Dimethyl-Dioctadecyl-Ammonium Bromide/Poly(lactic acid) Nanoadjuvant Enhances the Immunity and Cross-Protection of an NM2e-Based Universal Influenza Vaccine.

For most frequent respiratory viruses, there is an urgent need for a universal influenza vaccine to provide cross-protection against intra- and heterosubtypes. We previously developed an Escherichia coli fusion protein expressed extracellular domain of matrix 2 (M2e) and nucleoprotein, named NM2e, and then combined it with an aluminum adjuvant, forming a universal vaccine. Although NM2e has demonstrated a protective effect against the influenza virus in mice to some extent, further improvement is still needed for the induction of immune responses ensuring adequate cross-protection against influenza. Herein, we fabricated a cationic solid lipid nanoadjuvant using poly(lactic acid) (PLA) and dimethyl-dioctadecyl-ammonium bromide (DDAB) and loaded NM2e to generate an NM2e@DDAB/PLA nanovaccine (Nv). In vitro experiments suggested that bone marrow-derived dendritic cells incubated with Nv exhibited ∼4-fold higher antigen (Ag) uptake than NM2e at 16 h along with efficient activation by NM2e@DDAB/PLA Nv. In vivo experiments revealed that Ag of the Nv group stayed in lymph nodes (LNs) for more than 14 days after initial immunization and DCs in LNs were evidently activated and matured. Furthermore, the Nv primed T and B cells for robust humoral and cellular immune responses after immunization. It also induced a ratio of IgG2a/IgG1 higher than that of NM2e to a considerable extent. Moreover, NM2e@DDAB/PLA Nv quickly restored body weight and improved survival of homo- and heterosubtype influenza challenged mice, and the cross-protection efficiency was over 90%. Collectively, our study demonstrated that NM2e@DDAB/PLA Nv could offer notable protection against homo- and heterosubtype influenza virus challenges, offering the potential for the development of a universal influenza vaccine.

Recent advances in asymmetric synthesis of chiral amides and peptides: racemization-free coupling reagents.

Over past decades, chiral amides and peptides have emerged as powerful and versatile compounds due to their various biological activities and interesting molecular architectures. Although some chiral condensation reagents have been applied successfully for their synthesis, the introduction of racemization-free methods of amino acid activation have shown lots of advantages in terms of their low cost and low toxicity. In this review, advancements in amide and peptide synthesis using racemization-free coupling reagents over the last 10 years are summarized. Various racemization-free coupling reagents have been applied in the synthesis of enantioselective amides and peptides, including ynamides, allenones, HSi[OCH(CF3)2]3, Ta(OMe)5, Nb(OEt)5, Ta(OEt)5, TCFH-NMI, water-removable ynamides, DBAA, DATB, o-NosylOXY, TCBOXY, Boc-Oxyma, NDTP, 9-silafluorenyl dichlorides, the Mukaiyama reagent, EDC and T3P. The racemization-free reagents described in this review provide an alternative greener option for the asymmetric synthesis of chiral amides and peptides. We hope that this review will inspire further studies and developments in this field.

Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian randomization study.

Background: Systemic inflammation has been proposed to be associated with the incidence of atrial fibrillation (AF), but whether it is a cause or a consequence of AF remains uncertain. We sought to explore the causal associations between systemic inflammation and AF using bidirectional Mendelian randomization (MR) analysis. Methods: Independent genetic variants strongly associated with AF were selected as instrumental variables from the largest genome-wide association study (GWAS) with up to 1,030,836 individuals. Regarding inflammation traits, genetic associations with 41 inflammatory cytokines and 5 inflammatory biomarkers were obtained from their corresponding GWASs databases. Effect estimates were primarily evaluated using the inverse-variance weighted (IVW) method, supplemented by sensitivity analyses using MR-Egger, weighted median, and MR-PRESSO methods. Results: In our initial MR analyses, we observed suggestive associations of genetically predicted interleukin-17 (IL-17), interleukin-2 receptor subunit alpha (IL-2rα), and procalcitonin (PCT) with AF. One standard deviation (SD) increase in IL-17, IL-2rα, and PCT caused an increase in AF risk by 6.3 % (OR 1.063, 95 %CI 1.011---1.118, p = 0.018), 4.9 % (OR 1.049, 95 %CI 1.007---1.094, p = 0.023) and 3.4 % (OR 1.034, 95 %CI 1.005---1.064, p = 0.022), respectively. Furthermore, our reverse MR analyses indicated that genetically predicted AF contributed to a suggestive increase in the levels of macrophage inflammatory protein-1ß (MIP1ß) (ß 0.055, 95 %CI 0.006 to 0.103, p = 0.028), while a decrease in the levels of fibrinogen (Fbg) (ß -0.091, 95 %CI -0.140 to -0.041, p < 0.001), which remained significant after multiple test correction. Conclusions: Our MR study identified several inflammatory biomarkers with suggestive causal associations regarding the upstream and downstream regulation of AF occurrence, offering new insights for therapeutic exploitation of AF. Further research is required to validate the underlying link between systemic inflammation and AF in larger cohorts.

Pt/Zn-TCPP Nanozyme-Based Flexible Immunoassay for Dual-Mode Pressure-Temperature Monitoring of Low-Abundance Proteins.

Pressure and temperature, as common physical parameters, are important for monitoring human health. In contrast, single-mode monitoring is prone to causing experimental errors. Herein, we innovatively designed a dual-mode flexible sensing platform based on a platinum/zinc-meso-tetrakis(4-carboxyphenyl)porphyrin (Pt/Zn-TCPP) nanozyme for the quantitative monitoring of carcinoembryonic antigen (CEA) in biological fluids with pressure and temperature readouts. The Pt/Zn-TCPP nanozyme with catalytic and photothermal efficiencies was synthesized by means of integrating photosensitizers into porous materials. The flexible sensing system after the antigen-antibody reaction recognized the pressure using a flexible skin-like pressure sensor with a digital multimeter readout, whereas the temperature was acquired via the photoheat conversion system of the Pt/Zn-TCPP nanozyme under 808 nm near-infrared (NIR) irradiation using a portable NIR imaging camera on a smartphone. Meanwhile, the dual-mode flexible sensing system was carried out on a homemade three-dimensional (3D)-printed device. Results revealed that the developed dual-mode immunosensing platform could exhibit good pressure and temperature responses within the dynamic range of 0.5-100 ng mL-1 CEA with the detection limits of 0.24 and 0.13 ng mL-1, respectively. In addition, the pressure and temperature were sensed simultaneously without crosstalk interference. Importantly, the dual-mode flexible immunosensing system can effectively avoid false alarms during the measurement, thus providing great potential for simple and low-cost development for point-of-care testing.

A Comparison of the Association of Septal Scar Burden on Responses to LBBAP-CRT and BVP-CRT.

BACKGROUND: Left bundle branch area pacing (LBBAP) is an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). However, despite the presence of left bundle branch block, whether cardiac substrate may influence the effect between the 2 strategies is unclear. OBJECTIVES: This study aims to assess the association of septal scar on reverse remodeling and clinical outcomes of LBBAP compared with BVP. METHODS: We analyzed patients with nonischemic cardiomyopathy who had CRT indications undergoing preprocedure cardiac magnetic resonance examination. Changes in left ventricular ejection fraction (LVEF) and echocardiographic response (ER, ≥5% absolute LVEF increase) were assessed at 6 months. The clinical outcome was the composite of all-cause mortality, heart failure hospitalization, or major ventricular arrhythmia. RESULTS: There were 147 patients included (51 LBBAP and 96 BVP). Among patients with low septal scar burden (below median 5.7%, range: 0 to 5.3%), LVEF improvement was higher in the LBBAP than the BVP group (17.5% ± 10.9% vs 12.3% ± 11.8%; P = 0.037), with more than 3-fold increased odds of ER (odds ratio: 4.35; P = 0.033). In high sepal scar subgroups (≥5.7%, range: 5.7% to 65.9%), BVP trended towards higher LVEF improvement (9.2% ± 9.4% vs 6.4% ± 12.4%; P = 0.085). Interaction between septal scar burden and pacing strategy was significant for ER (P = 0.002) and LVEF improvement (P = 0.011) after propensity score adjustment. During median follow-up of 33.7 (Q1-Q3: 19.8 to 42.1) months, the composite clinical outcome occurred in 34.7% (n = 51) of patients. The high-burden subgroups had worse clinical outcomes independent of CRT method. CONCLUSIONS: Remodeling response to LBBAP and BVP among nonischemic cardiomyopathy patients is modified by septal scar burden. High septal scar burden was associated with poor clinical prognosis independent of CRT methods.

LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis.

The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.

Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet's uveitis.

Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.

Recycling of Polydicyclopentadiene Enabled with N-Coordinated Boronic Ester Bonds.

In this contribution, the transformation of polydicyclopentadiene (PDCPD) from thermoset into vitrimer is introduced. First, two N-coordinated diboronic diols are successfully synthesized via the reaction of N,N,N-tri(2-hydroxyethyl)amine and/or N,N,N",N"-tetrakis(2-hydroxyethyl)ethylene diamine with 4-(hydroxymethyl) phenylboronic acid and then they are transformed into two N-coordinated cyclic boronic diacrylates. The latter two dienes carrying electron-withdrawing substituents are used for the ring opening insertion metathesis copolymerization (ROIMP) of dicyclopentadiene to afford the crosslinked PDCPD. In the crosslinked PDCPD networks, N-coordinated cyclic boronic ester bonds are integrated. It is found that the as-obtained PDCPD networks displayed the excellent reprocessing properties. In the meantime, the fracture toughness is significantly improved. Owing to the inclusion of N-coordinated cyclic boronic ester bonds, the modified PDCPDs have the thermal stability much superior to plain PDCPD. The results reported in this work demonstrate that PDCPD can successfully be transformed into the vitrimers via the introduction of N-coordinated cyclic boronic ester bonds.

Lesion Indexes Predict Early Neurologic Deterioration in Lenticulostriate Single Small Subcortical Infarction.

BACKGROUND AND PURPOSE: Early neurologic deterioration (END) often occurs during hospitalization in single small subcortical infarction (SSSI). The objective was to identify imaging predictors of END. MATERIALS AND METHODS: SSSIs in the lenticulostriate artery within 72 hours of stroke onset from January 2015 to June 2021 were consecutively enrolled. The posteriority and laterality indexes were assessed on the second section from the top of the corona radiata section showing the lateral ventricle on DWI. A multivariate logistic analysis was used to explore the predictors of END. RESULTS: A total of 402 patients were included in this study, among whom 93 (23.1%) experienced END. The optimal cutoff points of the posteriority and laterality indexes for predicting END were given by a receiver operating characteristic curve. A multivariate logistic analysis showed that the posteriority index of ≥0.669 (OR: 2.53; 95% CI: 1.41-4.56; P = .002) and the laterality index of ≥0.950 (OR: 2.03; 95% CI: 1.03-4.00; P = .042) were independently associated with the risk of END. Accordingly, the SSSIs were further divided into 4 types: anterior lateral type (AL-type), anterior medial type (AM-type), posterior lateral type (PL-type), and posterior medial type (PM-type). After the multivariate analysis, in comparison with the AL-type, the AM-type (OR: 3.26; 95% CI: 1.10-9.65), PL-type (OR: 4.68; 95% CI: 1.41-15.56), and PM-type (OR: 6.77; 95% CI: 2.53-18.04) carried significantly elevated risks of END. The PM-type was associated with the highest risk of END. CONCLUSIONS: The PM-type was found to be associated with the highest risk of END.

Entrepreneurial fear of failure among college students: A scoping review of literature from 2010 to 2023.

Entrepreneurial fear of failure (EFoF) is a psychological barrier to college entrepreneurship. Current research on EFoF among college students is at an emerging stage, and relevant evidence, such as the factors influencing EFoF, remains unclear and unsystematic. Most EFoF studies treat college students as general entrepreneurs, neglecting their unique social identities and situational contexts that influence their EFoF, such as parents and education. It is essential to provide a thorough and organized review to comprehensively understand the role of the EFoF in college student entrepreneurship. A scoping review was conducted following the PRISMA-ScR protocol to offer a broad exploration and mapping of the literature. This review identified 35 studies published from 2010 to 2023 through a rigorous search and sift across five prominent databases. Descriptive and thematic analyses revealed 1) the characteristics of the included studies, 2) the exogenous and endogenous factors that influence college students' EFoF, 3) the outcomes of EFoF on college students, and 4) research gaps. By mapping and synthesizing the literature, this scoping review contributes to the theory by providing a comprehensive overview of EFoF among college students and identifying research gaps, which illuminates future research directions. The findings also offer practical insights for entrepreneurship practitioners, including college student entrepreneurs, policymakers, and educators, to better understand the role of EFoF among college students, thus effectively promoting the development of college student entrepreneurship.

Multiband Omnidirectional Invisibility Cloak.

Transformation optics (TO) provides a powerful tool to manipulate electromagnetic waves, enabling the design of invisibility cloaks, which can render objects invisible. Despite many years of research, however, invisibility cloaks experimentally realized thus far can only operate at a single frequency. The narrow bandwidth significantly restricts the practical applications of invisibility cloaks and other TO devices. Here, a general design strategy is proposed to realize a multiband anisotropic metamaterial characterized by two principal permittivity components, i.e., one infinite and the other spatially gradient. Through a proper transformation and combination of such metamaterials, an omnidirectional invisibility cloak is experimentally implemented, which is impedance-matched to free space at multiple frequencies. Both far-field numerical simulations and near-field experimental mappings confirm that this cloak can successfully suppress scattering from multiple large-scale objects simultaneously at 5 and 10 GHz. The design strategy and corresponding practical realization bring multiband transformation optical devices one step closer to reality.

Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production.

Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.

Impacts of microplastic type on the fate of antibiotic resistance genes and horizontal gene transfer mechanism during anaerobic digestion.

Microplastics (MPs) and antibiotic resistance genes (ARGs) are important pollutants in waste activated sludge (WAS), but their interactions during anaerobic digestion (AD) still need to be further explored. This study investigated variations in ARGs, mobile genetic elements (MGEs), and host bacteria during AD under the pressure of polyamide (PA), polyethylene (PE), and polypropylene (PP). The results showed that the MPs increased methane production by 11.7-35.5%, and decreased ARG abundance by 5.6-24.6%. Correlation analysis showed that the decrease of MGEs (plasmid, prophage, etc.) promoted the decrease of the abundance of multidrug, aminoglycoside and tetracycline resistance genes. Metagenomic annotation revealed that the reduction of key host bacteria (Arenimonas, Lautropia, etc.) reduced the abundance of major ARGs (rsmA, rpoB2, etc.). Moreover, PP MPs contributed to a reduction in the abundance of functional genes related to the production of reactive oxygen species, ATP synthesis, and cell membrane permeability, which was conducive to reducing the potential for horizontal gene transfer of ARGs. These findings provide insights into the treatment of organic waste containing MPs.

Novel inflammatory and insulin resistance indices provide a clue in cerebral amyloid angiopathy.

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.

Disease burden of mental disorders among children and adolescents considering both co-morbidities and suicide in Northeastern China.

BACKGROUND: Few studies have assessed the burden of mental disorders among children and adolescents considering the impact of co-morbidities and suicide on disability adjusted life years (DALYs). METHODS: This was a multicenter cross-sectional study. Our survey data in Liaoning Province (LN) were used to estimate the burden of six mental disorders, supplemented with data from other investigative studies conducted in China to assess four other disorders. DALYs were derived from the sum of years lived with a disability (YLDs) adjusted for co-morbidities, and the years of life lost (YLLs) adjusted for suicide. The changes in DALYs, YLDs, and YLLs were compared with and without adjustment for co-morbidities and suicide. RESULTS: The DALYs rate of mental disorders among children and adolescents in LN decreased from 1579.6/105 to 1391.4/105, after adjusting for both co-morbidities and suicide (-11.9%). The DALYs rate for major depression, anxiety disorder, and conduct disorder (-80.8/105, -75.0/105 and -30.2/105, respectively) were the top three contributors to the DALYs reduction (-188.2/105). The YLDs decreased from 72724.8 to 62478.5 after co-morbidity adjustment (-17.8%), mainly due to the reduction by major depression (-35.3%) and attention deficit/hyperactivity disorder [ADHD] (-34.2%). The YLLs increased from 130 to 1697.8 after adjusting for suicides (+ 56.9% of all suicide YLLs), mainly due to the contribution of major depression (+ 32.4%) and anxiety disorder (+ 10.4%). Compared to GBD 2010, the estimated DALY rate for mental disorders in LN was to be about 80%, with the proportion of DALYs and DALY rates explained by major depressive disorder accounted for only approximately one-third (14.6% vs. 41.9% and 202.6 vs. 759.9, respectively). But the proportion and absolute level of DALY rates explained by anxiety disorders were approximately 2-fold higher (39.7% vs. 19.6% and 552.2 vs. 323.3, respectively). CONCLUSIONS: The DALYs of mental disorders among Chinese children and adolescents were approximately 80% of the global level, with anxiety disorders imposing about 2 times the global level. Co-morbidity and suicide must be adjusted when calculating DALYs.

miR-4645-3p attenuates podocyte injury and mitochondrial dysfunction in diabetic kidney disease by targeting Cdk5.

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.

Phased Telomere-to-Telomere Reference Genome and Pangenome Reveal an Expansion of Resistance Genes during Apple Domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Previous versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the highly heterozygous genome, which impeded genetic studies and breeding programs in apple. In this study, we assembled a haplotype-resolved telomere-to-telomere reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on twelve assemblies from wild and cultivated apples to investigate different types of resistance gene analogs (RGAs). Our results revealed the dynamics of the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Interestingly, our analyses demonstrated a higher prevalence of RGAs in cultivated apples than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Other types of structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR (TNL), NB-ARC-LRR (NL), and CC-NB-ARC-LRR (CNL) genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding programs.

Polydopamine Nanocarriers with Cascade-Activated Nitric Oxide Release Combined Photothermal Activity for the Therapy of Drug-Resistant Bacterial Infections.

Antibiotic abuse leads to increased bacterial resistance, and the surviving planktonic bacteria aggregate and secrete extracellular polymers to form biofilms. Conventional antibacterial agents find it difficult to penetrate the biofilm, remove the bacteria wrapped in it, and produce an excellent therapeutic effect. In this study, a dual pH- and NIR-responsive nanocomposite (A-Ca@PDA) was developed to remove drug-resistant bacteria through a cascade of catalytic nitric oxide (NO) release and photothermal clearance. NO can melt in the outer package of the biofilm, facilitating the nanocomposites to have better permeability. Thermal therapy further inhibits the growth of planktonic bacteria. The locally generated high temperature and the burst release of NO together aggravate the biofilm collapse and bacterial death after NIR irradiation. The nanocomposites achieved a remarkable photothermal conversion efficiency of 47.5%, thereby exhibiting significant advancements in energy conversion. The nanocomposites exhibited remarkable efficacy in inhibiting multidrug-resistant (MDR) Escherichia coli and MDR Staphylococcus aureus, thus achieving an inhibition rate of >90%. Moreover, these nanocomposites significantly improved the wound-healing process in the MDR S. aureus-infected mice. Thus, this novel nanocomposite offers a novel strategy to combat drug-resistant bacterial infections.

Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.