Sialic Acid Conjugate-Modified Cationic Liposomal Paclitaxel for Targeted Therapy of Lung Metastasis in Breast Cancer: What a Difference the Cation Content Makes.

Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells in vitro due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis in vivo. By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.

Decidual macrophage: a reversible role in immunotolerance between mother and fetus during pregnancy.

The tolerance of the semi-allogeneic fetus by the maternal immune system is an eternal topic of reproductive immunology for ensuring a satisfactory outcome. The maternal-fetal interface serves as a direct portal for communication between the fetus and the mother. It is composed of placental villi trophoblast cells, decidual immune cells, and stromal cells. Decidual immune cells engage in maintaining the homeostasis of the maternal-fetal interface microenvironment. Furthermore, growing evidence has shown that decidual macrophages play a crucial role in maternal-fetal tolerance during pregnancy. As the second largest cell population among decidual immune cells, decidual macrophages are divided into two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 polarization is critical for placentation and embryonic development. Cytokines, exosomes, and metabolites regulate the polarization of decidual macrophages, and thereby modulate maternal-fetal immunotolerance. Explore the initial relationship between decidual macrophages polarization and maternal-fetal immunotolerance will help diagnose and treat the relevant pregnancy diseases, reverse the undesirable outcomes of mothers and infants.

Single-timepoint low-dimensional characterization and classification of acute versus chronic multiple sclerosis lesions using machine learning.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease characterized by the appearance of focal lesions across the central nervous system. The discrimination of acute from chronic MS lesions may yield novel biomarkers of inflammatory disease activity which may support patient management in the clinical setting and provide endpoints in clinical trials. On a single timepoint and in the absence of a prior reference scan, existing methods for acute lesion detection rely on the segmentation of hyperintense foci on post-gadolinium T1-weighted magnetic resonance imaging (MRI), which may underestimate recent acute lesion activity. In this paper, we aim to improve the sensitivity of acute MS lesion detection in the single-timepoint setting, by developing a novel machine learning approach for the automatic detection of acute MS lesions, using single-timepoint conventional non-contrast T1- and T2-weighted brain MRI. The MRI input data are supplemented via the use of a convolutional neural network generating "lesion-free" reconstructions from original "lesion-present" scans using image inpainting. A multi-objective statistical ranking module evaluates the relevance of textural radiomic features from the core and periphery of lesion sites, compared within "lesion-free" versus "lesion-present" image pairs. Then, an ensemble classifier is optimized through a recursive loop seeking consensus both in the feature space (via a greedy feature-pruning approach) and in the classifier space (via model selection repeated after each pruning operation). This leads to the identification of a compact textural signature characterizing lesion phenotype. On the patch-level task of acute versus chronic MS lesion classification, our method achieves a balanced accuracy in the range of 74.3-74.6% on fully external validation cohorts.

Glial fibrillary acidic protein and multiple sclerosis progression independent of acute inflammation.

BACKGROUND: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified. OBJECTIVE: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS). METHODS: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses. RESULTS: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed. CONCLUSION: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression.

Preeclampsia impedes foetal kidney development by delivering placenta-derived exosomes to glomerular endothelial cells.

BACKGROUND: Foetal renal dysplasia is still the main cause of adult renal disease. Placenta-derived exosomes are an important communication tool, and they may play an important role in placental (both foetal and maternal) function. We hypothesize that in women with preeclampsia, foetal renal dysplasia is impeded by delivering placenta-derived exosomes to glomerular endothelial cells. METHODS: In the present study, we established a PE trophoblast oxidative stress model to isolate exosomes from supernatants by ultracentrifugation (NO-exo and H/R-exo) and collected normal and PE umbilical cord blood plasma to isolate exosomes by ultracentrifugation combined with sucrose density gradient centrifugation (N-exo and PE-exo), then we investigated their effects on foetal kidney development by in vitro, ex vivo and in vivo models. RESULTS: The PE trophoblast oxidative stress model was established successfully. After that, in in vitro studies, we found that H/R-exo and PE-exo could adversely affect glomerular endothelial cell proliferation, tubular formation, migration, and barrier functions. In ex vivo studies, H/R-exo and PE-exo both inhibited the growth and branch formation of kidney explants, along with the decrease of VE-cadherin and Occludin. In in vivo studies, we also found that H/R-exo and PE-exo could result in renal dysplasia, reduced glomerular number, and reduced barrier function in foetal mice. CONCLUSIONS: In conclusion, we demonstrated that PE placenta-derived exosomes could lead to foetal renal dysplasia by delivering placenta-derived exosomes to foetal glomerular endothelial cells, which provides a novel understanding of the pathogenesis of foetal renal dysplasia. Video Abstract.

Exosomal miR-146a-5p derived from human umbilical cord mesenchymal stem cells can alleviate antiphospholipid antibody-induced trophoblast injury and placental dysfunction by regulating the TRAF6/NF-κB axis.

Exosomes originating from human umbilical cord mesenchymal stem cells (hucMSC-exos) have become a novel strategy for treating various diseases owing to their ability to regulate intercellular signal communication. However, the potential of hucMSC-exos to improve placental injury in obstetric antiphospholipid syndrome and its underlying mechanism remain unclear. Our objective was to explore the potential application of hucMSC-exos in the treatment of obstetric antiphospholipid syndrome and elucidate its underlying mechanism. In our study, hucMSC-exos ameliorated the functional impairment of trophoblasts caused by antiphospholipid antibodies in vitro and attenuated placental dysfunction in mice with obstetric antiphospholipid syndrome by delivering miR-146a-5p. Exosomal miR-146a-5p suppressed the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibited the activation of NF-κB signaling, leading to the down-regulation of IL-1ß and IL-18 to rescue inflammation and modulation of Cleaved-CASP3, BAX, and BCL2 to inhibit apoptosis in HTR8/SVneo cells and mice placenta. This study identified the potential molecular basis of how hucMSC-exos improved antiphospholipid antibody-induced placental injury and highlighted the functional importance of the miR-146a-5p/TRAF6 axis in the progression of obstetric antiphospholipid syndrome. More importantly, this study provided a fresh outlook on the promising use of hucMSC-exos as a novel and effective treatment approach in obstetric antiphospholipid syndrome.

DeepLearnMOR: a deep-learning framework for fluorescence image-based classification of organelle morphology.

The proper biogenesis, morphogenesis, and dynamics of subcellular organelles are essential to their metabolic functions. Conventional techniques for identifying, classifying, and quantifying abnormalities in organelle morphology are largely manual and time-consuming, and require specific expertise. Deep learning has the potential to revolutionize image-based screens by greatly improving their scope, speed, and efficiency. Here, we used transfer learning and a convolutional neural network (CNN) to analyze over 47,000 confocal microscopy images from Arabidopsis wild-type and mutant plants with abnormal division of one of three essential energy organelles: chloroplasts, mitochondria, or peroxisomes. We have built a deep-learning framework, DeepLearnMOR (Deep Learning of the Morphology of Organelles), which can rapidly classify image categories and identify abnormalities in organelle morphology with over 97% accuracy. Feature visualization analysis identified important features used by the CNN to predict morphological abnormalities, and visual clues helped to better understand the decision-making process, thereby validating the reliability and interpretability of the neural network. This framework establishes a foundation for future larger-scale research with broader scopes and greater data set diversity and heterogeneity.

Controllable perfect optical vortex generated by complex amplitude encoding.

We propose a new paradigm for generating the perfect optical vortex (POV) with a controlled structure and orbital angular momentum (OAM) distribution in the focal region of a tightly focused system. The superiority of the proposed technique is demonstrated with an experiment involving the dynamic manipulation of small particles. This technique for creating the POV could open new routes to optical manipulation based on OAM.

Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.

BACKGROUND: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. OBJECTIVE: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. METHODS: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. RESULTS: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. CONCLUSION: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.

Connecting the Light Absorption of Atmospheric Organic Aerosols with Oxidation State and Polarity.

The light-absorbing organic aerosol (OA) constitutes an important fraction of absorbing components, counteracting major cooling effect of aerosols to climate. The mechanisms in linking the complex and changeable chemistry of OA with its absorbing properties remain to be elucidated. Here, by using solvent extraction, ambient OA from an urban environment was fractionated according to polarity, which was further nebulized and online characterized with compositions and absorbing properties. Water extracted high-polar compounds with a significantly higher oxygen to carbon ratio (O/C) than methanol extracts. A transition O/C of about 0.6 was found, below and above which the enhancement and reduction of OA absorptivity were observed with increasing O/C, occurring on the less polar and high polar compounds, respectively. In particular, the co-increase of nitrogen and oxygen elements suggests the important role of nitrogen-containing functional groups in enhancing the absorptivity of the less polar compounds (e.g., forming nitrogen-containing aromatics), while further oxidation (O/C > 0.6) on high-polar compounds likely led to fragmentation and bleaching chromophores. The results here may reconcile the previous observations about darkening or whitening chromophores of brown carbon, and the parametrization of O/C has the potential to link the changing chemistry of OA with its polarity and absorbing properties.

Fabrication of an accurate guide plane template for removable partial dentures by using CAD-CAM.

This technique enables the establishment of an accurate reciprocation distance to resist undesirable forces on abutments and ensure the parallelism of removable partial denture placement on the guide template by using computer-aided design and computer-aided manufacture techniques and to ensure accurate abutment preparation.

Three-dimensional macroscopical quantification of plaque accumulation on implant-supported fixed complete dental prostheses surfaces: A methodological pilot study.

STATEMENT OF PROBLEM: Area calculation is the primary method for quantitatively analyzing accumulated plaque on the intaglio surfaces of implant-supported fixed complete dental prostheses (IFCDPs). However, the classic calculation method for stained dental plaque is based on two-dimensional (2D) photographs, which could mislead the three-dimensional (3D) representation of an object's actual morphology, especially when a surface is not flat. PURPOSE: This pilot in vitro study, used for methodological purposes, evaluated the repeatability and precision of a 3D area calculation method to analyze simulated accumulated biofilm on the intaglio surfaces of an IFCDP. MATERIAL AND METHODS: The titanium framework of an IFCDP with a smooth intaglio surface was prepared with 8 milled sites and scanned by microcomputed tomography. Out of these, 4 sites were cubic (set sides lengths=1, 2, 3, and 4 mm), and 4 sites were hemispherical (set diameters=1, 2, 3, and 4 mm). A green-colored aerosol was sprayed onto the carved-out intaglio sites. The framework intaglio surface was 3D-scanned (n=10) and 2D-photographed (n=10) at 10 different photo angles. Two raters twice measured the 3D and 2D data from the carved-out sites' green-colored area one week apart. Intraobserver repeatability and interobserver reliability were evaluated with an independent t test. The deviation between the measurements and the microtomography values was calculated. Pearson's correlation coefficient (r) evaluated the repeatability of multiple measurements. A standard level of significance was set at α=.05. RESULTS: The differences between the 2D photographs and the microtomography values were statistically significant (P<.001), whereas the differences between the 3D scans and the microtomography values were not significant (P=.063). The overall differences between the microtomography values and the 3D measurements were smaller (2.15 ±2.30 mm2 vs. 18.91 ±22.78 mm2, P=.055) than the differences between the microtomography values and the 2D measurements. The percentage differences between the microtomography values and the 3D measurements were significantly smaller (10.41 ±8.33% vs. 65.66 ±19.22%, P<.001) than the microtomography differences values with the 2D measurements. The measurement differences between the microtomography value and the 3D measured hemispherical site data were significantly smaller than the measurement differences between the microtomography values and the 3D measured cubical site data (P=.026). The 2D method had "poor" repeatability among the 10 different shot angles (r=0.391, P<.001), whereas the 3D method had "good" repeatability among the 10 scans (r=0.999, P<.001). CONCLUSIONS: An irregular intaglio surface of an IFCDP could accurately and repeatedly be recorded and analyzed by a 3D area calculation method. This color-matching assessment of the topological environment is expected to be adopted in future studies.

Assessing the influence of environmental conditions on secondary organic aerosol formation from a typical biomass burning compound.

The atmospheric chemistry in complex air pollution remains poorly understood. In order to probe how environmental conditions can impact the secondary organic aerosol (SOA) formation from biomass burning emissions, we investigated the photooxidation of 2,5-dimethylfuran (DMF) under different environmental conditions in a smog chamber. It was found that SO2 could promote the formation of SOA and increase the amounts of inorganic salts produced during the photooxidation. The formation rate of SOA and the corresponding SOA mass concentration increased gradually with the increasing DMF/OH ratio. The addition of (NH4)2SO4 seed aerosol accelerated the SOA formation rate and significantly shortened the time for the reaction to reach equilibrium. Additionally, a relatively high illumination intensity promoted the formation of OH radicals and, correspondingly, enhanced the photooxidation of DMF. However, the enhancement of light intensity accelerated the aging of SOA, which led to a gradual decrease of the SOA mass concentration. This work shows that by having varying influence on atmospheric chemical reactions, the same environmental factor can affect SOA formation in different ways. The present study is helpful for us to better understand atmospheric complex pollution.

Effect of NOx and SO2 on the photooxidation of methylglyoxal: Implications in secondary aerosol formation.

Methylglyoxal (CH3COCHO, MG), which is one of the most abundant α-dicarbonyl compounds in the atmosphere, has been reported as a major source of secondary organic aerosol (SOA). In this work, the reaction of MG with hydroxyl radicals was studied in a 500 L smog chamber at (293 ± 3) K, atmospheric pressure, (18 ± 2)% relative humidity, and under different NOx and SO2. Particle size distribution was measured by using a scanning mobility particle sizer (SMPS) and the results showed that the addition of SO2 can promote SOA formation, while different NOx concentrations have different influences on SOA production. High NOx suppressed the SOA formation, whereas the particle mass concentration, particle number concentration and particle geometric mean diameter increased with the increasing NOx concentration at low NOx concentration in the presence of SO2. In addition, the products of the OH-initiated oxidation of MG and the functional groups of the particle phase in the MG/OH/SO2 and MG/OH/NOx/SO2 reaction systems were detected by gas chromatography mass spectrometry (GC-MS) and attenuated total reflection fourier transformed infrared spectroscopy (ATR-FTIR) analysis. Two products, glyoxylic acid and oxalic acid, were detected by GC-MS. The mechanism of the reaction of MG and OH radicals that follows two main pathways, H atom abstraction and hydration, is proposed. Evidence is provided for the formation of organic nitrates and organic sulfate in particle phase from IR spectra. Incorporation of NOx and SO2 influence suggested that SOA formation from anthropogenic hydrocarbons may be more efficient in polluted environment.

Silica-Mediated Formation of Nickel Sulfide Nanosheets on CNT Films for Versatile Energy Storage.

An effective, nondestructive, and universal strategy to homogeneously modify freestanding carbon nanotube (CNT) films with various active species is essential to achieve functional electrodes for flexible electrochemical energy storage, which is challenging and has attracted considerable research interest. In this work, a generalizable concept, to utilize silicon oxide as the intermediate to uniformly decorate various metal sulfide nanostructures throughout CNT films is reported. Taking nickel sulfide nanosheet/CNT (NS/CNT) films, in which the NS nanosheets are homogeneously attached on the intact few-walled CNTs, as an example, the sheet-like NS provides sufficient active sites for redox reactions and the CNT network acts as an efficient electron highway, maintaining the structural integrity of the composite and also buffering volume changes. These merits enable NS/CNT films to meet the requirements of versatile energy storage applications. When used for supercapacitors, a high specific capacitance (2699.7 F g-1 /10 A g-1 ), outstanding rate performance at extremely high rates (1527 F g-1 /250 A g-1 ), remarkable cycling stability, and excellent flexibility can be achieved, among the best performance so far. Moreover, it also delivers excellent performance in the storage of Li and Na ions, meaning it is also potentially suitable for Li/Na ion batteries.

Gas-Phase Reaction of Methyl n-Propyl Ether with OH, NO3, and Cl: Kinetics and Mechanism.

Rate constants at room temperature (293 ± 2 K) and atmospheric pressure for the reaction of methyl n-propyl ether (MnPE), CH3OCH2CH2CH3, with OH and NO3 radicals and the Cl atom have been determined in a 100 L FEP-Teflon reaction chamber in conjunction with gas chromatography-flame ionization detector (GC-FID) as the detection technique. The obtained rate constants k (in units of cm3 molecule-1 s-1) are (9.91 ± 2.30) × 10-12, (1.67 ± 0.32) × 10-15, and (2.52 ± 0.14) × 10-10 for reactions with OH, NO3, and Cl, respectively. The products of these reactions were investigated by gas chromatography-mass spectrometry (GC-MS), and formation mechanisms are proposed for the observed reaction products. Atmospheric lifetimes of the studied ether, calculated from rate constants of the different reactions, reveal that the dominant loss process for MnPE is its reaction with OH, while in coastal areas and in the marine boundary layer, MnPE loss by Cl reaction is also important.

Personalized Orthodontic Accurate Tooth Arrangement System with Complete Teeth Model.

The accuracy, validity and lack of relation information between dental root and jaw in tooth arrangement are key problems in tooth arrangement technology. This paper aims to describe a newly developed virtual, personalized and accurate tooth arrangement system based on complete information about dental root and skull. Firstly, a feature constraint database of a 3D teeth model is established. Secondly, for computed simulation of tooth movement, the reference planes and lines are defined by the anatomical reference points. The matching mathematical model of teeth pattern and the principle of the specific pose transformation of rigid body are fully utilized. The relation of position between dental root and alveolar bone is considered during the design process. Finally, the relative pose relationships among various teeth are optimized using the object mover, and a personalized therapeutic schedule is formulated. Experimental results show that the virtual tooth arrangement system can arrange abnormal teeth very well and is sufficiently flexible. The relation of position between root and jaw is favorable. This newly developed system is characterized by high-speed processing and quantitative evaluation of the amount of 3D movement of an individual tooth.

Optical Force Effects of Rayleigh Particles by Cylindrical Vector Beams.

High-order cylindrical vector beams possess flexible spatial polarization and exhibit new effects and phenomena that can expand the functionality and enhance the capability of optical systems. However, building a general analytical model for highly focused beams with different polarization orders remains a challenge. Here, we elaborately develop the vector theory of high-order cylindrical vector beams in a high numerical aperture focusing system and achieve the vectorial diffraction integrals for describing the tight focusing field with the space-variant distribution of polarization orders within the framework of Richards-Wolf diffraction theory. The analytical formulae include the exact three Cartesian components of electric and magnetic distributions in the tightly focused region. Additionally, utilizing the analytical formulae, we can achieve the gradient force, scattering force, and curl-spin force exerted on Rayleigh particles trapped by high-order cylindrical vector beams. These results are crucial for improving the design and engineering of the tightly focused field by modulating the polarization orders of high-order cylindrical vector beams, particularly for applications such as optical tweezers and optical manipulation. This theoretical analysis also extends to the calculation of complicated optical vortex vector fields and the design of diffractive optical elements with high diffraction efficiency and resolution.