Genome-wide association analysis identifies candidate genes for carcass yields in Peking ducks.

Poultry meat, particularly Peking ducks, holds a significant global market share, prized for their high meat yield and fat content. However, understanding of the molecular genetic mechanisms influencing carcass yield in ducks is limited. This research aims to use genome-wide association analysis to uncover single-nucleotide polymorphisms influencing carcass yield in Peking ducks, followed by identifying candidate genes linked to carcass traits. In this study, we analyzed seven traits of 643 Peking ducks at age 42 days and identified novel loci associated with these traits. A total of 35 significant loci were detected, with eight SNPs reaching genome-wide significance. KIF20B, AGBL5, SGSM1, MRO, PLAG1, XKR4, and TGS1 were considered as important candidate genes influencing carcass yield in ducks. This study adds to the list of genes affecting Peking duck body traits, aiding marker-assisted breeding and enhancing economic yield.

Effect of Hydroxyapatite Nanoparticle Crystallinity and Colloidal Stability on Cytotoxicity.

Hydroxyapatite nanoparticles (nHA) have gained attention as potential intracellular drug delivery vehicles due to their high binding affinity for various biomolecules and pH-dependent solubility. Yet, the dependence of nHA cytocompatibility on their physicochemical properties remains unclear since numerous studies have revealed starkly contrasting results. These discrepancies may be attributed to differences in size, shape, crystallinity, and aggregation state of nHA, which complicates fundamental understanding of the factors driving nHA cytotoxicity. Here, we hypothesize that nHA cytotoxicity is primarily driven by intracellular calcium levels following the internalization of nHA nanoparticles. By investigating the cytotoxicity of spherical nHA with different crystallinity and dispersity, we find that both lower crystallinity and increased agglomeration of nHA raise cytotoxicity, with nanoparticle agglomeration being the more dominant factor. We show that the internalization of nHA enhances intracellular calcium levels and increases the production of reactive oxygen species (ROS). However, only subtle changes in intracellular calcium are observed, and their physiological relevance remains to be confirmed. In conclusion, we show that nHA agglomeration enhances ROS production and the associated cytotoxicity. These findings provide important guidelines for the future design of nHA-containing formulations for biomedical applications, implying that nHA crystallinity and especially agglomeration should be carefully controlled to optimize biocompatibility and therapeutic efficacy.

Antibacterial Activity of Zinc-Doped Hydroxyapatite and Vancomycin-Loaded Gelatin Nanoparticles against Intracellular Staphylococcus aureus in Human THP-1 Derived Macrophages.

Treating bone infections with common antibiotics is challenging, since pathogens like Staphylococcus aureus can reside inside macrophages. To target these intracellular bacteria, we have proposed nanoparticles (NPs) as drug carriers. This study aims to investigate the efficacy of hydroxyapatite and gelatin NPs, selected in view of their bone mimicry and potential for targeted delivery, as carriers for the antibacterial agents zinc and vancomycin. Therefore, two distinct NPs are fabricated: zinc-doped hydroxyapatite (ZnHA) and vancomycin-loaded gelatin (VGel) NPs. The NPs are characterized based on morphology, size, chemical composition, cellular internalization, and intracellular bactericidal efficacy. Specifically, the intracellular bactericidal efficacy is tested using a validated coculture model of human THP-1 derived macrophages and phagocytosed S. aureus bacteria. Scanning electron microscopy (SEM) and Fourier transform-infrared spectroscopy (FTIR) results show that the spherical NPs are synthesized successfully. These NPs are internalized by THP-1 cells and show >75% colocalization with lysosomes without compromising the viability of the THP-1 cells. Both ZnHA and VGel NPs substantially reduce the intracellular survival of S. aureus compared to the direct addition of dissolved zinc and vancomycin. Concluding, our NPs are highly effective drug delivery vehicles to kill intracellular S. aureus, which stress the potential of these NPs for future clinical translation.

[Clinical characteristics and risk factors analysis of dengue fever incidence in Xishuangbanna, Yunnan Province in 2023].

OBJECTIVE: To analyze the clinical characteristics of dengue fever patients, summarize the course and characteristics of the disease, and analyze the risk factors that affect the condition. METHODS: Retrospective collection of general information, clinical symptoms, medical history, laboratory tests, prognosis and other clinical data of dengue fever patients that admitted to Jinghong First People's Hospital and severe dengue fever patients at People's Hospital of Xishuangbanna Dai Autonomous Prefecture from June to December 2023 was conducted using a case report form (CRF). According to the diagnostic criteria of the World Health Organization (WHO), patients were divided into dengue fever group, dengue fever with warning signs group, and severe dengue fever group. The differences in clinical data between different groups of patients were analyzed and compared. Binary multiple factor Logistic regression analysis was used to explore the risk factors affecting the severity of dengue fever in patients. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of prediction models constructed for various risk factors for severe dengue fever. Subgroup analysis was performed on the prognosis of severe dengue fever patients, and the differences in clinical data between two groups of patients with different prognoses were compared. Binary multivariate Logistic regression analysis was used to explore the risk factors affecting the prognosis of severe dengue fever patients. ROC curve was drawn to analyze the predictive value of prediction models constructed for various risk factors on the prognosis of severe dengue fever patients. RESULTS: A total of 2 264 patients were included, including 499 cases in the dengue fever group, 1 379 cases in the dengue fever with warning signs group, and 386 in the severe dengue fever group (43 deaths and 343 survivors). The most common symptom of dengue fever patients was fever (94.70%), followed by muscle soreness (70.54%), headache (63.12%), fatigue (58.92%), and chills (46.02%). Compared with the dengue fever group and the dengue fever with warning signs group, the ratio of thalassemia and the levels of cardiac troponin (cTnI, cTnT), MB isoenzyme of creatine kinase (CK-MB), and myoglobin were significantly increased in patients with severe dengue fever group, albumin (Alb) was significantly decreased in patients with severe dengue fever group. The levels of cTnT and myoglobin in patients with dengue fever with warning signs group were significantly higher than those in the dengue fever group, and the level of Alb in patients with dengue fever with warning signs group was significantly lower than that in the dengue fever group, the differences were statistically significant (all P < 0.05). Binary multivariate Logistic regression analysis showed that thalassemia [odds ratio (OR) = 6.214, 95% confidence interval (95%CI) was 2.337-16.524, P < 0.001], Alb ≤ 36 g/L (OR = 6.297, 95%CI was 4.270-9.286, P < 0.001), and cTnT levels (OR = 1.008, 95%CI was 1.002-1.015, P = 0.016) were risk factors for severe dengue fever. ROC curve analysis showed that the area under the ROC curve (AUC) for predicting severe dengue fever based on the prediction models constructed for the above risk factors was 0.856, with the best predictive value of 0.067, sensitivity of 67.1%, and specificity of 99.4%. In the subgroup analysis of patients with severe dengue fever, compared with the survival group, the levels of hematocrit (HCT), cTnT, and CK-MB in the death group patients were significantly increased, while the level of Alb was significantly decreased, and the differences were statistically significant. Binary multivariate Logistic regression analysis showed that Alb (OR = 0.839, 95%CI was 0.755-0.932, P = 0.001), HCT (OR = 1.086, 95%CI was 1.010-1.168, P = 0.025), elevated troponin level (OR = 10.119, 95%CI was 2.596-39.440, P < 0.001), and CK-MB (OR = 1.081, 95%CI was 1.032-1.133, P < 0.001) were risk factors for mortality in patients with severe dengue fever. ROC curve analysis showed that the AUC for predicting death in severe dengue fever patients based on the prediction models constructed for the above risk factors was 0.881, with the best predictive value of 0.113, sensitivity of 75.0%, and specificity of 88.9%. CONCLUSIONS: Thalassemia, Alb ≤ 36 g/L, and cTnT level are risk factors for severe dengue fever, while HCT level, Alb level, CK-MB level, and elevated troponin level are risk factors for death in patients with severe dengue fever.

Dexamethasone as an emerging environmental pollutant: Disruption of cholesterol-dependent synaptogenesis in the hippocampus and subsequent neurobehavioral impacts in offspring.

When fetuses are exposed to abnormally high levels of glucocorticoids in utero, irreversible damage to neuronal synaptogenesis occurs, leading to long-term cognitive and emotional behavioral abnormalities after birth. In this study, we investigated how maternal exposure to a novel environmental pollutant-synthetic glucocorticoid dexamethasone-affects offspring cognitive and emotional behaviors enduringly. We noted that offspring subjected to maternal dexamethasone exposure (MDE) displayed cognitive and emotional neurobehavioral deficits beginning in infancy, and these impairments persisted into adulthood. The principal mechanism involves MDE-induced damage to hippocampal neuronal synapse formation in the offspring, primarily due to a cholesterol deficiency which destabilizes neuronal membranes, thereby affecting normal synapse formation and ultimately leading to cognitive and emotional deficiencies. Specifically, we demonstrated abnormal activation of glucocorticoid receptors in hippocampal astroglial cells of MDE offspring, which triggers changes in the miR-450a-3p/HAT1/ABCG1 signaling axis, causing impaired cholesterol efflux in astroglial cells and insufficient cholesterol supply to neurons, further impairing synaptogenesis. This research not only underscores the significant impact of prenatal environmental pollutants on long-term health outcomes in offspring but also broadens our understanding of how prenatal exposure to glucocorticoids affects brain development in the progeny, providing new insights for interventions in neurodevelopmental and psychiatric disorders of fetal origin.

Development and validation of an explainable machine learning model for predicting multidimensional frailty in hospitalized patients with cirrhosis.

We sought to develop and validate a machine learning (ML) model for predicting multidimensional frailty based on clinical and laboratory data. Moreover, an explainable ML model utilizing SHapley Additive exPlanations (SHAP) was constructed. This study enrolled 622 patients hospitalized due to decompensating episodes at a tertiary hospital. The cohort data were randomly divided into training and test sets. External validation was carried out using 131 patients from other tertiary hospitals. The frail phenotype was defined according to a self-reported questionnaire (Frailty Index). The area under the receiver operating characteristics curve was adopted to compare the performance of five ML models. The importance of the features and interpretation of the ML models were determined using the SHAP method. The proportions of cirrhotic patients with nonfrail and frail phenotypes in combined training and test sets were 87.8% and 12.2%, respectively, while they were 88.5% and 11.5% in the external validation dataset. Five ML algorithms were used, and the random forest (RF) model exhibited substantially predictive performance. Regarding the external validation, the RF algorithm outperformed other ML models. Moreover, the SHAP method demonstrated that neutrophil-to-lymphocyte ratio, age, lymphocyte-to-monocyte ratio, ascites, and albumin served as the most important predictors for frailty. At the patient level, the SHAP force plot and decision plot exhibited a clinically meaningful explanation of the RF algorithm. We constructed an ML model (RF) providing accurate prediction of frail phenotype in decompensated cirrhosis. The explainability and generalizability may foster clinicians to understand contributors to this physiologically vulnerable situation and tailor interventions.

First report of Trichoderma roseum causing tea leaf rot in China.

Tea (Camellia sinensis) is consumed worldwide for its numerous benefits and China lead the world production. In March 2023, leaf spots were observed on approximately 10% of tea plants in a 50-ha commercial tea plantation in Menghai (21°46'13"N, 100°30'6"E), Yunnan, China. Initial symptoms appeared as small spots, which progressively expanded and spread over the entire leaf surface. Subsequently, pale pink mold layers developed from the lesions (Fig. S1). To isolate the pathogen, small leaf pieces (3 × 3 mm) were cut from the margins of the lesions, sterilized with 75% ethanol for 30 sec and 0.5% NaClO for another 30 sec, and rinsed three times with sterile water. The pieces were placed on acidified potato dextrose agar (PDA) plates and incubated in darkness at 28°C. A total of 15 fungal isolates with identical morphologies were collected. The colonies appeared pale pink with white mycelia initially then turned orange-pink at the center and light white at the edges. After 10-15 days, exhibiting a powdery texture and concentric rings with uniform edges. Conidia were found at the apex peduncle and were inverted pear-shaped or oval, either non-septate (15.3 ± 2 × 7.8 ± 1.8 µm in size, n = 60) or septate, with a slightly constricted spore base featuring papillary projecvtions (14.8 ± 1.5 × 7.4 ± 0.7 µm in size, n = 60). The morphology closely resembled Trichoderma roseum (Oh et al. 2014). To confirm the species, the strain CYB5 was selected for identification by sequencing the ribosomal internal transcribed spacer (ITS) and large subunit (LSU) genes using polymerase chain reaction (PCR) (White et al.1990). The ITS (GenBank accession OR889657) and LSU (PQ270526) gene sequences exhibited 98% similarity with the Trichoderma roseum sequence KP317992 from NCBI database. A phylogenetic tree was constructed using MEGA 11 (Felsenstein 1981) based on the concatenated sequences (ITS and LSU) of the strain CYB5 and reference strains (Fig. S2). The analysis confirmed that CYB5 is T. roseum (Inácio et al. 2011). Pathogenicity tests were conducted on detached healthy tea leaves placed on wet filter paper in petri dishes. Micro-wounds were made on leaves using a sterilized needle, followed by inoculation with a 6-mm plug of CYB5. Control leaves were inoculates with fungus-free agar disks. The dishes were incubated at 25°C in the dark for 7 days. The leaves inoculated with CYB5 developed reddish brown to dark brown lesions around the inoculated sites, while control leaves remained asymptomatic. The fungus was reisolated from the lesion, and the isolates were morphologically identical to the original cultures. A second pathogenicity test was conducted on potted tea plants of the cultivar 'Yunkang No. 10.' Three plants scratched with a needle and three non-wounded plants were inoculated by spraying 20 ml of a spore suspension (105 spores/ml) of CYB5. Plants sprayed with sterile water served as controls. All plants were maintained in a growth chamber at 28°C, and 70% relative humidity. The lesions developed three days post-inoculation, and typical symptoms appeared after 10 days on spore-inoculated plants only. T. roseum was reisolated and reidentified based on the morphology and molecular analyses, thus fulfilling Koch's postulates. To our best knowledge, this is the first report of T. roseum causing tea leaf rot in China.

Dual-Activated Photoacoustic Probe for Reliably Detecting Hydroxyl Radical in Ischemic Cardiovascular Disease in Mouse and Human Samples.

Cardiovascular disease (CVD) is a chronic disease characterized by the accumulation of lipids and fibrous tissue within the arterial walls, potentially leading to vascular obstruction and an increased risk of heart disease and stroke. Hydroxyl radicals play a significant role in the formation and progression of CVD as they can instigate lipid peroxidation, resulting in cellular damage and inflammatory responses. However, precisely detecting hydroxyl radicals in CVD lesions presents significant challenges due to their high reactivity and short lifespan. Herein, we present the development and application of a novel activatable optical probe, Cy-OH-LP, designed to detect hydroxyl radicals in lipid-rich environments specifically. Built on the Cy7 molecular skeleton, Cy-OH-LP exhibits near-infrared absorption and fluorescence characteristics, and its specific response to hydroxyl radicals enables a turn-on signal in both photoacoustic and fluorescence spectra. The probe demonstrated excellent selectivity and stability in various tests. Furthermore, Cy-OH-LP was successfully applied in an in vivo model to detect hydroxyl radicals in mouse models, providing a potential tool for diagnosing and monitoring AS. The biosafety of Cy-OH-LP was also verified, showing low cytotoxicity and no significant organ damage in mice. The findings suggest that Cy-OH-LP is a promising tool for the specific detection of hydroxyl radicals in lipid-rich environments, providing new possibilities for research and clinical applications in the field of oxidative stress-related diseases.

The construction of an inflammation classification model for HDPCs applied in guiding pulpotomy based on single-cell Raman spectroscopy.

The immune defense and the repair function of the pulp tissue serve as the biological foundation of pulpotomy. The precise evaluation of the pulp inflammation extent and determining its reversibility are essential for the success of pulpotomy. The objective of this study was to classify the molecular-level of dental pulp cell physiology and inflammatory state based on the biochemical changes obtained by single-cell Raman spectroscopy. Firstly, we differentiated the growth of HDPCs (human dental pulp cells) under physiological states by employing Raman spectroscopy with multivariate statistical analysis. Raman spectroscopy reflected the biochemical changes at different growth phases, including the lag phase, log phase, and stationary phase. Secondly, we evaluated the optimal concentration and duration of Porphyromonas gingivalis lipopolysaccharide (P.g.LPS) stimulation to establish a six-level inflammation classification model of HDPCs. Thirdly, we performed label-free characterization of biological component changes in cells of different inflammation grades by Raman spectroscopy. As a result, the differences of peaks in the region 600-1800 cm-1 demonstrated the biochemical molecular alterations in the different inflammation grades of HDPCs. As inflammation progresses in steps, protein peaks increased first and then decreased, while lipid and nucleic acid peaks gradually decreased compared to unstimulated cells. However, when the inflammatory stimulation reached grade V, the changes in the biological properties were characterized by a recovery in protein and lipid content, and a decrease in nucleic acid content. We then established the diagnostic model using the Raman spectra of HDPCs in physiological and inflammatory states, which had a prediction accuracy of 100 % and 97.4 %, respectively. Finally, we determined the reversibility threshold of HDPCs at different grades of inflammation. We observed that the inflammation of grade I and II cells had potential reversibility and could be attempted to be retained. In conclusion, Raman spectroscopy combined with multivariate statistical analysis has potential possibility to effectively distinguish the degree of inflammation in the dental pulp, thus providing new tools and perspectives on pulpotomy in clinical practice.

Fullerene Derivatives for Tumor Treatment: Mechanisms and Application.

Fullerenes hold tremendous potential as alternatives to conventional chemotherapy or radiotherapy for tumor treatment due to their abilities to photodynamically kill tumor cells, destroy the tumor vasculature, inhibit tumor metastasis and activate anti-tumor immune responses, while protecting normal tissue through antioxidative effects. The symmetrical hollow molecular structures of fullerenes with abundant C=C bonds allow versatile chemical modification with diverse functional groups, metal clusters and biomacromolecules to synthesize a wide range of fullerene derivatives with increased water solubility, improved biocompatibility, enhanced photodynamic properties and stronger targeting abilities. This review introduces the anti-tumor mechanisms of fullerenes and summarizes the most recent works on the functionalization of fullerenes and the application of fullerene derivatives in tumor treatment. This review aims to serve as a valuable reference for further development and clinical application of anti-tumor fullerene derivatives.

Selenium Attenuates Radiation Colitis by Regulating cGAS-STING Signaling.

Radiation colitis is one of the most common complications in patients undergoing pelvic radiotherapy and there is no effective treatment in the clinic. Therefore, searching for effective agents for the treatment of radiation colitis is urgently needed. Herein, it is found that the essential element selenium (Se) is protective against radiation colitis through inhibiting X-ray-induced apoptosis, cell cycle arrest, and inflammation with the involvement of balancing the generation of reactive oxygen species after the irradiation. Mechanistically, Se, especially for selenium nanoparticles (SeNPs), induced selenoprotein expression and then functioned to effectively restrain DNA damage response, which reduced X-ray-induced intestinal injury. Additionally, SeNPs treatment also restrained the cyclic GMP-AMP synthas (cGAS)- stimulator of interferon genes (STING)-TBK1-IRF3 signaling pathway cascade, thereby blocking the transcription of inflammatory cytokine gene, IL-6 and TNF-α, and thus alleviating inflammation. Moreover, inducing selenoprotein expression, such as GPX4, with SeNPs in vivo can regulate intestinal microenvironment immunity and gut microbiota to attenuate radiation-induced colitis by inhibiting oxidative stress and maintaining microenvironment immunity homeostasis. Together, these results unravel a previously unidentified modulation role that SeNPs restrained radiation colitis with the involvement of inducing selenoprotein expression but suppressing cGAS-STING-TBK1-IRF3 cascade.

Adult attachment, social anxiety, and problematic social media use: A meta-analysis and meta-analytic structural equation model.

The relationship between adult attachment (anxious attachment and avoidant attachment) and problematic social media use is controversial and contradictory. Hence, the present study clarified the relationship between adult attachment dimensions and problematic social media use through meta-analysis. To better explain the relationship, this study also established meta-analytic structural equation modeling to examine the mediating role of social anxiety in the relationship. This study used CMA and R software for data analysis. Forty-five effect sizes were included in the study, including 11,746 individuals. Results showed that anxious attachment was strongly correlated with problematic social media use (r = 0.319, 95 %CI[0.271, 0.366]), whereas avoidant attachment was weakly correlated with problematic social media use (r = 0.091, 95 %CI[0.011,0.170]). Moderating effects showed that the relationship between anxious attachment and problematic social media use was moderated by the measurement instrument. Meta-analytic structural equation modeling showed that anxious attachment had a significant positive effect on PSMU through social anxiety, anxious attachment had a significant positive effect on PSMU through social anxiety. This study clarifies inconsistencies in the existing literature through meta-analysis, providing reliable conclusions and novel perspectives. It assists clinical practitioners in developing tailored treatment programs for practical interventions. It is suggested that treatment for problematic social media use requires attention to individuals with insecure adult attachment and social anxiety. For individuals with high anxious attachment and social anxiety, it is essential to help them manage their social media use effectively and reduce their dependence on it. Concurrently, interventions for attachment avoidant individuals should focus on enhancing their social self-confidence to reduce the influence of social anxiety on their social media use.

Metabolomics ravels flavor compound formation and metabolite transformation in rapid fermentation of salt-free fish sauce from catfish frames induced by mixed microbial cultures.

This study demonstrates that the co-inoculation with Lactiplantibacillus plantarum, Pichia fermentans and Staphylococcus saprophyticus accelerates catfish frame fish sauce fermentation. Over a 3-day period, significant changes occurred in physicochemical properties, microbial profiles, flavor compounds, and metabolomic spectra. Notable increases in acidity coupled with decreases in glucose underscored the robust environmental adaptability of the employed microorganisms. A reduction in total amino acids, alongside a rise in umami amino acids, suggested flavor enhancement. GC-MS analysis identified 40 key volatile compounds, with esters and aldehydes crucial for aroma development. UPLC-QTOF-MS-based untargeted analysis identified 934 metabolites, with 377 differential metabolites being vital (VIP > 1.5, P < 0.05), including amino acids, peptides, organic acids, nucleic acids, and fatty acids. Metabolites linked to amino acid metabolism, particularly phenylalanine and arginine, were associated with fermentation duration. These findings offer a theoretical basis for optimizing flavor and quality in fish sauces from fish by-products through accelerated fermentation.

Divergent Reactions of α-Diazo 1,3-Dicarbonyl Compounds with Allylic Carbonates Involving Ketene versus Carbene Intermediates Enabled by Cooperative Rh(II)/Pd(0) Dual Catalysis.

A cooperative Rh(II)/Pd(0) dual-catalysis strategy that enabled divergent reactions of α-diazo 1,3-dicarbonyl compounds with allylic carbonates involving ketene versus carbene intermediates is described. The efficient synthesis of α-quaternary allylated ß-keto-esters was accomplished by the Rh(II)/Pd(0) dual-catalysis allylic alkylation of α-diazo 1,3-dicarbonyl compounds. Alternatively, an unprecedented (1+4) annulation of α-diazo 1,3-dicarbonyl compounds with 2-(hydroxymethyl)allyl carbonates via Rh(II)/Pd(0) dual catalysis was also successfully developed, affording a wide variety of α-quaternary tetrahydrofurans in good to high yields.

Momentum-space spin texture induced by strain gradient in nominally centrosymmetric SrIrO3 films.

Spin texture in k-space is a consequence of spin splitting due to strong spin-orbit coupling and inversion symmetry breaking. It underlies fertile spin transport phenomena and is of crucial importance for spintronics. Here, we observe the spin texture in k-space of nominally centrosymmetric SrIrO3 grown on NdGaO3 (110) substrates, using non-linear magnetotransport measurements. We demonstrate that the spin texture is not only induced by the interface, which inherently breaks the inversion symmetry in strong spin-orbit coupled SrIrO3 films, but also originates from the film bulk. Structural analysis reveals that thicker SrIrO3 films exhibit a strain gradient, which could be considered as a continuous change in the lattice constant across different layers and breaks the inversion symmetry throughout the entire SrIrO3 films, giving rise to the spin texture in k-space. First-principles calculations reveal that the strain gradient creates large spin-splitting bands, inducing the spin texture with anisotropy, which is consistent with our experimental observations. Our results offer an efficient method for inducing the spin textures in k-space.

A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion.

Intratumoral regulatory T cells (Tregs) express high levels of CD25 and TIGIT, which are also recognized as markers of effector T cell (Teff) activation. Targeting these molecules each alone with monoclonal antibodies (mAbs) poses a risk of concurrently depleting both Teffs and peripheral Tregs, thereby compromising the effectiveness and selectivity of intratumoral Treg depletion. Here, leveraging the increased abundance of CD25+ TIGIT+ double-positive Tregs in the solid tumor microenvironment (but not in peripheral tissues), we explore the feasibility of using a CD25×TIGIT bispecific antibody (bsAb) to selectively deplete intratumoral Tregs. We initially constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210, and found that NSWm7210 conferred enhanced intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. We subsequently constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ double-positive cells over single-positive cells in vitro. NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Our study illustrates the use of CD25×TIGIT bsAbs as effective agents against solid tumors based on selective depletion of intratumoral Tregs.

A dynamic regulome of shoot-apical-meristem-related homeobox transcription factors modulates plant architecture in maize.

BACKGROUND: The shoot apical meristem (SAM), from which all above-ground tissues of plants are derived, is critical to plant morphology and development. In maize (Zea mays), loss-of-function mutant studies have identified several SAM-related genes, most encoding homeobox transcription factors (TFs), located upstream of hierarchical networks of hundreds of genes. RESULTS: Here, we collect 46 transcriptome and 16 translatome datasets across 62 different tissues or stages from the maize inbred line B73. We construct a dynamic regulome for 27 members of three SAM-related homeobox subfamilies (KNOX, WOX, and ZF-HD) through machine-learning models for the detection of TF targets across different tissues and stages by combining tsCUT&Tag, ATAC-seq, and expression profiling. This dynamic regulome demonstrates the distinct binding specificity and co-factors for these homeobox subfamilies, indicative of functional divergence between and within them. Furthermore, we assemble a SAM dynamic regulome, illustrating potential functional mechanisms associated with plant architecture. Lastly, we generate a wox13a mutant that provides evidence that WOX13A directly regulates Gn1 expression to modulate plant height, validating the regulome of SAM-related homeobox genes. CONCLUSIONS: The SAM-related homeobox transcription-factor regulome presents an unprecedented opportunity to dissect the molecular mechanisms governing SAM maintenance and development, thereby advancing our understanding of maize growth and shoot architecture.

Improved Liver Intravital Microscopic Imaging Using a Film-Assisted Stabilization Method.

Intravital microscopy (IVM) is a valuable method for biomedical characterization of dynamic processes, which has been applied to many fields such as neuroscience, oncology, and immunology. During IVM, vibration suppression is a major challenge due to the inevitable respiration and heartbeat from live animals. In this study, taking liver IVM as an example, we have unraveled the vibration inhibition effect of liquid bridges by studying the friction characteristics of a moist surface on the mouse liver. We confirmed the presence of liquid bridges on the liver through fluorescence imaging, which can provide microscale and nondestructive liquid connections between adjacent surfaces. Liquid bridges were constructed to sufficiently stabilize the liver after abdominal dissection by covering it with a polymer film, taking advantage of the high adhesion properties of liquid bridges. We further prototyped a microscope-integrated vibration-damping device with adjustable film tension to simplify the sample preparation procedure, which remarkably decreased the liver vibration. In practical application scenarios, we observed the process of liposome phagocytosis by liver Kupffer cells with significantly improved image and video quality. Collectively, our method not only provided a feasible solution to vibration suppression in the field of IVM, but also has the potential to be applied to vibration damping of precision instruments or other fields that require nondestructive ″soft″ vibration damping.

Local mRNA Delivery from Nanocomposites Made of Gelatin and Hydroxyapatite Nanoparticles.

Local delivery of messenger ribonucleic acid (mRNA) is increasingly being advocated as a promising new strategy to enhance the performance of biomaterials. While extensive research has been dedicated to the complexation of these oligonucleotides into nanoparticles to facilitate systemic delivery, research on developing suitable biomaterial carriers for the local delivery of mRNA is still scarce. So far, mRNA-nanoparticles (mRNA-NPs) are mainly loaded into traditional polymeric hydrogels. Here, we show that calcium phosphate nanoparticles can be used for both reinforcement of nanoparticle-based hydrogels and the complexation of mRNA. mRNA was incorporated into lipid-coated calcium phosphate nanoparticles (LCPs) formulated with a fusogenic ionizable lipid in the outer layer of the lipid coat. Nanocomposites of gelatin and hydroxyapatite nanoparticles were prepared at various ratios. Higher hydroxyapatite nanoparticle content increased the viscoelastic properties of the nanocomposite but did not affect its self-healing ability. Combination of these nanocomposites with peptide, lipid, and the LCP mRNA formulations achieved local mRNA release as demonstrated by protein expression in cells in contact with the biomaterials. The LCP-based formulation was superior to the other formulations by showing less sensitivity to hydroxyapatite and the highest cytocompatibility.