Rapid Initiation of Antiretroviral Therapy With Coformulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide Versus Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate in HIV-Positive Men Who Have Sex With Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV. METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV (400 mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/mL) at 48 weeks per US Food and Drug Administration Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression, and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (P < .001), respectively, discontinued treatment because of adverse effects, death, or lost to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (P = .020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < .001). CONCLUSIONS: BIC/FTC/TAF was more efficacious and safer than EFV (400 mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides.

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.

Enhanced Hydrogen Evolution Catalysis of Pentlandite due to the Increases in Coordination Number and Sulfur Vacancy during Cubic-Hexagonal Phase Transition.

The search for new phases is an important direction in materials science. The phase transition of sulfides results in significant changes in catalytic performance, such as MoS2 and WS2. Cubic pentlandite [cPn, (Fe, Ni)9S8] can be a functional material in batteries, solar cells, and catalytic fields. However, no report about the material properties of other phases of pentlandite exists. In this study, the unit-cell parameters of a new phase of pentlandite, sulfur-vacancy enriched hexagonal pentlandite (hPn), and the phase boundary between cPn and hPn are determined for the first time. Compared to cPn, the hPn shows a high coordination number, more sulfur vacancies, and high conductivity, which result in significantly higher hydrogen evolution performance of hPn than that of cPn and make the non-nano rock catalyst hPn superior to other most known nanosulfide catalysts. The increase of sulfur vacancies during phase transition provides a new approach to designing functional materials.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

PURPOSE: This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. METHODS: The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. RESULTS: [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 µSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. CONCLUSIONS: We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.

Photocatalytic Generation of H2O2 Via a Hydrogen-Abstraction Pathway by Bi2.15WO6 under Visible Light.

Photocatalytic technology is a popular research area for converting solar energy into environmentally friendly chemicals and is considered the greenest approach for producing H2O2. However, the corresponding reactive oxygen species (ROS) and pathway involved in the photocatalytic generation of H2O2 by the Bi2.15WO6-glucose system are still not clear. Quenching experiments have established that neither •OH nor h+ contribute to the formation of H2O2, and show that the formed surface superoxo (≡Bi-OO•) and peroxo (≡Bi-OOH) species are the predominant ROS in H2O2 generation. In addition, various characterizations indicate the enhanced electron-transfer on the surface of Bi2.15WO6 with increasing contents of glucose via the ligand-to-metal charge transfer pathway, confirming H-transfer from glucose to ≡Bi-OO• or ≡Bi-OOH. The increased production of H2O2 with decreasing bond dissociation energy (BDEO-H) values of various phenolic compounds again supports the H-transfer mechanism from phenolic compounds to ≡Bi-OO• and then to ≡Bi-OOH. DFT calculations further reveal that on the Bi2.15WO6 surface, oxygen is sequentially reduced to ≡Bi-OO• and ≡Bi-OOH, while H-transfer from H2O or glucose to ≡Bi-OO• and ≡Bi-OOH, resulting in the production of H2O2. The lower energy barrier of H-transfer from adsorbed glucose (0.636 eV) than that from H2O (1.157 eV) indicates that H-transfer is more favorable from adsorbed glucose. This work gives new insight into the photocatalytic generation of H2O2 by Bi2.15WO6 in the presence of glucose/phenolic compounds via the H-abstraction pathway.

Structural Elucidation of Glycosaminoglycans in the Tissue of Flounder and Isolation of Chondroitin Sulfate C.

Glycosaminoglycans (GAGs) are valuable bioactive polysaccharides with promising biomedical and pharmaceutical applications. In this study, we analyzed GAGs using HPLC-MS/MS from the bone (B), muscle (M), skin (S), and viscera (V) of Scophthalmus maximus (SM), Paralichthysi (P), Limanda ferruginea (LF), Cleisthenes herzensteini (G), Platichthys bicoloratus (PB), Pleuronichthys cornutus (PC), and Cleisthenes herzensteini (CH). Unsaturated disaccharide products were obtained by enzymatic hydrolysis of the GAGs and subjected to compositional analysis of chondroitin sulfate (CS), heparin sulfate (HS), and hyaluronic acid (HA), including the sulfation degree of CS and HS, as well as the content of each GAG. The contents of GAGs in the tissues and the sulfation degree differed significantly among the fish. The bone of S. maximus contained more than 12 µg of CS per mg of dry tissue. Although the fish typically contained high levels of CSA (CS-4S), some fish bone tissue exhibited elevated levels of CSC (CS-6S). The HS content was found to range from 10-150 ug/g, primarily distributed in viscera, with a predominant non-sulfated structure (HS-0S). The structure of HA is well-defined without sulfation modification. These analytical results are independent of biological classification. We provide a high-throughput rapid detection method for tissue samples using HPLC-MS/MS to rapidly screen ideal sources of GAG. On this basis, four kinds of CS were prepared and purified from flounder bone, and their molecular weight was determined to be 23-28 kDa by HPGPC-MALLS, and the disaccharide component unit was dominated by CS-6S, which is a potential substitute for CSC derived from shark cartilage.

Opioid Prescribing by Emergency Physicians: Trends Study of Medicare Part D Prescriber Data 2013-2019.

BACKGROUND: Emergency physicians play a critical role in mitigating the opioid epidemic in public health. OBJECTIVES: To analyze the prescribing of emergency physicians for opioids among Medicare beneficiaries enrolled in the Part D program from 2013 to 2019. METHODS: We conducted a retrospective, cross-sectional, descriptive analysis of Medicare Part D prescriber data, focusing on opioid claims between 2013 and 2019. The primary outcome variables evaluated included proportion of opioid claims, trends of the most prescribed opioids, cost of opioid claims, and days' supply per claim. RESULTS: A total of 63,586 emergency physicians were identified over the study period. Opioid prescription by emergency physicians decreased from 14.45% to 11.55%, and the cost spent on opioid drugs declined by 50%. The use of drugs such as hydrocodone-acetaminophen and oxycodone-acetaminophen declined substantially, whereas tramadol and acetaminophen-codeine prescription increased. The opioid prescribing rate and days' supply also decreased. CONCLUSIONS: The decline in traditional opioid agents such as hydrocodone-acetaminophen was partly offset by an increase in opioids like tramadol, which carry additional potential adverse events. Opioid prescribing rate, average days' supply, and cost of opioid drugs significantly decreased from 2015 to 2019, after a spike in 2015. All regions observed a decrease in emergency physicians, but opioid prescribing rates varied across regions. These trends highlight successful opioid stewardship practices in some areas and the need for further development in others. This information can aid in designing tailored guidelines and policies for emergency physicians to promote effective opioid stewardship practices.

Cu-Doped Iron Oxide for the Efficient Electrocatalytic Nitrate Reduction Reaction.

The electrochemical nitrate reduction reaction (NO3RR) is a promising alternative synthetic route for sustainable ammonia (NH3) production, because it not only eliminates nitrate (NO3-) from water but also produces NH3 under mild operating conditions. However, owing to the complicated eight-electron reaction and the competition from the hydrogen evolution reaction, developing catalysts with high activities and Faradaic efficiencies (FEs) is highly imperative to improve the reaction performance. In this study, Cu-doped Fe3O4 flakes are fabricated and demonstrated to be excellent catalysts for electrochemical conversion of NO3- to NH3, with a maximum FE of ∼100% and an NH3 yield of 179.55 ± 16.37 mg h-1 mgcat-1 at -0.6 V vs RHE. Theoretical calculations reveal that doping the catalyst surface with Cu results in a more thermodynamically facile reaction. These results highlight the feasibility of promoting the NO3RR activity using heteroatom doping strategies.

Coupling Nano and Atomic Electric Field Confinement for Robust Alkaline Oxygen Evolution.

The alkaline oxygen evolution reaction (OER) is a promising avenue for producing clean fuels and storing intermittent energy. However, challenges such as excessive OH- consumption and strong adsorption of oxygen-containing intermediates hinder the development of alkaline OER. In this study, we propose a cooperative strategy by leveraging both nano-scale and atomically local electric fields for alkaline OER, demonstrated through the synthesis of Mn single atom doped CoP nanoneedles (Mn SA-CoP NNs). Finite element method simulations and density functional theory calculations predict that the nano-scale local electric field enriches OH- around the catalyst surface, while the atomically local electric field improves *O desorption. Experimental validation using in situ attenuated total reflection infrared and Raman spectroscopy confirms the effectiveness of the nano-scale and atomically electric fields. Mn SA-CoP NNs exhibit an ultra-low overpotential of 189 mV at 10 mA cm-2 and stable operation over 100 hours at ~100 mA cm-2 during alkaline OER. This innovative strategy provides new insights for enhancing catalyst performance in energy conversion reactions.

Extracellular vesicle-circEHD2 promotes the progression of renal cell carcinoma by activating cancer-associated fibroblasts.

BACKGROUND: The encapsulation of circular RNAs (circRNAs) into extracellular vesicles (EVs) enables their involvement in intercellular communication and exerts an influence on the malignant advancement of various tumors. However, the regulatory role of EVs-circRNA in renal cell carcinoma (RCC) remains elusive. METHODS: The in vitro and in vivo functional experiments were implemented to measure the effects of circEHD2 on the phenotype of RCC. The functional role of EVs-circEHD2 on the activation of fibroblasts was assessed by collagen contraction assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). The mechanism was investigated by RNA pull-down assay, RNA immunoprecipitation, chromatin isolation by RNA purification, luciferase assay, and co-immunoprecipitation assay. RESULTS: We demonstrated that circEHD2 was upregulated in RCC tissues and serum EVs of RCC patients with metastasis. Silencing circEHD2 inhibited tumor growth in vitro and in vivo. Mechanistic studies indicated that FUS RNA -binding protein (FUS) accelerated the cyclization of circEHD2, then circEHD2 interacts with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH), which acts as a bridge to recruit circEHD2 and Yes1-associated transcriptional regulator (YAP) to the promoter of SRY-box transcription factor 9 (SOX9); this results in the sustained activation of SOX9. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) regulates the package of circEHD2 into EVs, then EVs-circEHD2 transmits to fibroblasts, converting fibroblasts to cancer-associated fibroblasts (CAFs). Activated CAFs promote the metastasis of RCC by secreting pro-inflammatory cytokines such as IL-6. Furthermore, antisense oligonucleotides (ASOs) targeting circEHD2 exhibited a strong inhibition of tumor growth in vivo. CONCLUSIONS: The circEHD2/YWHAH/YAP/SOX9 signaling pathway accelerates the growth of RCC. EVs-circEHD2 facilitates the metastasis of RCC by converting fibroblasts to CAFs. Our results suggest that EVs-circEHD2 may be a useful biomarker and therapeutic target for RCC.

N6-methyladenosine modified lncRNAs signature for stratification of biochemical recurrence in prostate cancer.

Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.

In Situ Probing of the Intrinsic Adhesion Strength of Single Anaerobic Microbial Cells.

Probing the single-cell mechanobiology in situ is imperative for microbial processes in the medical, industrial, and agricultural realms, but it remains a challenge. Herein, we present a single-cell force microscopy method that can be used to measure microbial adhesion strength under anaerobic conditions in situ. This method integrates atomic force microscopy with an anaerobic liquid cell and inverted fluorescence microscopy. We obtained the nanomechanical measurements of the single anaerobic bacterium Ethanoligenens harbinense YUAN-3 and the methanogenic archaeon Methanosarcina acetivorans C2A and their nanoscale adhesion forces in the presence of sulfoxaflor, a successor of neonicotinoid pesticides. This study presents a new tool for in situ single-cell force measurements of various anoxic and anaerobic species and provides new perspectives for evaluating the potential environmental risk of neonicotinoid applications in ecosystems.

A new histone deacetylase inhibitor remodels the tumor microenvironment by deletion of polymorphonuclear myeloid-derived suppressor cells and sensitizes prostate cancer to immunotherapy.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. METHODS: We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. RESULTS: We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. CONCLUSIONS: Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.

Synergy of Adsorption and Photocatalytic Reduction for Efficient Removal of Cr(VI) with Polyvinylidene Fluoride@Polyvinyl Alcohol-FeC2O4/Bi2.15WO6.

Although the photocatalytic reduction of Cr(VI) to Cr(III) by traditional powder photocatalysts is a promising method, the difficulty and poor recovery of photocatalysts from water hinder their wide practical applications. Herein, we present that FeC2O4/Bi2.15WO6 (FeC2O4/BWO) composites were tightly bonded to modified polyvinylidene fluoride (PVDF) membranes by chemical grafting with the aid of polyvinyl alcohol (PVA) to form photocatalytic composite membranes (PVDF@PVA-FeC2O4/BWO). The contact angle of PVDF@PVA-FeC2O4/BWO (0.06 wt % of FeC2O4/BWO) is 48.0°, which is much lower than that of the pure PVDF membrane (80.5°). Meanwhile, the permeate flux of 61.43 g m-2 h-1 and water flux of 250.60 L m-2 h-1 were observed for PVDF@PVA-FeC2O4/BWO composite membranes. The tensile strength of composite membranes reached 48.84 MPa, which was 9.8 times higher than that of PVDF membrane. It was found that the PVDF@PVA-FeC2O4/BWO membrane exhibited excellent photocatalytic Cr(VI) reduction performance under both simulated and real sunlight irradiation. The adsorption for Cr(VI) by PVDF@PVA-FeC2O4/BWO can reach 47.6% in the dark process within 30 min, and the removal percentage of Cr(VI) could reach 100% with a rate constant k value of 0.2651 min-1 after 10 min of light exposure, indicating a synergistic effect of adsorption and photoreduction for Cr(VI) removal by the composite membrane. The PVDF@PVA-FeC2O4/BWO membrane had good stability and reusability after seven consecutive cycles. Most importantly, the influences of foreign ions on Cr(VI) reduction were investigated to mimic real sewage, which revealed that no obvious adverse effects can be found with the presence of common foreign ions in sewage. The photocatalytic membrane material developed in this study provides a new idea for treating Cr(VI)-containing wastewater and has a more significant application prospect.

Kaistella polysaccharea sp. nov., isolated from Antarctic intertidal sediment produces a novel extracellular polymeric substance.

An exopolysaccharide-producing bacterial strain GW4-15T, belonging to the genus Kaistella, was isolated from intertidal sediment from King George Island, Antarctic. The strain was Gram-stain-negative, aerobic, rod-shaped, non-motile and yellow-pigmented. The strain was able to grow in the presence of 0-2 % (w/v) NaCl (optimum, 0 %), at 4-30 °C (optimum, 20-28 °C) and at pH 5.0-10.0 (optimum, pH 8.0). A phylogenetic tree based on 16S rRNA gene sequences showed that strain GW4-15T formed a lineage within the genus Kaistella with the closest phylogenetic neighbours Kaistella carnis NCTC 13525T (98.3 %), Kaistella gelatinilytica G5-32T (97.7 %), Kaistella antarctica LMG 24720T (97.4 %) and Kaistella yonginensis HMD1043T (96.9 %). Digital DNA-DNA hybridization values of strain GW4-15T with K. carnis NCTC 13525T, K. antarctica LMG 24720T, K. gelatinilytica G5-32T and K. yonginensis HMD1043T were 22.8, 22.0, 21.7 and 21.6 %, respectively. The average nucleotide identity values between strain GW4-15T and K. carnis NCTC 13525T , K. antarctica LMG 24720T, K. gelatinilytica G5-32T and K. yonginensis HMD1043T were 79.3, 78.6, 77.5 and 77.2 %, respectively. The G+C content of the genome was 36.2 mol%. The major phospholipids were phosphatidylethanolamine and aminophospholipid. The predominant menaquinone was MK-6. The major fatty acids were anteiso-C15 : 0 (28.7 %), iso-C16 : 0 3-OH (15.7 %), iso-C16 : 0 H (10.0 %), iso-C16 : 0 (5.4 %), summed feature 9 (comprising iso-C17 : 1 ω9c and/or 10-methyl C16 : 0; 5.2 %) and iso-C15 : 0 (5.1 %). The monosaccharide composition of the new type of extracellular polymeric of GW4-15T was Glc, GalN, GlcN, Rha, Man and Gal with a molar ratio of 3.14 : 3.83 : 8.38 : 5.16 : 1 : 2.82. Based on phenotypic, phylogenetic and genotypic data, a novel species, Kaistella polysaccharea sp. nov., is proposed with the type strain GW4-15T (=CGMCC 1.19368T=KCTC 92753T).

Determinants of DNMT2/TRDMT1 preference for substrates tRNA and DNA during the evolution.

RNA methyltransferase DNMT2/TRDMT1 is the most conserved member of the DNMT family from bacteria to plants and mammals. In previous studies, we found some determinants for tRNA recognition of DNMT2/TRDMT1, but the preference mechanism of this enzyme for substrates tRNA and DNA remains to be explored. In the present study, CFT-containing target recognition domain (TRD) and target recognition extension domain (TRED) in DNMT2/TRDMT1 play a crucial role in the substrate DNA and RNA selection during the evolution. Moreover, the classical substrate tRNA for DNMT2/TRDMT1 had a characteristic sequence CUXXCAC in the anticodon loop. Position 35 was occupied by U, making cytosine-38 (C38) twist into the loop, whereas C, G or A was located at position 35, keeping the C38-flipping state. Hence, the substrate preference could be modulated by the easily flipped state of target cytosine in tRNA, as well as TRD and TRED. Additionally, DNMT2/TRDMT1 cancer mutant activity was collectively mediated by five enzymatic characteristics, which might impact gene expressions. Importantly, G155C, G155V and G155S mutations reduced enzymatic activities and showed significant associations with diseases using seven prediction methods. Altogether, these findings will assist in illustrating the substrate preference mechanism of DNMT2/TRDMT1 and provide a promising therapeutic strategy for cancer.

MiR-483-5p downregulation alleviates ox-LDL induced endothelial cell injury in atherosclerosis.

BACKGROUND: In light of the abnormal expression of microRNA (miR-483-5p) in patients with atherosclerosis (AS), its role in vascular endothelial cell injury was explored. And the mechanisms related to autophagy were also elucidated. METHODS: Human umbilical vein endothelial cells (HUVECs) were given 100 mg/L ox-LDL to induce endothelial injury. Cell transfection was done to regulate miR-483-5p levels. Cell viability and apoptosis were detected. qRT-PCR was employed for the mRNA levels' detection. RESULTS: Autophagic flux impairment of HUVECs was detected after ox-LDL treatment, along with the upregulation of miR-483-5p. Ox-LDL inhibited cell viability and promoted cell apoptosis, but these influences were changed by miR-483-5p downregulation. MiR-483-5p downregulation decreased the mRNA levels of IL-1ß, IL-6, ICAM-1 and VCAM-1. 3-MA, the autophagy inhibitor, reversed the beneficial role of miR-483-5p downregulation in ox-LDL-induced HUVECs' injury. TIMP2 acts as a target gene of miR-483-5p, and was downregulated in HUVEC models. CONCLUSION: MiR-483-5p downregulation alleviated ox-LDL-induced endothelial injury via activating autophagy, this might be related to TIMP2.

Moderate static magnetic field promotes fracture healing and regulates iron metabolism in mice.

BACKGROUND: Fractures are the most common orthopedic diseases. It is known that static magnetic fields (SMFs) can contribute to the maintenance of bone health. However, the effect and mechanism of SMFs on fracture is still unclear. This study is aim to investigate the effect of moderate static magnetic fields (MMFs) on bone structure and metabolism during fracture healing. METHODS: Eight-week-old male C57BL/6J mice were subjected to a unilateral open transverse tibial fracture, and following treatment under geomagnetic field (GMF) or MMF. The micro-computed tomography (Micro-CT) and three-point bending were employed to evaluate the microarchitecture and mechanical properties. Endochondral ossification and bone remodeling were evaluated by bone histomorphometric and serum biochemical assay. In addition, the atomic absorption spectroscopy and ELISA were utilized to examine the influence of MMF exposure on iron metabolism in mice. RESULTS: MMF exposure increased bone mineral density (BMD), bone volume per tissue volume (BV/TV), mechanical properties, and proportion of mineralized bone matrix of the callus during fracture healing. MMF exposure reduced the proportion of cartilage in the callus area during fracture healing. Meanwhile, MMF exposure increased the number of osteoblasts in callus on the 14th day, and reduced the number of osteoclasts on the 28th day of fracture healing. Furthermore, MMF exposure increased PINP and OCN levels, and reduced the TRAP-5b and ß-CTX levels in serum. It was also observed that MMF exposure reduced the iron content in the liver and callus, as well as serum ferritin levels while elevating the serum hepcidin concentration. CONCLUSIONS: MMF exposure could accelerate fracture healing via promote the endochondral ossification and bone formation while regulating systemic iron metabolism during fracture healing. This study suggests that MMF may have the potential to become a form of physical therapy for fractures.

Design, synthesis, and biological evaluation of phenylurea indole derivatives as ABCG2 inhibitors.

Three series of phenylurea indole derivatives were synthesized with potent inhibitory activities on ABCG2 with simple and efficient synthetic routes. Among these compounds, four phenylurea indole derivatives 3c-3f with extended π system were discovered as the most potent ABCG2 inhibitors, while these compounds showed no inhibition on ABCB1. Compounds 3c and 3f were selected for further investigation to explore the mechanisms of action on reversing ABCG2-mediated multidrug resistance (MDR). The results revealed that compounds 3c and 3f increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing cells, but they did not alter the expression level or localization of ABCG2 in cells. In addition, both 3c and 3f significantly stimulated the ATP hydrolysis of ABCG2 transporter indicating that they can be competitive substrates of ABCG2 transporter, and thereby increase the accumulation of mitoxantrone in ABCG2-overexpressing H460/MX20 cells. Both 3c and 3f was docked into the drug-binding site of the human ABCG2 transporter protein (PDB 6FFC) with high affinities. This study showed that extending the π system of phenylurea indole derivatives enhanced their inhibitory activities on ABCG2, which may provide a clue for the further research to discover more potent ABCG2 inhibitors.

Efficacy of upper-incisor torque control with clear aligners: a retrospective study using cone-beam computed tomography.

OBJECTIVES: The objectives of this retrospective clinical study were to evaluate the efficacy of clear aligners on upper-incisor torque control, with the expectation of providing guidance for clinics. MATERIALS AND METHODS: Pretreatment (T0) and posttreatment (T1) cone-beam computed tomography (CBCT) scans of 47 patients with a nonextraction treatment using clear aligners were obtained and 120 upper-incisors with torque ≥5° were selected. Voxel-based superimpositions were performed using Dolphin imaging software and achieved movements were then measured. Difference between achieved and predicted movement (DAPM) and the efficiency for upper-incisor torque were used to evaluate the torque control efficacy. RESULTS: The achieved torque movement with clear aligners was lower than predicted significantly, as the mean efficiency was 46.81±33.95%. Additionally, the achieved incisor movement of the crown and root differed significantly from the predicted movement, especially root movement. CONCLUSIONS: Clear aligners struggle to control upper-incisor torque, particularly root movement. In that case, overcorrection is necessary to prevent torque loss. CLINICAL RELEVANCE: Clear aligners remain a limitation on torque control and overcorrection should be considered.