Paired Electrolysis-Enabled Arylation of Quinoxalin-2(1H)-ones.

The first paired electrolysis-enabled arylation of quinoxalin-2(1H)-ones was achieved using cyanoarenes as the arylation reagents. A variety of 3-arylquinoxalin-2(1H)-ones with various important functional groups were obtained in moderate to good yields under metal- and chemical oxidant-free conditions. With a pair of reductive and oxidative processes occurring among the substrates and reaction intermediates, the power consumption can be dramatically reduced.

NPh3-Mediated WO3-Photocatalyzed Semiheterogeneous Hydroxylation of Aryl and Alkyl Boronic Acids.

With an inexpensive and commercially available WO3 semiconductor as the heterogeneous photocatalyst, a catalytic amount of NPh3 as the single-electron donor, and ambient air as the single-electron acceptor and oxygen source, the semiheterogeneous photocatalytic hydroxylation of alkyl and aryl boronic acids was developed. A broad range of hydroxylated compounds can be obtained in excellent yields.

Effect of Industrial Solid Waste as Fillers on the Rheology and Surface Free Energy of Asphalt Mastic.

The continuous growth of industrial solid waste production has generated many environmental problems. We evaluated the potential of industrial solid waste as a substitute filler in asphalt mastic, with the aim of increasing the use of sustainable road construction materials. In this study, X-ray fluorescence spectroscopy (XRF) and scanning electron microscopy (SEM) were used to characterize the oxide composition and micromorphology of limestone (LS), red mud (RM), steel slag (SS), and ground granulated blast-furnace slag (GGBFS). Four asphalt mastics containing LS, RM, SS, and GGBFS with a filler-to-binder weight ratio of one were prepared. An evaluation of the rheology and wetting of the solid-waste-filler asphalt mastic was conducted using a frequency sweep, temperature sweep, linear amplitude sweep (LAS), multiple stress creep and recovery (MSCR), and surface free energy (SFE) methods. The results showed that SS increased the complex modulus, elastic component of the asphalt mastic and decreased the nonrecoverable creep compliance at stress levels of 0.1 and 3.2 kPa, which improved the rutting resistance of the asphalt mastic and reduced deformation under high-temperature conditions. The RM and GGBFS increased the fatigue performance of the asphalt mastic under strain loading, enhanced its fatigue life, and maintained good performance under long-term loading. The dispersive component of the SFE parameter of the solid-waste-filler asphalt mastic was larger than the polar component for the largest share of the surface energy composition. The SFE of the asphalt mastic prepared from the industrial solid-waste filler was reduced; however, the difference was insignificant compared to the limestone asphalt mastic. Solid-waste-filler asphalt mastic has performance characteristics, and its actual application can be based on different performance characteristics to select an appropriate solid-waste filler. The results of this study provide new technological solutions for solving the utilization rate of solid waste materials and sustainable road construction in the future.

Precast Assembled Road Paving Technology: Progress and Prospects.

This article presents a systematic review of the most cutting-edge research on precast pavement technology for the first time. Firstly, precast pavement is divided into two categories, precast cement concrete pavement and precast carpeted flexible pavement, according to the application of precast technology in pavement engineering. Subsequently, the structural characteristics, advantages, and disadvantages of various precast pavement systems are compared and analyzed; technical problems in precast pavement systems are explained; and future development directions are identified. In addition, the text specifically mentions the great contribution of precast carpeted flexible pavement technology in reducing the harmful effects of asphalt fumes on humans and the environment. This work will promote the application of prefabrication in road engineering and provide suggestions and references for subsequent research.

Unraveling the hydrogeochemical characteristics and pollution sources of groundwater in an intensive industrial area, East China.

It is challenging to interpret hydrogeochemical datasets with complex natural and anthropogenic genesis in intensive industrial areas. This paper elucidates the hydrogeochemical characteristics and pollution sources of groundwater in an industrial park, East China, combining the self-organizing map (SOM), hydrochemical graphs, and correlation analysis. The results show that the total dissolved solids of groundwater range from 73.45 to 997.92 mg/L and can be regarded as freshwater. The pH varies greatly from 6.44 to 9.90, most of samples belonging to weakly acidic-weakly alkaline. The groundwater can be classified into five clusters by SOM, representing the non- or least-polluted groundwater (cluster D), high salt groundwater (cluster A), high NH4+-N and HCO3- groundwater (cluster B), high Fe and Mn groundwater (cluster C), and high pH groundwater (cluster E), which were contaminated by industrial salts, historical agriculture activity, industrial reducing substances, and industrial alkali, respectively. The natural evolution of groundwater (cluster D) in the study area is mainly controlled by mineral weathering/dissolution. The contributions of calcite, dolomite, gypsum, halite, and silicate mineral to groundwater solute are 55.8-66.3%, 15.1-18.0%, 9.0-10.7%, 2.5-10.1%, and 2.3-9.4%, respectively, based on the mass conservation. The contaminated groundwaters (all other clusters except for cluster D) have different hydrochemical characteristics associated with the pollution sources. In addition, the relatively reductive environment in quaternary flu-lacustrine sediments favored the formation of high level of Fe, Mn, and NH4+-N in groundwater. This study provides a new insight into the characteristic contaminants and their distributions in groundwater and the associated pollution sources based on the large datasets in an intensive industrial area. The data evaluation methods and results of this study could be useful to the groundwater usage management and pollution control in this area and other industrial areas.

Utilizing noncatalytic ACE2 protein mutant as a competitive inhibitor to treat SARS-CoV-2 infection.

Introduction: Angiotensin converting-enzyme 2 (ACE2) is an enzyme catalyzing the conversion of angiotensin 2 into angiotensin 1-7. ACE2 also serves as the receptor of several coronaviruses, including SARS-CoV-1 and SARS-CoV-2. Therefore, ACE2 could be utilized as a therapeutic target for treating these coronaviruses, ideally lacking enzymatic function. Methods: Based on structural analysis, specific mutations were introduced to generate mutants of ACE2 and ACE2-Fc (fusion protein of ACE2 and Fc region of IgG1). The enzyme activity, binding affinity, and neutralization abilities were measured. Results and discussion: As predicted, five mutants (AMI081, AMI082, AMI083, AMI084, AMI090) have completely depleted ACE2 enzymatic activities. More importantly, enzyme-linked receptor-ligand assay (ELRLA) and surface plasmon resonance (SPR) results showed that 2 mutants (AMI082, AMI090) maintained binding activity to the viral spike proteins of SARS-CoV-1 and SARS-CoV-2. In An in vitro neutralization experiment using a pseudovirus, SARS-CoV-2 S1 spike protein-packed lentivirus particles, was also performed, showing that AMI082 and AMI090 significantly reduced GFP transgene expression. Further, in vitro virulent neutralization assays using SARS-CoV-2 (strain name: USA-WA1/2020) showed that AMI082 and AMI090 had remarkable inhibitory effects, indicated by comparable IC50 to wildtype ACE2 (5.33 µg/mL). In addition to the direct administration of mutant proteins, an alternative strategy for treating COVID-19 is through AAV delivery to achieve long-lasting effects. Therefore, AAV5 encoding AMI082 and AMI090 were packaged and transgene expression was assessed. In summary, these ACE2 mutants represent a novel approach to prevent or treat COVID-19 and other viruses with the same spike protein.

Evaluation of recombinant baculovirus clearance during rAAV production in Sf9 cells using a newly developed fluorescent-TCID50 assay.

Introduction: Recombinant adeno-associated virus (rAAV) vectors provide a safe and efficient means for in vivo gene delivery, although its large-scale production remains challenging. Featuring high manufacturing speed, flexible product design, and inherent safety and scalability, the baculovirus/Sf9 cell system offers a practical solution to the production of rAAV vectors in large quantities and high purity. Nonetheless, removal and inactivation of recombinant baculoviruses during downstream purification of rAAV vectors remain critical prior to clinical application. Methods: The present study utilized a newly developed fluorescent-TCID50 (F-TCID50) assay to determine the infectious titer of recombinant baculovirus (rBV) stock after baculovirus removal and inactivation, and to evaluate the impact of various reagents and solutions on rBV infectivity. Results and discussion: The results showed that a combination of sodium lauryl sulfate (SLS) and Triton X-100 lysis, AAVx affinity chromatography, low pH hold (pH3.0), CsCl ultracentrifugation, and NFR filtration led to effective removal and/or inactivation of recombinant baculoviruses, and achieved a log reduction value (LRV) of more than 18.9 for the entire AAV purification process. In summary, this study establishes a standard protocol for downstream baculovirus removal and inactivation and a reliable F-TCID50 assay to detect rBV infectivity, which can be widely applied in AAV manufacturing using the baculovirus system.

Da-Jian-Zhong decoction alleviates diarrhea-predominant irritable bowel syndrome via modulation of gut microbiota and Th17/Treg balance.

ETHNOPHARMACOLOGICAL RELEVANCE: Da-Jian-Zhong decoction (DJZD) is a herbal formula clinically used for abdominal pain and diarrhea induced by spleen-Yang deficiency syndrome. Recently, treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with DJZD has received increasing attention, but the underlying mechanism of action remains elusive. AIM OF THE STUDY: We aimed to evaluate the therapeutic effect of DJZD on IBS-D rats and to elucidate the underlying mechanisms. MATERIALS AND METHODS: An IBS-D rats model was constructed using a two-factor superposition method of neonatal maternal separation and Senna folium aqueous extract lavage. Moreover, the effect of DJZD was evaluated based on the body weight, rectal temperature, abdominal withdrawal reflex (AWR), and Bristol stool scale score (BSS). The factors that regulate the DJZD effects on IBS-D were estimated using whole microbial genome, transcriptome sequencing (RNA-Seq), flow cytometry, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses. RESULTS: We found that DJZD alleviated the symptoms of IBS-D rats, with the low-dose (2.4 g/kg) as the better ones, as shown by the higher body weight and lower AWR score and BSS. At the phylum level, the relative abundance of Bacteroidetes was obviously increased, and at the genus level, Lactobacillus and Parabacteroides were increased, while that of Firmicutes_bacterium_424 and Ruminococcus gnavus was decreased in DJZD group. Furthermore, the significantly enriched GO terms after treatment with DJZD mainly included the immune response, positive regulation of activated T cell proliferation, and positive regulation of interleukin-17 (IL-17) production. Importantly, flow cytometry analysis further revealed that the T helper cell type 17/regulatory T cell (Th17/Treg) balance contributed to the DJZD-induced alleviation of IBS-D symptoms, as DJZD downregulated Th17/Treg ratio and Th17 cell-related cytokines IL-17 and IL-6 levels in the colon. CONCLUSIONS: These results demonstrated that DJZD has a good therapeutic effect on IBS-D rats, probably by maintaining the homeostasis of gut microbiota and regulating Th17/Treg balance and its related inflammatory factors.

Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases.

Metabolic reprogramming contributes to the progression and prognosis of various kidney diseases. Glutamine is the most abundant free amino acid in the body and participates in more metabolic processes than other amino acids. Altered glutamine metabolism is a prominent feature in different kidney diseases. Glutaminolysis converts glutamine into the TCA cycle metabolite, alpha-ketoglutarate, via a cascade of enzymatic reactions. This metabolic pathway plays pivotal roles in inflammation, maladaptive repair, cell survival and proliferation, redox homeostasis, and immune regulation. Given the crucial role of glutaminolysis in bioenergetics and anaplerotic fluxes in kidney pathogenesis, studies on this cascade could provide a better understanding of kidney diseases, thus inspiring the development of potential methods for targeted therapy. Emerging evidence has shown that targeting glutaminolysis is a promising therapeutic strategy for ameliorating kidney disease. In this narrative review, equation including keywords related to glutamine, glutaminolysis and kidney are subjected to an exhaustive search on Pubmed database, we identified all relevant articles published before 1 April, 2024. Afterwards, we summarize the regulation of glutaminolysis in major kidney diseases and its underlying molecular mechanisms. Furthermore, we highlight therapeutic strategies targeting glutaminolysis and their potential clinical applications.

Cholesterol reduction by immunization with a PCSK9 mimic.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination.

Antibodies targeting the fusion peptide on the HIV envelope provide protection to rhesus macaques against mucosal SHIV challenge.

The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV)BG505 challenge. VRC34.01 neutralized SHIVBG505 with a 50% inhibitory concentration (IC50) of 0.58 µg/ml, whereas DF1W-a.01 and DFPH-a.15 were 4- or 30-fold less potent, respectively. VRC34.01 was infused into four rhesus macaques at a dose of 10 mg/kg and four rhesus macaques at a dose of 2.5 mg/kg. The animals were intrarectally challenged 5 days later with SHIVBG505. In comparison with all 12 control animals that became infected, all four animals infused with VRC34.01 (10 mg/kg) and three out of four animals infused with VRC34.01 (2.5 mg/kg) remained uninfected. Because of the lower potency of DF1W-a.01 and DFPH-a.15 against SHIVBG505, we infused both Abs at a higher dose of 100 mg/kg into four rhesus macaques each, followed by SHIVBG505 challenge 5 days later. Three of four animals that received DF1W-a.01 were protected against infection, whereas all animals that received DFPH-a.15 were protected. Overall, the protective serum neutralization titers observed in these animals were similar to what has been observed for other bNAbs in similar SHIV infection models and in human clinical trials. In conclusion, FP-directed mAbs can thus provide dose-dependent in vivo protection against mucosal SHIV challenges, supporting the development of prophylactic vaccines targeting the HIV-1 Env FP.

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.

Extraordinary Titer and Broad Anti-SARS-CoV-2 Neutralization Induced by Stabilized RBD Nanoparticles from Strain BA.5.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA.5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA.5-RBD nanoparticles to degrade substantially after a few days at 37 °C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA.5-RBD nanoparticle was retained after one week at 37 °C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 µg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA.5-RBD nanoparticle induced homologous titers of 12,795 ID50 and heterologous titers against WA1 of 1767 ID50. Assessment against a panel of ß-coronavirus variants revealed both the stabilized BA.5-RBD nanoparticle and the stabilized WA1-BA.5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA.5 make them strong candidates for next-generation COVID-19 vaccines.

Spatial-temporal graph convolutional neural network for schizophrenia recognition / 中国医学物理学杂志

A spatial-temporal convolutional neural network-based method is proposed for schizophrenia classification.Unlike the mainstream methods that only analyze the temporal frequency features in EEG and ignore the spatial features between brain regions,the model mainly obtains the spatial-frequency features by convolving the adjacency matrix composed of wavelet coherence coefficients between different channels and EEG sequences,and then extracts the temporal-frequency features through one-dimensional temporal convolution.The processed matrix is flattened after multiple convolutions and input to the classification model.Experimental results show that the method has a classification accuracy of 96.32%on the publicly available dataset Zenodo,demonstrating its effectiveness and exhibiting the advantages of fusing temporal-frequency and spatial-frequency features for schizophrenia diagnosis.

Efficacy of metoprolol versus ivabradine in treatment of POTS in elderly patients after COVID-19 infection / 中华老年心脑血管病杂志

Objective To explore the difference in efficacy of metoprolol versus ivabradine in the treatment of postural orthostatic tachycardia syndrome(POTS)in the elderly after COVID-19 infection.Methods A total of 110 patients diagnosed with POTS at our department from Decem-ber 1,2022 to January 31,2023 were included.According to their drug regimen,they were divided into metoprolol group(62 patients)and ivabradine group(48 patients).On the 28th day of out-patient follow-up,the resting heart rate,heart rate of 10 min of standing,symptom disappearance rate,hospitalization rate,and mortality rate were compared between the two groups.Results On the 28th day of treatment,the resting heart rate and postural heart rate for 10 min were decreased in both groups when compared with the levels at initial diagnosis(P＜0.01).And there were no significant differences in the two types of heart rate between the two groups on the 28th day(71.0±7.0 vs 72.1±7.0,P=0.401;76.5±7.2 vs 77.4±7.6,P=0.573).No obvious differences were observed between the two groups in symptom disappearance rate,hospitalization rate,or mortality rate(88.7％vs 89.6％,3.2％vs2.1％,0％vs 0％,P＞0.05).Conclusion Metoprolol and ivabradine can effectively treat POTS in the elderly patients after COVID-19 infection.

A method of lung puncture path planning based on multi-level constraint / 生物医学工程学杂志

Percutaneous pulmonary puncture guided by computed tomography (CT) is one of the most effective tools for obtaining lung tissue and diagnosing lung cancer. Path planning is an important procedure to avoid puncture complications and reduce patient pain and puncture mortality. In this work, a path planning method for lung puncture is proposed based on multi-level constraints. A digital model of the chest is firstly established using patient's CT image. A Fibonacci lattice sampling is secondly conducted on an ideal sphere centered on the tumor lesion in order to obtain a set of candidate paths. Finally, by considering clinical puncture guidelines, an optimal path can be obtained by a proposed multi-level constraint strategy, which is combined with oriented bounding box tree (OBBTree) algorithm and Pareto optimization algorithm. Results of simulation experiments demonstrated the effectiveness of the proposed method, which has good performance for avoiding physical and physiological barriers. Hence, the method could be used as an aid for physicians to select the puncture path.

Relationship between professional identity and work engagement in policemen of Tibetan Area in Sichuan Province / 中国职业医学

OBJECTIVE: To explore the current status of professional identity and work engagement in policemen of Tibetan Area in Sichuan Province and analyze their relationship. METHODS: A total of 167 policemen from Tibetan Area of Sichuan Province were selected as research subjects using typical sampling method. Policemen Professional Identity Scale and Work Engagement Scale were used to investigate their professional identity and work engagement. RESULTS: The average scores of professional identity and work engagement of research subjects were(3.9±0.7) and(4.4±1.0) respectively. The scores of professional identity and work engagement in policemen with length of service <5 years were higher than those with length of service 5-9 years and 10-14 years(all P<0.05). The score of professional identity in research subjects was positively correlated with the work engagement score(P<0.01). The results of multiple linear regression analysis showed that after excluding the influence of confounding factors such as gender, marital status, education level and length of service as a policeman, the role perception, professional values and professional pride could positively predict the score of work engagement(all P<0.01). CONCLUSION: Professional identity of policemen of Tibetan Area in Sichuan Province can affect their work engagement. Enhancing professional identity of the policemen can help improve their work engagement level.

Effects of Rehmannia glutinosa polysaccharides on bone tissue structure and skeletal muscle atrophy in rats with disuse

ABSTRACT Purpose To study effects of Rehmannia glutinosa polysaccharides (RGP) on bone tissue structure and skeletal muscle atrophy in rats with disuse. Methods A rat model of disuse osteoporosis combined with muscle atrophy was established by removing the bilateral ovaries of rats and fixing their hind limbs for a long time. Forty SD rats were administered intragastrically for 12 weeks. The bone histomorphometry parameters and the level of oxidative stress were measured. In addition, the changes of muscle atrophy F-box (MAFbx), muscle RING-finger protein-1 (MuRF1), forkhead box O1 (FOXO1) mRNA expression in skeletal muscle of rats were observed. Results RGP significantly increased the percentage of fluorescence perimeter and bone mineralization deposition rate of the second lumbar vertebrae of rats. It also significantly increased the wet weight ratio and muscle fiber cross-sectional area of the gastrocnemius muscle of rats. At the same time, RGP significantly increased the levels of super oxide dismutase (SOD) and catalase (CAT) in the skeletal muscle of rats, and reduced the content of malondialdehyde (MDA). Rehmannia glutinosa polysaccharides also significantly reduced the expression levels of FOXO1, MAFbx and MuRF1 mRNA in rat skeletal muscle. Conclusions RGP could improve the bone structure of osteoporotic rats. It could also improve muscle that atrophy may be related to the inhibition of FOXO1-mediated ubiquitin-proteasome pathway.