Targeting the chromatin structural changes of antitumor immunity.

Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.

Enhancing intercropping sustainability: Manipulating soybean rhizosphere microbiome through cropping patterns.

Understanding the responses of soybean rhizosphere and functional microbiomes in intercropping scenarios holds promise for optimizing nitrogen utilization in legume-based intercropping systems. This study investigated three cropping layouts under film mulching: sole soybean (S), soybean-maize intercropping in one row (IS), and soybean-maize intercropping in two rows (IIS), each subjected to two nitrogen levels: 110 kg N ha-1 (N110) and 180 kg N ha-1 (N180). Our findings reveal that cropping patterns alter bacterial and nifh communities, with approximately 5 % of soybean rhizosphere bacterial amplicon sequence variants (ASVs) and 42 % of rhizosphere nifh ASVs exhibiting altered abundances (termed sensitive ASVs). Root traits and soil properties shape these communities, with root traits exerting greater influence. Sensitive ASVs drive microbial co-occurrence networks and deterministic processes, predicting 85 % of yield variance and 78 % of partial factor productivity of nitrogen, respectively. These alterations impact bacterial and nifh diversity, complexity, stability, and deterministic processes in legume-based intercropping systems, enhancing performance in terms of yield, nitrogen utilization efficiency, land equivalent ratio, root nodule count, and nodule dry weight under IIS patterns with N110 compared to other treatments. Our findings underscore the importance of field management practices in shaping rhizosphere-sensitive ASVs, thereby altering microbial functions and ultimately impacting the productivity of legume-based intercropping systems. This mechanistic understanding of soybean rhizosphere microbial responses to intercropping patterns offers insights for sustainable intercropping enhancements through microbial manipulation.

Mesoscale size-promoted targeted therapy for acute kidney injury through combined RONS scavenging and inflammation alleviation strategy.

Acute kidney injury (AKI) is a heterogeneous, high-mortality clinical syndrome with diverse pathogenesis and prognosis, but it lacks the effective therapy clinically. Its pathogenesis is associated with production of reactive oxygen/nitrogen species and infiltration of inflammatory cells. To overcome these pathogenic factors and improve the therapeutic efficiency, we synthesized triptolide-loaded mesoscale polydopamine melanin-mimetic nanoparticles (MeNP4TP) as the antioxidant plus anti-inflammatory therapeutic platform to synergistically scavenge reactive oxygen/nitrogen species (RONS), inhibit the activity of macrophages and dendritic cells, and generate Treg cells for AKI therapy. It was demonstrated that mesoscale size was beneficial for MeNP4TP to specifically accumulate at renal tubule cells, and MeNP4TP could significantly attenuate oxidative stress, reduce proinflammatory immune cells in renal, and repair renal function in cisplatin-induced AKI mouse model. MeNP4TP might be a potential candidate to inhibit oxidative damages and inflammatory events in AKI.

Effect of two surgical approaches on the lung function and prognosis of patients with combined esophagogastric cancer.

BACKGROUND: Adenocarcinoma of the esophagogastric junction has a center of origin within 5 cm of the esophagogastric junction. Surgical resection remains the main treatment. A transthoracic approach is recommended for Siewert I adenocarcinoma of the esophagogastric junction and a transabdominal approach is recommended for Siewert III adenocarcinoma of the esophagogastric junction. However, there is a need to determine the optimal surgical approach for Siewert II adenocarcinoma of the esophagogastric junction to improve lung function and the prognosis of patients. AIM: To investigate and compare the surgical effects, postoperative changes in pulmonary function, and prognoses of two approaches to treating combined esophagogastric cancer. METHODS: One hundred and thirty-eight patients with combined esophagogastric cancer treated by general and thoracic surgeries in our hospital were selected. They were divided into group A comprising 70 patients (transabdominal approach) and group B comprising 68 patients (transthoracic approach) based on the surgical approach. The indexes related to surgical trauma, number of removed lymph nodes, indexes of lung function before and after surgery, survival rate, and survival duration of the two groups were compared 3 years after surgery. RESULTS: The duration of surgery, length of hospital stay, and postoperative drainage duration of the patients in group A were shorter than those of the patients in group B, and the volume of blood loss caused by surgery was lower for group A than for group B (P < 0.05). At the one-month postoperative review, the first second, maximum ventilation volume, forceful lung volume, and lung volume values were higher for group A than for group B (P < 0.05). Preoperatively, the QLQ-OES18 scale scores of the patients in group A were higher than those in group B on re-evaluation at 3 mo postoperatively (P < 0.05). The surgical complication rate of the patients in group A was 10.00%, which was lower than that of patients in group B, which was 23.53% (P < 0.05). CONCLUSION: Transabdominal and transthoracic surgical approaches are comparable in treating combined esophagogastric cancer; however, the former results in lesser surgical trauma, milder changes in pulmonary function, and fewer complications.

Bacterial Magnetosome-Hitchhiked Quick-Frozen Neutrophils for Targeted Destruction of Pre-Metastatic Niche and Prevention of Tumor Metastasis.

Premetastatic niche (PMN) is a prerequisite for tumor metastasis. Destruction of PMN can significantly suppress the tumor metastasis. Bone marrow-derived cells are usually recruited into the premetastatic organs to support PMN formation, which can be orchestrated by tumor-derived secreted factors. Neutrophils can chemotactically migrate towards the inflammatory sites and consume tumor-derived secreted factors, capable of acting as therapeutic agents for a broad-spectrum suppression of PMN formation and metastasis. However, neutrophils in response to inflammatory signals can release neutrophil extracellular traps (NETs), promoting the tumor metastasis. Herein, live neutrophils are converted into dead neutrophils (C NE) through a quick-frozen process to maintain PMN-targeting and tumor-derived secreted factor-consuming abilities but eliminate NET-releasing shortcomings. Considering macrophages-regulated remodeling of the extracellular matrix in PMN, bacterial magnetosomes (Mag) are further hitchhiked on the surface of C NE to form C NEMag , which can repolarize macrophages from M2 to M1 phenotype for further disruption of PMN formation. A series of in vitro and in vivo assessments have been applied to confirm the effectiveness of C NEMag in suppression of PMN formation and metastasis. This study presents a promising strategy for targeted anti-metastatic therapy in clinics.

Targeted hollow pollen silica nanoparticles for enhanced intravesical therapy of bladder cancer.

Bladder cancer (BC), such as non-muscle invasive bladder cancer (NMIBC), has a significantly high recurrence rate even after intravesical therapy because traditional intravesical chemotherapeutic drugs have short retention time in the bladder and lack efficient uptake in BC cells. Pollen structure usually shows potent adhesion ability to tissue surfaces, different from traditional electronic interaction or covalent binding. 4-Carboxyphenylboric acid (CPBA) has high affinity to sialic acid residues that are overexpressed on BC cells. In the present study, hollow pollen silica (HPS) nanoparticles (NPs) were prepared and modified with CPBA to form CHPS NPs, which could be further loaded with pirarubicin (THP) to form THP@CHPS NPs. THP@CHPS NPs showed high adhesion to skin tissues and could be more efficiently internalized by a mouse bladder cancer cell line (MB49) than THP, inducing more significant apoptotic cells. After intravesical instillation into a BC mouse model through an indwelling catheter, THP@CHPS NPs could more significantly accumulate at the bladder than THP at 24 h post-instillation, and after 8 days of intravesical treatments, magnetic resonance imaging (MRI) revealed that the bladders treated with THP@CHPS NPs showed more smooth bladder lining and more reduction in size and weights than those with THP. Moreover, THP@CHPS NPs exhibited excellent biocompatibility. THP@CHPS NPs hold great potential for intravesical treatment of bladder cancer.

Bacteria engineered with intracellular and extracellular nanomaterials for hierarchical modulation of antitumor immune responses.

Induction of immunogenic cell death (ICD) by hyperthermia can initiate adaptive immune responses, emerging as an attractive strategy for tumor immunotherapy. However, ICD can induce proinflammatory factor interferon-γ (IFN-γ) production, leading to indoleamine 2,3-dioxygenase 1 (IDO-1) activation and an immunosuppressive tumor microenvironment, which dramatically reduces the ICD-triggered immunotherapeutic efficacy. Herein, we developed a bacteria-nanomaterial hybrid system (CuSVNP20009NB) to systematically modulate the tumor immune microenvironment and improve tumor immunotherapy. Attenuated Salmonella typhimurium (VNP20009) that can chemotactically migrate to the hypoxic area of the tumor and repolarize tumor-associated macrophages (TAMs) was employed to intracellularly biosynthesize copper sulfide nanomaterials (CuS NMs) and extracellularly hitchhike NLG919-embedded and glutathione (GSH)-responsive albumin nanoparticles (NB NPs), forming CuSVNP20009NB. After intravenous injection into B16F1 tumor-bearing mice, CuSVNP20009NB could accumulate in tumor tissues and repolarize TAMs from the immunosuppressive M2 to immunostimulatory M1 phenotype and release NLG919 from extracellular NB NPs to inhibit IDO-1 activity. Under further near infrared laser irradiation, intracellular CuS NMs of CuSVNP20009NB could photothermally induce ICD including calreticulin (CRT) expression and high mobility group box 1 (HMGB-1) release, promoting intratumoral infiltration of cytotoxic T lymphocytes. Finally, CuSVNP20009NB with excellent biocompatibility could systematically augment immune responses and significantly inhibit tumor growth, holding great promise for tumor therapy.

First Report of Soft Rot Caused by Pectobacterium polaris on Lettuce in China.

Lettuce (Lactuca sativa) is a leafy vegetable that belongs to the family Asteraceae. It is widely cultivated and consumed around the world. In May 2022, lettuce plants (cv. 204) showing soft rot symptoms were observed in greenhouses in Fuhai District (25°18'N, 103°6'E), Kunming City, Yunnan Province, China. The disease incidence in three greenhouses (0.3 ha in size) was between 10% to 15%. The lower parts of the outer leaves showed brown and water-soaked symptoms, but at the same time the roots were asymptomatic. Sclerotinia species can cause soft decay on lettuce leaves, known as lettuce drop, which can produce symptoms partially resembling those of bacterial soft rot (Subbarao 1998). The absence of white mycelium or black sclerotia on the leaf surfaces of diseased plants indicated that Sclerotinia species were not responsible for the disease. Instead, it is more likely that bacterial pathogens were the cause. Fourteen diseased plants were sampled from three greenhouses, and potential pathogens were isolated from the leaf tissues of six plant individuals. Leaf samples were cut into pieces ca. 0.5 cm in length. The pieces were then surface-sterilized by dipping in 75% ethanol for 60 sec, followed by three successive rinses using sterile distilled water. The tissues were immersed in 250 µl of 0.9% saline in 2 mL microcentrifuge tubes and gently pressed down with grinding pestles for 10 sec. The tubes were let stand still for 20 min. Aliquots (20 µl) 100-fold dilutions of the tissue suspensions were plated onto Luria-Bertani (LB) plates and incubated at 28°C for 24 h. Three single colonies were picked from each LB plate and restreaked five times for purity. After purification, eighteen strains were obtained, and nine of these were identified by 16S rDNA sequencing using the universal primer pair 27F/1492R (Weisburg et al. 1991). Six out of nine strains (6/9) belonged to the genus Pectobacterium (OP968950-OP968952, OQ568892- OQ568894), two strains (2/9) belonged to the genus Pantoea (OQ568895 and OQ568896), and one strain (1/9) belonged to Pseudomonas sp. (OQ568897). Since the Pectobacterium strains shared identical 16S rDNA sequence, strains CM22112 (OP968950), CM22113 (OP968951) and CM22132 (OP968952) were selected as representative strains for further testing. The 16S rDNA sequences of Pectobacterium strains were 100% identical to that of the P. polaris strain NIBIO 1392 (NR_159086.1). To identify the strains to the species level, multilocus sequence analysis (MLSA) was performed using sequences of six housekeeping genes acnA, gapA, icdA, mdh, proA and rpoS (OP972517-OP972534) (Ma et al. 2007; Waleron et al. 2008). Phylogenetic analysis showed that the strains clustered with P. polaris type strain NIBIO1006T (Dees et al. 2017). They were all capable of utilizing citrate, which is an important biochemical feature in distinguishing P. polaris from its most closely related sister species P. parvum (Pasanen et al. 2020). Lettuce plants (cv. 204), at the rosette stage, were inoculated with the strains CM22112 and CM22132 by injecting 100 µl of bacterial suspensions (107 CFU·mL-1) into the lower parts of the leaf; for the controls, 100 µl of saline was used instead. Inoculated plants were incubated at room temperature (23°C) and 90% relative humidity. Five days after inoculation, only the bacteria-inoculated lettuce showed severe soft rot symptoms. Similar results were observed in two independent experiments. Bacterial colonies were obtained from the infected lettuce leaves, which showed identical sequences to P. polaris strains CM22112 and CM22132. Therefore, these strains fulfilled Koch's postulates for lettuce soft rot. P. polaris is prevalent on potato in many countries (Dees et al. 2017). To our knowledge, this is the first report of P. polaris causing soft rot on lettuce in China. This disease could seriously affect the appearance and saleability of lettuce. Further research on the epidemiology and management strategies of the disease is needed.

Effects of Dietary Phytosterol Supplementation on the Productive Performance, Egg Quality, Length of Small Intestine, and Tibia Quality in Aged Laying Hens.

This study aimed at investigating the effects of phytosterols on the productive performance, egg quality, length of small intestine, and tibia quality in aged laying hens. A total of 960 Dawu Jinfeng commercial laying hens (75 weeks of age) were randomly assigned to three groups. Each group had 16 replicates and every replicate contained four cages (five birds/cage). The control group hens received the basal diet without phytosterols. The hens in the experimental groups received a diet containing phytosterols at concentrations of 20 mg/kg and 40 mg/kg for 7 weeks. The results showed that phytosterols had a linearly increasing effect on egg weight, eggshell surface area, albumen height, and haugh unit at week 5 of experiment (p < 0.05). Supplemental phytosterols linearly and quadratically increased eggshell thickness (p < 0.05). At week 7 of the experiment, dietary supplementation of phytosterols linearly increased egg weight and eggshell weight (p < 0.05). Supplementation of 20 mg/kg, but not 40 mg/kg, phytosterols increased the length of the small intestine. However, dietary phytosterols had no effect on the laying rate, mortality, or liver index (p > 0.1). The results of tibia quality detected by micro-CT also showed no difference in the treatment of phytosterols. Therefore, supplementation with 20 mg/kg phytosterols in the diet improves egg quality and increases the length of small intestine, but has no effects on the quality of the tibia.

Dearomatizing [2+2+1] Spiroannulation of Indoles with Alkynes.

A palladium-catalyzed dearomatizing [2+2+1] spiroannulation of indoles with two molecular internal alkynes is developed in the presence of Cu(OAc)2/O2 as the oxidant, in which a domino sequence including C-H activation of indole followed by consecutive Heck reactions is involved. A range of 3,3'-spiroindolines bearing tetrasubstituted cyclopentadiene moieties and exocyclic C═C bonds at C2 are obtained in moderate to excellent yields.

Gold Nanobipyramid-Mediated Apoptotic Camouflage of Adipocytes for Obesity Immunotherapy.

Obesity treatment is a global public health challenge due to inadequate weight loss and weight regain even after endeavors with multimodal treatments. Considering the abundance of resident macrophages in adipose tissues, precise regulation of the interactions between macrophages and adipocytes may provide chances for immunotherapy of obesity. Herein, inspired by the phagocytosis of macrophages to clear apoptotic cells in homeostasis, an immunotherapy strategy for obesity treatment is proposed for the first time through apoptotic camouflage of adipocytes by PA Au BPs to activate macrophages for clearance, where PA Au BPs are gold nanobipyramids engineered with adipose-targeting and apoptotic cell-mimicking functions. During clearance, the macrophage is switched from pro-inflammatory M1 to anti-inflammatory M2, remarkably modulating the immune microenvironment of adipose tissues to prevent weight regain. After inguinal injection with PA Au BPs, the body weights of obese mice are effectively decreased by 24.4% and can be decreased by 33.3% when combined with photothermal lipolysis, and little weight regain is associated with these treatments. This study demonstrates that the strategy of camouflaging adipocytes with apoptotic features holds great potential for obesity immunotherapy.

Functional 2D Iron-Based Nanosheets for Synergistic Immunotherapy, Phototherapy, and Chemotherapy of Tumor.

Immunotherapy efficacy has been limited by tumor-associated macrophages (TAMs), which are the most abundant immune regulatory cells infiltrating around tumor tissues. The repolarization of pro-tumor M2 TAMs to anti-tumor M1 TAMs is a very promising immunotherapeutic strategy for cancer therapy. In this manuscript, multifunctional 2D iron-based nanosheets (FeNSs) are synthesized via a simple hydrothermal method for the first time, which not only possess photothermal and photodynamic properties, but also can repolarize TAMs from M2 to M1. After modifying with polyethylene glycol and loading with bioreductive prodrug banoxantrone (AQ4N), abbreviated as AP FeNSs, it can effectively repolarize TAMs from M2 to M1 and deliver AQ4N to tumor microenvironment (TME). Moreover, the repolarized M1 TAMs overexpress inducible nitric oxide synthase, which can convert nontoxic AQ4N to cytotoxic AQ4 under hypoxic TME, enabling immunomodulation-activated chemotherapy. A series of in vitro and in vivo results corroborate that AP FeNSs effectively exert photothermal and photodynamic effects and repolarize M2 TAMs to M1 TAMs, releasing inflammatory factors and activating the chemotherapeutic effect, thereby realizing synergistic tumor therapy.

Upregulation of MHC-I and downregulation of PD-L1 expression by doxorubicin and deferasirox codelivered liposomal nanoparticles for chemoimmunotherapy of melanoma.

Tumor immunotherapy is a promising strategy to activate the immune system and eliminate tumors. Major histocompatibility complex I (MHC-I) is usually applied to potentiate antigen presentation, but it is associated with upregulation of programmed death ligand 1 (PD-L1) expression, which is unfavorable for activation of immune responses. Moreover, poor permeability of various therapeutic antibodies results in the limited immune response rates of most patients. It is necessary to develop combined small molecule drug delivery systems for simultaneous upregulation of MHC-I expression and downregulation of PD-L1 expression, promoting effective tumor treatment. A moderate dose of doxorubicin hydrochloride (DOX) can induce upregulation of MHC-I expression, while deferasirox (DFX) can inhibit the PI3K-Akt pathway, which potentially downregulates PD-L1 expression. In the present study, we designed a pH-sensitive liposome to incorporate DOX in the hydrophilic cavity and embed DFX in the hydrophobic shell, forming a dual delivery system (DOX-DFXL). In a B16F10 melanoma-bearing mouse model, DOX and DFX were released in acidic tumor microenvironment, which further lead to enhanced antigen presentation and infiltration of T cells into tumor tissues as a result of tumor remission. This codelivery system holds great potential for clinical applications of tumor immunotherapy.

Decreased carbon footprint and increased grain yield under ridge-furrow plastic film mulch with ditch-buried straw returning: A sustainable option for spring maize production in China.

Ditch-buried straw returning with ridge-furrow plastic film mulch (RP+S) is a novel tillage measure in semiarid regions, but it is unclear whether RP+S can increase maize yield while reducing the carbon footprint (CF). Therefore, a six-year continuous experiment was conducted from 2016 to 2021 to quantify the effect of four straw returning and film mulching measures [conventional flat cultivation (CK), conventional flat cultivation with ditch-buried straw returning (CK+S), ridge-furrow plastic film mulch (RP), and RP+S] on soil organic carbon sequestration (SOCS), greenhouse gas (GHG) emissions, CF, and economic benefits. Straw returning and film mulching measures significantly increased total GHG emissions across the six seasons. For all treatments, nitrogen fertilizer was the most important source of GHG emissions (≥73%), followed by diesel (8-11%) and plastic film (8%, RP and RP+S only). RP+S significantly increased yield and partial factor productivity of nitrogen fertilizer by 8.7-59.1%, and net economic benefit by 7.37-57.76%, but decreased CF by 34-61% and CF per net return by 33-61% relative to the other treatments. RP+S had the highest GHG emissions, increasing by 6.11-16.47% relative to the other treatments. However, compared with the initial 0-40 cm SOCS in 2016, RP+S had the highest carbon sequestration rate (678.17 kg·ha-1·yr-1), increasing by 2.29% after six years, followed by CK+S (1.78%), CK (0.89%), and RP (-0.49%). Thus, RP+S had the lowest CF and CF per net return in four treatments. This comprehensive analysis of agronomic and environmental benefits revealed that RP+S is a high-yielding, economically and environmentally friendly measure in semiarid areas.

Exploring the clinical efficacy of a self-made acne prescription based on high-throughput sequencing.

BACKGROUND: We used high-throughput sequencing on skin microbial flora to assess the effectiveness of an acne prescription to formulate evidence for clinical decision-making. METHODS: We randomized 20 outpatients into two groups. The treatment group was given the acne formula orally. The control group took capsules of the Chinese patent medicine Qingre Anchuang. Both groups used a chloramphenicol tincture externally. After 14 days of treatment, we collected their skin samples and extracted the deoxyribonucleic acid for analysis. RESULTS: Forty samples were sequenced in this experiment, and of these, 1865 operational taxonomic units were obtained, belonging to 736 genera and 853 strains of 34 phyla. By alpha and beta diversity analysis, the abundance of microbial species in both the experimental and control groups before treatment was higher than after treatment, indicating the intervention drugs in this experiment had a bacteriostatic effect. Through the analysis of variance, we found that Subdoligranulum, Bifidobacterium, Bacteroides, and Akkermansia displayed large changes during the treatment. According to the linear discriminant analysis effect size, we discovered the bacteria groups with the greatest changes in the control group after treatment were Firmicutes, Clostridia, Proteobacteria, and Gammaproteobacteria. The flora of the experimental group before and after treatment were Corynebacteriaceae, Corynebacteriales, Cutibacterium, Propionibacteriales, Propionibacteriaceae, and Actinobacteria. CONCLUSION: The acne prescription had a reliable intervention effect on some epidermal microbial flora of patients with acne vulgaris and could inhibit the growth of acne-related microbial flora, such as Propionibacterium.

Property-activity relationship between physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome.

Air pollution is becoming severe environment factor affecting human health. More and more research has indicated that fine particulate matter (PM2.5) plays a critical role in causing pulmonary inflammation or fibrosis, which potentially is ascribed to the activation of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. However, the underlying property-activity relationship between the physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome remains unclear. Herein, various ways, such as metal chelation, organic extraction, ROS consumption, charge neutralization and particle dispersion, were applied to interfere with the effects of metal ion, polycyclic aromatic hydrocarbons (PAHs), reactive oxygen species (ROS), charge and size. It was found that aggregated size and PAHs could activate the NLRP3 inflammasome through lysosome rupture and potassium efflux, respectively. Metal ion, PAHs and surface ROS could also activate the NLRP3 inflammasome through mitochondrial ROS production. However, neutralization of PM2.5 with the negative surface charge could not relieve the activation of NLRP3 inflammasome. Furthermore, oropharyngeal aspiration of various modified PM2.5 were adopted to explore their effects on lung fibrosis, which showed the consistent results with those in cellular levels. Removal of metal ion, PAHs and ROS as well as reduction of size of PM2.5 could reduce collagen deposition in the lung tissue of mice, while the charge neutralization of PM2.5 increased this collagen deposition. This study provides great insights to clarify the property-activity relationship of PM2.5.

A Comparison of Two Supplementary Doses of Vitamin A on Performance, Intestine and Immune Organ Development, as well as Gene Expression of Inflammatory Factors in Young Hy-Line Brown Laying Pullets.

The objective of this study was to compare two supplementary doses (6000 vs. 12,000 IU/kg) of vitamin A (VA) on the performance, development of intestine and immune organs, as well as gene expression of inflammatory factors in young Hy-Line Brown laying pullets. A total of 288 one-day-old Hy-Line Brown laying pullets (weighing 42.15 ± 0.23 g) were allotted into two treatments with 12 replicate cages and 12 birds per cage. During the 35-day period, the pullets were fed a basal diet supplemented with different doses of VA (6000 IU/kg VA in control group; 12,000 IU/kg VA in treatment group), respectively. The results showed that supplementary high doses of VA reduced the feed-to-gain ratio from day 21 to 35 (p < 0.05). Moreover, the pullets fed high doses of VA diets had increased length and relative weight of duodenum, jejunum, and ileum (p < 0.05). From observations on morphology, high doses of VA diets increased the villus height and the ratio of villus height to crypt depth in the jejunum and ileum (p < 0.05). High doses of VA diets also increased the relative weight of immune organs (p < 0.05). Furthermore, the gene expressions of inflammatory factors were decreased in the thymus of the pullets fed high doses of VA diets (p < 0.05). In summary, supplementary 12,000 IU/kg doses of VA improved performance and intestine and immune organ development, and alleviated gene expressions of inflammatory factors in young Hy-Line Brown laying pullets.

CXCL10 conditions alveolar macrophages within the premetastatic niche to promote metastasis.

Formation of the premetastatic niche is triggered by primary tumors and contributes to cancer metastasis. Evidence indicating the roles of macrophages in metastatic niche formation and organ-specific metastatic tropism has been steadily accumulating. However, the role of tissue-resident macrophages in the establishment of the premetastatic niche is not clearly defined. Here, we report that alveolar macrophages (AMs), which are lung tissue-resident macrophages, play a critical role in initiating the recruitment of monocytic myeloid-derived suppressor cells (mo-MDSCs) and the subsequent premetastatic niche formation by increasing CCL12 expression. We found that CXCL10 can induce CCL12 expression by activating CXCR3 and TLR4 in AMs. CXCR3/TLR4 deficiency or inhibition of its activity reduces CCL12 expression in AMs and subsequent mo-MDSC recruitment to the premetastatic niche, thereby attenuating lung metastasis. In addition, Ube2o is a negative modulator of CXCL10-induced CCL12 expression. Downregulation of Ube2o in AMs under tumor conditions enhances TAK1-NF-κB/ERK/JNK signaling and CXCL10-induced CCL12 expression by promoting TRAF6 polyubiquitination and inhibiting DDX3X degradation. Targeting mo-MDSC recruitment via the CXCL10-CXCR3/TLR4-CCL12 axis in AMs may have therapeutic potential for suppressing lung metastasis.

Inter-spacecraft offset frequency setting strategy in the Taiji program.

For controlling the beat frequency of heterodyne interferometry so that the Taiji program can detect gravitational waves in space, an offset frequency setting strategy based on a linear programming algorithm is proposed. Considering factors such as Doppler frequency shift, phase-locking scheme, laser relative intensity noise, and phase detector bandwidth, inter-spacecraft offset frequency setting results suitable for the Taiji program are obtained. During the six years of running the detection process, the use of frequency bounds in the range of [5 MHz, 25 MHz] showed that offset frequencies will remain unchanged for a maximum of 1931 days. If the upper and lower bounds are adjusted, and the relative motion between spacecraft is further constrained, the offset frequencies do not need to change during the time of the mission. These results may provide insights into selecting the phase detector and designing operation parameters such as orbit and laser modulation frequency in the Taiji program.