Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

AI-based digital pathology provides newer insights into lifestyle intervention-induced fibrosis regression in MASLD: An exploratory study.

BACKGROUND AND AIMS: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Designing Symmetric Gradient Honeycomb Structures with Carbon-Coated Iron-Based Composites for High-Efficiency Microwave Absorption.

The impedance matching of absorbers is a vital factor affecting their microwave absorption (MA) properties. In this work, we controllably synthesized Material of Institute Lavoisier 88C (MIL-88C) with varying aspect ratios (AR) as a precursor by regulating oil bath conditions, followed by one-step thermal decomposition to obtain carbon-coated iron-based composites. Modifying the precursor MIL-88C (Fe) preparation conditions, such as the molar ratio between metal ions and organic ligands (M/O), oil bath temperature, and oil bath time, influenced the phases, graphitization degree, and AR of the derivatives, enabling low filler loading, achieving well-matched impedance, and ensuring outstanding MA properties. The MOF-derivatives 2 (MD2)/polyvinylidene Difluoride (PVDF), MD3/PVDF, and MD4/PVDF absorbers all exhibited excellent MA properties with optimal filler loadings below 20 wt% and as low as 5 wt%. The MD2/PVDF (5 wt%) achieved a maximum effective absorption bandwidth (EAB) of 5.52 GHz (1.90 mm). The MD3/PVDF (10 wt%) possessed a minimum reflection loss (RLmin) value of - 67.4 at 12.56 GHz (2.13 mm). A symmetric gradient honeycomb structure (SGHS) was constructed utilizing the high-frequency structure simulator (HFSS) to further extend the EAB, achieving an EAB of 14.6 GHz and a RLmin of - 59.0 dB. This research offers a viable inspiration to creating structures or materials with high-efficiency MA properties.

Enhancing osteoporosis treatment using a targeted, sustained-release drug delivery system based on macrocyclic amphiphile.

Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems.

Enzymatic Synthesis of Unprotected α,ß-Diamino Acids via Direct Asymmetric Mannich Reactions.

α,ß-Diamino acids are important structural motifs and building blocks for numerous bioactive natural products, peptidomimetics, and pharmaceuticals, yet efficient asymmetric synthesis to access these stereoarrays remains a challenge. Herein, we report the development of a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is engineered to catalyze stereoselective Mannich-type reactions between free α-amino acids and enolizable cyclic imines. This biocatalyst enabled one-step asymmetric enzymatic synthesis of the unusual pyrrolidine-containing amino acid L-tambroline at gram-scale with high enantio- and diastereocontrol. Furthermore, this enzymatic platform is capable of utilizing a diverse range of α-amino acids as the Mannich donor and various cyclic imines as the acceptor. By coupling with different imine-generating enzymes, we established versatile biocatalytic cascades and demonstrated a general, concise, versatile, and atom-economic approach to access unprotected α,ß-diamino acids, including structurally complex α,α-disubstituted α,ß-diamino acids with contiguous stereocenters.

Association between perioperative change in red cell distribution width and mortality in patients with brain tumor craniotomy.

OBJECTIVE: An elevated preoperative red cell distribution width (RDW) is associated with adverse prognostic outcomes in various diseases. However, the correlation between changes in RDW (ΔRDW) and the prognosis following brain tumor craniotomy remains unclear. Accordingly, this study aimed to investigate the prognostic significance of perioperative changes in RDW in patients undergoing brain tumor craniotomy. METHODS: This retrospective cohort study included patients undergoing craniotomy for brain tumors at West China Hospital, Sichuan University, from January 2011 to March 2021. We defined perioperative changes in RDW: group A (non-significant RDW changes, ΔRDW ≤0.4%), group B (drop in RDW, ΔRDW < -0.4%), and group C (rise in RDW, ΔRDW >0.4%). The relationship between the changes in RDW and all-cause mortality was analyzed by categorizing the patients according to perioperative ΔRDW (RDW at postoperative one week - RDW at admission). RESULTS: The present study included a total of 9589 patients who underwent craniotomy for the treatment of brain tumors. A rise in RDW was significantly associated with increased mortality, with an adjusted OR of 3.56 (95% CI: 2.56-4.95) for 30-day mortality and 1.57 (95% CI: 1.33-1.85) for one-year mortality compared to those with non-significant RDW changes (ΔRDW ≤0.4%). Conversely, a decrease in RDW showed no significant association with 30-day mortality (adjusted OR: 1.04, 95% CI: 0.53-2.04) and one-year mortality (adjusted OR: 1.18, 95% CI: 0.92-1.53). These findings were also supported by restricted cubic spline, which shows that increases in RDW were significantly associated with lower survival rates compared to stable RDW levels during the follow-up period. CONCLUSIONS: Among patients undergoing craniotomy for a brain tumor, a rise in RDW was associated with 30-day mortality and higher long-term mortality risks, even if patients' admissions for RDW values were within the normal range. It was worth noting that maintaining stable RDW levels during this period was associated with better survival.

The first two complete mitochondrial genomes for the genus Anagyrus (Hymenoptera, Encyrtidae) and their phylogenetic implications.

Anagyrus, a genus of Encyrtidae (Hymenoptera, Chalcidoidea), represents a successful group of parasitoid insects that attack various mealybug pests of agricultural and forestry plants. Until now, only 20 complete mitochondrial genomes have been sequenced, including those in this study. To enrich the diversity of mitochondrial genomes in Encyrtidae and to gain insights into their phylogenetic relationships, the mitochondrial genomes of two species of Anagyrus were sequenced, and the mitochondrial genomes of these species were compared and analyzed. Encyrtid mitochondrial genomes exhibit similarities in nucleotide composition, gene organization, and control region patterns. Comparative analysis of protein-coding genes revealed varying molecular evolutionary rates among different genes, with six genes (ATP8, ND2, ND4L, ND6, ND4 and ND5) showing higher rates than others. A phylogenetic analysis based on mitochondrial genome sequences supports the monophyly of Encyrtidae; however, the two subfamilies, Encyrtinae and Tetracneminae, are non-monophyletic. This study provides valuable insights into the phylogenetic relationships within the Encyrtidae and underscores the utility of mitochondrial genomes in the systematics of this family.

Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts.

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-ß and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-ß of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise "doubly orthogonal" modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide-saccharide-biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

Correction: Boorboori, M.R.; Zhang, H.-Y. Arbuscular Mycorrhizal Fungi Are an Influential Factor in Improving the Phytoremediation of Arsenic, Cadmium, Lead, and Chromium. J. Fungi 2022, 8, 176.

In the original publication [...].

Adsorption properties of cellulose-derived hydrogel and magnetic hydrogels from Sophora flavescens on Cu2+ and Congo red.

This study synthesized a robust, magnetically responsive hydrogel from Sophora flavescens-modified cellulose and chitosan, employing Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA and DTG), and scanning electron microscopy (SEM) to confirm the preservation of cellulose's intrinsic properties and the hydrogel's remarkable elasticity, toughness, and porosity. These hydrogels integrate cellulose's structural backbone with functional moieties from chitosan, enhancing adsorption capabilities for Cu2+ ions and Congo red (CR) dye. Kinetic and thermodynamic analyses reveal that adsorption is spontaneous and endothermic, following a pseudo-second-order model and the Freundlich isotherm. Notably, Cu2+ adsorption capacity increases with pH, while CR adsorption initially decreases before rising, demonstrating the hydrogels' potential as effective, sustainable adsorbents for removing pollutants from water.

Structural basis of tolvaptan binding to the vasopressin V2 receptor.

The vasopressin V2 receptor (V2R) is a validated therapeutic target for autosomal dominant polycystic kidney disease (ADPKD), with tolvaptan being the first FDA-approved antagonist. Herein, we used Gaussian accelerated molecular dynamics simulations to investigate the spontaneous binding of tolvaptan to both active and inactive V2R conformations at the atomic-level. Overall, the binding process consists of two stages. Tolvaptan binds initially to extracellular loops 2 and 3 (ECL2/3) before overcoming an energy barrier to enter the pocket. Our simulations result highlighted key residues (e.g., R181, Y205, F287, F178) involved in this process, which were experimentally confirmed by site-directed mutagenesis. This work provides structural insights into tolvaptan-V2R interactions, potentially aiding the design of novel antagonists for V2R and other G protein-coupled receptors.

Copper Difluorocarbene Enables Catalytic Difluoromethylation.

Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBH3CN and low-cost difluorocarbene precursor BrCF2CO2K, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.

Operative Mortality After Type A Aortic Dissection Surgery: Differences Based on Sex and Age.

Background: There is controversy regarding sex differences in short-term mortality in acute type A aortic dissection (ATAAD). Objectives: This study aimed to investigate the impact of sex differences on 30-day operative mortality after ATAAD surgery and to determine if other covariates modify the association. Methods: Consecutive patients (N = 5670) with surgically repaired ATAAD were identified from the multicenter China 5A study. The primary outcome was operative mortality. The age dependency was modeled using a cubic spline curve. Results: There were 1,503 females (26.5%) and 4,167 males (73.5%). Females were older and had a lower percentage of comorbidities compared with males. Females had higher mortality compared to males (10.2% vs 8.2%, P = 0.019); however, there was no difference after propensity analyses (adjusted OR: 1.334 [95% CI: 0.918-1.938]). There was an interaction with sex and age (P interaction = 0.035): older age was associated with higher odds of operative mortality among females (OR: 1.045 [95% CI: 1.029-1.061]) compared with males (OR: 1.025 [95% CI: 1.016-1.035]). The risk of mortality for males and females appears to diverge at 55 years of age (P interaction = 0.019): females under 55 years of age had similar odds to males (OR: 0.852 [95% CI: 0.603-1.205]) but higher odds when over 55 years (OR: 1.420 [95% CI: 1.096-1.839]) compared to males. Conclusions: Under the age of 55 years, females have similar odds of operative mortality compared with males; however, over the age of 55 years females have higher odds than males. Understanding differences in risk allows for individualized treatment strategies. (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy; NCT04398992).

Van der Waals Schottky Junction Photodetector with Ultrahigh Rectifying Ratio and Switchable Photocurrent Generation.

Metal-semiconductor junctions play an important role in the development of electronic and optoelectronic devices. A Schottky junction photodetector based on two-dimensional (2D) materials is promising for self-powered photodetection with fast response speed and large signal-to-noise ratio. However, it usually suffers from an uncontrolled Schottky barrier due to the Fermi level pinning effect arising from the interface states. In this work, all-2D Schottky junctions with near-ideal Fermi level depinning are realized, attributed to the high-quality interface between 2D semimetals and semiconductors. We further demonstrate asymmetric diodes based on multilayer graphene/MoS2/PtSe2 with a current rectification ratio exceeding 105 and an ideality factor of 1.2. Scanning photocurrent mapping shows that the photocurrent generation mechanism in the heterostructure switches from photovoltaic effect to photogating effect at varying drain biases, indicating both energy conversion and optical sensing are realized in a single device. In the photovoltaic mode, the photodetector is self-powered with a response time smaller than 100 µs under the illumination of a 405 nm laser. In the photogating mode, the photodetector exhibits a high responsivity up to 460 A/W originating from a high photogain. Finally, the photodetector is employed for single-pixel imaging, demonstrating its high-contrast photodetection ability. This work provides insight into the development of high-performance self-powered photodetectors based on 2D Schottky junctions.

Multiomics analysis of the effects of manure-borne doxycycline combined with oversized fiber microplastics on pak choi growth and the risk of antibiotic resistance gene transmission.

In this study, oversized microplastics (OMPs) were intentionally introduced into soil containing manure-borne doxycycline (DOX). This strategic approach was used to systematically examine the effects of combined OMP and DOX pollution on the growth of pak choi, analyze alterations in soil environmental metabolites, and explore the potential migration of antibiotic resistance genes (ARGs). The results revealed a more pronounced impact of DOX than of OMPs. Slender-fiber OMPs (SF OMPs) had a more substantial influence on the growth of pak choi than did coarse-fiber OMPs (CF OMPs). Conversely, CF OMPs had a more significant effect on the migration of ARGs within the system. When DOX was combined with OMPs, the negative effects of DOX on pak choi growth were mitigated through the synthesis of indole through the adjustment of carbon metabolism and amino acid metabolism in pak choi roots. In this process, Pseudohongiellaceae and Xanthomonadaceae were key bacteria. During the migration of ARGs, the potential host bacterium Limnobacter should be considered. Additionally, the majority of potential host bacteria in the pak choi endophytic environment were associated with tetG. This study provides insights into the intricate interplay among DOX, OMPs, ARGs, plant growth, soil metabolism, and the microbiome.

Recyclable V2O5/g-C3N4 Heterojunction-Catalyzed Visible-Light-Promoted C3-H Trifluoromethylation of Quinoxalin-2-(1H)-ones.

A visible-light-initiated C-H trifluoromethylation of quinoxalin-2(1H)-ones was established using a Z-scheme V2O5/g-C3N4 heterojunction as a recyclable photocatalyst in an inert atmosphere at room temperature under additive-free and mild conditions. A variety of trifluoromethylated quinoxalin-2-(1H)-one derivatives were heterogeneously generated in moderate to high yields, exhibiting good functional group tolerance. Remarkably, the recyclable V2O5/g-C3N4 catalyst could be reused five times with a slight loss of catalytic activity.

Correlation of Computed Tomography Angiography to Digital Subtraction Angiography in Carotid Stenosis with Real-World Assessment of Overestimation of Carotid Stenosis on Computed Tomography Angiography.

OBJECTIVE: Computed tomography angiography (CTA) is a well-established diagnostic modality for carotid stenosis. However, false-positive CTA results may expose patients to unnecessary procedural complications in cases where surgical intervention is not warranted. We aim to assess the correlation of CTA to digital subtraction angiography (DSA) in carotid stenosis and characterize patients who were referred for intervention based on CTA and did not require it based on DSA. METHODS: We retrospectively reviewed 186 patients who underwent carotid angioplasty and stenting following preprocedural CTA at our institution from April 2017 to December 2022. RESULTS: Twenty-one of 186 patients (11.2%) were found to have <50% carotid stenosis on DSA (discordant group). Severe plaque calcification on CTA was associated with a discordant degree of stenosis on DSA (LR+=7.4). Among 186 patients, agreement between the percentage of stenosis from CTA and DSA was weak-moderate (r2=0.27, P<0.01). Among concordant pairs, we found moderate-strong agreement between CTA and DSA (adj r2=0.37) (P < 0.0001). Of 186 patients, 127 patients had CTA stenosis of ≥70%, and 59 had CTA of 50%-69%. Correlation between CTA and DSA in severe CTA stenosis was weak (r2=0.11, P<0.01). CONCLUSIONS: In patients with stenosis found on CTA, over 88% also had stenosis on DSA, with this positive predictive value in line with previous studies. The percent-stenosis value from CTA and DSA was weakly correlated but does not affect the overall clinical judgement of stenosis. Severe calcification found on CTA may potentially indicate nonstenosis on DSA.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

A method to detect uniformity of road base course based on impact imaging technology.

The damage of road base course has the characteristics of strong concealment and difficulty in detecting. For this reason, the impact imaging method has been used for detection of road base course. This paper discussed systematically collection points setting, excitation mode and data processing method. Through the application in testing for highway pavement base before and after grouting maintenance, the results show that the method is simple and accurate. The detection results can be displayed in a two-dimensional image form and it is easy to be used in road maintenance. This method can be used to identify and locate the damages of the pavement base, to judge the uniformity of the pavement base structure. It can also be used to evaluate the effectiveness of internal damage after grouting repairing.

Vibration-Dependent Dual-Phosphorescent Cu4 Nanocluster with Remarkable Piezochromic Behavior.

The dual emission (DE) characteristics of atomically precise copper nanoclusters (Cu NCs) are of significant theoretical and practical interest. Despite this, the underlying mechanism driving DE in Cu NCs remains elusive, primarily due to the complexities of excited state processes. Herein, a novel [Cu4(PPh3)4(C≡C-p-NH2C6H4)3]PF6 (Cu4) NC, shielded by alkynyl and exhibiting DE, was synthesized. Hydrostatic pressure was applied to Cu4, for the first time, to investigate the mechanism of DE. With increasing pressure, the higher-energy emission peak of Cu4 gradually disappeared, leaving the lower-energy emission peak as the dominant emission. Additionally, the Cu4 crystal exhibited notable piezochromism transitioning from cyan to orange. Angle-dispersive synchrotron X-ray diffraction results revealed that the reduced inter-cluster distances under pressure brought the peripheral ligands closer, leading to the formation of new C-H⋅⋅⋅N and N-H⋅⋅⋅N hydrogen bonds in Cu4. It is proposed that these strengthened hydrogen bond interactions limit the ligands' vibration, resulting in the vanishing of the higher-energy peak. In situ high-pressure Raman and vibrationally resolved emission spectra demonstrated that the benzene ring C=C stretching vibration is the structural source of the DE in Cu4.