Antibiotic-induced microbiome depletion promotes intestinal colonization by Campylobacter jejuni in mice.

BACKGROUND: To establish a method to induce Campylobacter jejuni colonization in the intestines of C57BL/6 mice through antibiotic-induced microbiome depletion. RESULTS: Fifty-four female C57BL/6 mice were divided into the normal, control, and experimental groups. The experimental group was administered intragastric cefoperazone sodium and sulbactam sodium (50 mg/mL) for 2 days; then, the experimental and control mice were intragastrically administered 200 µL C. jejuni, which was repeated once more after 2 days. Animal feces were collected, and the HipO gene of C. jejuni was detected using TaqMan qPCR from day 1 to day 14 after modeling completion. Immunofluorescence was used to detect intestinal C. jejuni colonization on day 14, and pathological changes were observed using hematoxylin and eosin staining. Additionally, 16S rDNA analyses of the intestinal contents were conducted on day 14. In the experimental group, C. jejuni was detected in the feces from days 1 to 14 on TaqMan qPCR, and immunofluorescence-labeled C. jejuni were visibly discernable in the intestinal lumen. The intestinal mucosa was generally intact and showed no significant inflammatory-cell infiltration. Diversity analysis of the colonic microbiota showed significant inter-group differences. In the experimental group, the composition of the colonic microbiota differed from that in the other 2 groups at the phylum level, and was characterized by a higher proportion of Bacteroidetes and a lower proportion of Firmicutes. CONCLUSIONS: Microbiome depletion induced by cefoperazone sodium and sulbactam sodium could promote long-term colonization of C. jejuni in the intestines of mice.

Prediction of ovarian cancer prognosis using statistical radiomic features of ultrasound images.

Ovarian cancer is the deadliest gynecologic malignancy worldwide. Ultrasound is the most useful non-invasive test for preoperative diagnosis of ovarian cancer. In this study, by leveraging multiple ultrasound images from the same patient to generate personalized, informative statistical radiomic features, we aimed to develop improved ultrasound image-based prognostic models for ovarian cancer. A total of 2,057 ultrasound images from 514 ovarian cancer patients, including 355 patients with epithelial ovarian cancer, from two hospitals in China were collected for this study. The models were constructed using our recently developed Frequency Appearance in Multiple Univariate pre-Screening (FAMUS) feature selection algorithm and Cox proportional hazards model. The models showed high predictive performance for overall survival (OS) and recurrence-free survival (RFS) in both epithelial and nonepithelial ovarian cancer, with concordance indices (C-index) ranging from 0.773 to 0.794. Radiomic scores predicted 2-year OS and RFS risk groups with significant survival differences (log-rank test, P<1.0e-4 for both validation cohorts). OS and RFS hazard ratios between low- and high-risk groups were 15.994 and 30.692 (internal cohort) and 19.339 and 19.760 (external cohort), respectively. The improved performance of these newly developed prognostic models was mainly attributed to the use of multiple preoperative ultrasound images from the same patient to generate statistical radiomic features, rather than simply using the largest tumor ROI among them. The models also revealed that the roundness of tumor lesion shape was positively correlated with prognosis for ovarian cancer. In summary, the newly developed prognostic models based on statistical radiomic features from ultrasound images were highly predictive of the risk of cancer-related death and possible recurrence not only for patients with epithelial ovarian cancer but also for those with nonepithelial ovarian cancer. They thereby provide reliable, non-invasive markers for individualized prognosis evaluation and clinical decision-making for patients with ovarian cancer.

TODO-Net: Temporally Observed Domain Contrastive Network for 3-D Early Action Prediction.

Early action prediction aiming to recognize which classes the actions belong to before they are fully conveyed is a very challenging task, owing to the insufficient discrimination information caused by the domain gaps among different temporally observed domains. Most of the existing approaches focus on using fully observed temporal domains to "guide" the partially observed domains while ignoring the discrepancies between the harder low-observed temporal domains and the easier highly observed temporal domains. The recognition models tend to learn the easier samples from the highly observed temporal domains and may lead to significant performance drops on low-observed temporal domains. Therefore, in this article, we propose a novel temporally observed domain contrastive network, namely, TODO-Net, to explicitly mine the discrimination information from the hard actions samples from the low-observed temporal domains by mitigating the domain gaps among various temporally observed domains for 3-D early action prediction. More specifically, the proposed TODO-Net is able to mine the relationship between the low-observed sequences and all the highly observed sequences belonging to the same action category to boost the recognition performance of the hard samples with fewer observed frames. We also introduce a temporal domain conditioned supervised contrastive (TD-conditioned SupCon) learning scheme to empower our TODO-Net with the ability to minimize the gaps between the temporal domains within the same action categories, meanwhile pushing apart the temporal domains belonging to different action classes. We conduct extensive experiments on two public 3-D skeleton-based activity datasets, and the results show the efficacy of the proposed TODO-Net.

D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities.

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity in an ongoing phase 1 trial (NCT05410145).

The Translation of Nanomedicines in the Contexts of Spinal Cord Injury and Repair.

PURPOSE OF THIS REVIEW: Manipulating or re-engineering the damaged human spinal cord to achieve neuro-recovery is one of the foremost challenges of modern science. Addressing the restricted permission of neural cells and topographically organised neural tissue for self-renewal and spontaneous regeneration, respectively, is not straightforward, as exemplified by rare instances of translational success. This review assembles an understanding of advances in nanomedicine for spinal cord injury (SCI) and related clinical indications of relevance to attempts to design, engineer, and target nanotechnologies to multiple molecular networks. RECENT FINDINGS: Recent research provides a new understanding of the health benefits and regulatory landscape of nanomedicines based on a background of advances in mRNA-based nanocarrier vaccines and quantum dot-based optical imaging. In relation to spinal cord pathology, the extant literature details promising advances in nanoneuropharmacology and regenerative medicine that inform the present understanding of the nanoparticle (NP) biocompatibility-neurotoxicity relationship. In this review, the conceptual bases of nanotechnology and nanomaterial chemistry covering organic and inorganic particles of sizes generally less than 100 nm in diameter will be addressed. Regarding the centrally active nanotechnologies selected for this review, attention is paid to NP physico-chemistry, functionalisation, delivery, biocompatibility, biodistribution, toxicology, and key molecular targets and biological effects intrinsic to and beyond the spinal cord parenchyma. SUMMARY: The advance of nanotechnologies for the treatment of refractory spinal cord pathologies requires an in-depth understanding of neurobiological and topographical principles and a consideration of additional complexities involving the research's translational and regulatory landscapes.

The effect of white grub (Maladera Verticalis) larvae feeding on rhizosphere microbial characterization of aerobic rice (Oryza sativa L.) in Puer City, Yunnan Province, China.

BACKGROUND: Rhizosphere microorganisms are vital in plants' growth and development and these beneficial microbes are recruited to the root-zone soil when experiencing various environmental stresses. However, the effect of white grub (Maladera verticalis) larvae feeding on the structure and function of rhizosphere microbial communities of aerobic rice (Oryza sativa L.) is unclear. RESULTS: In this study, we compared physicochemical properties, enzyme activities, and microbial communities using 18 samples under healthy and M. verticalis larvae-feeding aerobic rice rhizosphere soils at the Yunnan of China. 16 S rRNA and ITS amplicons were sequenced using Illumina high throughput sequencing. M. verticalis larvae feeding on aerobic rice can influence rhizosphere soil physicochemical properties and enzyme activities, which also change rhizosphere microbial communities. The healthy and M. verticalis larvae-feeding aerobic rice rhizosphere soil microorganisms had distinct genus signatures, such as possible_genus_04 and Knoellia genera in healthy aerobic rice rhizosphere soils and norank_f__SC - I-84 and norank_f__Roseiflexaceae genera in M. verticalis larvae-feeding aerobic rice rhizosphere soils. The pathway of the metabolism of terpenoids and polyketides and carbohydrate metabolism in rhizosphere bacteria were significantly decreased after M. verticalis larvae feeding. Fungal parasite-wood saprotroph and fungal parasites were significantly decreased after M. verticalis larvae feeding, and plant pathogen-wood saprotroph and animal pathogen-undefined saprotroph were increased after larvae feeding. Additionally, the relative abundance of Bradyrhizobium and Talaromyces genera gradually increased with the elevation of the larvae density. Bacterial and fungal communities significantly correlated with soil physicochemical properties and enzyme activities, respectively. CONCLUSIONS: Based on the results we provide new insight for understanding the adaptation of aerobic rice to M. verticalis larvae feeding via regulating the rhizosphere environment, which would allow us to facilitate translation to more effective measures.

How would you describe a mentally healthy college student based on Chinese culture? A qualitative research from the perspective of college students.

BACKGROUND: Promoting college students' mental health remains a significant concern, necessitating a clear understanding of what constitutes good mental health. Variations in the conceptualizations of mental health across cultures, typically derived from academic and authoritative perspectives, have overlooked insights from laypeople. This study aims to investigate the characteristics of mentally healthy college students within Chinese cultural contexts, emphasizing perspectives provided by college students themselves. METHODS: Undergraduates with self-reported mental health scores ≥ 7 were randomly selected for in-depth interviews. The sample (N = 17, 59% female) had a mean age of 20.82 ± 1.33 years and represented diverse regions, backgrounds, and academic fields. Thematic analysis was used in the analysis of the qualitative data, involving initial coding to identify 168 manifestations of mental health among college students, followed by categorizing them into 18 characteristics through focused coding. These characteristics were then organized into five themes via core coding. The Delphi method was utilized to validate the themes with 3 experts, ensuring the trustworthiness of the final findings. RESULTS: Eighteen characteristics of mentally healthy college students emerged from the interviews, categorized into 5 themes: (1)Value Pursuit (i.e. Having a sense of responsibility and mission and being willing to dedicate oneself to the country at any time.); (2)Life Attitude (i.e. Staying positive and having the ability and quality to cope with hardships.); (3)Interpersonal Ideals (i.e., Showing filial respect to parents appropriately.); (4)Behavior Ability(i.e., Studying diligently and learning well.); and (5)Self-cultivation (i.e., Possessing good qualities advocated by Confucianism, Buddhism, and Taoism coexist harmoniously.). Most of these characteristics directly reflect traditional Chinese culture or culture that has changed with the times. At the same time, some are a reflection of modern Chinese new culture. CONCLUSIONS: On the whole, the characteristics of mentally healthy college students are diverse and with rich connotations, focusing on the individual's relationship with the country, family, and others, and are good expressions of Chinese cultural features, such as the balance of Yin and Yang, the coexistence of Confucianism, Buddhism, and Taoism, and highlight moral attributes. In essence, these traits hold profound importance in advancing the mental health of Chinese college students.

Neural Tracing Protein-Functionalized Nanoparticles Capable of Fast Retrograde Axonal Transport in Live Neurons.

Neural tracing proteins like horseradish peroxidase-conjugated wheat germ agglutinin (WGA-HRP) can target the central nervous system (CNS) through anatomic retrograde transport without crossing the blood-brain barrier (BBB). Conjugating WGA-HRP to nanoparticles may enable the creation of BBB-bypassing nanomedicine. Microfluidics and two-photon confocal microscopy is applied to screen nanocarriers for transport efficacy and gain mechanistic insights into their interactions with neurons. Protein modification of gold nanoparticles alters their cellular uptake at the axonal terminal and activates fast retrograde transport. Trajectory analysis of individual endosomes carrying the nanoparticles reveals a run-and-pause pattern along the axon with endosomes carrying WGA-HRP-conjugated gold nanoparticles exhibiting longer run duration and faster instantaneous velocity than those carrying nonconjugated nanoparticles. The results offer a mechanistic explanation of the different axonal transport dynamics as well as a cell-based functional assay of neuron-targeted nanoparticles with the goal of developing BBB-bypassing nanomedicine for the treatment of nervous system disorders.

Angularly stable terahertz multiband LiNbO3-polymer hybrid metamaterial for microfluidic refractive index sensing.

A terahertz (THz) L i N b O 3-polymer hybrid metamaterial (LPHM) consisting of three-layer Au patterns and two medium interval layers is demonstrated, and the bulk refractive index (RI) sensing performance is also studied. The parameter optimizations and sensing performances of the LPHM are simulated by the finite-element method (FEM). The results show that the reflection or absorption spectrum of the LPHM has four peaks in the 1-10 THz band, and the peaks move toward the lower frequency when the period (P) of the LPHM or the side length (a) of the notched square frame increases but shift to the higher frequency when w 1 or w 2 increases. Moreover, the LPHM has a wide angular stability and good structural stability. The sensing performance shows that the LPHM can achieve an RI sensitivity of 11.5 µm/RIU with a detection limit (DL) of 2.9×10-4 R I U. The LPHM has potential applications in pharmacological biodevices, THz immunosensing, modern medical and clinical practices, and detection of thin films and biochemical substances, and it can be expected to realize multiphysical parameter measurements.

Fulvic Acid Promotes Legume-Rhizobium Symbiosis by Stimulating Endogenous Flavonoids Synthesis and Secretion.

Fulvic acid (FA) promotes symbiosis between legumes and rhizobia. To elucidate from the aspect of symbiosis, the effects of root irrigation of water-soluble humic materials (WSHM) or foliar spraying of its highly active component, FA, on soybean root exudates and on rhizosphere microorganisms were investigated. As a result, WSHM/FA treatments significantly altered root exudate metabolite composition, and isoflavonoids were identified as key contributors in both treatments compared to the control. Increased expression of genes related to the isoflavonoid biosynthesis were validated by RT-qPCR in both treatments, which notably elevated the synthesis of symbiotic signals genistein, daidzin, coumestrol, and biochanin A. Moreover, the WSHM/FA treatments induced a change in rhizosphere microbial community, coupled with an increase in the relative abundance of rhizobia. Our findings showed that WSHM/FA promotes symbiosis by stimulating the endogenous flavonoid synthesis and leads to rhizobia accumulation in the rhizosphere. This study provides new insights into mechanisms underlying the FA-mediated promotion of symbiosis.

Ultrasound-Assisted Multi-Enzyme Extraction for Highly Efficient Extraction of Polysaccharides from Ulva lactuca.

Ulva polysaccharides present several physiological activities including antiviral, antitumor and anti-plasmodial effects. However, current processing usually results in low yields and high prices, thus lacking commercialization potential. The aim of this study was to develop an efficient method for the extraction of Ulva polysaccharides with high biological activity. The effect of cell wall-degrading enzymes including cellulase, hemicellulase, pectinase and protease on Ulva polysaccharide extraction was studied by statistical mixing design. Using the most effective enzyme preparations as the basic components, the optimal proportions of the enzyme mixture were determined as follows: cellulase 35.3%, pectinase 34.5%, alkaline protease 30.2%, which increased the polysaccharide yield from 6.43% in the absence of enzymes to 26.68%. Subsequently, through response surface analysis, the optimal conditions were determined: enzyme concentration of 1.5%, enzymatic time of 1.1 h, ultrasonic time of 90 min and enzymatic temperature of 60 °C. Under the optimal extraction conditions, the extraction yield of Ulva polysaccharides could be increased to 30.14%. Moreover, extracted polysaccharides exhibit strong antioxidant properties in DPPH, ABTS, hydroxyl radical, superoxide radical and H2O2-induced cellular damage models. This study laid a solid foundation for the use and development of Ulva polysaccharides.

The protective effect of traditional Chinese medicine Jinteng Qingbi granules on rats with rheumatoid arthritis.

Introduction: Jinteng Qingbi granules (JTQBG), a traditional Chinese medicine formulation, are widely used for the treatment of rheumatoid arthritis (RA) due to their satisfactory therapeutic efficacy. However, the underlying mechanism of action remains unclear. This study aims to investigate the protective effects of JTQBG against RA and elucidates its potential molecular mechanisms. Methods: A collagen-induced arthritis (CIA) rat model was utilized, and JTQBG (1.25, 2.5, 5 g/kg/day) or methotrexate (MTX, 1 mg/kg/week) was orally administered. The rats' weight, arthritis index (AI), and paw volume were measured weekly. Synovial hyperplasia of the joints was detected using a small animal ultrasound imaging system. Joint destruction was assessed using an X-ray imaging system. Histopathological examinations were performed using hematoxylin-eosin (H&E), Saffron-O and fast green staining. Serum inflammatory cytokines were detected using ELISA. Furthermore, 4D label-free quantitative proteomics of synovial tissues and non-targeted metabolomics of blood serum were conducted to analyze the molecular mechanisms. Results: JTQBG exerted a significant therapeutic effect on CIA rats by reducing inflammatory cell infiltration, synovial hyperplasia, cartilage erosion, and bone destruction. It also decreased the spleen index, inhibited hyperplasia of the white pulp, and decreased the serum levels of IL-1ß and IL-18. Proteomics analysis identified 367 differentially expressed proteins (DEPs) between the Model and Normal groups, and 71 DEPs between the JTQBG and Model groups. These DEPs were significantly enriched in the NF-κB pathway. 11 DEPs were significantly reversed after treatment with JTQBG. Western blot results further validated the expression levels of Nfkb1, Pdk1, and Pecam1, and analyzed the expression levels of p-IKK, p-IκBα, and IκBα. The therapeutic efficacy of JTQBG was partly attributed to the suppression of the NF-κB pathway in synovial tissues. Serum metabolomics identified 17 potential biomarkers for JTQBG treatment of CIA rats, which were closely related to Alanine, aspartate and glutamate metabolism, Tryptophan metabolism, Ascorbate and aldarate metabolism, Arginine metabolism, and Inositol phosphate metabolism. Conclusion: Our findings demonstrated that JTQBG was effective against RA by alleviating synovial inflammation, synovial hyperplasia, and joint destruction. The anti-RA properties of JTQBG were likely attributed to the inhibition of the NF-κB pathway and the regulation of serum metabolite disorders.

Dynamic surveillance of lymphocyte subsets in patients with non-small cell lung cancer during chemotherapy or combination immunotherapy for early prediction of efficacy.

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Lymphocytes are the primary executors of the immune system and play essential roles in tumorigenesis and development. We investigated the dynamic changes in peripheral blood lymphocyte subsets to predict the efficacy of chemotherapy or combination immunotherapy in NSCLC. Methods: This retrospective study collected data from 81 patients with NSCLC who received treatments at the First Affiliated Hospital of Zhengzhou University from May 2021 to May 2023. Patients were divided into response and non-response groups, chemotherapy and combination immunotherapy groups, and first-line and multiline groups. We analyzed the absolute counts of each lymphocyte subset in the peripheral blood at baseline and after each treatment cycle. Within-group and between-group differences were analyzed using paired Wilcoxon signed-rank and Mann-Whitney U tests, respectively. The ability of lymphocyte subsets to predict treatment efficacy was analyzed using receiver operating characteristic curve and logistic regression. Results: The absolute counts of lymphocyte subsets in the response group significantly increased after the first cycle of chemotherapy or combination immunotherapy, whereas those in the non-response group showed persistent decreases. Ratios of lymphocyte subsets after the first treatment cycle to those at baseline were able to predict treatment efficacy early. Combination immunotherapy could increase lymphocyte counts compared to chemotherapy alone. In addition, patients with NSCLC receiving chemotherapy or combination immunotherapy for the first time mainly presented with elevated lymphocyte levels, whereas multiline patients showed continuous reductions. Conclusion: Dynamic surveillance of lymphocyte subsets could reflect a more actual immune status and predict efficacy early. Combination immunotherapy protected lymphocyte levels from rapid decrease and patients undergoing multiline treatments were more prone to lymphopenia than those receiving first-line treatment. This study provides a reference for the early prediction of the efficacy of clinical tumor treatment for timely combination of immunotherapy or the improvement of immune status.

Metabolomic biomarkers in liquid biopsy: accurate cancer diagnosis and prognosis monitoring.

Liquid biopsy, a novel detection method, has recently become an active research area in clinical cancer owing to its unique advantages. Studies on circulating free DNA, circulating tumor cells, and exosomes obtained by liquid biopsy have shown great advances and they have entered clinical practice as new cancer biomarkers. The metabolism of the body is dynamic as cancer originates and progresses. Metabolic abnormalities caused by cancer can be detected in the blood, sputum, urine, and other biological fluids via systemic or local circulation. A considerable number of recent studies have focused on the roles of metabolic molecules in cancer. The purpose of this review is to provide an overview of metabolic markers from various biological fluids in the latest clinical studies, which may contribute to cancer screening and diagnosis, differentiation of cancer typing, grading and staging, and prediction of therapeutic response and prognosis.

Effect of Different Edible Trichosanthes Germplasm on Its Seed Oil to Enhance Antioxidant and Anti-Aging Activity in Caenorhabditis elegans.

The seeds of various Trichosanthes L. plants have been frequently used as snacks instead of for traditional medicinal purposes in China. However, there is still a need to identify the species based on seeds from Trichosanthes germplasm for the potential biological activities of their seed oil. In this study, 18 edible Trichosanthes germplasm from three species were identified and distinguished at a species level using a combination of seed morphological and microscopic characteristics and nrDNA-ITS sequences. Seed oil from the edible Trichosanthes germplasm significantly enhanced oxidative stress tolerance, extended lifespan, delayed aging, and improved healthspan in Caenorhabditis elegans. The antioxidant activity of the seed oil exhibits a significant positive correlation with its total unsaturated fatty acid content among the 18 edible Trichosanthes germplasm, suggesting a genetic basis for this trait. The biological activities of seed oil varied among species, with T. kirilowii Maxim. and T. rosthornii Harms showing stronger effects than T. laceribractea Hayata.

Treatment of children with refractory/relapse high risk langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone.

BACKGROUND: The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO + LCH) have poor prognosis. The patients with MS-LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective for refractory/relapse MS-RO + LCH, with low toxicity. METHODS: We retrospectively analyzed pediatric refractory/relapse MS-RO + LCH patients treated with the low-dose Ara-c (100mg/m2/d×5days) or high-dose Ara-c (500mg/m2/d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, outcomes and adverse events were analyzed. RESULTS: From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were included in the study. 11 (84.6%) of the 13 patients treated with the LAC regimen and 6 (85.7%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up and the 3-year event-free survival rate (EFS) was 53.7% and 85.7% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.5% (5/13) and 42.9% (3/7) of the patients receiving the LAC and HAC regimen. CONCLUSIONS: A combination of Ara-c, VDS and prednisone was effective and safe for some patients with refractory/relapse MS-RO + LCH. The high-dose Ara-c regimen was associated with a numerically higher EFS rate.

Selective regulation of endophytic bacteria and gene expression in soybean by water-soluble humic materials.

BACKGROUND: As part of the plant microbiome, endophytic bacteria play an essential role in plant growth and resistance to stress. Water-soluble humic materials (WSHM) is widely used in sustainable agriculture as a natural and non-polluting plant growth regulator to promote the growth of plants and beneficial bacteria. However, the mechanisms of WSHM to promote plant growth and the evidence for commensal endophytic bacteria interaction with their host remain largely unknown. Here, 16S rRNA gene sequencing, transcriptomic analysis, and culture-based methods were used to reveal the underlying mechanisms. RESULTS: WSHM reduced the alpha diversity of soybean endophytic bacteria, but increased the bacterial interactions and further selectively enriched the potentially beneficial bacteria. Meanwhile, WSHM regulated the expression of various genes related to the MAPK signaling pathway, plant-pathogen interaction, hormone signal transduction, and synthetic pathways in soybean root. Omics integration analysis showed that Sphingobium was the genus closest to the significantly changed genes in WSHM treatment. The inoculation of endophytic Sphingobium sp. TBBS4 isolated from soybean significantly improved soybean nodulation and growth by increasing della gene expression and reducing ethylene release. CONCLUSION: All the results revealed that WSHM promotes soybean nodulation and growth by selectively regulating soybean gene expression and regulating the endophytic bacterial community, Sphingobium was the key bacterium involved in plant-microbe interaction. These findings refined our understanding of the mechanism of WSHM promoting soybean nodulation and growth and provided novel evidence for plant-endophyte interaction.

Soluble humic acid suppresses plant immunity and ethylene to promote soybean nodulation.

Symbiotic nitrogen fixation (SNF) is a crucial process for nitrogen geochemical cycling and plant-microbe interactions. Water-soluble humic acid (WSHM), an active component of soil humus, has been shown to promote SNF in the legume-rhizobial symbiosis, but its molecular mechanism remains largely unknown. To reveal the SNF-promoting mechanism, we conducted transcriptomic analysis on soybean treated with WSHM. Our findings revealed that up- and downregulated differentially expressed genes (DEGs) were mainly involved in plant cell-wall/membrane formation and plant defence/immunity in the early stage, while the late stage was marked by the flavonoid synthesis and ethylene biosynthetic process. Further study on representative DEGs showed that WSHM could inhibit GmBAK1d-mediated immunity and BR signalling, thereby promoting rhizobial colonisation, infection, and nodulation, while not favoring pathogenic bacteria colonisation on the host plant. Additionally, we also found that the ethylene pathway is necessary for promoting the soybean nodulation by WSHM. This study not only provides a significant advance in our understanding of the molecular mechanism of WSHM in promoting SNF, but also provides evidence of the beneficial interactions among the biostimulator, host plant, and soil microbes, which have not been previously reported.

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare immune disorder and hematopoietic stem cell transplan- tation (HSCT) is the only potentially curative treatment. Given the high pre-HSCT mortality of pHLH patients reported in the HLH-2004 study (17%), more regimens to effectively control the disease and form a bridge with HSCT are needed. We conducted a retrospective study of pHLH children treated by ruxolitinib (RUX)-based regimen. Generally, patients received RUX until HSCT or unacceptable toxic side-effect. Methylprednisolone and etoposide were added sequentially when the disease was suboptimally controlled. The primary end point was 1-year overall survival. Twenty-one pHLH patients (12 previously treated and 9 previously untreated) were included with a median follow-up of 1.4 years. At last follow-up, 17 (81.0%) patients were alive with a 1-year overall survival of 90.5% (95% confidence interval: 84.1-96.9). Within the first 8 weeks, all patients had an objective response, of which 19 (90.5%) achieved complete response (CR) and two (9.5%) achieved partial response (PR) as a best response. Seventeen (81.0%) patients received HSCT, of which 13 (76.5%) had CR, three (17.6%) had PR and one (5.9%) had disease reactivation at the time of HSCT. Fifteen (88.2) patients were alive post- HSCT. Notably, eight (38.1%) patients received zero doses of etoposide, suggesting the potential of RUX-based regimen to reduce chemotherapy intensity. Patients tolerated RUX-based regimen well and the most frequently observed adverse events were hematologic adverse events. Overall, RUX-based regimen was effective and safe and could be used as a bridge to HSCT for pHLH children.

Size-Dependent Penetration of Nanoparticles in Tumor Spheroids: A Multidimensional and Quantitative Study of Transcellular and Paracellular Pathways.

Tumor penetration of nanoparticles is crucial in nanomedicine, but the mechanisms of tumor penetration are poorly understood. This work presents a multidimensional, quantitative approach to investigate the tissue penetration behavior of nanoparticles, with focuses on the particle size effect on penetration pathways, in an MDA-MB-231 tumor spheroid model using a combination of spectrometry, microscopy, and synchrotron beamline techniques. Quasi-spherical gold nanoparticles of different sizes are synthesized and incubated with 2D and 3D MDA-MB-231 cells and spheroids with or without an energy-dependent cell uptake inhibitor. The distribution and penetration pathways of nanoparticles in spheroids are visualized and quantified by inductively coupled plasma mass spectrometry, two-photon microscopy, and synchrotron X-ray fluorescence microscopy. The results reveal that 15 nm nanoparticles penetrate spheroids mainly through an energy-independent transcellular pathway, while 60 nm nanoparticles penetrate primarily through an energy-dependent transcellular pathway. Meanwhile, 22 nm nanoparticles penetrate through both transcellular and paracellular pathways and they demonstrate the greatest penetration ability in comparison to other two sizes. The multidimensional analytical methodology developed through this work offers a generalizable approach to quantitatively study the tissue penetration of nanoparticles, and the results provide important insights into the designs of nanoparticles with high accumulation at a target site.