Expression of MAF bZIP transcription factor B protects against ulcerative colitis through the inhibition of the NF-κB pathway.

PURPOSE: The aim of this study was to explore whether MAF bZIP transcription factor B (MAFB) might alleviate ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced mice and LPS-induced IEC-6 cells. METHODS: UC in vivo and in vitro model was established by using DSS and LPS, respectively. The mice body weight and disease activity index (DAI) score were recorded daily, and colon length was measured. Moreover, the permeability was evaluated utilizing a fluorescein isothiocyanate dextran (FITC-Dextran) probe. Histopathological changes of DSS-induced colitis mice was assessed utilizing H&E staining. Next, qRT-PCR was performed to detect IL-1ß, IL-6, TNF-α, and IL-10 level in in vivo and in vitro. Furthermore, the level of MDA, SOD, CAT, and GSH were evaluated in colon tissues. Besides, the expressions of tight junction proteins and NF-κB pathway relative proteins were examined in colitis mice and IEC-6 cells using western blot, immunohistochemistry and immunofluorescence. RESULTS: MAFB level was downregulated in DSS-induced colitis mice. Moreover, the upregulation of MAFB protected mice from DSS-induced colitis by suppressing DSS-induced inflammation, oxidative stress, and intestinal barrier impairment. We also demonstrated that the upregulation of MAFB inactivated NF-κB pathway in DSS-caused colitis mice. Subsequently, we observed that MAFB upregulation could inhibit LPS-caused epithelial barrier impairment and inflammation in IEC-6 cells. Additionally, MAFB overexpression could suppress the activation of NF-κB pathway in IEC-6 cells. CONCLUSION: The upregulation of MAFB could protect against UC via the suppression of inflammation and the intestinal barrier impairment through inhibiting the NF-κB pathway.

Selective Clearance of Circulating Histones Based on Dodecapeptide-Grafted Copolymer Material for Sepsis Blood Purification.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Research indicates that circulating histones, as pathogenic factors, may represent a therapeutic target for sepsis. However, effectively clearing circulating histones poses a challenge due to their structural similarity to normal blood proteins, their low abundance in the bloodstream, and serious interference from other blood biomacromolecules. Here we design a dodecapeptide-based functional polymer that can selectively adsorb circulating histones from the blood. The peptide, named P1 (HNHHQLALVESY), was discovered through phage display screening and demonstrated a strong affinity for circulating histones while exhibiting negligible affinities for common proteins in the blood, such as human serum albumin (HSA), immunoglobulin G (IgG), and transferrin (TRF). Furthermore, the P1 peptide was incorporated into a functional polymer design, poly(PEGMA-co-P1), which was immobilized onto a silica gel surface through reversible addition-fragmentation chain transfer polymerization. The resulting material was characterized using solid nuclear magnetic resonance, thermogravimetric analysis, and X-ray photoelectron spectroscopy. This material demonstrated the ability to selectively and efficiently capture circulating histones from both model solutions and whole blood samples while also exhibiting satisfactory blood compatibility, good antifouling properties, and resistance to interference. Satisfactory binding affinity and efficient capture capacity toward histone were also observed for the other screened peptide P2 (QMSMDLFGSNFV)-grafted polymer, validating phage display as a reliable ligand screening strategy. These findings present an approach for the specific clearance of circulating histones and hold promise for future clinical applications in blood purification toward sepsis.

[Report of a child with Bainbridge-Ropers syndrome due to a novel variant of ASXL3 gene and a literature review].

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Bainbridge-Ropers syndrome (BRPS). METHODS: A child with BRPS who had visited Nanjing Children's Hospital on June 26, 2019 was selected as the study subject. Clinical data of the child was reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child was a 6-month-old girl with peculiar facial features, feeding difficulties, malnutrition, global developmental delay, hypotonia, mildly elevated aminotransferase and ulnar deviation. Results of WES showed that she has harbored a c.1533_1534del variant of the ASXL3 gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. No similar case had been retrieved from the HGMD and ClinVar databases. No frequency for this variant among Asian populations was available in the ExAC, 1000 Genomes, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1533_1534del variant of the ASXL3 gene was determined to be likely pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The ASXL3 gene c.1533_1534del variant probably underlay the BRPS in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling for children with similar disorders.

FTO-mediated m 6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis.

The activation of hepatic stellate cells (HSCs) is central to the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals, and N 6-methyladenosine (m 6A) modification is closely related to autophagy. In this study, we find that the m 6A demethylase fat mass and obesity-associated protein (FTO), which is the m 6A methylase with the most significant difference in expression, is upregulated during HSC activation and bile duct ligation (BDL)-induced hepatic fibrosis. Importantly, we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is a target of FTO because FTO mainly mediates the m 6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and the activation of HSCs. Notably, the m 6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level by recognizing the m 6A binding site and ultimately inhibiting autophagy and HSC activation. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.

Malondialdehyde and Zinc May Relate to Severity of Microvascular Complications in Diabetes: A Preliminary Study on Older Adults with Type 2 Diabetes Mellitus in Northeast China.

Background: Serum trace elements and oxidative stress factors are related to diabetic microvascular complications. The study was to investigate the complex relationship between trace elements, oxidative stress factors, and the severity of microvascular complications of diabetes in older adults. Methods: The present study included patients with or without type 2 diabetes, and blood glucose, blood lipids, trace elements (iron, magnesium, zinc), oxidative stress factors (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC)) were evaluated. Risk factors for the severity of diabetic microvascular complications in older adults with diabetes were also estimated. Results: There were statistically significant differences in fasting blood glucose (FBG), triglycerides (TG), low density lipoprotein (LDL), glycated hemoglobin (HbAlc), MDA, NO, SOD, T-AOC, magnesium, and zinc between the two groups (P<0.05). Iron (rZinc = 0.147, rSOD = 0.180, rT-AOC = 0.193, P < 0.05) was positively correlated with zinc, SOD and T-AOC. Iron was negatively correlated with MDA (rMDA = -0.146, P < 0.05). Magnesium was positively correlated with SOD (rMagnesium = 0.147, P < 0.05). Zinc (rSOD = 0.616, rT-AOC = 0.575, P < 0.01) was positively correlated with SOD and T-AOC. Zinc (rMDA =-0.636, rNO=-0.616, P<0.01) was positively correlated with MDA and negatively correlated with NO. The course of disease (18.653, [5.726; 60.764], P <0.01), FBG (1.265, [1.059; 1.511], P <0.05), HbAlc (1.545, [1.431; 1.680], P <0.01), MDA (2.989, [1.900; 4.702], P <0.01) were risk factor for the severity of diabetic microvascular complications. Zinc (0.680, [0.503; 0.919], P < 0.05) and SOD (0.820, [0.698; 0.964], P < 0.05) were protective factors for the severity of diabetic microvascular complications. Conclusion: Serum trace elements are related to oxidative stress levels in older adults with type 2 diabetes. The more stable trace element in older adults with diabetes, the lower the oxidative stress and the fewer microvascular complications of diabetes.

Inhibiting miR-618 Promotes Keratinocytes Proliferation and Migration to Enhance Wound Healing in Mice.

The delay in wound healing caused by chronic wounds or pathological scars is a pressing issue in clinical practice, imposing significant economic and psychological burdens on patients. In particular, with the aging of the population and the increasing incidence of diseases such as diabetes, impaired wound healing is one of the growing health problems. MicroRNA (miRNA) plays a crucial role in wound healing and regulates various biological processes. Our results show that miR-618 was significantly upregulated during the inflammatory phase of wound healing.Subsequently, miR-618 promotes the secretion of pro-inflammatory cytokines and regulates the proliferation and migration of keratinocytes. Mechanistically, miR-618 binds to the target gene-Atp11b and inhibits the PI3K-Akt signaling pathway, inhibiting the epithelial-mesenchymal transition (EMT) of keratinocytes. In addition, the PI3K-Akt signaling pathway induces the enrichment of nuclear miR-618, and miR-618 binds to the promoter of Lin7a to regulate gene transcription. Intradermal injection of miR-618 antagomir around full-thickness wounds in peridermal mice effectively accelerates wound closure compared to control. In conclusion, miR-618 antagomir can be a potential therapeutic agent for wound healing.

Mapping the current trends of autophagy in retinal diseases: A bibliometric analysis.

Background: Several scholarly publications have thoroughly examined the significant role of autophagy in the pathogenesis, progression, and treatment of retinal diseases. This research utilized bibliometric analysis to identify the primary areas of focus and emerging trends within the discipline and offer a comprehensive summary. Methods: The research articles and reviews regarding autophagy and retinal diseases from 2009-01-01 to 2022-12-31 were from the Web of Science Core Collection (WOSCC). The software VOSviewer and CiteSpace were applied to analyze and visualize maps of countries, organizations, authors, journals, keyword networks, and citations in the field of autophagy in retinal diseases. Results: 854 qualified records (721 articles and 133 reviews) were retrieved in this research. The annual publication output of literature shows a growing trend. China is the most productive country, and the author with the most publications is Kai Kaarniranta. Journal Autophagy published the most articles in this field. Keywords analysis can effectively reflect the research hot spots and indicate that diabetic retinopathy and glaucoma have drawn more attention recently. Researchers have shifted the research emphasis on "AMPK", "angiogenesis", "mutation", and "inflammation". Conclusions: With the bibliometric analysis approach, we presented the number of publications, countries, regions, authors, institutions, keywords, and citations, which further helps researchers understand the hot spots and trends in the field of autophagy in retinal diseases and explore the issues in the rapidly developing area.

Role of RIPK3 in lipid metabolism and postnatal overfeeding-induced metabolic disorders in mice.

Postnatal overfeeding can increase the long-term risk of metabolic disorders, such as obesity, but the underlying mechanisms remain unclear and treatment approaches are limited. Receptor-interacting protein kinase 3 (RIPK3) is associated with several metabolic diseases. We investigated the effects of RIPK3 on neonatal overfeeding-related metabolic disorders. On postnatal day 3, litter sizes were adjusted to 9-10 (normal litters, NL) or 2-3 (small litters, SL) mice per dam to mimic postnatal overfeeding. After weaning, NL and SL mouse were fed normal diet. We generated an adeno-associated virus (AAV) carrying short hairpin RNA (shRNA) against Ripk3 and an empty vector as a control. The NL and SL groups were treated intravenously with 1×1012 vector genome of AAV vectors at week 6. The SL group showed a higher body weight than the NL group from week 3 of age through adulthood. At weeks 6 and 13, the SL group exhibited impaired glucose and insulin tolerance, RIPK3 up-regulation, and lipid accumulation in liver and adipose tissues. In the SL group, the genes involved in lipid synthesis and lipolysis were increased, whereas fatty acid ß-oxidation-related genes were weakened in adipose tissue and liver. At week 13, AAV-shRNA-Ripk3 ameliorated adipose tissue hypertrophy, hepatic steatosis, insulin resistance, and dysregulated lipid metabolism in the adipose tissue and liver of SL mice. These findings support a novel mechanism underlying the pathogenesis of postnatal overfeeding-related metabolic disorders and suggest potential therapeutic targets.

CD57 defines a novel cancer stem cell that drive invasion of diffuse pediatric-type high grade gliomas.

BACKGROUND: Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies. METHODS: Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGGINV) and tumor core (HGGTC) cells. RESULTS: pHGGINV cells were intrinsically more invasive than their matching pHGGTC cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57+CD133- cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57+CD133- > CD57+CD133+ > CD57-CD133+ > CD57-CD133- cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57+CD133- cells in the HGGINV front (HGGINV/CD57+CD133- cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57+ (CD57+/CD133- and CD57+/CD133+) cells into mouse brains reconstituted diffusely invasion, while depleting CD57+ cells (i.e., CD57-CD133+) abrogated pHGG invasion. CONCLUSION: We revealed significantly increased invasive capacities in HGGINV cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57+CD133- and CD57+CD133+ cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.

Development of a Physiologically Based Pharmacokinetic Population Model for Diabetic Patients and its Application to Understand Disease-drug-drug Interactions.

INTRODUCTION: The activity changes of cytochrome P450 (CYP450) enzymes, along with the complicated medication scenarios in diabetes mellitus (DM) patients, result in the unanticipated pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interactions (DDIs). Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool for assessing the influence of disease status on CYP enzymes and the resulting DDIs. This work aims to develop a novel diabetic PBPK population model to facilitate the prediction of PK and DDI in DM patients. METHODS: First, mathematical functions were constructed to describe the demographic and non-CYP physiological characteristics specific to DM, which were then incorporated into the PBPK model to quantify the net changes in CYP enzyme activities by comparing the PK of CYP probe drugs in DM versus non-DM subjects. RESULTS: The results show that the enzyme activity is reduced by 32.3% for CYP3A4/5, 39.1% for CYP2C19, and 27% for CYP2B6, while CYP2C9 activity is enhanced by 38% under DM condition. Finally, the diabetic PBPK model was developed through integrating the DM-specific CYP activities and other parameters and was further used to perform PK simulations under 12 drug combination scenarios, among which 3 combinations were predicted to result in significant PK changes in DM, which may cause DDI risks in DM patients. CONCLUSIONS: The PBPK modeling applied herein provides a quantitative tool to assess the impact of disease factors on relevant enzyme pathways and potential disease-drug-drug-interactions (DDDIs), which may be useful for dosing regimen optimization and minimizing the DDI risks associated with the treatment of DM.

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis.

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

Mechanism of acoustic pressure spectrum shifting toward lower frequencies in applied current thermoacoustic imaging.

Objective. Thermoacoustic tomography (TAT) is a promising imaging technique used for early cancer diagnosis, tumor therapy, animal study and brain imaging. Although it is widely known that the TAT frequency response depends on the pulse width of the source and the size of the object, a thorough comprehension of the quantitative frequency modulation in TAT and the mechanism governing the shift in the thermoacoustic pressure spectrum towards lower frequencies with respect to the excitation source is still lacking. This study aims to understand why the acoustic pressure spectrum and the final voltage signals shift towards lower frequencies in TAT.Approach. We employed a linear time-invariant model. In the proposed model, the applied current thermoacoustic imaging (ACTAI) process is divided into the thermoacoustic stage and the acoustoelectric stage. These two stages are characterized by the thermoacoustic transfer function(TATF) and the transducer transfer function (TDTF), respectively. We confirmed the effectiveness of our model through a rigorous examination involving both simulations and experiments.Main results. Simulation results indicate that the TATF behaves as a low-pass filter. The inherent low-pass nature induces a shift towards low frequencies in the acoustic pressure spectrum. Experiments further confirm this behavior, demonstrating that the final electrical voltage also shifts towards low frequencies. Notably, employing the proposed model, there is a remarkable consistency between the main frequency bands of the synthesized and measured final voltage spectrum.Significance. The proposed model thoroughly explains how the TATF causes shifts to low frequencies in both the acoustic pressure spectrum and the final voltage spectrum in TAT. These insights deepen our understanding of optimizing TAT systems in the frequency domain, including aspects like filter design and transducer selection. Furthermore, we underscore the potential significance of this discovery for medical applications, particularly in the context of cancer diagnosis.

Direct Implantation of Patient Brain Tumor Cells into Matching Locations in Mouse Brains for Patient-Derived Orthotopic Xenograft Model Development.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

Tunable photo/thermochromic properties of Cd(II)-viologen coordination polymers modulated by coordination modes for flexible imaging films and anti-counterfeiting.

Two photochromic Cd(II)-CPs were obtained based on the viologen ligand using different synthetic routes, named {[Cd4(p-BDC)4(CPB)2(H2O)2]·2H2O·EtOH}n (1) and {[Cd(p-BDC)(CPB)(H2O)]·(L)·DMF}n (2) (p-H2BDC = 1,4-benzene-dicarboxylate, HCPB·Cl = 1-(4-carboxyphenyl)-4,4'-bipyridinium·Cl, L = 2,4-dinitrochlorobenzene, and DMF = N,N-dimethylformamide), respectively. Due to different coordination modes, the two Cd(II)-CPs show different structures. Compound 1 exhibits a three-dimensional (3D) framework with bimetallic nodes, while compound 2 displays a 2-fold interpenetrated (4,4) net topology. Notably, the two Cd(II)-CPs exhibit substantial disparities in photo/thermochromism, which can be attributed to variations in donor-acceptor (D-A) distances arising from structural differences. Compound 1 showed visually sensitive photo- and thermochromic behavior due to multi-pathway electron transfer and short D-A distances, which is relatively rare in electron-transfer type photochromic systems. In contrast, 2 only demonstrates insensitive photochromic behavior, with a slight deepening of the color observed after 2 hours of UV light, which is due to the mono-pathway electron transfer and long D-A distance. Moreover, we first combined Cd(II)-viologen CPs with polydimethylsiloxane (PDMS) to prepare a 1@PDMS flexible UV imaging film. 1@PDMS exhibits excellent bendability and stretchability and maintains good photochromic properties after 100 bending cycles. To demonstrate the rapid color response and distinct color contrast of 1, its application in anti-counterfeiting is also demonstrated.

Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Transient Receptor Potential Channels in Sensory Mechanisms of the Lower Urinary Tract.

BACKGROUND: Urine storage and excretion require a network of interactions in the urinary tract and the central nervous system, which is mediated by a reservoir of water in the bladder and the outlet to the bladder neck, urethra, and external urethral sphincter. Through communicating and coordinating each other, micturition system eventually showed a switch-like activity pattern. SUMMARY: At cervicothoracic and lumbosacral spine, the spinal reflex pathway of the lower urinary tract (LUT) received mechanosensory input from the urothelium to regulate the bladder contraction activity, thereby controlled urination voluntarily. Impairment of above-mentioned any level could result in lower urinary tract dysfunction, placed a huge burden on patients and society. Specific expression of purinergic receptors and transient receptor potential (TRP) channels are thought to play an important role in urinary excretion in the LUT. KEY MESSAGES: This article reviewed the knowledge about the voiding reflex and described the role and function of TRP channels during voiding.

Colon Targeting pH-Responsive Coacervate Microdroplets for Treatment of Ulcerative Colitis.

Ulcerative colitis (UC), an immune-mediated chronic inflammatory disease, drastically impacts patients' quality of life and increases their risk of colorectal cancer worldwide. However, effective oral targeted delivery and retention of drugs in colonic lesions are still great challenges in the treatment of UC. Coacervate microdroplets, formed by liquid-liquid phase separation, are recently explored in drug delivery as the simplicity in fabrication, spontaneous enrichment on small molecules and biological macromolecules, and high drug loading capacity. Herein, in this study, a biocompatible diethylaminoethyl-dextran hydrochloride/sodium polyphenylene sulfonate coacervates, coated with eudragit S100 to improve the stability and colon targeting ability, named EU-Coac, is developed. Emodin, an active ingredient in traditional Chinese herbs proven to alleviate UC symptoms, is loaded in EU-Coac (EMO@EU-Coac) showing good stability in gastric acid and pepsin and pH-responsive release behavior. After oral administration, EMO@EU-Coac can effectively target and retain in the colon, displaying good therapeutic effects on UC treatment through attenuating inflammation and oxidative stress response, repairing colonic epithelia, as well as regulating intestinal flora balance. In short, this study provides a novel and facile coacervate microdroplet delivery system for UC treatment.

Inferior Alveolar Nerve Canal Segmentation on CBCT Using U-Net with Frequency Attentions.

Accurate inferior alveolar nerve (IAN) canal segmentation has been considered a crucial task in dentistry. Failing to accurately identify the position of the IAN canal may lead to nerve injury during dental procedures. While IAN canals can be detected from dental cone beam computed tomography, they are usually difficult for dentists to precisely identify as the canals are thin, small, and span across many slices. This paper focuses on improving accuracy in segmenting the IAN canals. By integrating our proposed frequency-domain attention mechanism in UNet, the proposed frequency attention UNet (FAUNet) is able to achieve 75.55% and 81.35% in the Dice and surface Dice coefficients, respectively, which are much higher than other competitive methods, by adding only 224 parameters to the classical UNet. Compared to the classical UNet, our proposed FAUNet achieves a 2.39% and 2.82% gain in the Dice coefficient and the surface Dice coefficient, respectively. The potential advantage of developing attention in the frequency domain is also discussed, which revealed that the frequency-domain attention mechanisms can achieve better performance than their spatial-domain counterparts.

Silicon induces ROS scavengers, hormone signalling, antifungal metabolites, and silicon deposition against brown stripe disease in sugarcane.

Bipolaris setariae is known to cause brown stripe disease in sugarcane, resulting in significant yield losses. Silicon (Si) has the potential to enhance plant growth and biotic resistance. In this study, the impact of Si on brown stripe disease was investigated across susceptible and resistant sugarcane varieties, utilizing four Si concentrations (0, 15, 30, and 45 g per barrel of Na2SiO3·5H2O). Si significantly reduced the incidence of brown stripe disease (7.41-59.23%) and alleviated damage to sugarcane growth parameters, photosynthetic parameters, and photosynthetic pigments. Submicroscopic observations revealed that Si induced the accumulation of silicified cells in leaves, reduced spore accumulation, decreased stomatal size, and protected organelles from B. setariae damage. In addition, Si increased the activity of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), reduced reactive oxygen species production (malondialdehyde and hydrogen peroxide) and modulated the expression of genes associated with hormone signalling (PR1, TGA, AOS, AOC, LOX, PYL8, and SnRK2), leading to the accumulation of abscisic acid and jasmonic acid and inhibiting SA synthesis. Si also activated the activity of metabolism-related enzymes (polyphenol oxidase and phenylalanine ammonia lyase) and the gene expression of PAL-dependent genes (PAL, C4H, and 4CL), regulating the accumulation of metabolites, such as chlorogenic acid and lignin. The antifungal test showed that chlorogenic acid (15ug µL-1) had a significant inhibitory effect on the growth of B. setariae. This study is the first to demonstrate the inhibitory effect of Si on B. setariae in sugarcane, highlighting Si as a promising and environmentally friendly strategy for managing brown stripe disease.

Assessing Pharmacogenomic loci Associated with the Pharmacokinetics of Vamorolone in Boys with Duchenne Muscular Dystrophy.

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero-order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.