Provable Unrestricted Adversarial Training without Compromise with Generalizability.

Adversarial training (AT) is widely considered as the most promising strategy to defend against adversarial attacks and has drawn increasing interest from researchers. However, the existing AT methods still suffer from two challenges. First, they are unable to handle unrestricted adversarial examples (UAEs), which are built from scratch, as opposed to restricted adversarial examples (RAEs), which are created by adding perturbations bound by an lp norm to observed examples. Second, the existing AT methods often achieve adversarial robustness at the expense of standard generalizability (i.e., the accuracy on natural examples) because they make a tradeoff between them. To overcome these challenges, we propose a unique viewpoint that understands UAEs as imperceptibly perturbed unobserved examples. Also, we find that the tradeoff results from the separation of the distributions of adversarial examples and natural examples. Based on these ideas, we propose a novel AT approach called Provable Unrestricted Adversarial Training (PUAT), which can provide a target classifier with comprehensive adversarial robustness against both UAE and RAE, and simultaneously improve its standard generalizability. Particularly, PUAT utilizes partially labeled data to achieve effective UAE generation by accurately capturing the natural data distribution through a novel augmented triple-GAN. At the same time, PUAT extends the traditional AT by introducing the supervised loss of the target classifier into the adversarial loss and achieves the alignment between the UAE distribution, the natural data distribution, and the distribution learned by the classifier, with the collaboration of the augmented triple-GAN. Finally, the solid theoretical analysis and extensive experiments conducted on widely-used benchmarks demonstrate the superiority of PUAT.

A spatial transcriptome map of the developing maize ear.

A comprehensive understanding of inflorescence development is crucial for crop genetic improvement, as inflorescence meristems give rise to reproductive organs and determine grain yield. However, dissecting inflorescence development at the cellular level has been challenging owing to a lack of specific marker genes to distinguish among cell types, particularly in different types of meristems that are vital for organ formation. In this study, we used spatial enhanced resolution omics-sequencing (Stereo-seq) to construct a precise spatial transcriptome map of the developing maize ear primordium, identifying 12 cell types, including 4 newly defined cell types found mainly in the inflorescence meristem. By extracting the meristem components for detailed clustering, we identified three subtypes of meristem and validated two MADS-box genes that were specifically expressed at the apex of determinate meristems and involved in stem cell determinacy. Furthermore, by integrating single-cell RNA transcriptomes, we identified a series of spatially specific networks and hub genes that may provide new insights into the formation of different tissues. In summary, this study provides a valuable resource for research on cereal inflorescence development, offering new clues for yield improvement.

Diagnosis of Canine Tumours and the Value of Combined Detection of VEGF, P53, SF and NLRP3 for the Early Diagnosis of Canine Mammary Carcinoma.

The average life of a dog is generally maintained at ten to fifteen years, and tumours are the predominant reason that leads to the death of dogs, especially canine mammary carcinoma. Therefore, early diagnosis of tumours is very important. In this study, tumor size, morphology, and texture could be seen through general clinical examination, tumor metastasis could be seen through imaging examination, inflammatory reactions could be seen through hematological examination, and abnormal cell morphology could be seen through cytological and histopathological examination. In the 269 malignant cases and 179 benign cases, we randomly selected 30 cases each, and an additional 30 healthy dogs were selected for the experiment (healthy dogs: dogs in good physical condition without any tumor or other diseases). We used RT-qPCR and ELISA to determine the relative expression of vascular endothelial growth factor (VEGF), tumor protein P53 (P53), serum ferritin (SF), and NOD-like receptor protein 3 (NLRP3) in 30 healthy dogs, 30 dogs with benign mammary tumours, and 30 dogs with malignant mammary tumours. In the results, the same expression trend was obtained both in serum and tissues, and the expression of the four markers was the highest in malignant mammary tumours, with highly significant differences compared with the benign and healthy/paracancerous groups. By plotting the ROC curves, it was found that the results of combined tests were better than a single test and the combination of the four markers was the best for the early diagnosis. In conclusion, this can assist the clinical early diagnosis to a certain extent, and also provides some references and assistance for the development of tumor detection kits in clinical practice.

Single-nucleus transcriptional and chromatin accessible profiles reveal critical cell types and molecular architecture underlying chicken sex determination.

INTRODUCTION: Understanding the sex determination mechanisms in birds has great significance for the biological sciences and production in the poultry industry. Sex determination in chickens is a complex process that involves fate decisions of supporting cells such as granulosa or Sertoli cells. However, a systematic understanding of the genetic regulation and cell commitment process underlying sex determination in chickens is still lacking. OBJECTIVES: We aimed to dissect the molecular characteristics associated with sex determination in the gonads of chicken embryos. METHODS: Single-nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq) analysis were conducted on the gonads of female and male chickens at embryonic day 3.5 (E3.5), E4.5, and E5.5. RESULTS: Here, we provided a time-course transcriptional and chromatin accessible profiling of gonads during chicken sex determination at single-cell resolution. We uncovered differences in cell composition and developmental trajectories between female and male gonads and found that the divergence of transcription and accessibility in gonadal cells first emerged at E5.5. Furthermore, we revealed key cell-type-specific transcription factors (TFs) and regulatory networks that drive lineage commitment. Sex determination signaling pathways, dominated by BMP signaling, are preferentially activated in males during gonadal development. Further pseudotime analysis of the supporting cells indicated that granulosa cells were regulated mainly by the TEAD gene family and that Sertoli cells were driven by the DMRT1 regulons. Cross-species analysis suggested high conservation of both cell types and cell-lineage-specific TFs across the six vertebrates. CONCLUSIONS: Overall, our study will contribute to accelerating the development of sex manipulation technology in the poultry industry and the application of chickens as a unique model for studying cell fate decisions.

Diagnosis of Arboleda-Tham syndrome by whole-exome sequencing in an Asian girl with severe developmental delay.

OBJECTIVE: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in the KAT6A gene. METHODS: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing. RESULTS: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function. CONCLUSION: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome's pathology.

H2S is involved in drought-mediated stomatal closure through PLDα1 in Arabidopsis.

MAIN CONCLUSION: PLDα1 promoted H2S production by positively regulating the expression of LCD. Stomatal closure promoted by PLDα1 required the accumulation of H2S under drought stress. Phospholipase Dα1 (PLDα1) acting as one of the signal enzymes can respond to drought stress. It is well known that hydrogen sulfide (H2S) plays an important role in plant responding to biotic or abiotic stress. In this study, the functions and relationship between PLDα1 and H2S in drought stress resistance in Arabidopsis were explored. Our results indicated that drought stress promotes PLDα1 and H2S production by inducing the expression of PLDα1 and LCD genes. PLDα1 and LCD enhanced plant tolerance to drought by regulating membrane lipid peroxidation, proline accumulation, H2O2 content and stomatal closure. Under drought stress, the H2O2 content of PLDα1-deficient mutant (pldα1), L-cysteine desulfhydrase (LCD)-deficient mutant (lcd) was higher than that of ecotype (WT), the stomatal aperture of pldα1 and lcd was larger than that of WT. The transcriptional and translational levels of LCD were lower in pldα1 than that in WT. Exogenous application of the H2S donor NaHS or GYY reduced the stomatal aperture of WT, pldα1, PLDα1-CO, and PLDα1-OE lines, while exogenous application of the H2S scavenger hypotaurine (HT) increased the stomatal aperture. qRT-PCR analysis of stomatal movement-related genes showed that the expression of CAX1, ABCG5, SCAB1, and SLAC1 genes in pldα1 and lcd were down-regulated, while ACA1 and OST1 gene expression was significantly up-regulated. Thus, PLDα1 and LCD are required for stomatal closure to improve drought stress tolerance.

Numerical simulation of temperature field of a new type of freezing device under seepage effect.

In order to investigate the development of the temperature field of a new type of freezing reinforcement under seepage conditions, in this paper, COMSOL finite element software was used to simplify the model and simulate the effect of groundwater seepage on the development of the temperature field of frozen pipes by coupling the Darcy's law module and the heat transfer module for porous media. The heads of water were also varied to simulate the change in seepage velocity to further investigate the effect of seepage velocity on the temperature field. The results of the study show that the freezing wall formed in the high head region was thinner than that in the low head region due to the effect of seepage, and this phenomenon was aggravated with the increase of seepage rate; The effect of seepage action on the temperature field had a hysteresis along the seepage direction; When the seepage rate was greater than 1.65 m/d, the soil in the center of the device feezed better and could form a tight and dense freezing wall comparable to the size of the freezing device; When the seepage rate was greater than 5.78 m/d, the temperature of the center soil body gradually increased, and eventually the freezing curtain cannot be formed.

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

Effect of Lycium barbarum polysaccharide on osteoblast proliferation and differentiation in postmenopausal osteoporosis.

OBJECTIVE: We aimed to investigate the effect of Lycium barbarum polysaccharide (LBP) on the proliferation and differentiation of osteoblasts in postmenopausal individuals with osteoporosis using in vitro cell experiments. METHODS: We assessed the effect of long-term LBP consumption on the intestinal metabolites of individuals using a simulation of the human intestinal microbiota ecosystem. We also tested the capacity of LBP in proliferating MC3T3-E1 cells using the cell counting kit-8 (CCK-8) method and analyzed the effect of intestinal metabolites on the osteogenic differentiation of MC3T3-E1 cells by testing bone metabolism viability with relevant indicators. RESULTS: The level of short-chain fatty acids (SCFAs) significantly increased (p < 0.05), and the concentrations of acetic acid, propionic acid, and butyric acid all showed an upward trend after the treatment using LBP. At appropriate concentrations, the fermentation supernatant can enhance osteoblast proliferation by significantly increasing the active expression of bone-alkaline phosphatase (B-ALP) and osteocalcin (OCN) in osteoblasts (p < 0.05). CONCLUSION: By modulating the metabolites of intestinal microbiota, production of SCFAs, the prebiotic properties of LBP can enhance osteoblast differentiation through in vitro simulation experiment and cell-based assay.

Quantifying the Relationship Between Unilateral Induced Metamorphopsia and Stereopsis Impairment.

Purpose: To investigate the relationship between unilateral metamorphopsia, characterized by visual distortions in one eye, and impaired stereopsis. Methods: Utilizing both near and distance measurements through advanced testing systems, including 4K smartphones and an active shutter three-dimensional system, we simulated varying degrees of unilateral metamorphopsia in 30 healthy young adults aged between 21 and 29 years. Two types of contour-based stereotest symbols, lines and squares, were developed. Distortions were classified into six distinct patterns, each further divided into eight grades of severity. Participants were tasked with identifying visual targets, and their stereothresholds were determined under different conditions of induced distortion. Stereopsis was measured within a range of 2.9 to 1.0 log arcsec, at 0.2 log arcsec intervals. Stereopsis changes under different distortion scenarios were analyzed using the generalized estimating equations, with a sequential Bonferroni adjustment applied for pairwise comparisons. Results: A direct and quantifiable correlation was observed between the severity of metamorphopsia and reductions in stereopsis. As the degree of visual distortion increased, notably in both frequency and amplitude, there was a corresponding decline in stereopsis. This relationship held true in both near and distance measurements of stereopsis. Statistical analyses further reinforced these findings, highlighting a significant detrimental effect of distortion components on stereoacuity. Conclusions: The findings highlight the clinical significance of understanding the interplay between unilateral metamorphopsia and stereopsis. Early interventions in conditions leading to metamorphopsia might be critical to maintaining optimal stereopsis.

sCD155 as a potential marker for diagnosing the vascular invasion in hepatic alveolar echinococcosis.

BACKGROUND: Alveolar Echinococcosis (AE) is a malignant zoonotic disease caused by Echinococcus multilocularis infection. Considering whether the lesion is accompanied by vascular invasion (VI) is crucial for treatment strategies. A cost-effective and convenient clinical diagnostic method is urgently needed to supplement current techniques. Consequently, we detected soluble CD155 (sCD155) as a potential biomarker for diagnosing VI in hepatic alveolar echinococcosis (HAE). METHODS: Blood samples were from 42 AE patients and 49 healthy controls (HCs). Based on the computed tomography (CT) and contrast-enhanced CT, AE patients were further categorized into HAE with VI (VIAE; 27 cases) and HAE without VI (NVAE; 15 cases). The sCD155 concentration was measured by an enzyme-linked immunosorbent assay (ELISA). Correlations between sCD155 expression levels and clinicopathological features of AE patients were analyzed using SPSS and GraphPad Prism software. RESULTS: The sCD155 concentrations in AE patients were significantly higher than in HCs. The serum sCD155 level significantly differed between the VIAE and NVAE groups. The univariate analysis showed that VI of AE was significantly correlated with the sCD155 level when the sCD155 was greater than 11 ng/mL. After adjusting for potential confounding factors, the multivariable analysis showed that sCD155 had an independent effect on VI of HAE. The receiver operating characteristic (ROC) curve showed that sCD155 could differentially diagnose VI of HAE at the cut-off value of 11.08 ng/mL with an area under the curve (AUC) value of 0.75. The sensitivity and specificity were 74.07 % and 66.67 %, respectively; the positive and negative predictive values were 74.07 % and 60.00 %, respectively. CONCLUSION: The sCD155 could be a VI biomarker for HAE. Elevated sCD155 levels are indicative of an increased likelihood of concomitant VI in HAE patients, necessitating a thorough evaluation of vascular impairment and the formulation of individualized management strategies.

SIRT1 and ZNF350 as novel biomarkers for osteoporosis: a bioinformatics analysis and experimental validation.

BACKGROUND: Osteoporosis (OP) is characterized by bone mass decrease and bone tissue microarchitectural deterioration in bone tissue. This study identified potential biomarkers for early diagnosis of OP and elucidated the mechanism of OP. METHODS: Gene expression profiles were downloaded from Gene Expression Omnibus (GEO) for the GSE56814 dataset. A gene co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to identify key modules associated with healthy and OP samples. Functional enrichment analysis was conducted using the R clusterProfiler package for modules to construct the transcriptional regulatory factor networks. We used the "ggpubr" package in R to screen for differentially expressed genes between the two samples. Gene set variation analysis (GSVA) was employed to further validate hub gene expression levels between normal and OP samples using RT-PCR and immunofluorescence to evaluate the potential biological changes in various samples. RESULTS: There was a distinction between the normal and OP conditions based on the preserved significant module. A total of 100 genes with the highest MM scores were considered key genes. Functional enrichment analysis suggested that the top 10 biological processes, cellular component and molecular functions were enriched. The Toll-like receptor signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, osteoclast differentiation, JAK-STAT signaling pathway, and chemokine signaling pathway were identified by Kyoto Encyclopedia of Genes and Genomes pathway analysis. SIRT1 and ZNF350 were identified by Wilcoxon algorithm as hub differentially expressed transcriptional regulatory factors that promote OP progression by affecting oxidative phosphorylation, apoptosis, PI3K-Akt-mTOR signaling, and p53 pathway. According to RT-PCR and immunostaining results, SIRT1 and ZNF350 levels were significantly higher in OP samples than in normal samples. CONCLUSION: SIRT1 and ZNF350 are important transcriptional regulatory factors for the pathogenesis of OP and may be novel biomarkers for OP treatment.

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.

Further clarification of cognitive processes of prospective memory in schizophrenia by comparing eye-tracking and ecologically-valid measurements.

The aim of this study is to compare ecologically-valid measure (the Cambridge Prospective Memory Test, CAMPROMPT) and laboratory measure (eye-tracking paradigm) in assessing prospective memory (PM) in individuals with schizophrenia spectrum disorders (SSDs). In addition, eye-tracking indices are used to examine the relationship between PM and other cognitive domains in SSDs patients. Initially, the study sample was formed by 32 SSDs patients and 32 healthy control subjects (HCs) who were matched in sociodemographic profile and the performance on CAMPROMPT. An eye-tracking paradigm was employed to examine the differences in PM accuracy and key cognitive processes (e.g., cue monitoring) between the two groups. Additional 31 patients were then recruited to investigate the relationship between PM cue monitoring, other cognitive functions, and the severity of clinical symptoms within the SSDs group. The monitoring of PM cue was reflected in total fixation time and total fixation counts for distractor words. Cognitive functions were assessed using the Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathology. SSDs patients exhibited fewer total fixation counts for distractor words and lower PM accuracy compared to HCs, even though they were priori matched on CAMPROMPT. Correlation analysis within the SSDs group (63 cases) indicated a negative correlation between PM accuracy and PANSS total score, and a positive correlation with working memory and attention/vigilance. Regression analysis within the SSDs group revealed that higher visual learning and lower PANSS total scores independently predicted more total fixation counts on distractor words. Impairment in cue monitoring is a critical factor in the PM deficits in SSDs. The eye-tracking laboratory paradigm has advantages over the ecologically-valid measurement in identifying the failure of cue detection, making it a more sensitive tool for PM deficits in patients with SSDs.

Paternity bias and cryptic female choice in chickens.

Sperm competition and cryptic female choice (CFC) are 2 significant mechanisms of postcopulatory sexual selection that greatly impact fertilization success in various species. Despite extensive research has conducted on sperm competition and the evolution of sperm traits in internal fertilization, our understanding of the female preferences in selecting sperm is still limited. Here, we aimed to investigate the characteristics of CFC in chickens by utilizing artificial insemination with mixed semen to control for variations in male fertilization success caused by female perception of male quality and mating order. Our results revealed that the offspring from multiple-mated females exhibited mixed paternity. Although the males had an equal number of viable sperm, 1 male consistently exhibited a 15% higher success rate on average, regardless of whether the insemination was performed with fresh or diluted semen. This result suggested that this male demonstrates superior performance in sperm competition, and exhibited a potential advantage in fertilization success. While the dominant male generally made a greater genetic contribution to most offspring, the degree of this advantage varied greatly, ranging from 11.11 to 75%. Furthermore, our study provided evidence of female preferences influenced the precedence of sperm from certain males over others. Interestingly, this bias is not consistently observed among all individuals, as offspring derived from some females were predominantly sired by an overall disadvantaged male while others were predominantly by a different disadvantaged male. Overall, these results underscored the complex processes involved in sperm selection and emphasized the importance of females in sexual selection theory.

The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment.

Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1-/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.

Combination of miR159 Mimics and Irinotecan Utilizing Lipid Nanoparticles for Enhanced Treatment of Colorectal Cancer.

Colorectal cancer (CRC) ranks as the third most prevalent global malignancy, marked by significant metastasis and post-surgical recurrence, posing formidable challenges to treatment efficacy. The integration of oligonucleotides with chemotherapeutic drugs emerges as a promising strategy for synergistic CRC therapy. The nanoformulation, lipid nanoparticle (LNP), presents the capability to achieve co-delivery of oligonucleotides and chemotherapeutic drugs for cancer therapy. In this study, we constructed lipid nanoparticles, termed as LNP-I-V by microfluidics to co-deliver oligonucleotides miR159 mimics (VDX05001SI) and irinotecan (IRT), demonstrating effective treatment of CRC both in vitro and in vivo. The LNP-I-V exhibited a particle size of 118.67 ± 1.27 nm, ensuring excellent stability and targeting delivery to tumor tissues, where it was internalized and escaped from the endosome with a pH-sensitive profile. Ultimately, LNP-I-V significantly inhibited CRC growth, extended the survival of tumor-bearing mice, and displayed favorable safety profiles. Thus, LNP-I-V held promise as an innovative platform to combine gene therapy and chemotherapy for improving CRC treatment.

Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

BACKGROUND: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). AIMS: To explore the role of HTG in the pathogenesis of AP. METHODS: Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. RESULTS: In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1ß, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). CONCLUSIONS: HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.

A novel fast hybrid capture sequencing method for high-efficiency common human coronavirus whole-genome acquisition.

Rapid and accurate sequencing of the entire viral genome, coupled with continuous monitoring of genetic changes, is crucial for understanding the epidemiology of coronaviruses. We designed a novel method called micro target hybrid capture system (MT-Capture) to enable whole-genome sequencing in a timely manner. The novel design of probes used in target binding exhibits a unique and synergistic "hand-in-hand" conjugation effect. The entire hybrid capture process is within 2.5 hours, overcoming the time-consuming and complex operation characteristics of the traditional liquid-phase hybrid capture (T-Capture) system. By designing specific probes for these coronaviruses, MT-Capture effectively enriched isolated strains and 112 clinical samples of coronaviruses with cycle threshold values below 37. Compared to multiplex PCR sequencing, it does not require frequent primer updates and has higher compatibility. MT-Capture is highly sensitive and capable of tracking variants.IMPORTANCEMT-Capture is meticulously designed to enable the efficient acquisition of the target genome of the common human coronavirus. Coronavirus is a kind of virus that people are generally susceptible to and is epidemic and infectious, and it is the virus with the longest genome among known RNA viruses. Therefore, common human coronavirus samples are selected to evaluate the accuracy and sensitivity of MT-Capture. This method utilizes innovative probe designs optimized through probe conjugation techniques, greatly shortening the time and simplifying the handwork compared with traditional hybridization capture processes. Our results demonstrate that MT-Capture surpasses multiplex PCR in terms of sensitivity, exhibiting a thousandfold increase. Moreover, MT-Capture excels in the identification of mutation sites. This method not only is used to target the coronaviruses but also may be used to diagnose other diseases, including various infectious diseases, genetic diseases, or tumors.