses the outstanding anti-inflammation and anti-apoptosis effects in the process of IDD in vitro and in vivo, which may be a promising medicine for the prevention and treatment of IDD-related low back pain.

Scutellarin ameliorates osteoarthritis by protecting chondrocytes and subchondral bone microstructure by inactivating NF-κB/MAPK signal transduction.

Osteoarthritis (OA), a chronic degenerative disease, is a major cause of pain, disability, and reduced quality of life among the elderly worldwide. The key to treating it is early prevention and effective intervention. The anti-inflammatory effects of scutellarin (SCU), a flavonoid derived from Erigeron breviscapus, have been increasingly reported. However, the mechanism by which SCU affects OA remains unclear. This study aimed to investigate the therapeutic effects and potential molecular mechanisms of SCU in the development of OA. Here, we found that SCU inhibited interleukin (IL)- 1ß-induced degradation of the extracellular matrix (ECM) of cartilage through the NF-kappaB/mitogen-activated protein kinases (NF-κB/MAPK) signaling pathway. In addition, in vivo data showed that SCU significantly reduced cartilage damage in the destabilization of the medial meniscus (DMM) mouse model and ovariectomy (OVX)-induced subchondral bone loss and cartilage degeneration in mice. In summary, our data showed that SCU is expected to become a potentially effective candidate treatment strategy for OA.

Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF-κB and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells.

Intervertebral disc (IVD) degeneration (IVDD) is a characteristic of the dominating pathological processes of nucleus pulposus (NP) cell senescence, abnormal synthesis and irregular distribution of extracellular matrix (ECM), and tumor necrosis factor-α (TNF-α) induced inflammation. Nowadays, IVD acid environment variation which accelerates the pathological processes mentioned above arouses researchers' attention. KAN0438757 (KAN) is an effective inhibitor of selective metabolic kinase phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) that has both energy metabolism reprogramming and anti-inflammatory effects. Therefore, a potential therapeutic benefit of KAN lies in its ability to inhibit the development of IVDD. This study examined in vitro KAN toxicity in NP primary cells (NPPs). Moreover, KAN influenced tumor necrosis factor-α (TNF-α) induced ECM anabolism and catabolism; the inflammatory signaling pathway activation and the energy metabolism phenotype were also examined in NPPs. Furthermore, KAN's therapeutic effect was investigated in vivo using the rat tail disc puncture model. Phenotypically speaking, the KAN treatment partially rescued the ECM degradation and glycolysis energy metabolism phenotypes of NPPs induced by TNF-α. In terms of mechanism, KAN inhibited the activation of MAPK and NF-κB inflammatory signaling pathways induced by TNF-α and reprogramed the energy metabolism. For the therapeutic aspect, the rat tail disc puncture model demonstrated that KAN has a significant ameliorated effect on the progression of IVDD. To sum up, our research successfully authenticated the potential therapeutic effect of KAN on IVDD and declaimed its mechanisms of both novel energy metabolism reprogramming and conventional anti-inflammation effect.

Transition-Metal-Free, Site-Selective C-F Arylation of Polyfluoroarenes via Electrophotocatalysis.

Direct CAr-F arylation is effective and sustainable for synthesis of polyfluorobiaryls with different degrees of fluorination, which are important motifs in medical and material chemistry. However, with no aid of transition metals, the engagement of CAr-F bond activation has proved difficult. Herein, an unprecedented transition-metal-free strategy is reported for site-selective CAr-F arylation of polyfluoroarenes with simple (het)arenes. By merging N,N-bis(2,6-diisopropylphenyl)perylene-3,4,9,10-bis(dicarboximide)-catalyzed electrophotocatalytic reduction and anodic nitroxyl radical oxidation in an electrophotocatalytic cell, various polyfluoroaromatics (2F-6F and 8F), especially inactive partially fluorinated aromatics, undergo sacrificial-reagents-free C-F bond arylation with high regioselectivity, and the yields are comparable to those for reported transition-metal catalysis. This atom- and step-economic protocol features a paired electrocatalysis with organic mediators in both cathodic and anodic processes. The broad substrate scope and good functional-group compatibility highlight the merits of this operationally simple strategy. Moreover, the easy gram-scale synthesis and late-stage functionalization collectively advocate for the practical value, which would promote the vigorous development of fluorine chemistry.

Biomimetic Asymmetric Composite Dressing by Electrospinning with Aligned Nanofibrous and Micropatterned Structures for Severe Burn Wound Healing.

The surface structure and topography of biomaterials play a crucial role in directing cell behaviors and fates. Meanwhile, asymmetric dressings that mimic the natural skin structure have been identified as an effective strategy for enhancing wound healing. Inspired by the skin structure and the superhydrophobic structure of the lotus leaf, an asymmetric composite dressing was obtained by constructing an asymmetric structure and wettability surface modification on both sides of the sponge based on electrospinning. Among them, the collagen and quaternized chitosan sponge was fabricated by freeze-drying, followed by an aligned poly(ε-caprolactone) (PCL)/gelatin nanofiber hydrophilic inner layer and hierarchical micronanostructure PCL/polystyrene microsphere highly hydrophobic outer layer constructed on each side of the sponge. The proposed asymmetric composite dressing combines topological morphology with the material's properties to effectively prevent bacterial colonization/infection and promote wound healing by directing cellular behavior. In vitro experimental results confirmed that the aligned nanofiber inner layer effectively promotes cell adhesion, proliferation, directed cell growth, and migration. Meanwhile, the sponge has good water absorption and antibacterial properties, while the biomimetic hydrophobic outer layer exhibits strong mechanical properties and resistance to bacterial adhesion. In vivo results showed that the composite dressing can reduce inflammatory response, prevent infection, accelerate angiogenesis and epithelial regeneration, and significantly accelerate the healing of severe burns. Thus, the proposed bionic asymmetric dressing is expected to be a promising candidate for severe burn wound healing.

An injectable double network hydrogel with hemostasis and antibacterial activity for promoting multidrug-resistant bacteria infected wound healing.

Multidrug-resistant bacteria infections frequently occur in wound care due to the excessive use of antibiotics. It can cause scar formation, wound closure delay, multiple organ failure, and high mortality. Here, a double network hydrogel with injectability, hemostasis, and antibacterial activity was developed to prompt multidrug-resistant bacteria infected wound healing. The double network hydrogel is composed of gelatin methacryloyl (GelMA), oxidized dextran (ODex), ε-polylysine (EPL), and bacitracin, and formed through the Schiff-base and UV-initiated crosslinking reaction. The injectable hydrogel with an adhesion effect could adapt to the irregular shape of the wound and possesses good hemostatic ability. The hydrogel presents good flexibility and rapid resilience due to its double network structure, and it can prompt cell proliferation and migration. In particular, the hydrogel has broad-spectrum in vitro antimicrobial activities against S. aureus, E. coli, and methicillin-resistant S. aureus (MRSA), and disrupts E. coli and MRSA biofilms. In vivo results demonstrated that the hydrogel can completely heal MRSA-infected wound in rats within 15 days, through inhibiting the growth of bacteria, accelerating skin tissue reepithelialization, collagen deposition, and angiogenesis, as well as adjusting the expression of CD31, α-SMA, and TNF-α. The findings of this study suggest that the presented hydrogel could enhance multidrug-resistant bacteria infected wound healing and mitigate antimicrobial resistance.

Photoredox/Cobalt-Catalyzed C(sp3)-H Bond Functionalization toward Phenanthrene Skeletons with Hydrogen Evolution.

The first example of photoredox strategy for synthesis of phenanthrene skeletons through C(sp3)-H functionalization under external oxidant-free conditions is achieved. This transformation relies on the keto-enol tautomerism of 1,3 dicarbonyl moiety, i.e., the enol form of 1,3-dicarbonyl derivatives with relatively lower oxidation potential can be activated by the excited acridinium photocatalyst. The electron and proton eliminated from the substrate are immediately captured by a cobaloxime catalyst to exclusively afford a-carbonyl radical for highly substituted 10-phenanthrenols in good to excellent yields.

Comparison of Three Different Data Sources of Adverse Drug Reactions Using Adverse Drug Reaction Data of Fluorouracil for Gastric Cancer as an Example.

Various sources of information are available for identifying and evaluating adverse drug reactions (ADRs). However, some studies only used the ADR data from spontaneous reporting databases to evaluate the safety of post-marketing drugs. This study was performed to identify an appropriate method for evaluating the safety of post-marketing drugs by comparing the frequencies of ADRs among three datasets: randomized controlled trials, published case reports, and spontaneous reports. Taking ADR data for fluorouracil as an example, we collected the three types of data and extracted their ADR information. All listed ADRs were sorted by frequency from high to low, and the top five ADRs were chosen from each dataset. We assigned an index value of 1.0 to the frequency of one specific ADR (diarrhea) and then calculated the index values of the other ADRs relative to diarrhea. Ten different ADRs were mentioned in the top five ADRs of the three datasets, and only diarrhea and nausea/vomiting were included in all three datasets. The rank orders of the top five ADRs varied among the three datasets. Nausea and vomiting was the most frequent ADR in all three datasets; the remaining ADRs differed among the datasets. There were significant differences in the recording of ADRs and the frequency distributions among the three datasets. A comprehensive and reliable safety profile for post-marketing drugs should not be based on any one source. Spontaneous reports from monitoring institutions provided the most ADR data. Randomized controlled trials and case reports published in the literature can supplement the results from spontaneous reports.

Photoredox Catalysis of Aromatic ß-Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation.

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic ß-ketoesters by using a photocatalyst. Under visible-light irradiation, a small amount of photocatalyst fac-Ir(ppy)3 generates a transient α-carbonyl radical and persistent ketyl radical in situ. In contrast to the well-established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α-carbonyl radicals with alkynes to give a series of highly substituted 1-naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional-group tolerance make this reaction a useful synthetic tool.

Adverse drug reaction reporting in institutions across six Chinese provinces: a cross-sectional study.

BACKGROUND: Although China's adverse drug reaction (ADR) reporting and monitoring has developed rapidly, many challenges remain. This study assessed ADR monitoring and reporting in China and identified monitoring problems. RESEARCH DESIGN AND METHODS: A cross-sectional survey was conducted of ADR reporting institutions in six Chinese provinces in April-December 2014. Questionnaires assessed ADR systems, basic resources, and pharmacovigilance activity. RESULTS: Of 720 questionnaires distributed, the response rate was 81.8%. About 93% (n = 371) of pharmaceutical companies and medical institutions had established ADR monitoring departments/units. Few institutions (26%, n = 104) allocated an ADR budget; 7% (n = 30) had received ADR monitoring funding in the last year (2013). Almost all institutions (99%, n = 555) had computers and 47% (n = 263) had a network database. Many institutions conducted public education about drug safety (49%, n = 283), medicine utilization reviews/quality surveys (28%, n = 158), and medicine consultation services (88%, n = 511). Institutions in eastern, central, and western China differed significantly on implementation of existing regulations and pharmacovigilance activities. CONCLUSIONS: The institutions surveyed have established ADR monitoring systems. However, these systems have flaws. Urgent improvements are needed in funding, basic resources, reporting processes, and other pharmacovigilance activities.