Glycated CD59 is a potential biomarker for gestational diabetes mellitus.

Objective: To explore the diagnostic value of glycated CD59 (gCD59) in gestational diabetes mellitus (GDM). Methods: A total of 707 pregnant women who underwent the first visit in the obstetric outpatient clinic of the Affliated Suqian Hospital of Xuzhou Medical University from January 2022 to July 2023 were included, and were grouped according to the International Association of the Diabetes and Pregnancy Study Groups(IADPSG) diagnostic criteria, and finally 113 cases in the GDM group and 559 cases in the normal glucose tolerance (NGT) group were included, and the concentration of gCD59 was determined by enzyme-linked immunosorbent assay (ELISA). The baseline data characteristics of the two groups were compared, the risk factors for GDM were explored by multivariate binary logistic analysis, and the diagnostic value of gCD59 in predicting GDM was explored by receiver operating characteristic (ROC) curve analysis. Results: The level of gCD59 in the GDM group was significantly higher than that in the NGT group (1.49 SPU vs 0.87 SPU). Multivariate regression analysis showed that gCD59, diastolic blood pressure (DBP) and thyroid stimulating hormone (TSH) were independent risk factors for GDM.The area under the curve (AUC) of gCD59 for the diagnosis of GDM was 0.681 (95% CI: 0.583-0.717), with a sensitivity of 71.7% and a specificity of 58.3%. In combination with fasting glucose, gCD59 effectively diagnosed GDM with higher AUC of 0.871 (95% CI: 0.708-1.000). Conclusion: gCD59 is an independent risk factor for GDM and a good biomarker for the diagnosis of GDM.

Effects of phosphorus-solubilizing bacteria and biochar application on phosphorus availability and tomato growth under phosphorus stress.

BACKGROUND: Phosphorus-solubilizing bacteria (PSB) are vital in converting insoluble phosphorus into a soluble form that plants can readily absorb and utilize in soil. While previous studies have mainly focused on the extracellular secretion of microorganisms, few have explored the intricate intracellular metabolic processes involved in PSB-mediated phosphorus solubilization. RESULTS: Here, we uncovered that Ca3(PO4)2 could serve as a source of insoluble phosphorus for the PSB, Pseudomonas sp. NK2. High-performance liquid chromatography (HPLC) results indicated higher levels of organic acids released from insoluble phosphorus compared to a soluble phosphorus source (KH2PO4), with acetic acid released exclusively under insoluble phosphorus condition. Moreover, non-target metabolomics was employed to delve into the intracellular metabolic profile. It unveiled that insoluble phosphorus significantly enhanced the tricarboxylic acid cycle, glycolysis, glyoxylic acid metabolism, and other pathways, leading to the production of acetic acid, gluconic acid, oxalic acid, and citric acid for insoluble phosphorus solubilization. In our quest to identify suitable biochar carriers, we assessed seven types of biochar through the conjoint analysis of NBRIP medium culture and application to soil for 30 days, with cotton straw-immobilized NK2 emerging as the most potent phosphorus content provider. Lastly, NK2 after cotton straw immobilization demonstrated the ability to enhance biomass, plant height, and root development of Solanum lycopersicum L. cv. Micro Tom. CONCLUSIONS: Pseudomonas sp. NK2 with cotton straw biochar could enhance phosphorus availability and tomato growth. These findings bear significant implications for the practical application of phosphorus-solubilizing bacteria in agricultural production and the promotion of environmentally sustainable farming practices.

The atypical antipsychotics and sexual dysfunction: a pharmacovigilance-pharmacodynamic study.

Background: Atypical antipsychotics (AAPs)-induced sexual dysfunction (SD) is a frequent issue in clinical practice, often underestimated by clinicians and not extensively researched. The current study aimed to quantify the strength of association between the use of different AAPs and SD using real-world data from the FDA Adverse Event Reporting System (FAERS), as well as investigate the receptor mechanisms that are involved. Methods: Data from the FAERS database from the first quarter of 2004 to the third quarter of 2023 were queried through OpenVigil 2.1. Disproportionality analysis was estimated using the reporting odds ratio (ROR) and information component (IC) methods, and linear regression was used to investigate the relationship between ROR and receptor occupancy which was estimated using in vitro receptor binding profiles. Results: Our analysis yielded 4839 reports that co-mentioned AAP and SD events, and the findings revealed statistical associations between 12 AAPs and SD. The highest signal value was identified for iloperidone reporting retrograde ejaculation with iloperidone (ROR = 832.09, ROR025 = 552.77; IC = 9.58, IC025 = 6.36), followed by compulsive sexual behavior with aripiprazole (ROR = 533.02, ROR025 = 435.90; IC = 7.30, IC025 = 5.97), and psychosexual disorder for aripiprazole (ROR = 145.80, ROR025 = 109.57; IC025 = 6.47, IC025 = 4.86). Different characteristics of the SD side effects in each AAPs were discovered after further data mining. Regression analysis revealed potential effects for receptor occupancy of D2, D3, and 5-HT1A receptors on ROR. However, no significant correlation persisted following sensitivity analyses. Conclusion: This is the first study to investigate the AAP-SD associations by using FAERS. In this study, we report for the first time a significant association between aripiprazole and SD based on real-world data. The study suggests that different AAPs have varying levels of association with SD, and the D2, D3, and 5-HT1A receptor occupancy may contribute to potential mechanisms. The findings of this study warrant further validation of more studies and clinical causality assessment.

Effects of chain lengths and backbone chirality on the bone-targeting ability of poly(glutamic acid)s.

Anionic synthetic polypeptides are promising candidates as standalone bone-targeting drug carriers. Nevertheless, the structure-property relationship of the bone-targeting ability of polypeptides remains largely unexplored. Herein we report the optimization of the in vitro and in vivo bone-targeting ability of poly(glutamic acid)s (PGAs) by altering their chain lengths and backbone chirality. PGA 100-mers exhibited higher hydroxyapatite affinity in vitro, but their rapid macrophage clearance limited their targeting ability. Shorter PGA was therefore favored in terms of in vivo bone targeting. Meanwhile, the backbone chirality showed less significant impact on the in vitro and in vivo targeting behavior. This study highlights the modulation of structural parameters on the bone-targeting performance of anionic polypeptides, shedding light on the future design of polypeptide-based carriers.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

Molecular pharmacology and therapeutic advances of monoterpene perillyl alcohol.

BACKGROUND: Perillyl alcohol (POH) is a aroma monoterpene commonly obtained from various plants' essential oil. Recently, increasing researches have demonstrated that POH may be useful, not only as flavor compound, but also as bioactive molecule because of a variety of biological activities. PURPOSE: The aim of this review is to summarize the production, pharmacological activities and molecular mechanism, active derivatives, toxicity and parmacokinetics, and industrial application of POH. METHODS: A systematic search of published articles up to January 2024 in Web of Science, China Knowledge Network, and PubMed databases is conducted using the following keywords: POH, POH derivatives, biological or pharmacological, production or synthesis, pharmacokinetics, toxicity and application. RESULTS: Biotechnological production is considered to be a potential alternative approach to generate POH. POH provides diverse pharmacological benefits, including anticancer, antimicrobial, insecticidal, antioxidant, anti-inflammatory, hypotensive, vasorelaxant, antinociceptive, antiasthmatic, hepatoprotective effects, etc. The underlying mechanisms of action include modulation of NF-κB, JNK/c-Jun, Notch, Akt/mTOR, PI3K/Akt/eNOS, STAT3, Nrf2 and ERS response pathways, mitigation of mitochondrial dysfunction and membrane integrity damage, and inhibition of ROS accumulation, pro-inflammatory cytokines release and NLRP3 activation. What's more, the proteins or genes influenced by POH against diseases refer to Bax, Bcl-2, cyclin D1, CDK, p21, p53, HIF-1α, AP-1, caspase-3, M6P/IGF2R, PARP, VEGF, etc. Some clinical studies report that intranasal delivery of POH is a safe and effective treatment for cancer, but further clinical investigations are needed to confirm other health benefits of POH in human healthy. Depending on these health-promoting properties together with desirable flavor and safety, POH can be employed as dietary supplement, preservative and flavor additive in food and cosmetic fields, as building block in synthesis fields, as anticancer drug in medicinal fields, and as pesticides and herbicides in agricultural fields. CONCLUSION: This review systematically summarizes the recent advances in POH and highlights its therapeutic effects and potential mechanisms as well as the clinical settings, which is helpful to develop POH into functional food and new candidate drug for prevention and management of diseases. Future studies are needed to conduct more biological activity studies of POH and its derivatives, and check their clinical efficacy and potential side effects.

Epitope mapping and establishment of a blocking ELISA for mAb targeting the p72 protein of African swine fever virus.

The African swine fever virus (ASFV) has the ability to infect pigs and cause a highly contagious acute fever that can result in a mortality rate as high as 100%. Due to the viral epidemic, the pig industry worldwide has suffered significant financial setbacks. The absence of a proven vaccine for ASFV necessitates the development of a sensitive and reliable serological diagnostic method, enabling laboratories to effectively and expeditiously detect ASFV infection. In this study, four strains of monoclonal antibodies (mAbs) against p72, namely, 5A1, 4C4, 8A9, and 5E10, were generated through recombinant expression of p72, the main capsid protein of ASFV, and immunized mice with it. Epitope localization was performed by truncated overlapping polypeptides. The results indicate that 5A1 and 4C4 recognized the amino acid 20-39 aa, 8A9 and 5E10 are recognized at 263-282 aa, which is consistent with the reported 265-280 aa epitopes. Conserved analysis revealed 20-39 aa is a high conservation of the epitopes in the ASFV genotypes. Moreover, a blocking ELISA assay for detection ASFV antibody based on 4C4 monoclonal antibody was developed and assessed. The receiver-operating characteristic (ROC) was performed to identify the best threshold value using 87 negative and 67 positive samples. The established test exhibited an area under the curve (AUC) of 0.9997, with a 95% confidence interval ranging from 99.87 to 100%. Furthermore, the test achieved a diagnostic sensitivity of 100% (with a 95% confidence interval of 95.72 to 100%) and a specificity of 98.51% (with a 95% confidence interval of 92.02 to 99.92%) when the threshold was set at 41.97%. The inter- and intra-batch coefficient of variation were below 10%, demonstrating the exceptional repeatability of the method. This method can detect the positive standard serum at a dilution as high as 1:512. Subsequently, an exceptional blocking ELISA assay was established with high diagnostic sensitivity and specificity, providing a novel tool for detecting ASFV antibodies. KEY POINTS: • Four strains of ASFV monoclonal antibodies against p72 were prepared and their epitopes were identified. • Blocking ELISA method was established based on monoclonal antibody 4C4 with an identified conservative epitope. • The established blocking ELISA method has a good effect on the detection of ASFV antibody.

Combined control of plant diseases by Bacillus subtilis SL44 and Enterobacter hormaechei Wu15.

Co-incubation of plant growth promoting rhizobacteria (PGPRs) have been proposed as a potential alternative to pesticides for controlling fungal pathogens in crops, but their synergism mechanisms are not yet fully understood. In this study, combined use of Bacillus subtilis SL44 and Enterobacter hormaechei Wu15 could decrease the density of Colletotrichum gloeosporioides and Rhizoctonia solani and enhance the growth of beneficial bacteria on the mycelial surface, thereby mitigating disease severity. Meanwhile, PGPR application led to a reorganization of the rhizosphere microbial community through modulating its metabolites, such as extracellular polymeric substances and chitinase. These metabolites demonstrated positive effects on attracting and enhancing conventional periphery bacteria, inhibiting fungal pathogens and promoting soil health effectively. The improvement in the microbial community structure altered the trophic mode of soil fungal communities, effectively decreasing the proportion of saprotrophic soil and reducing fungal plant diseases. Certain combinations of PGPR have the potential to serve as precise instruments for managing plant pathogens.

Mn-Based Mullites for Environmental and Energy Applications.

Mn-based mullite oxides AMn2O5 (A = lanthanide, Y, Bi) is a novel type of ternary catalyst in terms of their electronic and geometric structures. The coexistence of pyramid Mn3+-O and octahedral Mn4+-O makes the d-orbital selectively active toward various catalytic reactions. The alternative edge- and corner-sharing stacking configuration constructs the confined active sites and abundant active oxygen species. As a result, they tend to show superior catalytic behaviors and thus gain great attention in environmental treatment and energy conversion and storage. In environmental applications, Mn-based mullites have been demonstrated to be highly active toward low-temperature oxidization of CO, NO, volatile organic compounds (VOCs), etc. Recent research further shows that mullites decompose O3 and ozonize VOCs from -20 °C to room temperature. Moreover, mullites enhance oxygen reduction reactions (ORR) and sulfur reduction reactions (SRR), critical kinetic steps in air-battery and Li-S batteries, respectively. Their distinctive structures also facilitate applications in gas-sensitive sensing, ionic conduction, high mobility dielectrics, oxygen storage, piezoelectricity, dehydration, H2O2 decomposition, and beyond. A comprehensive review from basic physicochemical properties to application certainly not only gains a full picture of mullite oxides but also provides new insights into designing heterogeneous catalysts.

Preparation of pH-sensitive carboxymethyl chitosan nanoparticles loaded with ginsenoside Rb1 and evaluation of drug release in vitro.

Oral absorption of ginsenoside Rb1 (Rb1) is often hindered by the gastrointestinal tract. Carboxymethyl chitosan deoxycholic acid loaded with ginsenoside Rb1 nanoparticles (CMDA@Rb1-NPs), were prepared as a delivery system using a self-assembly technique with amphipathic deoxycholic acid grafted carboxymethyl chitosan as the carrier, which improved the stability and embedding rate of Rb1. In addition, the CMDA@Rb1-NPs was encapsulated with sodium alginate by ion crosslinking method with additional layer (CMDAlg@Rb1-NPs). Scanning electron microscopy showed that the nanoparticles were spherical, evenly distributed, smooth and without obvious adhesion. By evaluating drug loading, entrapment efficiency, the encapsulation efficiency of Rb1 increased from 60.07 % to 72.14 % after grafting deoxycholic acid improvement and optimization. In vitro release results showed that the cumulative release of Rb1 by CMDAlg-NPs showed a pH dependent effect, which was <10 % in simulated gastric juice with pH 1.2, completely released with pH 7.4 for about 48 h. In addition, Rb1 and CMDAlg@Rb1-NPs had inhibitory effects on A549 cells, and the inhibitory effect of CMDAlg@Rb1-NPs was better. Therefore, all results indicated that CMDA/Alg@Rb1 nanoparticles might be a novel drug delivery system to improve the stability and embedding rate of Rb1, and has the potential to be applied in oral pharmaceutical preparations.

Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.

Assessing the intention to accept inquiry-based teaching pedagogy among Chinese university students: an extension of technology acceptance model.

Introduction: Due to the limitations of traditional didactic teaching, inquiry-based teaching has attracted increasing attention and has become an important content of curriculum teaching reform in college education. Nevertheless, it is vital to investigate students' subjective acceptance of inquiry-based instruction and its influencing factors before inquiry-based teaching methods are widely implemented. Methods: In light of this, taking into account the psychological factors of students, an acceptance model of inquiry-based teaching pedagogy was established based on the extended technology acceptance model (TAM). Three additional variables, namely self-efficacy, implementation quality, and risk perception, were incorporated into the TAM. Firstly, subjective evaluation data of the influencing factors of inquiry teaching acceptance were obtained through a network questionnaire survey from university students in Guangdong, China, using snowball sampling and convenient sampling. A total of 485 valid questionnaires were retrieved, with an effective response rate of 88.2%. Then, internal consistency and reliability, convergent validity and discriminant validity of the model and its hypothesis were tested with reliability and validity tests. Finally, path analysis was used to examine key determinants of students' acceptance of inquiry teaching and moderators. Results: Results indicated that the constructed model can explain the acceptability of inquiry teaching for college students by 88.6%; Attitude has a positive significant impact on behavioral intention; Perceived ease of use indirectly affects behavioral intention through perceived usefulness, while perceived usefulness indirectly affects behavioral intention through attitude; self-efficacy not only directly affects behavioral intention but also indirectly affects behavioral intention through implementation quality; implementation quality indirectly affects behavioral intention through perceived usefulness and attitude; students' risk perception of inquiry-based teaching has no negative impact on behavioral intention. Conclusion: Overall, this study has implications for policymakers, teachers or learners in terms of the implementation and promotion of inquiry-based teaching in college classroom.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

WITHDRAWN: Development of a double-antigen sandwich ELISA for African swine fever virus antibody detection based on K205R protein.

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Surface reconstruction of pyrite-type transition metal sulfides during oxygen evolution reaction.

Reconstruction universally occurs over non-layered transition metal sulfides (TMSs) during oxygen evolution reaction (OER), leading to the formation of active species metal (oxy)hydroxide and thus significantly influences the OER performance. However, the reconstruction process and underlying mechanism quantitatively remain largely unexplored. Herein, we proposed an electrochemical reaction mechanism, namely sulfide oxidation reaction (SOR), to elucidate the reconstruction process of pyrite-type TMSs. Based on this mechanism, we evaluated the reconstruction capability of NiS2 doped with transition metals V, Cr, Mn, Fe, Co, Cu, Mo, Ru, Rh, and Ir within different doped systems. Two key descriptors were thus proposed to describe the reconstruction abilities of TMSs: USOR (the theoretical electric potential of SOR) and ΔU (the difference between the theoretical electric potential of SOR and OER), representing the initiation electric potential of reconstruction and the intrinsic reconstruction abilities of TMSs, respectively. Our finding shows that a lower USOR readily initiate reconstruction at a lower potential and a larger ΔU indicating a poorer reconstruction ability of the catalyst during OER. Furthermore, Fe-doped CoS2 was used to validate the rationality of our proposed descriptors, being consistent with the experiment findings. Our work provides a new perspective on understanding the reconstruction mechanism and quantifying the reconstruction of TMSs.

Synergy between Cu and Co in a Layered Double Hydroxide Enables Close to 100% Nitrate-to-Ammonia Selectivity.

Nitrate electroreduction (NO3RR) holds promise as an energy-efficient strategy for the removal of toxic nitrate to restore the natural nitrogen cycle and mitigate the adverse impacts caused by overfertilization from suboptimal agricultural practices. However, existing catalysts suffer from limited electrocatalytic activity, poor selectivity, inadequate durability, and low scalability. To address this quadrilemma, in this study, we developed a cost-effective layered double hydroxide (LDH) electrocatalyst with a lamellar structure that presents trimetallic CuCoAl active sites on the nanomaterial surface. This codoping design enabled electrochemical upcycling of nitrate into ammonia exclusively and efficiently with an onset potential at 0 V vs RHE, where the electrocatalytic process is less energy intensive and has a lower carbon footprint than conventional practices. The synergistic interaction among Cu, Co, and Al further afforded a 99.5% Faradic efficiency (FE) and a yield rate of 0.22 mol h-1 g-1 for nitrate-to-ammonia electroreduction, surpassing the performance of state-of-the-art nonprecious metal NO3RR electrocatalysts over an extended operation period. To gain insights into the origin of the catalytic performance observed on LDH, control materials were employed to elucidate the roles of Cu and Co. Cu was found to improve the NO3RR onset potential despite displaying limited FE for ammonia synthesis, while Co was discovered to suppress the formation of nitrite byproduct though requiring large overpotential. Simulated wastewater containing phosphate and sulfate, which are typically present in industrial effluents, was used to further investigate the effect of electrolytes on NO3RR. Intriguingly, the use of phosphate buffer resulted in a superior yield rate and FE for ammonia production while simultaneously inhibiting nitrite byproduct formation compared with the sulfate case. These experimental findings were supported by density functional theory (DFT) calculations, which explored the adsorption strength of nitrate adducts adjacent to coadsorbed electrolytes on the LDH surface. Additionally, the relative free energies of NO3RR species were also computed to examine the proton-coupled electron transfer (PCET) mechanism on CuCoAl LDH, shedding light on the potential-dependent step (PDS) and the exclusive selectivity for nitrate-to-ammonia conversion. The CuCoAl LDH developed here offers scalability by eliminating the need for precious metals, rendering this earth-abundant catalyst particularly appealing for sustainable nitrate electrovalorization technology.

Development and Validation of Prediction Models for Exacerbation, Frequent Exacerbations and Severe Exacerbations of Chronic Obstructive Pulmonary Disease: A Registry Study in North China.

In COPD patients, exacerbation has a detrimental influence on the quality of life, disease progression and socioeconomic burden. This study aimed to develop and validate models to predict exacerbation, frequent exacerbations and severe exacerbations in COPD patients. We conducted an observational prospective multicenter study. Clinical data of all outpatients with stable COPD were collected from Beijing Chaoyang Hospital and Beijing Renhe Hospital between January 2018 and December 2019. Patients were followed up for 1 year. The data from Chaoyang Hospital was used for modeling dataset, and that of Renhe Hospital was used for external validation dataset. The final dataset included 456 patients, with 326 patients as the model group and 130 patients as the validation group. Using LABA + ICS, frequent exacerbations in the past year and CAT score were independent risk factors for exacerbation in the next year (OR = 2.307, 2.722 and 1.147), and FVC %pred as a protective factor (OR = 0.975). Combined with chronic heart failure, frequent exacerbations in the past year, blood EOS counts and CAT score were independent risk factors for frequent exacerbations in the next year (OR = 4.818, 2.602, 1.015 and 1.342). Using LABA + ICS, combined with chronic heart failure, frequent exacerbations in the past year and CAT score were independent risk factors for severe exacerbations in the next year (OR = 1.950, 3.135, 2.980 and 1.133). Based on these prognostic models, nomograms were generated. The prediction models were simple and useful tools for predicting the risk of exacerbation, frequent exacerbations and severe exacerbations of COPD patients in North China.

Multimaterial 3D and 4D Bioprinting of Heterogenous Constructs for Tissue Engineering.

Additive manufacturing (AM), which is based on the principle of layer-by-layer shaping and stacking of discrete materials, has shown significant benefits in the fabrication of complicated implants for tissue engineering (TE). However, many native tissues exhibit anisotropic heterogenous constructs with diverse components and functions. Consequently, the replication of complicated biomimetic constructs using conventional AM processes based on a single material is challenging. Multimaterial 3D and 4D bioprinting (with time as the fourth dimension) has emerged as a promising solution for constructing multifunctional implants with heterogenous constructs that can mimic the host microenvironment better than single-material alternatives. Notably, 4D-printed multimaterial implants with biomimetic heterogenous architectures can provide a time-dependent programmable dynamic microenvironment that can promote cell activity and tissue regeneration in response to external stimuli. This paper first presents the typical design strategies of biomimetic heterogenous constructs in TE applications. Subsequently, the latest processes in the multimaterial 3D and 4D bioprinting of heterogenous tissue constructs are discussed, along with their advantages and challenges. In particular, the potential of multimaterial 4D bioprinting of smart multifunctional tissue constructs is highlighted. Furthermore, this review provides insights into how multimaterial 3D and 4D bioprinting can facilitate the realization of next-generation TE applications.

Comparative proteomics unveils the bacteriostatic mechanisms of Ga(III) on the regulation of metabolic pathways in Pseudomonas aeruginosa.

Gallium has a long history as a chemotherapeutic agent. The mechanisms of action of Ga(III)-based anti-infectives are different from conventional antibiotics, which primarily result from the chemical similarities of Ga(III) with Fe(III) and substitution of gallium into iron-dependent biological pathways. However, more aspects of the molecular mechanisms of Ga(III) against human pathogens, especially the effects on bacterial metabolic processes, remain to be understood. Herein, by using conventional quantitative proteomics, we identified the protein changes of Pseudomonas aeruginosa (P. aeruginosa) in response to Ga(NO3)3 treatment. We show that Ga(III) exhibits bacteriostatic mode of action against P. aeruginosa through affecting the expressions of a number of key enzymes in the main metabolic pathways, including glycolysis, TCA cycle, amino acid metabolism, and protein and nucleic acid biosynthesis. In addition, decreased expressions of proteins associated with pathogenesis and virulence of P. aeruginosa were also identified. Moreover, the correlations between protein expressions and metabolome changes in P. aeruginosa upon Ga(III) treatment were identified and discussed. Our findings thus expand the understanding on the antimicrobial mechanisms of Ga(III) that shed light on enhanced therapeutic strategies. BIOLOGICAL SIGNIFICANCE: Mounting evidence suggest that the efficacy and resistance of clinical antibiotics are closely related to the metabolic homeostasis in bacterial pathogens. Ga(III)-based compounds have been repurposed as antibacterial therapeutic candidates against antibiotics resistant pathogens, and represent a safe and promising treatment for clinical human infections, while more thorough understandings of how bacteria respond to Ga(III) treatment are needed. In the present study, we provide evidences at the proteome level that indicate Ga(III)-induced metabolic perturbations in P. aeruginosa. We identified and discussed the interference of Ga(III) on the expressions and activities of enzymes in the main metabolic pathways in P. aeruginosa. In view of our previous report that the antimicrobial efficacy of Ga(III) could be modulated according to Ga(III)-induced metabolome changes in P. aeruginosa, our current analyses may provide theoretical basis at the proteome level for the development of efficient gallium-based therapies by exploiting bacterial metabolic mechanisms.