Engineering M1 macrophages with targeting aptamers for enhanced adoptive immunotherapy by modifying the cell surface.

Macrophages play a critical role in the body's defense against cancer by phagocytosing tumor cells, presenting antigens, and activating adaptive T cells. However, macrophages are intrinsically incapable of delivering targeted cancer immunotherapies. Engineered adoptive cell therapy introduces new targeting and antitumor capabilities by modifying macrophages to enhance the innate immune response of cells and improve clinical efficacy. In this study, we developed engineered macrophage cholesterol-AS1411-M1 (CAM1) for cellular immunotherapy. To target macrophages, cholesterol-AS1411 aptamers were anchored to the surface of M1 macrophages to produce CAM1 without genetic modification or cell damage. CAM1 induced significantly higher apoptosis/mortality than unmodified M1 macrophages in murine breast cancer cells. Anchoring AS1411 on the surface of macrophages provided a novel approach to construct engineered macrophages for tumor immunotherapy.

Phylogenetic indices and temporal and spatial scales shape the neighborhood effect on seedling survival in a mid-mountain moist evergreen broad-leaved forest, Gaoligong Mountains, Southwestern China.

Density dependence and habitat filtering have been proposed to aid in understanding community assembly and species coexistence. Phylogenetic relatedness between neighbors was used as a proxy for assessing the degree of ecological similarity among species. There are different conclusions regarding the neighborhood effect in previous studies with different phylogenetic indices or at different spatiotemporal scales. However, the effects of density dependence, neighbor phylogenetic relatedness, and habitat filtering on seedling survival with different phylogenetic indices or at different temporal and spatial scales are poorly understood. We monitored 916 seedlings representing 56 woody plant species within a 4-ha forest dynamics plot for 4 years (from 2020 to 2023) in a subtropical mid-mountain moist evergreen broad-leaved forest in the Gaoligong Mountains, Southwestern China. Using generalized linear mixed models, we tested whether and how four phylogenetic indices: total phylogenetic distance (TOTPd), average phylogenetic distance (AVEPd), relative average phylogenetic distance (APd'), and relative nearest taxon phylogenetic distance (NTPd'), three temporals (1, 2, and 3 years), and spatial scales (1, 2, and 4 ha) affect the effect of density dependence, phylogenetic density dependence, and habitat filtering on seedling survival. We found evidence of the effect of phylogenetic density dependence in the 4-ha forest dynamics plot. The effects of density dependence, phylogenetic density dependence, and habitat filtering on seedling survival were influenced by phylogenetic indices and temporal and spatial scales. The effects of phylogenetic density dependence and habitat filtering on seedling survival were more conspicuous only at 1-year intervals, compared with those at 2- and 3-year intervals. We did not detect any effects of neighborhood or habitat factors on seedling survival at small scales (1 and 2 ha), although these effects were more evident at the largest spatial scale (4 ha). These findings highlight that the effects of local neighborhoods and habitats on seedling survival are affected by phylogenetic indices as well as temporal and spatial scales. Our study suggested that phylogenetic index APd', shortest time scale (1 year), and largest spatial scales (4 ha) were suitable for neighborhood studies in a mid-mountain moist evergreen broad-leaved forest in Gaoligong Mountains. Phylogenetic indices and spatiotemporal scales have important impacts on the results of the neighborhood studies.

Comprehensive profiles of sulfur cycling microbial communities along a mangrove sediment depth.

The sulfur (S) cycle is an important biogeochemical cycle with profound implications for both cellular- and ecosystem-level processes by diverse microorganisms. Mangrove sediments are a hotspot of biogeochemical cycling, especially for the S cycle with high concentrations of S compounds. Previous studies have mainly focused on some specific inorganic S cycling processes without paying specific attention to the overall S-cycling communities and processes as well as organic S metabolism. In this study, we comprehensively analyzed the distribution, ecological network and assembly mechanisms of S cycling microbial communities and their changes with sediment depths using metagenome sequencing data. The results showed that the abundance of gene families involved in sulfur oxidation, assimilatory sulfate reduction, and dimethylsulfoniopropionate (DMSP) cleavage and demethylation decreased with sediment depths, while those involved in S reduction and dimethyl sulfide (DMS) transformation showed an opposite trend. Specifically, glpE, responsible for converting S2O32- to SO32-, showed the highest abundance in the surface sediment and decreased with sediment depths; in contrast, high abundances of dmsA, responsible for converting dimethyl sulfoxide (DMSO) to DMS, were identified and increased with sediment depths. We identified Pseudomonas and Streptomyces as the main S-cycling microorganisms, while Thermococcus could play an import role in microbial network connections in the S-cycling microbial community. Our statistical analysis showed that both taxonomical and functional compositions were generally shaped by stochastic processes, while the functional composition of organic S metabolism showed a transition from stochastic to deterministic processes. This study provides a novel perspective of diversity distribution of S-cycling functions and taxa as well as their potential assembly mechanisms, which has important implications for maintaining mangrove ecosystem functions.

Hypofractionated radiotherapy with simultaneous tumor bed boost (Hi-RISE) in breast cancer patients receiving upfront breast-conserving surgery: study protocol for a phase III randomized controlled trial.

BACKGROUND: The effectiveness and safety of moderately hypofractionated radiotherapy (HFRT) in patients undergoing breast-conserving surgery (BCS) has been demonstrated in several pivotal randomized trials. However, the feasibility of applying simultaneous integrated boost (SIB) to the tumor bed and regional node irradiation (RNI) using modern radiotherapy techniques with HFRT needs further evaluation. METHODS: This prospective, multi-center, randomized controlled, non-inferiority phase III trial aims to determine the non-inferiority of HFRT combined with SIB (HFRTsib) compared with conventional fractionated radiotherapy with sequential boost (CFRTseq) in terms of five-year locoregional control rate in breast cancer patients undergoing upfront BCS. A total of 2904 participants will be recruited and randomized in a 1:1 ratio into the HFRTsib and CFRTseq groups. All patients will receive whole breast irradiation, and those with positive axillary nodes will receive additional RNI, including internal mammary irradiation. The prescribed dose for the HFRTsib group will be 40 Gy in 15 fractions, combined with a SIB of 48 Gy in 15 fractions to the tumor bed. The CFRTseq group will receive 50 Gy in 25 fractions, with a sequential boost of 10 Gy in 5 fractions to the tumor bed. DISCUSSION: This trial intends to assess the effectiveness and safety of SIB combined with HFRT in early breast cancer patients following BCS. The primary endpoint is locoregional control, and the results of this trial are expected to offer crucial evidence for utilizing HFRT in breast cancer patients after BCS. TRIAL REGISTRATION: This trial was registered at ClincalTrials.gov (NCT04025164) on July 18, 2019.

Sarcocinerenolides A, an open-loop decarbonizing cembranolide, and sarcocinerenolides B-I, eight polyoxygenated cembranolides with anti-thrombotic activity from the South China Sea soft coral Sarcophyton cinereum.

A previously undescribed open-loop decarbonizing cembranolide, sarcocinerenolide A, and eight undescribed cembranolides, sarcocinerenolides B-I, characterized by poly-membered oxygen ring fragments were isolated from the soft coral Sarcophyton cinereum collected from the South China Sea. The structures and absolute configurations of these previously undescribed compounds were precisely determined by analysis of NMR data, DP4+ and ECD spectra. The bioactivities of the compounds were evaluated using zebrafish models and sarcocinerenolides C and H exhibited anti-thrombotic activity.

Efficacy and effect on lipid profiles of Ainuovirine-based regimen versus Efavirenz-based regimen in treatment-naïve people with HIV-1 at week 24: A real-world, retrospective, multi-center cohort study.

This study aimed to compare the efficacy and effect on lipid profiles of Ainuovirine (ANV)- and efavirenz (EFV) -based regimens in treatment-naïve people living with HIV-1 (PLWH) at week 24. The proportion of PLWH achieving HIV-1 RNA < the limit of quantification in the ANV group was significantly higher than that in the EFV group (89.18% vs. 76.04%, P = 0.002). The mean change of log10 HIV-1 RNA from baseline was greater (-4.34 vs. -4.18, P < 0.001), the median change from baseline in CD4+ T cell count increased more (106.00 cells/µL vs. 92.00 cells/µL, P = 0.007) in the ANV group, while the CD4+/CD8+ ratio was similar (0.15 vs. 0.20, P = 0.167) between the two groups. The mean changes from baseline in total cholesterol (-0.02 for ANV vs. 0.25 mmol/L for EFV, P < 0.001), triglyceride (-0.14 for ANV vs. 0.11 mmol/L for EFV, P = 0.024), and low-density lipoprotein cholesterol (-0.07 for ANV vs. 0.15 mmol/L for EFV, P < 0.001) was significantly different between the two groups. The percentage of patients with improved lipid profiles was significantly higher in the ANV group (37.44 %) than in the EFV group (29.55%, P = 0.0495). The incidence of any adverse events in the ANV group was significantly lower than that in the EFV group at week 12 (6.2% vs. 30.7%, P < 0.001) and was comparable at week 24 (3.6% vs. 5.5%, P = 0.28). The ANV-based regimen was well tolerated and lipid-friendly in treatment-naïve PLWH.

Metagenomic-based discovery and comparison of the lignin degrading potential of microbiomes in aquatic and terrestrial ecosystems via the LCdb database.

Lignin, as an abundant organic carbon, plays a vital role in the global carbon cycle. However, our understanding of the global lignin-degrading microbiome remains elusive. The greatest barrier has been absence of a comprehensive and accurate functional gene database. Here, we first developed a curated functional gene database (LCdb) for metagenomic profiling of lignin degrading microbial consortia. Via the LCdb, we draw a clear picture describing the global biogeography of communities with lignin-degrading potential. They exhibit clear niche differentiation at the levels of taxonomy and functional traits. The terrestrial microbiomes showed the highest diversity, yet the lowest correlations. In particular, there were few correlations between genes involved in aerobic and anaerobic degradation pathways, showing a clear functional redundancy property. In contrast, enhanced correlations, especially closer inter-connections between anaerobic and aerobic groups, were observed in aquatic consortia in response to the lower diversity. Specifically, dypB and dypA, are widespread on Earth, indicating their essential roles in lignin depolymerization. Estuarine and marine consortia featured the laccase and mnsod genes, respectively. Notably, the roles of archaea in lignin degradation were revealed in marine ecosystems. Environmental factors strongly influenced functional traits, but weakly shaped taxonomic groups. Null mode analysis further verified that composition of functional traits was deterministic, while taxonomic composition was highly stochastic, demonstrating that the environment selects functional genes rather than taxonomic groups. Our study not only develops a useful tool to study lignin degrading microbial communities via metagenome sequencing but also advances our understanding of ecological traits of these global microbiomes.

Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

A tale of two tumors: differential, but detrimental, effects of glioblastoma extracellular vesicles (EVs) on normal human brain cells.

Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM EVs dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). EVs from different patient-derived GBM spheroids induced differential transcriptomic, secretomic, and proteomic effects on cultured astrocytes/brain tissue slices as GBM EV recipients. The net outcome of brain cell differential changes nonetheless converges on increased tumorigenicity. GBM spheroids and brain slices were derived from neurosurgical patient tissues following informed consent. Astrocytes were commercially obtained. EVs were isolated from conditioned culture media by ultrafiltration, ultraconcentration, and ultracentrifugation. EVs were characterized by nanoparticle tracking analysis, electron microscopy, biochemical markers, and proteomics. Astrocytes/brain tissues were treated with GBM EVs before downstream analyses. EVs from different GBMs induced brain cells to alter secretomes with pro-inflammatory or TME-modifying (proteolytic) effects. Astrocyte responses ranged from anti-viral gene/protein expression and cytokine release to altered extracellular signal-regulated protein kinase (ERK1/2) signaling pathways, and conditioned media from EV-treated cells increased GBM cell proliferation. Thus, astrocytes/brain slices treated with different GBM EVs underwent non-identical changes in various 'omics readouts and other assays, indicating "personalized" tumor-specific GBM EV effects on the TME. This raises concern regarding reliance on "model" systems as a sole basis for translational direction. Nonetheless, net downstream impacts from differential cellular and TME effects still led to increased tumorigenic capacities for the different GBMs.

Effects of trigonelline, diosgenin, and Cistanche deserticola polysaccharide on the culture of female germline stem cells in vitro.

Female germline stem cells (FGSCs) are renewable sources of oocytes that play an indispensable role in re-establishing mammal fertility. Here, we have established FGSCs from neonatal mice, which exhibit characteristics of germline stem cells. We show that compared with monomeric trigonelline and diosgenin, macromolecular compounds Cistanche deserticola polysaccharides (CDPs) in Chinese herbal medicine can enhance the ability of FGSCs to differentiate into oocytes at appropriate concentrations while maintaining self-renewal in vitro. In contrast, trigonelline and diosgenin inhibited the expression of germ cell-specific genes while reducing cell proliferation activity. In summary, CDPs could induce the differentiation and self-renewal of FGSCs in vitro. The comparison of the effects of the active components of different types of Chinese medicine will provide a reference for the development of clinical drugs in the future, and help to elucidate the development process of FGSCs.

The association between hemoglobin level and sarcopenia in Chinese patients with Crohn's disease.

Sarcopenia and anemia are common complications in patients with Crohn's Disease (CD). However, few studies have shown the association between sarcopenia and hemoglobin levels in CD patients. This retrospective study aimed to explore such association in Chinese patients with CD. Two hundred and twelve adult CD inpatients who underwent computed tomography (CT) or magnetic resonance imaging (MRI) examinations from July 2019 to December 2021 were included in the study. Sarcopenia was defined according to the cutoff value of skeletal muscle index of lumbar spine 3 (SMI-L3) (< 44.77cm2/m2 for males and < 32.5cm2/m2 for females). The CD patients were divided into two groups based on the presence or absence of sarcopenia. Clinical data, hemoglobin levels, and other laboratory data were retrospectively collected. The association between hemoglobin levels and sarcopenia was analyzed by univariable and multivariable logistic regression analysis. Sarcopenia occurred in 114 CD patients (53.8%). Compared to patients without sarcopenia, patients with sarcopenia had a lower proportion of L1 (30.7% vs. 45.8%, p = 0.032) and B1 classification (58.8% vs. 72.4%, p = 0.037). Patients with sarcopenia had significantly lower levels of hemoglobin (Hb) (116.5 ± 22.8 vs. 128.1 ± 21.0, p < 0.001). The prevalence of sarcopenia increased with the decrease in hemoglobin level (p for trend < 0.05). Linear regression analysis showed that hemoglobin levels were associated with SMI-L3 (ß = 0.091, p = 0.001). Multivariable logistic regression analysis found that higher hemoglobin levels (OR:0.944; 95% CI: 0.947,0.998; p = 0.036) were independent protective factors for sarcopenia. Lower hemoglobin levels are independently associated factors of sarcopenia in adult Chinese patients with CD.

Scalable manufacturing of an amide-based nucleating agent for transparency and high heat resistance of polylactic acid.

The prevalent use of disposable plastic tableware presents notable environmental and health risks. An alternative, polylactic acid (PLA), often does not meet usage requirements due to its low crystallization rate. This research introduces an amide-based nucleating agent, BRE-T-100, developed through a straightforward method to enhance the heat resistance and crystallization rate of PLA. This study systematically investigates the impact of BRE-T-100 and other nucleating agents on the properties of PLA composites. The incorporation of 0.8 % BRE-T-100 increases the crystallization temperature of PLA from 109.6 °C to 131.9 °C. Further, the total crystallization time of PLA composites at 120 °C is reduced to <60 s, while maintaining good transparency. BRE-T-100 exhibits superior comprehensive properties compared to talcum, TMC-200, and TMC-300 and is nearly on par with LAK-301. Its application as a nucleating agent in PLA-based disposable tableware shows promise.

Efficacy and effect on lipid profiles of switching to ainuovirine-based regimen versus continuing efavirenz-based regimen in people with HIV-1: 24-week results from a real-world, retrospective, multi-center cohort study.

Ainuovirine (ANV), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), was approved in China in 2021. In a previous randomized phase 3 trial, ANV demonstrated non-inferior efficacy relative to efavirenz (EFV) and was associated with lower rates of dyslipidemia. In this study, we aimed to explore lipid changes in treatment-experienced people with human immunodeficiency virus (HIV)-1 (PWH) switching to ANV from EFV in real world. At week 24, 96.65% of patients in the ANV group and 93.25% in the EFV group had HIV-1 RNA levels below the limit of quantification (LOQ). Median changes from baseline in CD4 +T cell counts (37.0 vs 36.0 cells/µL, P = 0.886) and CD4+/CD8 +ratio (0.03 vs 0.10, P = 0.360) were similar between the two groups. The ANV group was superior to the EFV group in mean changes in total cholesterol (TC, -0.06 vs 0.26 mmol/L, P = 0.006), triglyceride (TG, -0.6 vs 0.14 mmol/L, P < 0.001), high-density lipoprotein cholesterol (HDL-C, 0.09 vs 0.08 mmol/L, P = 0.006), and low-density lipoprotein cholesterol (LDL-C, -0.18 vs 0.29 mmol/L, P < 0.001) at week 24. We also observed that a higher proportion of patients demonstrated improved TC (13.55% vs 4.45%, P = 0.015) or LDL-C (12.93% vs 6.89%, P = 0.017), and a lower proportion of patients showed worsened LDL-C (5.57% vs 13.52%, P = 0.017) with ANV than with EFV at week 24. In conclusion, we observed good efficacy and favorable changes in lipids in switching to ANV from EFV in treatment-experienced PWH in real world, indicating a promising switching option for PWH who may be more prone to metabolic or cardiovascular diseases.

Phantom study of a self-shielded X-ray bone age assessment instrument against scattered radiation in children.

Hand-wrist radiography is the most common and accurate method for evaluating children's bone age. To reduce the scattered radiation of radiosensitive organs in bone age assessment, we designed a small X-ray instrument with radioprotection function by adding metal enclosure for X-ray shielding. We used a phantom operator to compare the scattered radiation doses received by sensitive organs under three different protection scenarios (proposed instrument, radiation personal protective equipment, no protection). The proposed instrument showed greater reduction in the mean dose of a single exposure compared with radiation personal protective equipment especially on the left side which was proximal to the X-ray machine (≥80.0% in eye and thyroid, ≥99.9% in breast and gonad). The proposed instrument provides a new pathway towards more convenient and efficient radioprotection.

Terpenoids from the Soft Coral Stereonephthya bellissima.

A detailed chemical study of the extract from the soft coral Stereonephthya bellissima resulted in the isolation and identification of seven new sesquiterpenoids, bellissinanes A-G (1-7), along with four new diterpenes (8-11). Bellissinane A (1) is the third reported nardosinane-type sesquiterpene bearing a 6/5/6 tricyclic system. Bellissinanes C and D (3, 4) contain a phenylethylamine fragment, which is relatively unusual in marine organisms. Bellissinanes E-G (5-7) belong to the rare class of nornardosinane sesquiterpenoids. Structurally uncommon octahydro-1H-indenyl-type and prenyleudesmane-type skeletons were characterized for herpetopanone B (8) and bellissimain A (9), respectively. Bellissinane E (5) exhibited in vivo angiogenesis-promoting activity.

Hemodynamic Effects of Tortuosity and Stenosis in Superficial Temporal Artery-Middle Cerebral Artery Bypass for Moyamoya Disease.

BACKGROUND: Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass surgery has been widely adopted in treating moyamoya disease (MMD). Geometric variations including high tortuosity and stenosis exist in many cases, but the hemodynamic effects have not been comprehensively evaluated. We aim to evaluate the hemodynamic effects of bypass geometry variations based on patient-specific data. METHODS: In total, 17 patients with MMD who underwent STA-MCA bypass surgery with highly tortuous bypass geometry were included. For each patient, the original 3-dimensional structure of STA-MCA bypass was reconstructed from clinical imaging data. The bypass structure was virtually improved by removing the tortuosity and stenosis. Computational fluid dynamics simulation was performed on both bypass structures under identical patient-specific condition. The simulated hemodynamic parameters of the bypass and its distal branches were compared between the original and virtually improved bypass geometries in all cases using paired t-test or Wilcoxon signed-rank test. The changes of hemodynamic parameters were compared between the cases with and without mild-to-moderate stenosis (44.0-70.3% in diameter) in the bypass using t-test or Mann-Whitney U test. RESULTS: The virtual improvement of bypass geometry significantly increased the flow rate of the bypass and its distal branches (P < 0.05) and decreased the transcranial flow resistance (P < 0.05). The hemodynamic changes in cases with stenosis removal were significantly greater than those without stenosis (P < 0.05). CONCLUSIONS: High tortuosity and stenosis can significantly change the hemodynamics of STA-MCA bypass, and the optimization of bypass geometry deserves further consideration.

Interleukin-2 enhancer binding factor 2 negatively regulates the replication of duck hepatitis A virus type 1 by disrupting the RNA-dependent RNA polymerase activity of 3D polymerase.

The interaction between viral components and cellular proteins plays a crucial role in viral replication. In a previous study, we showed that the 3'-untranslated region (3'-UTR) is an essential element for the replication of duck hepatitis A virus type 1 (DHAV-1). However, the underlying mechanism is still unclear. To gain a deeper understanding of this mechanism, we used an RNA pull-down and a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay to identify new host factors that interact with the 3'-UTR. We selected interleukin-2 enhancer binding factor 2 (ILF2) for further analysis. We showed that ILF2 interacts specifically with both the 3'-UTR and the 3D polymerase (3Dpol) of DHAV-1 through in vitro RNA pull-down and co-immunoprecipitation assays, respectively. We showed that ILF2 negatively regulates viral replication in duck embryo fibroblasts (DEFs), and that its overexpression in DEFs markedly suppresses DHAV-1 replication. Conversely, ILF2 silencing resulted in a significant increase in viral replication. In addition, the RNA-dependent RNA polymerase (RdRP) activity of 3Dpol facilitated viral replication by enhancing viral RNA translation efficiency, whereas ILF2 disrupted the role of RdRP in viral RNA translation efficiency to suppress DHAV-1 replication. At last, DHAV-1 replication markedly suppressed the expression of ILF2 in DEFs, duck embryo hepatocytes, and different tissues of 1 day-old ducklings. A negative correlation was observed between ILF2 expression and the viral load in primary cells and different organs of young ducklings, suggesting that ILF2 may affect the viral load both in vitro and in vivo.