ABHD6 suppresses colorectal cancer progression via AKT signaling pathway.

Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.

Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics.

In recent years, the tumour microenvironment (TME) of solid tumours has attracted more and more attention from researchers, especially those non-tumour components such as immune cells. Infiltration of various immune cells causes tumour immune microenvironment (TIME) heterogeneity, and results in different therapeutic effects. Accumulating evidence showed that DNA methylation plays a crucial role in remodelling TIME and is associated with the response towards immune checkpoint inhibitors (ICIs). During carcinogenesis, DNA methylation profoundly changes, specifically, there is a global loss of DNA methylation and increased DNA methylation at the promoters of suppressor genes. Immune cell differentiation is disturbed, and exclusion of immune cells from the TME occurs at least in part due to DNA methylation reprogramming. Therefore, pharmaceutical interventions targeting DNA methylation are promising. DNA methyltransferase inhibitors (DNMTis) enhance antitumor immunity by inducing transcription of transposable elements and consequent viral mimicry. DNMTis upregulate the expression of tumour antigens, mediate immune cells recruitment and reactivate exhausted immune cells. In preclinical studies, DNMTis have shown synergistic effect when combined with immunotherapies, suggesting new strategies to treat refractory solid tumours.

Sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions and synthesis of 5-(3-oxindolyl)oxazoles.

Herein, we report a facile synthesis of 5-(3-oxindolyl)oxazole derivatives via a sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction exhibits good functional group tolerance with 30 examples of structurally diverse products prepared with moderate to good efficiencies (up to 88% yield), thus providing a generally applicable route to the biologically important 5-(3-indolyl)oxazole structural motifs. Key to the success of this sequential one-pot strategy is the utilization of DBU as a base to promote the isomerisation process of the corresponding intermediate annulation products.

Ag nanoparticle modified porous Si microspheres as high-performance anodes for Li-ion batteries.

This study aimed to address the challenges associated with silicon (Si) anode materials in Li-ion batteries, such as their large volume effect and poor electrical conductivity. To overcome these limitations, a novel composite microsphere called pSi/Ag was developed using quartz waste through a combination of high-energy ball-milling, spray drying, and magnesiothermic reduction techniques. The morphology and structure of the pSi/Ag composite were thoroughly characterized using various methods, including X-ray diffraction, field-emission scanning electron microscopy, and transmission electron microscopy. The results revealed that the Ag nanoparticles were uniformly dispersed within the porous micron-sized Si sphere particles, leading to enhanced electrochemical performance compared to pure porous silicon that did not undergo the spray drying process. The use of micron-sized Si prevented the excessive formation of the solid electrolyte interphase film, and the pSi/Ag-5 anode, prepared with 5 wt% AgNO3 as a precursor, demonstrated an impressive initial Coulombic efficiency of 92.8%. Moreover, a high specific capacity of 1251.4 mA h g-1 over 300 cycles at a current density of 4000 mA g-1 was attributed to the improved conductivity provided by the Ag nanoparticles in the Si matrix. The straightforward synthesis method employed in this study to produce pSi/Ag presents a promising approach for the future development of high-performance silicon anodes in Li-ion batteries.

Synthesis of α-Quaternary ß-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3 )-C(sp2 ) Cross-Coupling with Organoboronate Esters.

The copper-catalyzed enantioconvergent radical C(sp3 )-C(sp2 ) cross-coupling of tertiary α-bromo-ß-lactams with organoboronate esters could provide the synthetically valuable α-quaternary ß-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp3 )-C(sp2 ) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp3 )-P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.

Cascade Ring-Opening/Cyclization Reaction of Spiro(nitrocyclopropane)oxindoles with Huisgen Zwitterions and Synthesis of Pyrazolo[3,4-b]indoles.

Herein, we report a ring-opening/cyclization cascade reaction of spiro(nitrocyclopropane)oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction provides an array of polyfunctionalized pyrazolo[3,4-b]indole derivatives in moderate-to-excellent yields and generally high stereoselectivities with a broad substrate scope. The annulation products obtained from di-tert-butyl azodicarboxylates can be readily transformed into aromatic-substituted pyrazolo[3,4-b]indoles in moderate yields upon treatment with trifluoroacetic acid, thus providing a new entry to this fused heterocycle skeleton. In terms of nitro-substituted donor-acceptor cyclopropane, this work significantly broadens the substrate scope for the annulation reaction of nitrocyclopropanes and HZs. The dual roles of the oxindole moiety in the ring opening of cyclopropane and a plausible mechanism for the cascade reaction are also discussed.

Solid Oxide Cells with Phase-Inversion Tape-Casted Hydrogen Electrode and SrSc0.175Nb0.025Co0.8O3-δ Oxygen Electrode for High-Performance Reversible Power Generation and Hydrogen Production.

Solid oxide cells (SOCs) have been considered as a promising energy conversion and storage device. However, state-of-the-art cells' practical application with conventionally fabricated Ni-(Y2O3)0.08(ZrO2)0.92 (YSZ) cermet hydrogen electrode and La0.8Sr0.2MnO3 perovskite oxygen electrode is strongly limited by the unsatisfactory performance. Instead, new advances in cell materials and fabrication techniques that can lead to significant performance enhancements are urgently demanded. Here, we report a high-performance reversible SOC that consisted of a combination of SrSc0.175Nb0.025Co0.8O3-δ (SSNC) and phase-inversion tape-casted Ni-YSZ, which served as the oxygen and hydrogen electrode, respectively. The hydrogen electrode synthesized from phase-inversion tape-casting showed a high porosity of 60.8%, providing sufficient active sites for hydrogen oxidation in the solid oxide fuel cell (SOFC) mode and H2O electrolysis in the solid oxide electrolysis cell (SOEC) mode. Accordingly, it was observed that the maximum power density of 2.3 W cm-2 was attained at 750 °C in SOFC mode and a current density of -1.59 A cm-2 was obtained at 1.3 V in SOEC mode. Hence, these results reveal that the simultaneous optimization of oxygen and hydrogen electrodes is a pragmatic strategy that improves the performance of SOCs, which may significantly accelerate the commercialization of such an attractive technology.

Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp3 )-H/C(sp)-H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands.

The intermolecular asymmetric radical oxidative C(sp3 )-C(sp) cross-coupling of C(sp3 )-H bonds with readily available terminal alkynes is a promising method to forge chiral C(sp3 )-C(sp) bonds because of the high atom and step economy, but remains underexplored. Here, we report a copper-catalyzed asymmetric C(sp3 )-C(sp) cross-coupling of (hetero)benzylic and (cyclic)allylic C-H bonds with terminal alkynes that occurs with high to excellent enantioselectivity. Critical to the success is the rational design of chiral oxazoline-derived N,N,P(O)-ligands that not only tolerate the strong oxidative conditions which are requisite for intermolecular hydrogen atom abstraction (HAA) processes but also induce the challenging enantiocontrol. Direct access to a range of synthetically useful chiral benzylic alkynes and 1,4-enynes, high site-selectivity among similar C(sp3 )-H bonds, and facile synthesis of enantioenriched medicinally relevant compounds make this approach very attractive.

Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic Alkyl Bromides with Azole C(sp2 )-H Bonds.

The development of enantioconvergent cross-coupling of racemic alkyl halides directly with heteroarene C(sp2 )-H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp2 )-H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp2 )-H bond and the involvement of alkyl radical species under the reaction conditions.

Facile synthesis of spirooxindole-pyrazolines and spirobenzofuranone-pyrazolines and their fungicidal activity.

Novel spirooxindole-pyrazolines and spirobenzofuranone-pyrazolines have been synthesized in good to excellent yields via the annulation reactions of the corresponding 3-alkylideneoxindoles and 3-alkylidenebenzofuranones with Huisgen zwitterions. The preliminary bioassay demonstrated that some of the spiropyrazolines possess good in vitro fungicidal activity against several crop fungi at a concentration of 50 µg mL(-1).

Diastereoselective synthesis of functionalized spirocyclopropyl oxindoles via P(NMe2)3-mediated reductive cyclopropanation.

A P(NMe2)3-mediated reductive cyclopropanation reaction of α-keto esters or amides with isatin-derived alkenes has been developed, providing efficient and diastereoselective synthesis of highly functionalized spirocyclopropyl oxindoles bearing two all-carbon quaternary centers. This reaction also represents a complementary and nonmetal-involving protocol for the challenging cyclopropanation of electron-deficient alkenes.

A Review on Autism Spectrum Disorder Screening by Artificial Intelligence Methods.

PURPOSE: With the increasing prevalence of autism spectrum disorders (ASD), the importance of early screening and diagnosis has been subject to considerable discussion. Given the subtle differences between ASD children and typically developing children during the early stages of development, it is imperative to investigate the utilization of automatic recognition methods powered by artificial intelligence. We aim to summarize the research work on this topic and sort out the markers that can be used for identification. METHODS: We searched the papers published in the Web of Science, PubMed, Scopus, Medline, SpringerLink, Wiley Online Library, and EBSCO databases from 1st January 2013 to 13th November 2023, and 43 articles were included. RESULTS: These articles mainly divided recognition markers into five categories: gaze behaviors, facial expressions, motor movements, voice features, and task performance. Based on the above markers, the accuracy of artificial intelligence screening ranged from 62.13 to 100%, the sensitivity ranged from 69.67 to 100%, the specificity ranged from 54 to 100%. CONCLUSION: Therefore, artificial intelligence recognition holds promise as a tool for identifying children with ASD. However, it still needs to continually enhance the screening model and improve accuracy through multimodal screening, thereby facilitating timely intervention and treatment.

Revealing the gut microbiome mystery: A meta-analysis revealing differences between individuals with autism spectrum disorder and neurotypical children.

The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition in ASD and the effectiveness of probiotics are unclear. To address this, we performed a thorough meta-analysis of 28 studies spanning PubMed, PsycINFO, Web of Science, Scopus, and MEDLINE, involving 1,256 children with ASD and 1042 neurotypical children, up to February 2024. Using Revman 5.3, we analyzed the relative abundance of 8 phyla and 64 genera. While individuals with ASD did not exhibit significant differences in included phyla, they exhibited elevated levels of Parabacteroides, Anaerostipes, Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Lachnoclostridium, Catenibacterium, and Collinsella along with reduced percentages of Barnesiella, Odoribacter, Paraprevotella, Blautia, Turicibacter, Lachnospira, Pseudomonas, Parasutterella, Haemophilus, and Bifidobacterium. Notably, discrepancies in Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Catenibacterium, Odoribacter, and Bifidobacterium persisted even upon systematic exclusion of individual studies. Consequently, the GM of individuals with ASD demonstrates an imbalance, with potential increases or decreases in both beneficial and harmful bacteria. Therefore, personalized probiotic interventions tailored to ASD specifics are imperative, rather than a one-size-fits-all approach.

Application of Single-Cell Sequencing Technology in Research on Colorectal Cancer.

Colorectal cancer (CRC) is the third most prevalent and second most lethal cancer globally, with gene mutations and tumor metastasis contributing to its poor prognosis. Single-cell sequencing technology enables high-throughput analysis of the genome, transcriptome, and epigenetic landscapes at the single-cell level. It offers significant insights into analyzing the tumor immune microenvironment, detecting tumor heterogeneity, exploring metastasis mechanisms, and monitoring circulating tumor cells (CTCs). This article provides a brief overview of the technical procedure and data processing involved in single-cell sequencing. It also reviews the current applications of single-cell sequencing in CRC research, aiming to enhance the understanding of intratumoral heterogeneity, CRC development, CTCs, and novel drug targets. By exploring the diverse molecular and clinicopathological characteristics of tumor heterogeneity using single-cell sequencing, valuable insights can be gained into early diagnosis, therapy, and prognosis of CRC. Thus, this review serves as a valuable resource for identifying prognostic markers, discovering new therapeutic targets, and advancing personalized therapy in CRC.

Recruitment of ubiquitin E2 enzymes is determined jointly by the U-box domains and substrates of E3 ligases.

Ubiquitination is a cascade reaction involving E1, E2, and E3 enzymes. The orthogonal ubiquitin transfer (OUT) method has been previously established to identify potential substrates of E3 ligases. In this study, we verified the ubiquitination of five substrates mediated by the E3 ligases CHIP and E4B. To further explore the activity of U-box domains of E3 ligases, two mutants with the U-box domains interchanged between CHIP and E4B were generated. They exhibited a significantly reduced ubiquitination ability. Additionally, different E3s recruited similar E2 ubiquitin-conjugating enzymes when ubiquitinating the same substrates, highlighting that U-box domains determined the E2 recruitment, while the substrate determined the E2 selectivity. This study reveals the influence of substrates and U-box domains on E2 recruitment, providing a novel perspective on the function of U-box domains of E3 ligases.

Initial therapeutic evidence of a borosilicate bioactive glass (BSG) and Fe3O4 magnetic nanoparticle scaffold on implant-associated Staphylococcal aureus bone infection.

Implant-associated Staphylococcus aureus (S. aureus) osteomyelitis is a severe challenge in orthopedics. While antibiotic-loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe3O4) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well-established implant-related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo. RNA transcriptome sequencing demonstrated that BSG + 5%Fe3O4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5%Fe3O4 upregulated gene expression of NOD-like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro. Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-ß1 and IL-1Ra) and downregulation of pro-inflammatory genes (IL-6 and IL-1ß) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe3O4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

Prognostic Biomarker SPOCD1 and Its Correlation with Immune Infiltrates in Colorectal Cancer.

The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that the expression level of SPOCD1 was elevated in CRC, which was generally associated with shortened survival time and poor clinical indexes, including advanced T, N, and pathologic stages. Multivariate Cox regression analysis showed that elevated SPOCD1 expression was an independent factor for poor prognosis in CRC patients. Functional enrichment analysis of SPOCD1 and its co-expressed genes revealed that SPOCD1 could act as an oncogene by regulating gene expression in essential functions and pathways of tumorigenesis, such as extracellular matrix organization, chemokine signaling pathways, and calcium signaling pathways. In addition, immune cell infiltration results showed that SPOCD1 expression was associated with various immune cells, especially macrophages. Furthermore, our findings suggested a possible function for SPOCD1 in the polarization of macrophages from M1 to M2 in CRC. In conclusion, SPOCD1 is a promising diagnostic and prognostic marker for CRC, opening new avenues for research and treatment.

L3MBTL3 Is a Potential Prognostic Biomarker and Correlates with Immune Infiltrations in Gastric Cancer.

Recent research has linked lethal (3) malignant brain tumor-like 3 (L3MBTL3) to cancer aggressiveness and a dismal prognosis, but its function in gastric cancer (GC) is unclear. This research investigated the association between L3MBTL3 expression and clinicopathological characteristics of GC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that L3MBTL3 expression was upregulated in malignant GC tissues, which was associated with a shortened survival time and poor clinicopathological characteristics, including TNM staging. A functional enrichment analysis including GO/KEGG and GSEA illustrated the enrichment of different L3MBTL3-associated pathways involved in carcinogenesis and immune response. In addition, the correlations between L3MBTL3 and tumor-infiltrating immune cells were determined based on the TIMER database; the results showed that L3MBTL3 was associated with the immune infiltration of macrophages and their polarization from M1 to M2. Furthermore, our findings suggested a possible function for L3MBTL3 in the regulation of the tumor immune microenvironment of GC. In summary, L3MBTL3 has diagnostic potential, and it also offers new insights into the development of aggressiveness and prognosis in GC.