DNA-Conjugated Cyclopropane Derivatives Constructed from Sulfonium Ylides with α,ß-Unsaturated Ketones.

Here, we report a DNA-compatible reaction for the generation of cyclopropane derivatives using thiolides with α,ß-unsaturated ketones in the absence of transition metal and N2 protection, which is convenient for DNA encoded library (DEL) construction. This approach allows the rapid and efficient production of a series of DEL libraries of potentially biologically active cyclopropanes and spirocyclopropyl oxindole derivatives.

A case presentation of acquired membranous ventricular septum aneurysm as a rare delayed complication of ventricular septal defect repair surgery: 10-year follow-up.

BACKGROUND: Rare as membranous ventricular septal aneurysms (MVSA) is, the possibility that occurs after ventricular septum defect (VSD) repair surgery is even more uncommon. PRESENTATION: A girl developed a MVSA 3 years after the VSD repair surgery at the age of 1 and increasing growth was noted during the follow-up. Aneurysm plication was carried done when she was 11 years old because it was observed to have a close relationship to the right coronary and obstructed the right ventricular outflow tract. Postoperative echocardiography follow-up revealed no abnormalities. CONCLUSION: Though the prognosis of most patients with VSD repaired surgery was good, there remains varieties type of complications despite surgical advances. Accurate and rapid diagnosis of acute and delayed complications is essential to improve prognosis. In this case, the aneurysm was diagnosed by multiple imaging modalities and the girl underwent successful surgery again which provides direction for awareness and knowledge of delayed complications of VSD repair.

Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies.

As a naturally occurring cytolytic peptide, melittin (MLT) not only exhibits a potent direct tumor cell-killing effect but also possesses various immunomodulatory functions. MLT shows minimal chances for developing resistance and has been recognized as a promising broad-spectrum antitumor drug because of this unique dual mechanism of action. However, MLT still displays obvious toxic side effects during treatment, such as nonspecific cytolytic activity, hemolytic toxicity, coagulation disorders, and allergic reactions, seriously hampering its broad clinical applications. With thorough research on antitumor mechanisms and the rapid development of nanotechnology, significant effort has been devoted to shielding against toxicity and achieving tumor-directed drug delivery to improve the therapeutic efficacy of MLT. Herein, we mainly summarize the potential antitumor mechanisms of MLT and recent progress in the targeted delivery strategies for tumor therapy, such as passive targeting, active targeting and stimulus-responsive targeting. Additionally, we also highlight the prospects and challenges of realizing the full potential of MLT in the field of tumor therapy. By exploring the antitumor molecular mechanisms and delivery strategies of MLT, this comprehensive review may inspire new ideas for tumor multimechanism synergistic therapy.

Regulating Spin-State Switching by Integrating Polyoxometalate Anion into Spin Crossover System.

Polyoxometalate (POM) anions were successfully integrated into Fe(II) spin crossover (SCO) system, which demonstrates an effective role in regulating spin-state switching properties. Specifically, three drastically different magnetic behaviors of Fe(II) ion in the identical cation [Fe(bpp)2]2+ were achieved by leveraging [Mo6O19]2-, [Mo8O26]4-, and [Na(Mo8O26)]3-, respectively.

Laboratory and clinical evaluation of a microarray for the detection of ATP7B mutations in Wilson disease in China.

BACKGROUND AND OBJECTIVE: Wilson disease (WD) is an autosomal recessive copper metabolic disorder caused by mutations in ATP7B. Sanger sequencing is currently used for ATP7B variant identification. However, the ATP7B gene contains 21 exons, which makes sequencing of the entire gene both complex and time-consuming. Therefore, a simpler assay is urgently needed. METHODS: We performed a laboratory and clinical evaluation of an oligonucleotide microarray for the detection of 24 ATP7B recurrent mutations (except p.P992L) in Chinese patients with WD. RESULTS: The accuracy of the microarray was evaluated by screening for ATP7B mutations in 126 patients including 106 suspected WD samples and 20 patients with other liver diseases as negative control. Results were confirmed by Sanger sequencing. We established a reliable microarray system for the rapid detection of the 24 ATP7B mutations, with a sensitivity of 30 ng/test genomic DNA and specificity of 100% for all loci; the coefficient of variation in repeatability tests was <10%. Clinical evaluation showed an overall concordance between the microarray detection and sequencing of 100%, and 81.13% (86/106) of suspected WD cases showed ATP7B mutations by microarray detection. Microarray and Sanger sequencing identified p.R778L (50.94%), p.A874V (17.92%), p.P992L (11.32%), p.V1106I (11.32%), and p.I1148T (6.60%) as the most common mutations in WD patients. CONCLUSIONS: Our microarray system is customizable and easily used for high-throughput detection of certain recurrent ATP7B mutations, providing a simpler method suitable for WD genetic diagnosis in China.

14-kDa phosphohistidine phosphatase is a potential therapeutic target for liver fibrosis.

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration, and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.NEW & NOTEWORTHY PHP14 inhibition via adeno-associated virus (AAV)-mediated gene silencing could potently attenuate carbon tetrachloride (CCl4)-induced liver fibrosis. PHP14 could regulate the migration of macrophages to the site of injury in vivo. PHP14 knockdown in vivo influenced the environment of fibrogenesis and relevant signaling pathways, subsequently affecting myofibroblast activation.

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants.

Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the evaluation of the functional consequences of ATP7B variants, which is essential for WD cases that are difficult to interpret.

Glucose-Induced Transition among Three States of a Doped Microgel Colloidal Crystal.

For the first time here, we report a colloid crystal capable of undergoing transition among three states in response to external stimuli. The colloidal crystal was assembled from poly( N-isopropylacrylamide) (PNIPAM) microgel and doped with poly( N-isopropylacrylamide- co-2-acrylamido-phenylboronic acid) (P(NIPAM-2-AAPBA)) microgel. The ordered structure was locked by in situ photopolymerization. Taking advantage of the different responses of the two microgels to external stimuli, defect state can be induced and erased reversibly. Particularly, because the dopant, that is, P(NIPAM-2-AAPBA) microgel sphere, shrinks with increasing glucose concentration, its size changes from larger than the host, that is, PNIPAM microgel sphere, to equal to the host, and finally smaller than the host. Therefore, upon addition of glucose, the crystal undergoes transition from a state with acceptor-type defect, to no defect state, and then to a state with donor-type defect. The transition among the three states is fully reversible. In addition, the response of the doped crystal to glucose is relatively fast.

Zero-order release of polyphenolic drugs from dynamic, hydrogen-bonded LBL films.

Drug carriers capable of releasing drugs at a constant rate, or following zero-order kinetics, can lead to the best control of plasma drug concentration. Here we demonstrated that zero-order release of polyphenolic drugs, including tannic acid, epigallocatechin gallate, proanthocyanidins, and theaflavin-3'-gallate, could be achieved using hydrogen-bonded layer-by-layer films as the drug carrier. The films were fabricated using the polyphenolic drugs as hydrogen donors and polyethylene glycol (PEG) as the hydrogen acceptor. Because the drugs and PEG are bonded with reversible, dynamic hydrogen bonds, the films disintegrate gradually in aqueous solutions, and thus release the drugs into the media. Furthermore, because the PEG polymers have a narrow molecular weight distribution, the films disintegrate and release the polyphenolic drugs at a constant rate. Besides allowing for zero-order release, the drug carrier developed here also provides various ways to tune the drug release rate. The drug release rate increases with decreasing molecular weight of PEG. More importantly, the release rate could be tuned using external stimuli. Increasing the pH or temperature results in accelerated drug release, while the addition of salt retards the drug release.

Photonic Crystals with a Reversibly Inducible and Erasable Defect State Using External Stimuli.

The controlled introduction of artificial extrinsic defects is critical to achieve the functions of photonic crystals. Smart defects capable of responding to external stimuli lead to more advanced applications. Here we report a microgel colloidal crystal with a defect state which could be induced and erased reversibly by external stimuli. The crystal was assembled from PNIPAM microgel and P(NIPAM-AAc) microgel of the same size. The resulting doped crystal does not exhibit a defect state in its stop band because of the similar optical properties of the dopant and the host. By increasing the pH value, however, the dopant P(NIPAM-AAc) spheres swell to a larger size and turn into real defects in the crystal, resulting in the appearance of defect state. Adjusting the pH value back restores the size of the dopant spheres, and thus erases the defect state. Temperature, a second external stimulus, could also be used to induce and erase defect states of the crystal.

Case Report: Technical description and clinical evaluation of three cases of unilateral biportal endoscopic decompression for symptomatic spinal epidural lipomatosis.

Objective: To investigate the clinical characteristics and outcomes of three patients with symptomatic Spinal epidural lipomatosis (SEL) treated using Unilateral Biportal Endoscopic (UBE) surgery. Methods: This report retrospectively analyzed the clinical data of three patients with SEL admitted to our hospital. The analysis covers onset characteristics, clinical manifestations, and the most recent radiologic grading system of neural compression (Manjila classification). Furthermore, it details the decompression accomplished through the application of a minimally invasive UBE surgical technique, specifically targeting the removal of proliferated fat responsible for nerve and spinal cord compression. Results: This technique was performed successfully in 3 patients with SEL. Radiating pain was reduced, and the functional disability and radiologic compression were improved in all three patients. Postoperative spinal instability and surgical complications related to the procedure were not observed. Conclusions: For SEL, timely diagnosis and appropriate intervention can prevent the progression of neurological disability. UBE is a minimally invasive muscle-preserving technique that achieves neural decompression directly by the removal of excessive intraspinal adipose tissue buildup.

Advances in precision gene editing for liver fibrosis: From technology to therapeutic applications.

This review presents a comprehensive exploration of gene editing technologies and their potential applications in the treatment of liver fibrosis, a condition often leading to serious complications such as liver cancer. Through an in-depth review of current literature and critical analysis, the study delves into the intricate signaling pathways underlying liver fibrosis development and examines the promising role of gene editing in alleviating this disease burden. Gene editing technologies offer precise, efficient, and reproducible tools for manipulating genetic material, holding significant promise for basic research and clinical practice. The manuscript highlights the challenges and potential risks associated with gene editing technology. By synthesizing existing knowledge and exploring future perspectives, this study aims to provide valuable insights into the potential of precision gene editing to combat liver fibrosis and its associated complications, ultimately contributing to advances in liver fibrosis research and therapy.

Risk factors for recurrence of differentiated thyroid carcinoma in children and adolescents: A retrospective cohort study.

This study aimed to provide a recent clinical evaluation of the outcome of treatment and the predictors of recurrence for Chinese children and adolescents with differentiated thyroid carcinoma (DTC). This is a retrospective cohort study at the Yunnan Cancer Hospital from May 2002 to August 2021. We analyzed several risk factors related to the recurrence of DTC in children and adolescents. The Chi-square test, Kaplan-Meier log-rank tests, and Cox regression analysis were used in the statistical analysis. A P-value <.05 was considered statistically significant. A total of 103 patients were enrolled, including 68 girls (66.0%) and 35 boys (34.0%) with a median age of 18 years (range: 7-20 years). All enrolled patients received standard treatment. Children (≤14years) tended to have multifocality and higher levels of thyroid imaging reporting and data system, higher pN stage, and higher American Thyroid Association (ATA) pediatric risk compared with adolescents (P < .05). The chief complaints and clinical treatment differed between children and adolescents. During a follow-up of 6 to 239 months (average 74.7 months, median 59 months), all patients survived, but recurrence occurred in 22 patients (22.4%). The disease-free survival rates at 1, 2, 5, and 10 years were 91.2%, 78.4%, 77.1%, and 77.1%, respectively. Univariate Cox regression and log-rank tests showed that positive preoperative thyroglobulin level, bilaterality, extrathyroidal extension, high pT/pN/pM stage, and high ATA pediatric risk were the risk factors for DTC recurrence in children and adolescents. Multivariate Cox regression found that extrathyroidal extension and ATA pediatric risk were independent risk factors for the recurrence of DTC in children and adolescents. Additionally, among the 38 cases with cN0 stage, one who had bilateral, and multifocal thyroid nodules experienced recurrence, while the remaining 37 cases with cN0 stage had no recurrence. In conclusion, compared with adolescents, children present with more highly malignant disease and are more prone to metastasis. The significant risk factors associated with the recurrence of DTC in children and adolescents were positive preoperative thyroglobulin level, bilaterality, high pT/pN/pM stage, extrathyroidal extension, and high ATA pediatric risk, with the latter 2 being independent risk factors. The surgical approach for cN0 patients should be personalized taking into account invasive features.

Xylan Plastic.

The increasing accumulation of plastic waste has brought serious environmental issues. Biodegradable plastics are promising candidates to solve the problem but still remain a scientific challenge. Here, xylan plastic (XP) was fabricated by a strategy of double cross-linking through etherification combined with hot pressing. The mechanical properties, particularly the toughness of XP, were significantly enhanced by the incorporation of chemical and physical cross-linking domains. The tensile strength, toughness, and modulus of XP can reach up to 55 MPa, 2.2 MJ/m3, and 1.7 GPa, respectively, which are superior to most traditional plastics. Dynamic mechanical analysis (DMA) characterizations confirmed that XP is thermoplastic and can be hot formed. Additionally, the reversible hydrogen bond interaction between xylan chains could be simply regulated by water molecules, rendering XP readily transformed and repeatedly reprogrammed into versatile 2D/3D shapes. Moreover, XP showed a low thermal expansion coefficient and excellent optical properties. Cytotoxicity and degradability tests demonstrated that XP had excellent nontoxicity and can be biodegraded in 60 days. This work thus suggests an avenue for the scalable production of high-performance xylan-based plastics, in which the raw material comes from industrial wastes and exhibits great potential in response to plastic pollution.

Up-regulation of Core 1 Beta 1, 3-Galactosyltransferase Suppresses Osteosarcoma Growth with Induction of IFN-γ Secretion and Proliferation of CD8+ T Cells.

AIM: Abnormal glycosylation often occurs in tumor cells. T-synthase (core 1 beta 1,3- galactosyltransferase, C1GALT1, or T-synthase) is a key enzyme involved in O-glycosylation. Although T-synthase is known to be important in human tumors, the effects of T-synthase and T-antigen on human tumor responses remain poorly defined. METHODS: In this study, a T-synthase-specific short hairpin RNA (shRNA) or T-synthase-specific eukaryotic expression vector(pcDNA3.1(+)) was transfected into murine Osteosarcoma LM8 cells to assess the effects of T-synthase on T cells and cytokines. RESULTS: The up-regulation of T-synthase promoted the proliferation of osteosarcoma cells in vitro, but it promoted the proliferation of tumor initially up to 2-3 weeks but showed significant growth inhibitory effect after 3 weeks post-implantation in vivo. Osteosarcoma cells with high T-synthase expression in vitro promoted the proliferation and inhibited the apoptosis of CD8+ T cells. Further, T-synthase upregulation promoted CD8+ T-cell proliferation and the increased production of CD4+ T cell-derived IFN-γ cytokines to induce the increased tumor lethality of CTLs. CONCLUSION: Our data suggest that high T-synthase expression inhibits tumor growth by improving the body's anti-tumor immunity. Therefore, using this characteristic to prepare tumor cell vaccines with high immunogenicity provides a new idea for clinical immunotherapy of osteosarcoma.

Unveiling lignin structures and lignin-carbohydrate complex (LCC) linkages of bamboo (Phyllostachys pubescens) fibers and parenchyma cells.

Bamboo (Phyllostachys pubescens) is an attractive biomass block to develop biorefining industry, however, less emphasis has been placed on elucidating the chemical linkage variations of lignin and LCC between different bamboo cell walls. Here, purified milled wood lignin (MWLp) and lignin-carbohydrate complex (LCC) were isolated from bamboo (Phyllostachys pubescens) fibers (BF) and parenchyma cells (PC), respectively. The variations of structure features and chemical linkages of lignin and LCC were investigated via FT-IR, 2D HSQC NMR, and 31P NMR techniques. 2D HSQC NMR revealed that ß-O-4 alkyl-aryl ether linkages and resinol (ß-ß) substructure were the main substructures in BF-MWLp and PC-MWLp. ß-1 linkages existed in the PC-MWLp (3.18/100 Ar), but not in BF-MWLp. Moreover, tricin, as a flavonoid compound, was only detected in the BF-MWLp. The amount of the syringyl (S) units of PC-MWLp was higher than BF-MWLp. The results indicated that phenyl glycoside (PhGlc) bonds (mainly lignin and xylan) were the predominant chemical linkage type of LCC bonds in BF-LCC and PC-LCC, and the high contents of PhGlc bonds (45.53/100 Ar) were presented in PC. Our finding can provide a reference for the structural variations of lignin and LCC between the different bamboo cell walls.

Clinical Features and Outcomes of Spinal Tuberculosis in Central China.

Purpose: The appropriate management of spinal tuberculosis (TB) is challenging for clinicians and the key to treat spinal TB. Surgery and long course anti-TB chemotherapy may not be necessary to all situations. This study aimed to characterize the clinical features and factors affecting treatment outcomes. Patients and Methods: A retrospective study of patients with spinal TB over a 5-year period at a teaching hospital in central China was conducted. Features of patients with spinal TB who received different treatment modalities and factors associated with patient outcomes at the end of chemotherapy were analyzed. Results: Forty-five patients (21 men and 24 women) with spinal TB were available for analysis. The mean age was 55.39 ± 14.94 years. The most common vertebral area involved was the lumbar (42.2%). The mean number of vertebrae involved was 2.20 ± 0.59. 27 patients (60.0%) received surgical treatment, of which 21 (77.8%) received radical surgical treatment. Thirty-five patients (77.8%) had achieved a favorable status. Statistically, there was no significant correlation between favorable status and surgery, but among 27 surgical patients with spinal tuberculosis, patients receiving radical surgery tended to achieve good prognosis (P = 0.010; odds ratio = 0.053; 95% confidence interval 0.006-0.493). Moreover, there was no significant difference between long course and short course of anti-TB chemotherapy in prognosis in different treatment modalities. Conclusion: Although the patients with spinal TB who needed surgical treatment often got a better prognosis when they had radical surgery, surgery was not actually a factor for the favorable outcomes of patients with spinal TB. In different treatment modalities, there was no additional benefit in longer anti-TB chemotherapy periods.

Identification of potential modifier genes in Chinese patients with Wilson disease.

The mutations in modifier genes may contribute to some inherited diseases including Wilson disease (WD). This study was designed to identify potential modifier genes that contribute to WD. A total of 10 WD patients with single or no heterozygous ATP7B mutations were recruited for whole-exome sequencing (WES). Five hundred and thirteen candidate genes, of which the genetic variants present in at least two patients, were identified. In order to clarify which proteins might be involved in copper transfer or metabolism processes, the isobaric tags for relative and absolute quantitation (iTRAQ) was performed to identify the differentially expressed proteins between normal and CuSO4-treated cell lines. Thirteen genes/proteins were identified by both WES and iTRAQ, indicating that disease-causing variants of these genes may actually contribute to the aberrant copper ion accumulation. Additionally, the c.86C > T (p.S29L) mutation in the SLC31A2 gene (coding CTR2) has a relative higher frequency in our cohort of WD patients (6/191) than reported (0.0024 in gnomAD database) in our healthy donors (0/109), and CTR2S29L leads to increased intracellular Cu concentration and Cu-induced apoptosis in cultured cell lines. In conclusion, the WES and iTRAQ approaches successfully identified several disease-causing variants in potential modifier genes that may be involved in the WD phenotype.

Aldehyde dehydrogenase 1B1 is a potential marker of colorectal tumors.

Colorectal cancer (CRC) is common worldwide. Aldehyde dehydrogenase 1B1 (ALDH1B1), a member of the ALDH1 family, serves as a biomarker for cancer stem cells. We hypothesized that ALDH1B1 expression is associated with colorectal tumors. Immunohistochemistry was used to detect ALDH1B1 expression across a commercial colorectal tissue microarray. The signal intensities of the positively stained tissues were expressed using the mean integrated optical density (mean IOD). We also analyzed ALDH1B1 mRNA expression in the Oncomine database. The associations between ALDH1B1 expression and CRC stage and prognosis were then evaluated using the web-based tools, GEPIA and UALCAN. Analysis of the tissue microarray revealed that the expression of ALDH1B1 was significantly higher in colorectal adenomas and colorectal adenocarcinoma (IOD/area values=0.117±0.070 and 0.168±0.0168, respectively) compared with normal and cancer-adjacent tissues (IOD/area values=0.051±0.028 and 0.068±0.053). For samples collected in the hospital, ALDH1B1 was highly expressed in the adenoma (IOD/area=0.103±0.054) and CRC (IOD/area=0.116±0.059) tissues compared with the cancer-adjacent tissues (IOD/area=0.066±0.024, p<0.05). The expression of ALDH1B1 in tissues from two resources was not found to be significantly associated with CRC stage. In Oncomine, ALDH1B1 mRNA expression was increased in the colorectal tumor tissues compared with the normal colorectal tissues (p=0.024) and its expression was independent of CRC stage and prognosis (p<0.05). Thus, while the protein and mRNA expression of ALDH1B1 suggests that it is a potential marker of colorectal tumors, its expression is independent of CRC stage and prognosis.

Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma.

MarvelD3, a recently identified tight junction membrane protein, could be associated with hepatocellular carcinoma (HCC). We aimed to investigate the role of marvelD3 in Epithelial-Mesenchymal Transition (EMT) and migration of HCC and explore the underlying molecular mechanisms. First, we assessed marvlD3 expression in HCC and normal liver tissues and found loss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. Second, we detected that marvelD3 was downregulated in HCC cells with transforming growth factor ß1 and snail/slug-induced EMT. Finally, we analyzed expression of marvelD3 protein was significantly associated with EMT and the NF-κB signaling pathway. Our study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells along with inhibiting NF-κB signaling pathway.Abbreviations:HCC, Hepatocellular carcinoma; TJ, Tight junction; MARVEL, MAL and related proteins for vesicle trafficking and membrane link; EMT, Epithelial-mesenchymal transition; NF-κB, Nuclear factor kappa B; TAMPs, Tight junction-associated marvel proteins; TGF-ß1, Transforming growth factor-ß1; MMP9, matrix metallopeptidase 9; RT-PCR, Real-time PCR; IHC, Immunohistochemistry; IF, Immunofluorescence.