[Neurodevelopment and cerebral blood flow in children aged 2-6 years with autism spectrum disorder]. / 2~6å²å­¤ç‹¬ç—‡è°±ç³»éšœç¢å„¿ç«¥ç¥žç»å‘è‚²ä¸Žè„‘è¡€æµé‡çš„ç ”ç©¶.

OBJECTIVES: To investigate the neurodevelopmental characteristics of children with autism spectrum disorder (ASD), analyze the correlation between neurodevelopmental indicators and cerebral blood flow (CBF), and explore the potential mechanisms of neurodevelopment in ASD children. METHODS: A retrospective study was conducted on 145 children aged 2-6 years with newly-diagnosed ASD. Scores from the Gesell Developmental Diagnosis Scale and the Autism Behavior Checklist (ABC) and CBF results were collected to compare gender differences in the development of children with ASD and analyze the correlation between CBF and neurodevelopmental indicators. RESULTS: Fine motor and personal-social development quotient in boys with ASD were lower than those in girls with ASD (P<0.05). Gross motor development quotient in ASD children was negatively correlated with CBF in the left frontal lobe (r=-0.200, P=0.016), right frontal lobe (r=-0.279, P=0.001), left parietal lobe (r=-0.208, P=0.012), and right parietal lobe (r=-0.187, P=0.025). The total ABC score was positively correlated with CBF in the left amygdala (r=0.295, P<0.001). CONCLUSIONS: Early intervention training should pay attention to gender and developmental structural characteristics for precise intervention in ASD children. CBF has the potential to become a biological marker for assessing the severity of ASD.

Nanoalignment by critical Casimir torques.

The manipulation of microscopic objects requires precise and controllable forces and torques. Recent advances have led to the use of critical Casimir forces as a powerful tool, which can be finely tuned through the temperature of the environment and the chemical properties of the involved objects. For example, these forces have been used to self-organize ensembles of particles and to counteract stiction caused by Casimir-Liftshitz forces. However, until now, the potential of critical Casimir torques has been largely unexplored. Here, we demonstrate that critical Casimir torques can efficiently control the alignment of microscopic objects on nanopatterned substrates. We show experimentally and corroborate with theoretical calculations and Monte Carlo simulations that circular patterns on a substrate can stabilize the position and orientation of microscopic disks. By making the patterns elliptical, such microdisks can be subject to a torque which flips them upright while simultaneously allowing for more accurate control of the microdisk position. More complex patterns can selectively trap 2D-chiral particles and generate particle motion similar to non-equilibrium Brownian ratchets. These findings provide new opportunities for nanotechnological applications requiring precise positioning and orientation of microscopic objects.

Multiple plateaus of high-sideband generation from Floquet matters.

We theoretically report that high-order sideband generation (HSG) from Floquet matters driven by a strong terahertz light while engineered by weak infrared light can achieve multiple plateau HSG. The Floquet-engineering systems exhibit distinctive spectroscopic characteristics that go beyond the HSG processes in field-free band-structure systems. The spatial-temporal dynamics analyses under Floquet-Bloch and time-reversal-symmetry theories clarify the spectra and its odd-even characteristics in the HSG spectrum. Our work demonstrates the HSG of Floquet matters via Floquet engineering and indicates a promising way to extract Floquet material parameters in future experiments.

Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.

PURPOSE: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI). RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

Dual-functional thermosensitive hydrogel for reducing infection and enhancing bone regeneration in infected bone defects.

The contamination of bone defects is a serious therapeutic problem. The treatment of infected bone defects involves rigorous infection control followed by bone reconstruction. Considering these two processes, the development of biomaterials possessing antibacterial and osteogenic properties offers a promising approach for the treatment of infected bone defects. In this study, a dual-functional, thermosensitive, and injectable hydrogel composed of chitosan (CS), quaternized CS (QCS), and nano-hydroxyapatite (nHA) was designed, and the ratio of CS to QCS in the hydrogel was optimized to enhance the antibacterial efficacy of CS while reducing the cytotoxicity of QCS. In vitro studies demonstrated that the hydrogel with an 85 %:15 % ratio of CS to QCS exhibited excellent biocompatibility and antibacterial properties while also possessing suitable mechanical characteristics and degradability. The incorporation of nHA into the hydrogel enhanced MC3T3-E1 proliferation and osteogenic differentiation. Moreover, this hydrogel demonstrated superior in vivo therapeutic effectiveness in a rabbit model of infected bone defect. In summary, this study provides a promising material design and a comprehensive one-step treatment strategy for infected bone defects.

Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway.

Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.

Engineered three-dimensional bioactive scaffold for enhanced bone regeneration through modulating transplanted adipose derived mesenchymal stem cell and stimulating angiogenesis.

Titanium alloy materials are commonly used in orthopedic clinical treatments. However, conventional titanium implants usually lead to insufficient bone regeneration and integration because of mismatched biomechanics and poor bioactivities. To tackle these challenges, a porous titanium alloy scaffold with suitable mechanical properties was prepared using three-dimensional (3D) printing, and then an adipose-derived mesenchymal stem cell (ADSC) loaded platelet-rich plasma (PRP) gel was placed into the pores of the porous scaffold to construct a bioactive scaffold with dual functions of enhancing angiogenesis and osteogenesis. This bioactive scaffold showed good biocompatibility and supported cell viability proliferation and morphology of encapsulated ADSCs. Osteogenic and angiogenic growth factors in the PRP gel promoted the migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro and enhanced osteogenic-related gene and protein expression in ADSCs, thus promoting osteogenic differentiation. After implantation into the femoral defects of rabbits, the bioactive scaffold promoted vascular network formation and the expression of osteogenesis-related proteins, thus effectively accelerating bone regeneration. Therefore, the osteogenic and angiogenic bioactive scaffold comprising a 3D printed porous titanium alloy scaffold, PRP, and ADSCs provides a promising design for orthopedic biomaterials with clinical transformation prospects and an effective strategy for bone defect treatment.

Human transferrin receptor can mediate SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been detected in almost all organs of coronavirus disease-19 patients, although some organs do not express angiotensin-converting enzyme-2 (ACE2), a known receptor of SARS-CoV-2, implying the presence of alternative receptors and/or co-receptors. Here, we show that the ubiquitously distributed human transferrin receptor (TfR), which binds to diferric transferrin to traffic between membrane and endosome for the iron delivery cycle, can ACE2-independently mediate SARS-CoV-2 infection. Human, not mouse TfR, interacts with Spike protein with a high affinity (KD ~2.95 nM) to mediate SARS-CoV-2 endocytosis. TfR knock-down (TfR-deficiency is lethal) and overexpression inhibit and promote SARS-CoV-2 infection, respectively. Humanized TfR expression enables SARS-CoV-2 infection in baby hamster kidney cells and C57 mice, which are known to be insusceptible to the virus infection. Soluble TfR, Tf, designed peptides blocking TfR-Spike interaction and anti-TfR antibody show significant anti-COVID-19 effects in cell and monkey models. Collectively, this report indicates that TfR is a receptor/co-receptor of SARS-CoV-2 mediating SARS-CoV-2 entry and infectivity by likely using the TfR trafficking pathway.

Role of TGF-ß3 in modulating inflammatory responses and wound healing processes in ischemic ulcers in atherosclerotic patients.

Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF-ß3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF-ß3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross-sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF-ß3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF-ß3, pro-inflammatory and anti-inflammatory markers. A subset of patients were administered topical TGF-ß3 in order to evaluate its therapeutic effects. The expression pattern of TGF-ß3 was found to be stage-dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF-ß3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF-ß3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF-ß3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF-ß3, which functions as an anti-inflammatory and pro-inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.

Dual-functional 3D-printed porous bioactive scaffold enhanced bone repair by promoting osteogenesis and angiogenesis.

The treatment of bone defects is a difficult problem in orthopedics. The excessive destruction of local bone tissue at defect sites destroys blood supply and renders bone regeneration insufficient, which further leads to delayed union or even nonunion. To solve this problem, in this study, we incorporated icariin into alginate/mineralized collagen (AMC) hydrogel and then placed the drug-loaded hydrogel into the pores of a 3D-printed porous titanium alloy (AMCI/PTi) scaffold to prepare a bioactive scaffold with the dual functions of promoting angiogenesis and bone regeneration. The experimental results showed that the ACMI/PTi scaffold had suitable mechanical properties, sustained drug release function, and excellent biocompatibility. The released icariin and mineralized collagen (MC) synergistically promoted angiogenesis and osteogenic differentiation in vitro. After implantation into a rabbit radius defect, the composite scaffold showed a satisfactory effect in promoting bone repair. Therefore, this composite dual-functional scaffold could meet the requirements of bone defect treatment and provide a promising strategy for the repair of large segmental bone defects in clinic.

Transferrin Is Up-Regulated by Microbes and Acts as a Negative Regulator of Immunity to Induce Intestinal Immunotolerance.

Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms that regulate the cross-talks remain poorly understood. Here, we show that bacterial products up-regulate iron-transporter transferrin and transferrin acts as an immunosuppressor by interacting with cluster of differentiation 14 (CD14) to inhibit pattern recognition receptor (PRR) signaling and induce host immunotolerance. Decreased intestinal transferrin is found in germ-free mice and human patients with ulcerative colitis, which are characterized by impaired intestinal immunotolerance. Intestinal transferrin and host immunotolerance are returned to normal when germ-free mice get normal microbial commensalism, suggesting an association between microbial commensalism, transferrin, and host immunotolerance. Mouse colitis models show that transferrin shortage impairs host's tolerogenic responses, while its supplementation promotes immunotolerance. Designed peptide blocking transferrin-CD14 interaction inhibits immunosuppressive effects of transferrin. In monkeys with idiopathic chronic diarrhea, transferrin shows comparable or even better therapeutic effects than hydrocortisone. Our findings reveal that by up-regulating host transferrin to silence PRR signaling, commensal bacteria counteract immune activation induced by themselves to shape host immunity and contribute for intestinal tolerance.

Tailoring the Structure and Properties of Epitaxial Europium Tellurides on Si(100) through Substrate Temperature Control.

In this study, we improved the growth procedure of EuTe and realized the epitaxial growth of EuTe4. Our research demonstrated a selective growth of both EuTe and EuTe4 on Si(100) substrates using the molecular beam epitaxy (MBE) technique and reveals that the substrate temperature plays a crucial role in determining the structural phase of the grown films: EuTe can be obtained at a substrate temperature of 220 °C while lowering down the temperature to 205 °C leads to the formation of EuTe4. A comparative analysis of the transmittance spectra of these two films manifested that EuTe is a semiconductor, whereas EuTe4 exhibits charge density wave (CDW) behavior at room temperature. The magnetic measurements displayed the antiferromagnetic nature in EuTe and EuTe4, with Néel temperatures of 10.5 and 7.1 K, respectively. Our findings highlight the potential for controllable growth of EuTe and EuTe4 thin films, providing a platform for further exploration of magnetism and CDW phenomena in rare earth tellurides.

Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis.

The microbiota-associated factors that influence host susceptibility and immunity to enteric viral infections remain poorly defined. We identified that the herbal monomer ginsenoside Rg3 (Rg3) can shape the gut microbiota composition, enriching robust short-chain fatty acid (SCFA)-producing Blautia spp. Colonization by representative Blautia coccoides and Blautia obeum could protect germ-free or vancomycin (Van)-treated mice from enteric virus infection, inducing type I interferon (IFN-I) responses in macrophages via the MAVS-IRF3-IFNAR signaling pathway. Application of exogenous SCFAs (acetate/propionate) reproduced the protective effect of Rg3 and Blautia spp. in Van-treated mice, enhancing intracellular Ca2+- and MAVS-dependent mtDNA release and activating the cGAS-STING-IFN-I axis by stimulating GPR43 signaling in macrophages. Our findings demonstrate that macrophage sensing of metabolites from specific commensal bacteria can prime the IFN-I signaling that is required for antiviral functions.

Gearbox Fault Diagnosis Method Based on Multidomain Information Fusion.

Traditional methods of gearbox fault diagnosis rely heavily on manual experience. To address this problem, our study proposes a gearbox fault diagnosis method based on multidomain information fusion. An experimental platform consisting of a JZQ250 fixed-axis gearbox was built. An acceleration sensor was used to obtain the vibration signal of the gearbox. Singular value decomposition (SVD) was used to preprocess the signal in order to reduce noise, and the processed vibration signal was subjected to short-time Fourier transform to obtain a two-dimensional time-frequency map. A multidomain information fusion convolutional neural network (CNN) model was constructed. Channel 1 was a one-dimensional convolutional neural network (1DCNN) model that input a one-dimensional vibration signal, and channel 2 was a two-dimensional convolutional neural network (2DCNN) model that input short-time Fourier transform (STFT) time-frequency images. The feature vectors extracted using the two channels were then fused into feature vectors for input into the classification model. Finally, support vector machines (SVM) were used to identify and classify the fault types. The model training performance used multiple methods: training set, verification set, loss curve, accuracy curve and t-SNE visualization (t-SNE). Through experimental verification, the method proposed in this paper was compared with FFT-2DCNN, 1DCNN-SVM and 2DCNN-SVM in terms of gearbox fault recognition performance. The model proposed in this paper had the highest fault recognition accuracy (98.08%).

Functionalized Decellularized Bone Matrix Promotes Bone Regeneration by Releasing Osteogenic Peptides.

The decellularized bone matrix (DCB) provides a promising bone substitute for the treatment of bone defects because of its similar biochemical, biophysical, and mechanical properties to normal bone tissue. However, the decellularized procedure also greatly reduced its osteogenic induction activity. In this study, peptides derived from the knuckle epitope of bone morphogenetic protein-2 were incorporated into the thermo-sensitive hydrogel poloxamer 407, and the peptide-loaded hydrogel was then filled into the pores of DCB to construct a functionalized scaffold with enhanced osteogenesis. In vitro studies have shown that the functionalized DCB scaffold possessed appropriate mechanical properties and biocompatibility and exhibited a sustained release profile of osteogenic peptide. These performances critically facilitated cell proliferation and cell spreading of bone marrow mesenchymal stem cells and upregulated the expression of osteogenic-related genes by activating the Smad/Runx2 signaling pathway, thereby promoting osteogenic differentiation and extracellular matrix mineralization. Further in vivo studies demonstrated that the functionalized DCB scaffold accelerated the repair of critical radial defects in rabbits without inducing excessive graft-related inflammatory responses. These results suggest a clinically meaningful strategy for the treatment of large segmental bone defects, and the prepared osteogenic peptide modified composite DCB scaffold has great application potential for bone regeneration.

Video-Rate Switching of High-Reflectivity Hybrid Cavities Spanning All Primary Colors.

Dynamically tunable reflective structural colors are attractive for reflective displays (electronic paper). However, it is challenging to tune a thin layer of structural color across the full red-green-blue (RGB) basis set of colors at video rates and with long-term stability. In this work, this is achieved through a hybrid cavity built from metal-insulator-metal (MIM) "nanocaves" and an electrochromic polymer (PProDOTMe2 ). The reflective colors are modulated by electrochemically doping/dedoping the polymer. Compared with traditional subpixel-based systems, this hybrid structure provides high reflectivity (>40%) due to its "monopixel" nature and switches at video rates. The polymer bistability helps deliver ultralow power consumption (≈2.5 mW cm-2 ) for video display applications and negligible consumption (≈3 µW cm-2 ) for static images, compatible with fully photovoltaic powering. In addition, the color uniformity of the hybrid material is excellent (over cm-2 ) and the scalable fabrication enables large-area production.

Silymarin modified polysulfone hollow fiber membranes with antioxidant, anti-M1 macrophage polarization and hemocompatibility for blood purification.

Oxidative stress is highly prevalent in maintenance hemodialysis patients and increases the risk of cardiovascular morbidity and mortality. Silymarin (SM) is a natural compound extracted from plants, and has been shown to have pharmacological effects such as antioxidant, anti-inflammatory, cytoprotective, and anti-nephrotoxicity. SM-modified polysulfone (PSF) hemodialysis membranes were prepared by an immersion-precipitation phase transition method. The experimental results showed that the modified membranes effectively scavenged free radicals, significantly inhibited lipid peroxidation, and had good antioxidant stability (60 days). The PSF/SM antioxidant membranes (H-3) had no pro-inflammatory effect, which was confirmed by the result of anti-M1 macrophage polarization. Furthermore, the hemolysis rate (2%), blood cell deformation (3.7%), and inhibition of erythrocyte and platelet adhesion were improved by the SM-modified PSF membranes. All the results suggest that PSF/SM blended hollow fiber membranes are promising for application in hemodialysis membranes to improve oxidative stress status and reduce inflammation and complications in patients.

scTransSort: Transformers for Intelligent Annotation of Cell Types by Gene Embeddings.

Single-cell transcriptomics is rapidly advancing our understanding of the composition of complex tissues and biological cells, and single-cell RNA sequencing (scRNA-seq) holds great potential for identifying and characterizing the cell composition of complex tissues. Cell type identification by analyzing scRNA-seq data is mostly limited by time-consuming and irreproducible manual annotation. As scRNA-seq technology scales to thousands of cells per experiment, the exponential increase in the number of cell samples makes manual annotation more difficult. On the other hand, the sparsity of gene transcriptome data remains a major challenge. This paper applied the idea of the transformer to single-cell classification tasks based on scRNA-seq data. We propose scTransSort, a cell-type annotation method pretrained with single-cell transcriptomics data. The scTransSort incorporates a method of representing genes as gene expression embedding blocks to reduce the sparsity of data used for cell type identification and reduce the computational complexity. The feature of scTransSort is that its implementation of intelligent information extraction for unordered data, automatically extracting valid features of cell types without the need for manually labeled features and additional references. In experiments on cells from 35 human and 26 mouse tissues, scTransSort successfully elucidated its high accuracy and high performance for cell type identification, and demonstrated its own high robustness and generalization ability.