Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome.

AIM: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. METHODS AND RESULTS: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition. CONCLUSION: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.

Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums.

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This platform offers highly tunable and predictable conjugation and cleavage by rationally estimating the electron effect on the nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling were achieved based on this facile pyridinium-thiol-exchange protocol.

Performance of Artificial Intelligence Content Detectors Using Human and Artificial Intelligence-Generated Scientific Writing.

BACKGROUND: Few studies have examined the performance of artificial intelligence (AI) content detection in scientific writing. This study evaluates the performance of publicly available AI content detectors when applied to both human-written and AI-generated scientific articles. METHODS: Articles published in Annals of Surgical Oncology (ASO) during the year 2022, as well as AI-generated articles using OpenAI's ChatGPT, were analyzed by three AI content detectors to assess the probability of AI-generated content. Full manuscripts and their individual sections were evaluated. Group comparisons and trend analyses were conducted by using ANOVA and linear regression. Classification performance was determined using area under the curve (AUC). RESULTS: A total of 449 original articles met inclusion criteria and were evaluated to determine the likelihood of being generated by AI. Each detector also evaluated 47 AI-generated articles by using titles from ASO articles. Human-written articles had an average probability of being AI-generated of 9.4% with significant differences between the detectors. Only two (0.4%) human-written manuscripts were detected as having a 0% probability of being AI-generated by all three detectors. Completely AI-generated articles were evaluated to have a higher average probability of being AI-generated (43.5%) with a range from 12.0 to 99.9%. CONCLUSIONS: This study demonstrates differences in the performance of various AI content detectors with the potential to label human-written articles as AI-generated. Any effort toward implementing AI detectors must include a strategy for continuous evaluation and validation as AI models and detectors rapidly evolve.

Nerve Growth Factor/Tyrosine Kinase A Receptor Pathway Enhances Analgesia in an Experimental Mouse Model of Bone Cancer Pain by Increasing Membrane Levels of δ-Opioid Receptors.

BACKGROUND: The role of nerve growth factor (NGF)/tyrosine kinase A receptor (TrKA) signaling, which is activated in a variety of pain states, in regulating membrane-associated δ-opioid receptor (mDOR) expression is poorly understood. The hypothesis was that elevated NGF in bone cancer tumors could upregulate mDOR expression in spinal cord neurons and that mDOR agonism might alleviate bone cancer pain. METHODS: Bone cancer pain (BCP) was induced by inoculating Lewis lung carcinoma cells into the femoral marrow cavity of adult C57BL/6J mice of both sexes. Nociceptive behaviors were evaluated by the von Frey and Hargreaves tests. Protein expression in the spinal dorsal horn of animals was measured by biochemical analyses, and excitatory synaptic transmission was recorded in miniature excitatory synaptic currents. RESULTS: The authors found that mDOR expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.18 ± 0.01 g vs. mean ± SD: 0.13 ± 0.01 g, n = 4, P < 0.001) and that administration of the DOR agonist deltorphin 2 (Del2) increased nociceptive thresholds (Del2 vs. vehicle, median [25th, 75th percentiles]: 1.00 [0.60, 1.40] g vs. median [25th, 75th percentiles]: 0.40 [0.16, 0.45] g, n = 10, P = 0.001) and reduced miniature excitatory synaptic current frequency in lamina II outer neurons (Del2 vs. baseline, mean ± SD: 2.21 ± 0.81 Hz vs. mean ± SD: 2.43 ± 0.90 Hz, n = 12, P < 0.001). Additionally, NGF expression was increased in BCP mice (BCP vs. sham, mean ± SD: 0.36 ± 0.03 vs. mean ± SD: 0.16 ± 0.02, n = 4, P < 0.001), and elevated NGF was associated with enhanced mDOR expression via TrKA signaling. CONCLUSIONS: Activation of mDOR produces analgesia that is dependent on the upregulation of the NGF/TrKA pathway by increasing mDOR levels under conditions of BCP in mice.

Chiral Phosphine Ligands of COAP and SKP Switched Regiodivergent Asymmetric Allylic Alkylation of MBH Adducts.

The palladium-catalyzed highly regioselective asymmetric allylic alkylation of 3'-indolyl-3-oxindole derivatives with Morita-Baylis-Hillman (MBH) carbonates was developed to facilely construct chiral 3,3'-bisindole derivatives under mild reaction conditions. The regioselectivity (α/γ) of MBH carbonates was efficiently switched in the presence of chiral oxalamide phosphine or spiroketal-based diphosphine/Pd(0) complexes as a chiral catalyst. A series of multifunctional 3,3'-bisindole derivatives with all-carbon quaternary stereogenic centers were obtained in high yields with good to excellent enantio-, diastereo-, and regioselectivity. The present process is endowed with some salient features such as broad substrate scope, N-protecting group-free, excellent stereoselectivity, as well as adjustable regioselectivity.

Enhancement Effect Induced by the Second Metal to Promote Ozone Catalytic Oxidation of VOCs.

It is a promising research direction to develop catalysts with high stability and ozone utilization for low-temperature ozone catalytic oxidation of VOCs. While bimetallic catalysts exhibit excellent catalytic activity compared with conventional single noble metal catalysts, limited success has been achieved in the influence of the bimetallic effect on the stability and ozone utilization of metal catalysts. Herein, it is necessary to systematically study the enhancement effect in the ozone catalytic reaction induced by the second metal. With a simple continuous impregnation method, a platinum-cerium bimetallic catalyst is prepared. Also highlighted are studies from several aspects of the contribution of the second metal (Ce) to the stability and ozone utilization of the catalysts, including the "electronic effect" and "geometric effect". The synergistic removal rate of toluene and ozone is nearly 100% at 30 °C, and it still shows positive stability after high humidity and a long reaction time. More importantly, the instructive significance, which is the in-depth knowledge of enhanced catalytic mechanism of bimetallic catalysts resulting from a second metal, is provided by this work.

A GSH-resistant FK228 analogue containing a stable disulfide bond.

FK228 is a potent natural pan HDAC inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphoma as well as peripheral T-cell lymphoma. It is generally believed that the mechanism of FK228 acting on HDACs is by reducing its disulfide bond after entering the cell, and the dithiol group may chelate with Zn2+ and form a weak reversible covalent bond with cysteine in the catalytic pocket of HDACs, therefore inhibiting the activity of HDACs. However, due to the weak stability of the disulfide bond in FK228, it has been difficult to obtain direct evidence for the above conjecture. Thus, improving the stability of the FK228 disulfide bond will help to explore the exact mechanism of FK228. In this study, based on the stability and target-induced covalent properties of the Cysteine-Penicillamine (Cys-Pen) disulfide bond reported previously, the Pen was introduced into the modification of FK228. Specifically, the d-Cys in FK228 was replaced by d-Pen, the total synthetic pathway was optimized, and the novel synthetic FK228 analogue (FK-P) stability was verified. FK-P can also be used as a new drug molecule in the future to participate in the research of related biological mechanisms or the treatment of diseases.

Dynamic modulation of multicolor upconversion luminescence of Er3+ via excitation pulse width.

Lanthanide-doped upconversion (UC) luminescent materials display multicolor emissions, making them ideal for a variety of applications, such as multi-channel biological imaging, fluorescence encryption, anti-counterfeiting, and 3D display. Manipulating the UC emissions of the luminescent materials with a fixed composition is crucial for their applications. Herein, we propose a facile strategy to achieve pulse-width-dependent multicolor UC emissions in NaYF4:Yb/Er/Tm nanocrystals. Upon excitation with a 980 nm continuous-wave laser diode, Er3+ ions in NaYF4:20%Yb,15%Er,1%Tm nanocrystals exhibited UC emissions with a red-to-green (R/G) ratio of 11.3. Nevertheless, by employing a 980 nm pulse laser with pulse widths from 0.1 to 10 ms, the UC R/G ratio can be easily adjusted from 0.9 to 11.3, resulting in continuous and remarkable color transformation from green, yellow, orange, to red. By virtue of the dynamic luminescence color variation of these NaYF4:20%Yb,15%Er,1%Tm nanocrystals, we demonstrated their potential applications in the areas of anti-counterfeiting and information encryption. These findings provide deep insights into the excited-state dynamics and energy transfer of Er3+ in NaYF4:Yb/Er/Tm nanocrystals upon 980 nm pulse excitation, which may pave the way for designing multicolor UC materials toward versatile applications.

Three Cases of Non-Tuberculosis Mycobacterium Skin Infection Outbreak in Beauty Institutions.

BACKGROUND: From June 2021 to July 2021, our hospital confirmed 3 cases of Mycobacterium infection in skin abscesses. All 3 patients underwent thread embedding and weight loss surgery at the same informal beauty institution, with a history of silk protein injection. None of the patients had any other underlying diseases or surgical history. Symptoms and signs show that the disease is acute and the course of the disease is short. All patients have found subcutaneous masses in different parts of the body. In most cases, the masses show redness and swelling, and some of the masses are accompanied by tenderness, wave sensation, and rupture. After some of the masses rupture, purulent secretions can be seen. METHODS: The pus secreted by the skin lesions of the three patients were cultured to a single bacterium, which was identified by MALDI-TOF MS. Multiple locus sequence typing (MLST) was performed using three specific genes (hsp65, rpoB, and secA1) and seven housekeeping genes (argH, cya, glpK, gnd, murC, pta, and purH). The results were queried through the MLST database of Mycobacterium abscess. RESULTS: All three strains of bacteria were Mycobacterium abscess type ST279 massiliense subtype. Three antibacterial drugs including cefmetazole, amikacin, and clarithromycin were administered in combination with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). After 3 - 6 months, there was no obvious redness or swelling in the surrounding tissues of the wound, and no obvious purulent secretions were observed. All patients were cured and discharged from the hospital. After a follow-up of six months, there was no recurrence of the lesions. CONCLUSIONS: Medical institutions must strictly follow infection control guidelines and take preventive measures to prevent such incidents from happening again. ALA-PDT as a combination therapy for nontuberculous Mycobacterium (NTM) skin infections can improve treatment efficacy and shorten antibiotic usage time.

Lumbar Spine Infected by Mycobacterium tuberculosis and Cryptococcus neoformans: a Rare Case Report.

BACKGROUND: In July 2023, our hospital confirmed one case of lumbar spine infected complicated by Mycobacterium tuberculosis and Cryptococcus neoformans. The patient was admitted due to lower back pain for 1 year and a hard lump for 3 months. Symptoms and signs: Dressing can be seen fixed on the lower back, with severe bleeding. When the dressing is removed, a hard and protruding lump with a size of 6 cm x 8 cm, a sinus tract can be seen near the mass, with a slightly red wound and a sinus depth of about 3 cm. Light red fluid can be seen flowing out. There are no symptoms such as redness, swelling, or heat in the rest of the lower back, and the patient has no other underlying diseases or surgical history. METHODS: Lumbar magnetic resonance imaging and lumbar CT examination; Percutaneous puncture lumbar vertebral biopsy was performed, and the biopsy tissue was subjected to pathological examination, mNGS (metagenomic next-generation sequencing), and acid-fast staining; Extract pus from the lump for fungal culture and ink staining, and identify the fungi through MALDI-TOF MS. RESULTS: Bone destruction and bone marrow edema in the L5 vertebral body, compression of the spinal canal at the L5 vertebral body level; The pathological results of the biopsy tissue indicate granulomatous lesions. The acid-fast staining of the tissue is positive, and the mNGS of the tissue indicates infection with Mycobacterium tuberculosis. A single fungus was cultured from pus and identified by MALDI-TOF MS as Cryptococcus neoformans. Clinically, isoniazid 0.3 g ivgtt + rifampicin 0.45 g qd po + ethambutol 0.25 g qd po + pyrazinamide 0.75 g qd po + fluconazole 0.3 g qd po was administered for treatment. After 11 days, there was slight pain at the incision site, and the original symptoms were significantly relieved. The wound dressing was fixed in place, dry and without obvious exudation. Improved and discharged, followed up for 3 months with no recurrence of the lesion. CONCLUSIONS: mNGS is an effective identification technique that can be used to accurately diagnose suspected infection cases. MALDI-TOF MS has significant advantages over traditional detection methods in shortening detection time. This case achieved satisfactory treatment results for patients through a reasonable treatment plan, which is of great significance for exploring the diagnosis and treatment of similar disease infections.

Pathological Characteristics and Classification of Unstable Coronary Atherosclerotic Plaques.

Important forensic diagnostic indicators of sudden death in coronary atherosclerotic heart disease, such as acute or chronic myocardial ischemic changes, sometimes make it difficult to locate the ischemic site due to the short death process, the lack of tissue reaction time. In some cases, the deceased died of sudden death on the first-episode, resulting in difficulty for medical examiners to make an accurate diagnosis. However, clinical studies on coronary instability plaque revealed the key role of coronary spasm and thrombosis caused by their lesions in sudden coronary death process. This paper mainly summarizes the pathological characteristics of unstable coronary plaque based on clinical medical research, including plaque rupture, plaque erosion and calcified nodules, as well as the influencing factors leading to plaque instability, and briefly describes the research progress and technique of the atherosclerotic plaques, in order to improve the study on the mechanism of sudden coronary death and improve the accuracy of the forensic diagnosis of sudden coronary death by diagnosing different pathologic states of coronary atherosclerotic plaques.

Single-cell landscape and clinical outcomes of infiltrating B cells in colorectal cancer.

B cells constitute a major component of infiltrating immune cells in colorectal cancer (CRC). However, the characteristics of B cells and their clinical significance remain unclear. In this study, using single-cell RNA sequencing and multicolour immunofluorescence staining experiments, we identified five distinct subtypes of B cells with their marker genes, distribution patterns and functional properties in the CRC tumour microenvironment. Meanwhile, we found a higher proportion of IgG plasma cells in tumour sites than that in adjacent normal mucosal tissues. In addition, the CXCL13-producing CD8+ T cells in the tumour tissues could promote the formation of tertiary lymphoid structure (TLS) B cells, and the CCL28-CCR10 axis is pivotal for IgG plasma cell migration from the periphery of TLSs to the tumour stroma. Finally, we identified four distinct colon immune classes (CICs: A-D) and found that CD20+ B cells within TLSs were enriched in one immune-inflamed or hot tumour group (CIC D). This B cell-rich group, which was characterized by strong antigen presentation, IgG plasma cells accumulation, microsatellite instability-high (MSI-H) and high tumour mutation burden (TMB-H), as well as immunosuppressive property in particular, might become a potential predictive biomarker for future immunotherapy. Additionally, in an immunotherapy cohort, patients with the enrichment of B cells and TLSs were demonstrated to obtain significant therapeutic advantages. Together, our findings provide the detailed landscape of infiltrating B cells and their potential clinical significance in CRC.

Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach.

Proteolysis Targeting Chimera (PROTAC) technology represents a promising new approach for target protein degradation using a cellular ubiquitin-proteasome system. Recently, we developed a split-and-mix nanoplatform based on peptide self-assembly, which could serve as a self-adjustable platform for multifunctional applications. However, the lower drug efficacy limits further biomedical applications of peptide-based SM-PROTAC. In this study, we develop a novel split-and-mix PROTAC system based on liposome self-assembly (LipoSM-PROTAC), concurrent with modification of FA (folate) to enhance its tumor-targeting capabilities. Estrogen receptors (ERα) were chosen as the protein of interest (POI) to validate the efficacy of Lipo degraders. Results demonstrate that this PROTAC can be efficiently and selectively taken up into the cells by FA receptor-positive cells (FR+) and degrade the POI with significantly reduced concentration. Compared to the peptide-based SM-PROTACs, our designed LipoSM-PROTAC system could achieve therapeutic efficacy with a lower concentration and provide opportunities for clinical translational potential. Overall, the LipoSM-based platform shows a higher drug efficacy, which offers promising potential applications for PROTAC and other biomolecule regulations.

Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer.

Regulatory B cells (Bregs) contribute to tumor immunosuppression. However, how B cells acquire their regulatory features in tumors remain unclear. Exosomes are important messengers that transmit tumor information to remodel tumor immunity. Here we revealed that tumor-derived exosomes drive Bregs to suppress anti-tumor immunity by delivering long non-coding RNAs (lncRNAs). HOTAIR was screened by lncRNA profiling in both colorectal cancer (CRC)-derived exosomes and infiltrating B cells. Tumor-derived HOTAIR polarized B cells toward a regulatory feature marked by programmed cell death-ligand 1 (PDL1) in CRC, and induced PDL1+ B cells to suppress CD8+ T cell activity. Exosomal HOTAIR bound to and protected pyruvate kinase M2 (PKM2) against ubiquitination degradation, resulting in STAT3 activation and PDL1 expression. Results from CRC patients showed a positive correlation between exosomal HOTAIR and tumor-infiltrating PDL1+ B cells. These findings reveal how B cells acquire PDL1-dominant regulatory feature in CRC, implying the clinical significance of exosomal therapy targeting HOTAIR.

Association of dietary inflammatory index with helicobacter pylori infection and mortality among US population.

BACKGROUND: Limited research has been conducted on the potential relationship between the dietary inflammation index (DII) and mortality, particularly in individuals with Helicobacter pylori (H. pylori) infection. This study aimed to investigate the association between the DII and H. pylori infection, as well as their respective impacts on all-cause mortality in a cohort of individuals with or without H. pylori infection. METHODS: Data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) were utilized for this study, with a final of 4370 participants included. Both univariable and multivariable-adjusted logistic regression analyses were employed to explore the relationship between H. pylori infection and pertinent covariates. Cox regression analysis, as well as restricted regression cubic spline analysis, were utilized to assess the association between DII and all-cause mortality among individuals with or without H. pylori infection. RESULTS: The findings demonstrated a positive correlation between DII scores and H. pylori infection, even after adjusting for potential confounding factors. Moreover, higher DII scores were significantly associated with an elevated risk of mortality exclusively in individuals with H. pylori infection, while no such association was observed in the uninfected population. Additional analysis using restricted cubic spline modeling revealed a positive linear relationship between DII scores as a continuous variable and the adjusted risk of all-cause mortality specifically in H. pylori-infected patients. CONCLUSION: The results of this study indicated that DII was positively correlated with an increased risk of H. pylori infection and was associated with a heightened risk of all-cause mortality solely in individuals with H. pylori infection. Consequently, DII might serve as a useful tool for risk stratification in the H. pylori-infected population among U.S. adults. Further research is warranted to elucidate the underlying mechanisms and potential clinical implications of these findings.

COAP-Pd Catalyzed Asymmetric Allylic Alkylation of Azlactones with MBH Carbonates: Access to Unnatural α-Quaternary Stereogenic Glutamic Acid Derivatives.

A palladium-catalyzed regioselective and asymmetric allylic alkylation of azlactones with MBH carbonates has been developed with chiral oxalamide-phosphine ligands. The corresponding reaction afforded a range of optically active γ-arylidenyl glutamic acid derivatives bearing an α-chiral quaternary stereocenter in good yields with excellent linear regio- and high enantioselectivity. This protocol furnishes an alternative approach for the construction of enantio-enriched unnatural α-amino acid derivatives.

ß-Catenin-treated peptides effectively inhibit the proliferation of colorectal cancer.

To verify the inhibitory mechanism of ß-catenin-designed peptides in colorectal cancer(CRC) tumors, the following experiments were performed. In vitro colony formation, Transwell assays, and flow cytometry were performed to assess the biological effects of designed peptides (F18KD, F20A4-7k, F20A4-10k, and F20A3-9k + F20A4-10k + F20A5-9k) in HT-29 cells. In vivo xenograft experiments were performed and treated with peptides. Next, tumors were subjected to Hematoxylin and eosin staining (HE), immunohistochemical, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays to evaluate the inhibitory effect of peptides on tumors. ß-Catenin levels were quantified via western blotting (WB) and quantitative real-time polymerase chain reaction, and ß-catenin was located using confocal laser scanning microscopy. T-cell factor-4 (TCF-4), C-myc, and CCND1 levels were quantified via WB. Results were obtained as following. First, the peptides reduced viability, migration, and invasion; promoted apoptosis; and stabilized the S phase of HT-29 cells. Second, peptides suppressed tumor growth and downregulated the expression of CD34, vascular endothelial growth factor, and ß-catenin in tumors. Furthermore, we found that peptides downregulated ß-catenin expression in both the cytoplasm and nucleus; TCF-4, C-myc, and CCND1 expression was also downregulated. Notably, ß-catenin-targeting peptides had a better inhibitory effect on CRC than non-ß-catenin-target peptides, and a combination of peptides exerted a more potent inhibitory effect on CRC than single peptides. It suggested that ß-Catenin-targeting peptides promote apoptosis in CRC tumors by inhibiting activation of the Wnt/ß-catenin pathway.