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The conversion of tumor-promoting M2 macrophage phenotype to tumor-suppressing M1 macrophages is a promising therapeutic approach for cancer treatment. However, the tumor normally provides an abundance of M2 macrophage stimuli, which creates an M2 macrophage-dominant immunosuppressive microenvironment. In our study, docetaxel (DTX) as chemotherapeutic modularity was loaded into M1 macrophage-derived exosomes (M1-Exo) with M1 proinflammatory nature to establish DTX-M1-Exo drug delivery system. We found that DTX-M1-Exo induced naïve M0 macrophages to polarize to M1 phenotype, while failed to repolarize to M2 macrophages upon Interleukin 4 restimulation due to impaired mitochondrial function. This suggests that DTX-M1-Exo can achieve long-term robust M1 activation in immunosuppressive tumor microenvironment. The in vivo results further confirmed that DTX-M1-Exo has a beneficial effect on macrophage infiltration and activation in the tumor tissues. Thus, DTX-M1-Exo is a novel macrophage polarization strategy via combined chemotherapy and immunotherapy to achieve great antitumor therapeutic efficacy.

Purpose The aim of this study was to compare long-term outcomes after anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) repair and reconstruction at 5–10 years after surgery. Methods Forty-five patients who underwent surgical repair or reconstruction of both ATFL and CFL were retrospectively investigated in this study. American Orthopedic Foot and Ankle Society (AOFAS), Karlsson Score, and Tegner activity scale were used to evaluate the ankle function at a follow-up of 5–10 years. Ultrasound examination was used to evaluate the ATFL and CFL, and MRI was used to evaluate the cartilage. Results At final follow-up, no patient had recurrent ankle instability. There were no significant differences in AOFAS (92.6 ± 6.5 vs 89.6 ± 3.4; n.s.) or Karlsson Score (93 ± 8.2 vs 90.6 ± 5.0; n.s.) between the reconstruction group (twenty patients) and the repair group (twenty-five patients) postoperatively. There were also no significant differences in activity level as measured by the Tegner activity score (6 (range 4 to 8) vs 6 (range 5 to 7); n.s.). Five patients in the reconstruction group complained of some tightness of the ankles. Ultrasound showed the reconstructed ligaments maintained good continuity and were thicker than the repaired ligaments. Conclusion Patients in both the repair and the reconstruction cohort had high patient satisfaction with the outcomes and high function and activity levels that indicated recreational sports participation over a long period. Level of evidence III.

Viruses are believed to be responsible for the mortality of host organisms. However, some recent investigations reveal that viruses may be essential for host survival. To date, it remains unclear whether viruses are beneficial or harmful to their hosts. To reveal the roles of viruses in the virus-host interactions, viromes and microbiomes of sediment samples from three deep-sea hydrothermal vents were explored in this study. To exclude the influence of exogenous DNAs on viromes, the virus particles were purified with nuclease (DNase I and RNase A) treatments and cesium chloride density gradient centrifugation. The metagenomic analysis of viromes without exogenous DNA contamination and microbiomes of vent samples indicated that viruses had compensation effects on the metabolisms of their host microorganisms. Viral genes not only participated in most of the microbial metabolic pathways but also formed branched pathways in microbial metabolisms, including pyrimidine metabolism; alanine, aspartate, and glutamate metabolism; nitrogen metabolism and assimilation pathways of the two-component system; selenocompound metabolism; aminoacyl-tRNA biosynthesis; and amino sugar and nucleotide sugar metabolism. As is well known, deep-sea hydrothermal vent ecosystems exist in relatively isolated environments which are barely influenced by other ecosystems. The metabolic compensation of hosts mediated by viruses might represent a very important aspect of virus-host interactions. IMPORTANCE Viruses are the most abundant biological entities in the oceans and have very important roles in regulating microbial community structure and biogeochemical cycles. The relationship between virus and host microbes is broadly thought to be that of predator and prey. Viruses can lyse host cells to control microbial population sizes and affect community structures of hosts by killing specific microbes. However, viruses also influence their hosts through manipulation of bacterial metabolism. We found that viral genes not only participated in most microbial metabolic pathways but also formed branched pathways in microbial metabolisms. The metabolic compensation of hosts mediated by viruses may help hosts to adapt to extreme environments and may be essential for host survival. Viruses are the most abundant biological entities in the oceans and have very important roles in regulating microbial community structure and biogeochemical cycles. The relationship between virus and host microbes is broadly thought to be that of predator and prey. Viruses can lyse host cells to control microbial population sizes and affect community structures of hosts by killing specific microbes. However, viruses also influence their hosts through manipulation of bacterial metabolism. We found that viral genes not only participated in most microbial metabolic pathways but also formed branched pathways in microbial metabolisms. The metabolic compensation of hosts mediated by viruses may help hosts to adapt to extreme environments and may be essential for host survival.

Chromatin condensation is dynamically regulated throughout the cell cycle and plays key roles in modulating gene accessibility. The DNA-histone dynamics in the nucleosome are central to the regulation mechanisms of chromatin condensation, which remain poorly understood. Employing fluorescence recovery after photobleaching, optical super-resolution imaging, and microrheology with optical tweezers, we investigated the roles of various parameters in regulating phase-separation of 12-mer nucleosome arrays. Here, we show that histone H4 tail lysine residues are the main drivers of liquid-liquid phase separation of nucleosome arrays. We also show that the condensed liquid-like droplets comprise a mobile fraction and a relatively immobile structural scaffold. Histone chaperone Nap1 and histone H3 tail acetylation enhance DNA-histone dynamics within this scaffold, thereby lowering the overall viscosity of the droplets. These results suggest that histone chaperone and histone H3/H4 tails play critical roles in regulating chromatin condensation and gene accessibility in condensed chromatin. Chromatin condensation regulates gene accessibility through dynamic DNA-histone interactions. Here, the authors show that histone H4 tails drive nucleosome phase separation, while histone chaperone Nap1 and H3 acetylation enhance DNA-histone dynamics to modulate chromatin fluidity.

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease of unknown cause. Oxidative stress, an imbalance between oxidants and antioxidants, is implicated in IPF pathogenesis and prognosis but needs further study. We used transcriptome sequencing data (GSE70866) and oxidative stress-related genes from GeneCards. A prognostic risk model for IPF patients was constructed using LASSO. Functional and pathway differences were analyzed between risk score groups, along with comparisons of immune cells and functions. An IPF rat model with vitamin D3 (VD3) intervention was also established. Finally, we used IL-4 to induce M2 macrophages to explore the mechanism of action of CCL2. We identified 483 DEGs and 50 oxidative stress-related DEGs (OSDEGs). Single-factor COX regression identified 34 prognostic OSDEGs, and LASSO identified an 8-gene signature for the risk model. The high-risk group had more CD8 + T cells, macrophages, APC costimulation, and cytokine-cytokine receptor activity. CCL2 was significantly correlated with macrophages in IPF. VD3 inhibited the TGF-β signaling pathway and reduced macrophage M2 infiltration in the rat model. In the IL-4 induced M2 macrophage model, we found that M2 macrophages produced more CCL2, and the production of CCL2 was significantly reduced after VD3 intervention. We established prognostic markers of eight oxidative stress-related genes. The risk score effectively predicts adverse outcomes in IPF. VD3 may alleviate IPF by reducing macrophage infiltration and inhibiting the TGF-β signaling pathway.

Parkinson’s disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three motor stages of PD have been proposed (a silent period when nigrostriatal loss begins, a prodromal motor period with subtle focal manifestations, and clinical PD) with evidence that motor cortex abnormalities occur to produce clinical PD[8]. We directly assess structural changes in the primary motor cortex and corticospinal tract using parallel analyses of longitudinal clinical and cross-sectional pathological cohorts thought to represent different stages of PD. 18F-FP-CIT positron emission tomography and subtle motor features identified patients with idiopathic rapid-eye-movement sleep behaviour disorder (n = 8) that developed prodromal motor signs of PD. Longitudinal diffusion tensor imaging before and after the development of prodromal motor PD showed higher fractional anisotropy in motor cortex and corticospinal tract compared to controls, indicating adaptive structural changes in motor networks in concert with nigrostriatal dopamine loss. Histological analyses of the white matter underlying the motor cortex showed progressive disorientation of axons with segmental replacement of neurofilaments with α-synuclein, enlargement of myelinating oligodendrocytes and increased density of their precursors. There was no loss of neurons in the motor cortex in early or late pathologically confirmed motor PD compared to controls, although there were early cortical increases in neuronal neurofilament light chain and myelin proteins in association with α-synuclein accumulation. Our results collectively provide evidence of a direct impact of PD on primary motor cortex and its output pathways that begins in the prodromal motor stage of PD with structural changes confirmed in early PD. These adaptive structural changes become considerable as the disease advances potentially contributing to motor PD.

This study systematically analyzed the BBX gene family in kiwifruit ( Actinidia chinensis ) to investigate its roles in abiotic stress responses. Bioinformatics analyses were performed, including gene localization, collinearity assessment, gene structure characterization, phylogenetic reconstruction, three-dimensional protein modeling, protein-protein interaction networks, and cis-acting element screening. These approaches elucidated the evolutionary relationships and structural features of the kiwifruit BBX genes. Transcriptome data revealed differential expression patterns under boron deficiency, salt stress, and cadmium stress, visualized through heatmaps. Quantitative real-time PCR validation confirmed that AcBBX4 , AcBBX5 , AcBBX15 , AcBBX17 , and AcBBX36 were significantly differentially expressed under all three stress conditions, suggesting their coordinated function in stress adaptation. Protein-protein interaction analysis identified AcBBX17 as a central hub in the regulatory network. Promoter analysis indicated that AcBBX17 contains a high proportion of methyl jasmonate responsive elements, and functional enrichment supported its involvement in the jasmonic acid signaling pathway. Based on these findings, a jasmonic acid-mediated regulatory model centered on AcBBX17 was proposed. In summary, the BBX gene family functions as key transcriptional regulators in plant development and stress response pathways, with this study providing specific insights into its role in kiwifruit abiotic stress tolerance.

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte-derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.

Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer's disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain regions, the hippocampus is deficient in apoD. In comparison to other major organs and tissues (liver, spleen, kidney, adrenal gland, heart and skeletal muscle), brain apoD was approximately 10-fold higher (corrected for total protein levels). Our analysis also revealed that brain apoD was present at a lower apparent molecular weight than tissue and plasma apoD. Utilising peptide N-glycosidase-F and neuraminidase to remove N-glycans and sialic acids, respectively, we found that N-glycan composition (but not sialylation alone) were responsible for this reduction in molecular weight. We extended the studies to an analysis of human brain regions (hippocampus, frontal cortex, temporal cortex and cerebellum) where we found that the hippocampus had the lowest levels of apoD. We also confirmed that human brain apoD was present at a lower molecular weight than in plasma. In conclusion, we demonstrate apoD protein levels are variable across different brain regions, that apoD levels are much higher in the brain compared to other tissues and organs, and that cerebral apoD has a lower molecular weight than peripheral apoD; a phenomenon that is due to the N-glycan content of the protein.

Maintaining hemodynamic stability during anesthesia is crucial for patients with congenital heart disease. Remimazolam, a novel benzodiazepine, offers advantages, such as rapid onset, quick recovery, stable hemodynamics, and mild respiratory depression. We aimed to assess the effects of a single intravenous dose of remimazolam on hemodynamics in children with congenital heart disease. This self-controlled before-and-after study enrolled 40 children undergoing elective cardiac catheterization and transcatheter interventional closure at Shanghai Children's Hospital between June and September 2024. No special preoperative medications were administered. After entering the operating room, noninvasive hemodynamic parameters, such as heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SPO ), cardiac output (CO), and cardiac index (CI) were monitored. During the cardiac catheterization procedure, invasive hemodynamic parameters-including superior vena cava pressure (SVCP), right atrial pressure (RAP), right ventricular pressure (RVP), and pulmonary artery pressure (PAP)-were measured according to surgical requirements. Subsequently, remimazolam (0.3 mg/kg) was administered intravenously, and the same parameters were remeasured 3 min later. The impact of remimazolam on hemodynamics in children with CHD was evaluated by comparing the changes in these indicators before and after drug administration. Five patients were excluded due to incomplete data, leaving 35 for analysis (sex, 11 male, 24 female; median age, 6.67 [interquartile range: 4-11.5 years]). Following intravenous administration of remimazolam, all non-invasive hemodynamic parameters remained stable, showing no statistically significant differences before versus after medication: HR [(104.31 ± 20.27) vs. (104.91 ± 19.76) bpm, P = 0.485], MAP [61 (58, 65) vs. 61 (57, 66) mmHg, P = 0.313], CO [3.2 (2.34, 3.5) vs. 3 (2.41, 3.7) L/min, P = 0.133], and CI [3.3 (3, 3.6) vs. 3.3 (3, 3.71) L/min/m , P = 0.292]. Similarly, no statistically significant differences were observed in right heart system pressures before and after administration: mRAP [8 (6, 10) vs. 8.5 (6.75, 10.25) mmHg, P = 0.064] and mPAP [15.5 (14, 19) vs. 16 (14, 19.5) mmHg, P = 0.517]. No adverse reactions such as bradycardia, hypotension, or hypertension were observed after intravenous injection of remimazolam. During sevoflurane-maintained anesthesia, co-administration of remimazolam provides good hemodynamic stability for children with left-to-right shunt congenital heart disease undergoing cardiac catheterization.