Mulberry Leaf Lipid Nanoparticles: a Naturally Targeted CRISPR/Cas9 Oral Delivery Platform for Alleviation of Colon Diseases.

Oral treatment of colon diseases with the CRISPR/Cas9 system has been hampered by the lack of a safe and efficient delivery platform. Overexpressed CD98 plays a crucial role in the progression of ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). In this study, lipid nanoparticles (LNPs) derived from mulberry leaves are functionalized with Pluronic copolymers and optimized to deliver the CRISPR/Cas gene editing machinery for CD98 knockdown. The obtained LNPs possessed a hydrodynamic diameter of 267.2 nm, a narrow size distribution, and a negative surface charge (-25.6 mV). Incorporating Pluronic F127 into LNPs improved their stability in the gastrointestinal tract and facilitated their penetration through the colonic mucus barrier. The galactose end groups promoted endocytosis of the LNPs by macrophages via asialoglycoprotein receptor-mediated endocytosis, with a transfection efficiency of 2.2-fold higher than Lipofectamine 6000. The LNPs significantly decreased CD98 expression, down-regulated pro-inflammatory cytokines (TNF-α and IL-6), up-regulated anti-inflammatory factors (IL-10), and polarized macrophages to M2 phenotype. Oral administration of LNPs mitigated UC and CAC by alleviating inflammation, restoring the colonic barrier, and modulating intestinal microbiota. As the first oral CRISPR/Cas9 delivery LNP, this system offers a precise and efficient platform for the oral treatment of colon diseases.

Oral Nanomotor-Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo-Sono-Immunotherapy against Colon Cancer.

The therapeutic outcomes of oral nanomedicines against colon cancer are heavily compromised by their lack of specific penetration into the internal tumor, favorable anti-tumor activity, and activation of anti-tumor immunity. Herein, hydrogen peroxide (H2 O2 )/ultrasound (US)-driven mesoporous manganese oxide (MnOx )-based nanomotors are constructed by loading mitochondrial sonosensitizers into their mesoporous channels and orderly dual-functionalizing their surface with silk fibroin and chondroitin sulfate. The locomotory activities and tumor-targeting capacities of the resultant nanomotors (CS-ID@NMs) are greatly improved in the presence of H2 O2 and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H2 O2 in the tumor microenvironment (TME) is decomposed into hydroxyl radicals and oxygen by an Mn2+ -mediated Fenton-like reaction, and the produced oxygen participates in sonodynamic therapy (SDT), yielding abundant singlet oxygen. The combined Mn2+ -mediated chemodynamic therapy and SDT cause effective ferropotosis of tumor cells and accelerate the release of tumor antigens. Importantly, animal experiments reveal that the treatment of combining oral hydrogel (chitosan/alginate)-embedding CS-ID@NMs and immune checkpoint inhibitors can simultaneously suppress the growth of primary and distal tumors through direct killing, reversion of immunosuppressive TME, and potentiation of systemic anti-tumor immunity, demonstrating that the CS-ID@NM-based platform is a robust oral system for synergistic treatment of colon cancer.

Nematic-type Structure of the SnO2 (110) Surface at Room Temperature.

The most exposed (110) surface of SnO2 plays an important role in practical applications like gas sensors and catalysts. It has previously been considered to be amorphous at room temperature. In this study, the structure of the (110) surface stabilized at room temperature is determined using aberration-corrected transmission electron microscopy and first-principles calculations. The (110) surface has local order and is made of Sn2 O2 strands that partially cover underlying unsaturated Sn rows. The results indicate that the Sn2 O2 strands assemble as building blocks on the surface to form a partially ordered structure, quite like the nematic liquid crystal. Partial occupation of the Sn2 O2 strands along the [ 1 1 ‾ ${1\bar{1}}$ 0] direction avoids the interaction between neighboring Sn2 O2 strands and therefore makes the surface more stable. The novel phenomenon of the surface provides insight for understanding and developing catalysts and gas sensors based on SnO2 .

Trace elements apportionment in forage, soil, and livestock in rangeland ecosystems along climatic gradients.

BACKGROUND: Alpine meadows, typical steppes, and deserts are among the globally important rangeland types that are generally distributed along temperature and precipitation gradients. Mineral losses caused by grazing are one of the key factors that can lead to instability or even degradation of these rangeland ecosystems. METHODS: We examined the concentrations of Cu, Fe, Mn, and Zn in soil, forage, and livestock dungs from diverse rangeland types in northwest China, to determine the relationships between these trace elements (TEs) concentrations and climatic factors (i.e., temperature, precipitation, and humidity), and to evaluate the potential risks of TEs deficiencies or excesses in these rangeland ecosystems. RESULTS: Forage Zn concentrations in forage of all three types of rangeland, and Cu concentrations in forage of the alpine meadow did not meet the growth requirements of grazing livestock. Concentrations of Cu, Fe, and Mn in forage and Fe, Mn, and Zn in livestock dungs had quadratic parabola relationships with temperature, precipitation, and humidity, but the relationships between climate factors and Cu, Fe, and Mn concentrations in soil were not significant. In addition, the abilities of the plant to absorb Cu, Fe, and Zn from soil were stronger in the typical steppe than that in the alpine meadows and desert. Also, the abilities of livestock to return TEs to soil were stronger in the alpine meadow than that in the typical steppe and desert. CONCLUSION: We derived a conceptual mode that the ratio of TE concentrations of the plant to soil and of livestock dung to forage represents the abilities of plants to absorb TEs from the soil matrix and livestock to return TEs to soil or to absorb TEs from forage, respectively. Results indicate potentially more serious risks of TEs deficiencies, especially that of Zn than previously considered in typical steppes and desert rangelands.

The Association of Peripheral T Lymphocyte Subsets Disseminated Infection by Mycobacterium Tuberculosis in HIV-Negative Patients: A Retrospective Observational Study.

Background and Objective: This study was performed to investigate the association of peripheral T lymphocyte subsets with disseminated infection (DI) by Mycobacterium tuberculosis (MTB) in HIV-negative patients. Methods and Materials: The study included 587 HIV-negative tuberculosis (TB) patients. Results: In TB patients with DI, the proportion of CD4+ T cells decreased, the proportion of CD8+ T cells increased, and the ratio of CD4+/CD8+ T cells decreased. According to univariate analysis, smoking, alcohol consumption, rifampicin-resistance, retreatment, and high sputum bacterial load were linked to lower likelihood of developing MTB dissemination. Multivariate analysis indicated that after adjustment for alcohol use, smoking, retreatment, smear, culture, rifampicin-resistance, and CD4+/CD8+, the proportion of CD8+ T cells (but not CD4+ T cells) was independently and positively associated with the prevalence of DI in HIV-negative pulmonary TB (PTB) patients. Conclusions: Examining T lymphocyte subsets is of great value for evaluating the immune function of HIV-negative TB patients, and an increase in the CD8+ T cell proportion may be a critical clue regarding the cause of DI in such patients.

Expression profiling of TRIM gene family reveals potential diagnostic biomarkers for rifampicin-resistant tuberculosis.

The epidemic of pulmonary tuberculosis (TB), especially rifampin-resistant tuberculosis (RR-TB) presents a major challenge for TB control today. However, there is a lack of reliable and specific biomarkers for the early diagnosis of RR-TB. We utilized reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to profile the transcript levels of 72 tripartite motif (TRIM) genes from a discovery cohort of 10 drug-sensitive tuberculosis (DS-TB) patients, 10 RR-TB patients, and 10 healthy controls (HCs). A total of 35 differentially expressed genes (DEGs) were screened out, all of which were down-regulated. The bio functions and pathways of these DEGs were enriched in protein ubiquitination, regulation of the viral process, Interferon signaling, and innate immune response, etc. A protein-protein interaction network (PPI) was constructed and analyzed using STRING and Cytoscape. Twelve TRIM genes were identified as hub genes, and seven (TRIM1, 9, 21, 32, 33, 56, 66) of them were verified by RT-qPCR in a validation cohort of 95 subjects. Moreover, we established the RR-TB decision tree models based on the 7 biomarkers. The receiver operating characteristic (ROC) analyses showed that the models exhibited the areas under the curve (AUC) values of 0.878 and 0.868 in discriminating RR-TB from HCs and DS-TB, respectively. Our study proposes potential biomarkers for RR-TB diagnosis, and also provides a new experimental basis to understand the pathogenesis of RR-TB.

Establishment of a 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS-ester) based lectin microarray for efficiently detecting serum glycans in gastric cancers.

Development of cancers is involved in changes of a variety of glycans. Lectin microarray is one of the most powerful methodologies for investigation of glycan alterations in biological samples with its advantages of high through-put, selectivity and specificity of the technique. However, utilization of lectin microarrays available commercially keeps of great challenges. In this study, we took use of the molecular self-assembled monolayer technique to modify a gold surface with the reagent 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS-ester) in combination with 16-amino-1-hexadecanethiol hydrochloride. Cross-linking effect of DOTA-NHS-ester is brought about via activating three -OH ends to three terminals of succinylimidines, making selective binding of the terminal amino groups in proteins possible. We immobilized ten commercial lectins on the platform and measured changes of serum lectin-matched glycans in patients with gastric cancer. The results demonstrated that this biochip modification platform conferred impressive chemical surface stabilization, sensitivity and geometric images. We observed that all the serum glycans tested in the patients were significantly higher than those in the controls (P < 0.05). The biochip would provide a versatile platform for investigation of potential glycan biomarkers in making tumor diagnosis decision and analyzing escape of tumors from immunity.

Antiferromagnetic topological insulator MnBi2Te4: synthesis and magnetic properties.

Recently, MnBi2Te4 has been discovered as the first intrinsic antiferromagnetic topological insulator (AFM TI), and it will become a promising material to discover exotic topological quantum phenomena. In this work, we have realized the successful synthesis of high-quality MnBi2Te4 single crystals by solid-state reactions. The as-grown MnBi2Te4 single crystal exhibits a van der Waals layered structure, which is composed of septuple Te-Bi-Te-Mn-Te-Bi-Te sequences as determined by X-ray diffraction and high-resolution high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM). The magnetic order below 25 K as a consequence of A-type antiferromagnetic interaction between Mn layers in the MnBi2Te4 crystal suggests the unique interplay between antiferromagnetism and topological quantum states. Moreover, the transport measurements of MnBi2Te4 single crystals further confirm its magnetic transition. This study on the first AFM TI of MnBi2Te4 will guide the future research on other potential candidates in the MBixTey family (M = Ni, V, Ti, etc.).

Recent strategies, progress, and prospects of two-dimensional metal carbides (MXenes) materials in wastewater purification: A review.

With the rapid development of industrialization, water pollution directly leads to the serious shortage of fresh water. As reported by the World Water Council, nearly 3.8 billion people will face water scarcity by 2030. Therefore, developing advanced nanomaterials to realize wastewater purification is a major challenge. Two-dimensional (2D) transition metal carbides (MXenes), as the emerging 2D layered nanomaterials, have been investigated for the applications of water purification treatment since first reported in 2011. Over 40 different MXenes have been developed for environmental remediation, and dozens more structures and properties are theoretically predicted. Here, we review the advances from the aspects of synthesis strategies for MXenes, purification mechanism, and their applications in wastewater treatment processes. The major points are 1) the synthesis and modification approaches for MXenes such as multi-layered stacked MXenes and delaminated MXenes 2) a discussion of current water remediation over MXene-based materials, 3) a brief introduction for removal behaviors and deep interaction mechanisms, 4) optimization strategies and key points for boosting the remediation performance of MXenes.

Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction.

BACKGROUND: Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses. METHODS: Young (8-12 wk) and aged (18-20 mo) mice were subjected to carbon tetrachloride-induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed. RESULTS: Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride-induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis. CONCLUSIONS: Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.

Transparent silk fibroin film-facilitated infected-wound healing through antibacterial, improved fibroblast adhesion and immune modulation.

The clinical application of regenerated silk fibroin (RSF) films for wound treatment is restricted by its undesirable mechanical properties and lack of antibacterial activity. Herein, different pluronic polymers were introduced to optimize their mechanical properties and the RSF film with 2.5% pluronic F127 (RSFPF127) stood out to address the above issues owing to its satisfactory mechanical properties, hydrophilicity, and transmittance. Diverse antibacterial agents (curcumin, Ag nanoparticles, and antimicrobial peptide KR-12) were separately encapsulated in RSFPF127 to endow it with antibacterial activity. In vitro experiments revealed that the medicated RSFPF127 could persistently release drugs and had desirable bioactivities toward killing bacteria, promoting fibroblast adhesion, and modulating macrophage polarization. In vivo experiments revealed that medicated RSFPF127 not only eradicated methicillin-resistant Staphylococcus aureus in the wound area and inhibited inflammatory responses, but also facilitated angiogenesis and re-epithelialization, regardless of the types of antibacterial agents, thus accelerating the recovery of infected wounds. These results demonstrate that RSFPF127 is an ideal matrix platform to load different types of drugs for application as wound dressings.

Comparison of efficacies of different treatments for nontuberculous mycobacterial pulmonary disease in Anhui Province, China.

INTRODUCTION: Although nontuberculous mycobacterial (NTM) infection is a common cause of pulmonary disease worldwide, few studies have focused on epidemiological and therapeutic factors related to NTM cases in Anhui Province, China. This retrospective study aimed to identify aetiological and clinical factors, and treatment outcomes of patients with NTM pulmonary disease (NTMPD) in Anhui. METHODOLOGY: Retrospective clinical data obtained from medical records of NTMPD patients seeking care at Anhui Chest Hospital from July 2019 to June 2022 were analyzed. Treatment outcomes were compared between two patient groups: one receiving a standardised NTM treatment regimen and the other receiving precision treatment regimens. RESULTS: Genotypic analysis of 672 clinical NTMPD-associated isolates revealed that most were Mycobacterium intracellulare, while drug-susceptibility test results demonstrated diverse antibiotic resistance profiles for these isolates. Cough was the most common symptom for 101 NTMPD patients. After patients of both groups received treatment, symptoms improved, sputum culture conversion was observed for some patients, imaging findings stabilised; however, no statistically significant intergroup differences in treatment outcomes were found. CONCLUSIONS: In this study, M. intracellulare was the predominant NTM species identified in isolates obtained from NTMPD patients. Drug resistance profiles of our patient isolates were complex, highlighting the need for administration of timely, more effective, standardised treatments for patients with NTMPD in Anhui Province, China.

Accuracy of Nanopore Sequencing as a Diagnostic Assay for Pulmonary Tuberculosis versus Smear, Culture and Xpert MTB/RIF: A Head-to-Head Comparison.

Early diagnosis of pulmonary tuberculosis (PTB) is pivotal for achieving effective tuberculosis (TB) control. This study aimed to assess the effectiveness of nanopore sequencing of sputum, bronchoalveolar lavage fluid (BALF), and pleural fluid samples for achieving early PTB diagnosis and provided head-to-head comparisons of nanopore sequencing results versus results obtained using smear, culture, and Xpert MTB/RIF assays. Patients admitted from October 2021 to April 2023 were screened for PTB using diagnostic imaging and electronic medical records. A total of 172 patients (129 PTB, 43 non-TB patients) were included in the final analysis after the exclusion of patients who did not meet the study's inclusion criteria. PTB-positive rates were determined for each assay, and then, assay diagnostic efficacies were compared. The positive MTB-detection rates obtained using nanopore sequencing were 86.8% for all samples, 62.3% for BALF, and 84.6% for pleural fluid, all of which were significantly higher than the corresponding rates obtained using the other three assays. The overall sensitivity rates, specificity rates, and area under the curve (AUC) values obtained from smear testing were 5.4%, 95.3%, and 0.504, respectively, as compared to the respective results obtained via culture (18.6%, 100.0%, and 0.593), Xpert MTB/RIF (26.4%, 97.7%, and 0.620), and nanopore sequencing (85.3%, 95.4%, and 0.903). The diagnostic efficacy of nanopore sequencing surpassed the diagnostic efficacies of smear, culture, and Xpert MTB/RIF assays. Thus, nanopore sequencing holds promise as an alternative to Xpert MTB/RIF for early PTB detection, particularly for the testing of BALF and pleural fluid samples.

A simplified direct on-chip forward or reverse immunoassay for evaluating protein-protein interactions in the serum.

BACKGROUND: The identification of protein-protein interactions is a great challenge. In this study, we fabricated a gold surface-modified biochip with activated sophorolipids (SLs) in combination with 16-amino-1-hexadecanethiol hydrochloride to detect serum proteins. MAIN METHODS AND MAJOR RESULTS: The on-chip immunoassay reported here included a forward assay, in which a ligand is immobilized on the biochip surface and allowed to interact with its free specific receptor in liquid phase, and a reverse assay, in which a receptor is loaded on the biochip surface and combined with its free specific ligand in solution. The specificity of the molecular interactions on the biochip was evaluated using immunological blocking assays and chemiluminescent immunoassays (CLIA). Hemophagocytic lymphohistiocytosis (HLH) serum was used to test the potential utilization of the biochip. Reverse receptor CD25-based interleukin (IL)-2 and forward ligand IL-2-based CD25 assays revealed that the limit of detection of the target proteins was as low as 156 and 78 pg/ml, respectively. Using receptor- or ligand-based platforms, we found that the positive rates of free IL-2 and soluble CD25 (sCD25) monomers in the sera of HLH patients were 14.3% and 71.4%, respectively. In addition, the biochip showed good compatibility with CLIA for the measurement of sCD25 (r = 0.77, p < 0.01). CONCLUSIONS AND IMPLICATIONS: Biochip platforms, such as on-chip immunoprecipitation (IP), can be used to evaluate the interactions between proteins, ligands, and receptors, or enzymes and substrates in serum.

Field-free spin-orbit switching of perpendicular magnetization enabled by dislocation-induced in-plane symmetry breaking.

Current induced spin-orbit torque (SOT) holds great promise for next generation magnetic-memory technology. Field-free SOT switching of perpendicular magnetization requires the breaking of in-plane symmetry, which can be artificially introduced by external magnetic field, exchange coupling or device asymmetry. Recently it has been shown that the exploitation of inherent crystal symmetry offers a simple and potentially efficient route towards field-free switching. However, applying this approach to the benchmark SOT materials such as ferromagnets and heavy metals is challenging. Here, we present a strategy to break the in-plane symmetry of Pt/Co heterostructures by designing the orientation of Burgers vectors of dislocations. We show that the lattice of Pt/Co is tilted by about 1.2° when the Burgers vector has an out-of-plane component. Consequently, a tilted magnetic easy axis is induced and can be tuned from nearly in-plane to out-of-plane, enabling the field-free SOT switching of perpendicular magnetization components at room temperature with a relatively low current density (~1011 A/m2) and excellent stability (> 104 cycles). This strategy is expected to be applicable to engineer a wide range of symmetry-related functionalities for future electronic and magnetic devices.

Effectiveness of using group visit model to support diabetes patient self-management in rural communities of Shanghai: a randomized controlled trial.

BACKGROUND: Diabetes has become a major public health problem in China. Support of patient self-management is a key component of effective diabetes care and improved patient outcomes. A series of peer-led community-based disease-specific self-management programs including diabetes have been widely disseminated in urban communities of Shanghai since 1999. However, the strategy of using trained lay leaders to support patient self-management faces challenges in rural communities in Shanghai. This study developed a Chinese diabetes group visit program as an alternative approach to support patient self-management and examined its effectiveness on self-management behaviors, self-efficacy and health status for patients with type 2 diabetes in rural communities of Shanghai. METHODS: 208 patients with type 2 diabetes aged 35-80 years were randomly assigned to the intervention group (n=119) of 12 monthly group visit sessions or to a control group (n=89) of usual care. The trial was undertaken in two rural communities in Shanghai, China. Randomization and allocation to study group were carried out by using a random number table. Analysis of covariance was used to compare changes in the 17 self-management behavior, self-efficacy and health status related variables in two groups at 12 months' follow-up based on 176 patients (n=98; n=78). RESULTS: Compared with controls, the intervention patients, on average, increased their duration of aerobic exercise by more than 40 minutes per week (p=0.001); had significant increase of 0.71 in mean score on self-efficacy to manage diabetes (p=0.02); and had significant improvements in measures of illness intrusiveness and systolic blood pressure. The intervention patients attended an average of 10.1 of the 12 program sessions with 75.6% of them attended 10 and more sessions. CONCLUSION: The Chinese diabetes group visit model is a feasible, acceptable and effective alternative for supporting diabetes patient self-management in Chinese rural communities. The model requires larger studies to determine its effect on blood glucose control and health care utilization. TRIAL REGISTRATION: ISRCTN87909028.

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival.

Molecular classification based on transcriptional characteristics is often used to study tumor heterogeneity. Human cancer has different cell populations with distinct transcription in tumors, and their heterogeneity is the focus of tumor therapy. Our purpose was to explore the tumor heterogeneity of uveal melanoma (UM) through RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq). Based on the consensus clustering assays of the prognosis-related immune gene set, the immune subtype (IS) of UM and its corresponding immune characteristics were comprehensively analyzed. The heterogeneous cell groups and corresponding marker genes of UM were identified from GSE138433 using scRNA-seq analysis. Pseudotime trajectory analysis and SCENIC analysis were conducted to explore the trajectory of cell differentiation and the regulatory network of single-cell transcription factors (TFs). Based on 37 immune gene sets, UM was divided into two different immune subtypes (IS1 and IS2). The two kinds of ISs have different characteristics in prognosis, immune-related molecules, immune score, and immune cell infiltration. According to 11,988 cells of scRNA-seq data from six UM samples, 11 cell clusters and 10 cell types were identified. The subsets of C1, C4, C5, C8, and C9 were related to the prognosis of UM, and different TF-target gene regulatory networks were involved. These five cell subsets differentiated into 3 different states. Our results provided valuable information about the heterogeneity of UM tumors and the expression patterns of TFs in different cell types.

Oral antimicrobial peptide-EGCG nanomedicines for synergistic treatment of ulcerative colitis.

The pathogenesis of ulcerative colitis (UC) is associated with severe inflammation, damaged colonic barriers, increased oxidative stress, and intestinal dysbiosis. The majority of current medications strive to alleviate inflammation but fail to target additional disease pathologies. Addressing multiple symptoms using a single 'magic bullet' remains a challenge. To overcome this, a smart epigallocatechin-3-gallate (EGCG)-loaded silk fibroin-based nanoparticle (NP) with the surface functionalization of antimicrobial peptides (Cathelicidin-BF, CBF) was constructed, which could be internalized by Colon-26 cells and RAW 264.7 macrophages with high efficiencies. The resulting CBF-EGCG-NPs efficiently restored colonic epithelial barriers by relieving oxidative stress and promoting epithelium migration. They also alleviated immune responses through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and lipopolysaccharide (LPS) elimination. Interestingly, oral administration of hydrogel (chitosan/alginate)-embedding CBF-EGCG-NPs could not only retard progression and treat UC, but also modulate intestinal microbiota by increasing their overall diversity and richness and augmenting the abundance of beneficial bacteria (e.g., Firmicutes and Lactobacillaceae). Our work provides a "many birds with one stone" strategy for addressing UC symptoms using a single NP-based oral platform that targets immune microenvironment modulation, LPS clearance, and microbial remodeling.

Evaluation of a novel inhibitor of aspartate semialdehyde dehydrogenase as a potent antitubercular agent against Mycobacterium tuberculosis.

The in vitro activity of IMB-XMA0038, a novel inhibitor targeting Mycobacterial tuberculosis (Mtb) aspartate semialdehyde dehydrogenase, was evaluated. Minimum inhibitory concentrations (MICs) of IMB-XMA0038 were against 20 Mtb isolates, including H37Rv (ATCC 27294), ten clinical pan-sensitive isolates, and nine clinical multidrug-resistant (MDR) isolates. In addition, minimum bactericidal concentrations (MBCs) were also determined against the H37Rv and 6 MDR isolates (the background information is same as above in order). A model was generated to evaluate IMB-XMA0038 activity against dormant Mtb. The post-antibiotic effect (PAE), an important indicator of antimicrobial drug dosing schedules to obtain efficacy, was determined based on time required for regrowth of Mtb to 50% of the OD600max value after treatment with various concentrations of IMB-XMA0038 and INH. In addition, interactions between IMB-XMA0038 and other anti-tuberculosis drugs, measured using a checkerboard assay, revealed that IMB-XMA0038 MICs of 0.5-1 µg/mL could be achieved in combinations. Synergistic effects were observed for IMB-XMA0038 when used together with almost all other anti-tuberculosis drugs against most Mtb isolates. IMB-XMA0038 exhibited greater activity than rifampin against Mtb under hypoxic conditions, as reflected by CFU decreases of 1.1-log-unit versus 0.8-log-unit, respectively, for IMB-XMA0038 and rifampin concentrations of 4 × MIC. IMB-XMA0038-induced PAEs (9, 10, 11 days) were comparable to INH PAEs (10, 11, 12 days). These findings suggest that addition of IMB-XMA0038 to current therapeutic regimens could be useful to improve the efficacy of treatments for drug-resistant and drug-susceptible TB.

Epidemiology of concurrent extrapulmonary tuberculosis in inpatients with extrapulmonary tuberculosis lesions in China: a large-scale observational multi-centre investigation.

AIMS: A high proportion of all patients with tuberculosis (TB) present with extrapulmonary TB (EPTB), including concurrent EPTB involving more than one extrapulmonary lesion site. However, previous reports only characterized lesions of single-site EPTB cases. This study aimed to investigate epidemiological characteristics and association rules of concurrent EPTB cases in China. METHODS: An observational multi-centre study of 208,214 patients with EPTB lesions was undertaken in China from January 2011 to December 2017. Multi-variable logistic regression analysis was used to identify associations between gender and concurrent EPTB, and age and concurrent EPTB. Association rules were analysed for significance using the Apriori algorithm. RESULTS: The most common EPTB lesion was tuberculous pleurisy (49.8%), followed by bronchial TB (14.8%) and tuberculous meningitis (7.6%). The most common type of concurrent EPTB was tuberculous pleurisy concurrent with tuberculous peritonitis (1.80%). In total, 22 association rules, including 20 strong association rules, were identified; among these, the highest confidence rates were found for tuberculous myelitis concurrent with tuberculous meningitis, and sacral TB concurrent with lumbar vertebral TB. The association rules of EPTB concurrent with other EPTB types were found to vary with gender and age. The confidence rate of tuberculous myelitis concurrent with tuberculous meningitis was higher in females (83.67%) than males, and was highest in patients aged 25-34 years (87.50%). CONCLUSIONS: Many types of concurrent EPTB were found. Greater awareness of concurrent EPTB disease characteristics is needed to ensure timely clinical diagnosis and treatment of this disease.