Expression of CD44 is regulated by ELF3 in 5-FU treated colorectal cancer cells.

The development of chemoresistance in colorectal cancer (CRC) cells was usually thought to be inevitable as a result of continuing exposure to chemotherapeutic drugs. The existence of cancer stem cells (CSCs) within CRC tissues was recently suggested to play importance roles for this process. In this study, in order to mimic a dose schedule used in clinic (continuous infusion), low dose of fluorouracil (IC10 of 5-FU) was used to treat CRC cells. Our results showed that the expression of CD44, including some other CSCs markers were all increased after 5-FU treatment. The stemness properties of survived CRC cells were also observed to be enhanced. RNA-seq analysis revealed that ELF3, one of the members of ETS (E26 transformation-specific) transcription activator family, was increased along with CD44 after 5-FU treatment of CRC cells. Results from dual-luciferase reporter assay revealed that the transcription of CD44 could be activated by ELF3 in CRC cells. The induced CD44 expression in 5-FU treated CRC cells could also be decreased after the expression of ELF3 was inhibited. Moreover, it could be observed that the expression of ELF3 is significantly higher in CD44+ CRC cells. Taken together, our results suggested that CD44 expression might be regulated by ELF3 and could be induced after 5-FU treatment of CRC cells. Inhibition of ELF3 might be a promising treatment method when it was used in combination with chemotherapeutics to overcome chemoresistance formation during CRC treatment in clinic.

Facile constructing Ti3C2Tx/TiO2@C heterostructures for excellent microwave absorption properties.

Optimizing and enhancing the performance of electromagnetic wave (EMW) absorption materials relies on the modification of their composition and structure through heterogeneous interface engineering. Ti3C2Tx's high conductivity results in an impedance mismatch, which hinders efficient EMW absorption. Herein, a one-step catalytic chemical vapor deposition (CCVD) method is used to construct the Ti3C2Tx/TiO2@C heterogeneous structure. Upon annealing at 500 °C, amorphous carbon is uniformly deposited on the Ti3C2Tx surface, thereby incorporating the scale-like TiO2 generated during the process. The inclusion of the amorphous carbon layer and TiO2 reduces the substrate's conductivity, achieving optimized impedance matching. Additionally, building heterogeneous interfaces between Ti3C2Tx, TiO2, and C enriches multiple loss mechanisms involving dipole and interfacial polarization, ultimately enabling optimal EMW absorption performance. The minimum reflection loss (RLmin) value of Ti3C2Tx/TiO2@C-500 is -53.12 dB when its thickness and frequency are 1.15 mm and 13.80 GHz, respectively. Moreover, thermal infrared imaging confirms that coatings fabricated using Ti3C2Tx/TiO2@C-500 demonstrate a favorable heat dissipation rate, validating its effectiveness in addressing the challenge of efficient heat dissipation in electronic devices. This study significantly contributes to the progress of two-dimensional (2D) materials, enabling high-performance EMW absorption and expanding their applications in complex scenarios.

Artificial intelligence-assisted repair of peripheral nerve injury: a new research hotspot and associated challenges.

Artificial intelligence can be indirectly applied to the repair of peripheral nerve injury. Specifically, it can be used to analyze and process data regarding peripheral nerve injury and repair, while study findings on peripheral nerve injury and repair can provide valuable data to enrich artificial intelligence algorithms. To investigate advances in the use of artificial intelligence in the diagnosis, rehabilitation, and scientific examination of peripheral nerve injury, we used CiteSpace and VOSviewer software to analyze the relevant literature included in the Web of Science from 1994-2023. We identified the following research hotspots in peripheral nerve injury and repair: (1) diagnosis, classification, and prognostic assessment of peripheral nerve injury using neuroimaging and artificial intelligence techniques, such as corneal confocal microscopy and coherent anti-Stokes Raman spectroscopy; (2) motion control and rehabilitation following peripheral nerve injury using artificial neural networks and machine learning algorithms, such as wearable devices and assisted wheelchair systems; (3) improving the accuracy and effectiveness of peripheral nerve electrical stimulation therapy using artificial intelligence techniques combined with deep learning, such as implantable peripheral nerve interfaces; (4) the application of artificial intelligence technology to brain-machine interfaces for disabled patients and those with reduced mobility, enabling them to control devices such as networked hand prostheses; (5) artificial intelligence robots that can replace doctors in certain procedures during surgery or rehabilitation, thereby reducing surgical risk and complications, and facilitating postoperative recovery. Although artificial intelligence has shown many benefits and potential applications in peripheral nerve injury and repair, there are some limitations to this technology, such as the consequences of missing or imbalanced data, low data accuracy and reproducibility, and ethical issues (e.g., privacy, data security, research transparency). Future research should address the issue of data collection, as large-scale, high-quality clinical datasets are required to establish effective artificial intelligence models. Multimodal data processing is also necessary, along with interdisciplinary collaboration, medical-industrial integration, and multicenter, large-sample clinical studies.

Rapid Release of Halocarbons from Saline Water by Iron-Based Photochemistry.

Methyl halides play important roles in stratospheric ozone depletion, but their formation mechanisms are not well defined. This study demonstrated that iron-based photochemistry significantly enhanced alkyl halide production by promoting the reaction of the representative monomer of lignin with halide ions in saline water under solar light irradiation. The methyl chloride (CH3Cl) emission from the light/Fe(III) process was 2 orders of magnitude higher than dark treatment and in the absence of iron. In addition, bromide and iodide showed better reactivity in the formation of the corresponding methyl bromide (CH3Br) and methyl iodide (CH3I). Alkyl halides identified from seawater, brackish water, and salt pan water under sunlight irradiation were positively correlated with the Fe(III) concentrations, indicating that iron-based photochemistry is ubiquitous. This work suggested that the photoinduced formation of methyl radical and redox cycling of iron triggered by the Fenton-like reaction are responsible for the enhanced release of alkyl halides. This study represents an abiotic formation pathway of alkyl halides, which accounts for a portion of the unidentified sources of halocarbons in the ocean.

Cluster-in-Molecule Approach with Explicitly Correlated Methods for Large Molecules.

In this article, we present a series of explicitly correlated local correlation methods developed under the cluster-in-molecule (CIM) framework, including explicitly correlated second-order Møller-Plesset perturbation (MP2), coupled-cluster singles and doubles (CCSD), domain-based local pair natural orbital CCSD (DLPNO-CCSD), and DLPNO-CCSD with perturbative triples (DLPNO-CCSD(T)). In these methods, F12 correction is decomposed into contributions from each occupied local molecular orbital and then evaluated independently in a given cluster, which consists of a subset of localized orbitals. These newly developed methods allow F12 calculations of large molecules (up to 145 atoms for quasi-one-dimensional systems) on a single node. We use these methods to investigate the relative stability between extended and folded alkane C30H62, the relative stability of four secondary structures of a polyglycine Ace(Gly)10NH2, and the binding energies of two host-guest complexes. The results demonstrate that the combination of CIM with F12 methods is a promising way to investigate large molecules with small basis set errors.

Interaction Mechanism Characterized by Bond Performance and Diffusion Performance between TiO2@LDO and Asphalt Based on Molecular Dynamics Simulation.

In order to study the interaction between composite photocatalytic material TiO2@LDO and matrix asphalt, the four-component 12 molecular structure model of 70# matrix asphalt was optimized by using software Materials Studio 2020, and its heterostructure with TiO2@LDO composite was modeled. The bonding performance between asphalt and composite photocatalytic material was analyzed by interface energization, and the diffusion performance between asphalt and composite photocatalytic material was analyzed from the perspectives of particle movement and Z-direction density. By changing the temperature and other parameters in the simulation process, the change in bonding strength between TiO2@LDO and asphalt was investigated. Through the calculation and analysis of interaction energy, it was found that the adsorption and bonding strength between asphalt and TiO2@LDO were the strongest at 40 °C. At the same time, the diffusion performance was studied, and it was found that the molecular diffusion distribution of TiO2@LDO was more extensive at 60 °C, which laid the foundation for further blending of asphalt and TiO2@LDO. The simulation results show that TiO2@LDO molecules have a certain attraction to asphalt molecules and can modify the matrix asphalt to some extent.

Treatment Outcomes in COVID-19 Patients with Brucellosis: Case Series in Heilongjiang and Systematic Review of Literature.

Objective: Clinical characteristics and outcome in COVID-19 with brucellosis patients has not been well demonstrated, we tried to analyze clinical outcome in local and literature COVID-19 cases with brucellosis before and after recovery. Methods: We retrospectively collected hospitalization data of comorbid patients and prospectively followed up after discharge in Heilongjiang Infectious Disease Hospital from January 15, 2020 to April 29, 2022. Demographics, epidemiological, clinical symptoms, radiological and laboratory data, treatment medicines and outcomes, and follow up were analyzed, and findings of a systematic review were demonstrated. Results: A total of four COVID-19 with brucellosis patients were included. One patient had active brucellosis before covid and 3 patients had nonactive brucellosis before brucellosis. The median age was 54.5 years, and all were males (100.0%). Two cases (50.0%) were moderate, and one was mild and asymptomatic, respectively. Three cases (75.0%) had at least one comorbidity (brucellosis excluded). All 4 patients were found in COVID-19 nucleic acid screening. Case C and D had only headache and fever on admission, respectively. Four cases were treated with Traditional Chinese medicine, western medicines for three cases, no adverse reaction occurred during hospitalization. All patients were cured and discharged. Moreover, one case (25.0%) had still active brucellosis without re-positive COVID-19, and other three cases (75.0%) have no symptoms of discomfort except one case fell fatigue and anxious during the follow-up period after recovery. Conducting the literature review, two similar cases have been reported in two case reports, and were both recovered, whereas, no data of follow up after recovery. Conclusion: These cases indicate that COVID-19 patients with brucellosis had favorable outcome before and after recovery. More clinical studies should be conducted to confirm our findings.

CD5L Deficiency Protects Mice Against Bleomycin-Induced Pulmonary Fibrosis.

BACKGROUND: Pulmonary fibrosis (PF), the most common clinical type of irreversible interstitial lung disease with one of the worse prognoses, has a largely unknown molecular mechanisms that underlies its progression. CD5 molecule-like (CD5L) functions in an indispensable role during inflammatory responses; however, whether CD5L functions in regulating bleomycin (BLM)-induced lung fibrosis is less clear. METHODS: Herein, we describe the engineering of Cd5l knockout mice using CRISPR/Cas9 gene editing technology. The BLM-induced model of acute lung injury represents the most widely used experimental rodent model for PF. RESULTS: Taking advantage of this model, we demonstrated that both CD5L mRNA and protein were enriched in the lungs of mice following BLM-induced pulmonary fibrosis. Inhibition of CD5L prevented mice from BLM-induced lung fibrosis and injury. In particular, a lack of CD5L significantly attenuated inflammatory response and promoted M2 polarization in the lung of this pulmonary fibrosis model as well as suppressing macrophage apoptosis. CONCLUSIONS: Collectively, our data support that CD5L deficiency can suppress the development of pulmonary fibrosis, and also provides new molecular targets for the use of immunotherapy to treat lung fibrosis.

Describing and characterising variability in ALS disease progression.

Background, Objectives: Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization. Methods: We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389). Results: Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1-72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy. Discussion: This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.

SILAC proteomics based on 3D cell spheroids unveils the role of RAC2 in regulating the crosstalk between triple-negative breast cancer cells and tumor-associated macrophages.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is characterized by a high infiltration of tumor-associated macrophages (TAMs). TAMs contribute significantly to tumor progression by intricately interacting with tumor cells. Deeply investigating the interaction between TNBC cells and TAMs is of great importance for finding potential biomarkers and developing novel therapeutic strategies to further improve the clinical outcomes of TNBC patients. In this study, we confirmed the interplay using both 3D and 2D co-culture models. The stable-isotype labeling by amino acids in cell culture (SILAC)-based quantitative proteomics was conducted on 3D cell spheroids containing TNBC cells and macrophages to identify the potential candidate in regulating the crosstalk between TNBC and TAMs. Ras-related C3 botulinum toxin substrate 2 (RAC2) was identified as a potential molecule for further exploration, given its high expression in TNBC and positive correlation with M2 macrophage infiltration. The suppression of RAC2 inhibited TNBC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Meanwhile, knocking down RAC2 in TNBC cells impaired macrophage recruitment and M2 polarization. Mechanistically, RAC2 exerted its roles in TNBC cells and TAMs by regulating the activation of P65 NF-κB and P38 MAPK, while TAMs further elevated RAC2 expression and P65 NF-κB activation by secreting soluble mediators including IL-10. These findings highlight the significance of RAC2 as a crucial molecule in the crosstalk between TNBC and TAMs, suggesting it could be a promising therapeutic target in TNBC.

Association Between Nasal Colonization of Staphylococcus aureus and Eczema of Multiple Body Sites.

PURPOSE: Staphylococcus aureus is the critical pathogenic bacterium of eczema. The relationship between nasal colonization by S. aureus and eczema has not been well studied. We aimed to evaluate the associations between nasal colonization by S. aureus and eczema of multiple body sites, including persistent and ever-reported eczema. We further examined the associations between eczema and different subtypes of S. aureus, that is, methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). METHODS: The real-world data from the US National Health and Nutrition Examination Survey were used. The associations were calculated using survey-weighted multinomial logistic regression models and further calculated in subgroups stratified by demographic factors. RESULTS: In total, 2,941 adults were included. The prevalence rate of S. aureus nasal carriage was significantly higher in adults with persistent hand eczema (51.0%) than in those with ever-reported hand eczema (23.3%) and never eczema (26.9%). S. aureus nasal colonization was associated with an approximately two-fold increased risk of persistent hand eczema (odds ratios ranges in different models: 2.86-3.06) without significant heterogeneity in the association by demographic factors. No significant associations between S. aureus nasal colonization and persistent eczema of other body sites or ever-reported eczema of multiple body sites (including hands) were observed. Furthermore, similar significant association between nasal colonization of MSSA and persistent hand eczema was seen; the association was much stronger (odds ratios ranges in different models: 4.64-6.54) for MRSA, although with borderline significant. CONCLUSIONS: Nasal colonization of S. aureus was associated with increased risk of persistent hand eczema. Our findings imply that preventive measures targeting S. aureus for the anterior nares should be considered in preventing and treating eczema.

Surface-Modified Nano-Hydroxyapatite Uniformly Dispersed on High-Porous GelMA Scaffold Surfaces for Enhanced Osteochondral Regeneration.

Purpose: This study aims to investigate the impact of enhancing subchondral bone repair on the efficacy of articular cartilage restoration, thereby achieving improved osteochondral regeneration outcomes. Methods: In this study, we modified the surface of nano-hydroxyapatite (n-HAp) through alkylation reactions to prepare n-HApMA. Characterization techniques, including X-ray diffraction, infrared spectroscopy scanning, thermogravimetric analysis, particle size analysis, and electron microscopy, were employed to analyze n-HApMA. Bioinks were prepared using n-HApMA, high porosity GelMA hydrogel, and adipose tissue derived stromal cells (ADSCs). The rheological properties of the bioinks during photocuring were investigated using a rheometer. Based on these bioinks, a biphasic scaffold was constructed. The viability of cells within the scaffold was observed using live-dead cell staining, while the internal morphology was examined using scanning electron microscopy. The stiffness of the scaffold was evaluated through compression testing. Scaffolds were implanted into the osteochondral defects of New Zealand rabbit knees, and microCT was utilized to observe the subchondral bone repair. Hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and Safranin O/Fast Green staining were performed to assess the regeneration of subchondral bone and cartilage. Furthermore, immunohistochemical staining was employed to detect the expression of osteogenic and chondrogenic-related molecules. Results: Scaffold characterization revealed that surface modification enables the uniform distribution of n-HApMA within the GelMA matrix. The incorporation of 5% n-HApMA notably enhanced the elastic modulus and stiffness of the 6% high-porosity GelMA in comparison to n-HAp. Moreover, in-vivo study showed that the homogeneous dispersion of n-HApMA on the GelMA matrix facilitated the osteogenic differentiation of adipose-derived stem cells (ADSCs) and promoted osteochondral tissue regeneration. Conclusion: These findings suggest potential applications of the n-HApMA/GelMA composite in the field of tissue engineering and regenerative medicine.

Development of a highly sensitive immunoassay based on pentameric nanobodies for carcinoembryonic antigen detection.

BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM-5) is a well-characterized biomarker for the clinical diagnosis of various cancers. Nanobodies, considered the smallest antibody fragments with intact antigen-binding capacity, have gained significant attention in disease diagnosis and therapy. Due to their peculiar properties, nanobodies have become promising alternative diagnostic reagents in immunoassay. However, nanobodies-based immunoassay is still hindered by small molecular size and low antigen capture efficacy. Therefore, there is a pressing need to develop novel nanobody-based immunoassays with superior performance. RESULTS: A novel pentameric nanobodies-based immunoassay (PNIA) was developed with enhanced sensitivity and specificity for CEACAM-5 detection. The binding epitopes of three anti-CEACAM-5 nanobodies (Nb1, Nb2 and Nb3) were analyzed. To enhance the capture and detection efficacy of CEACAM-5 in the immunoassay, we engineered bispecific nanobodies (Nb1-Nb2-rFc) as the capture antibody, and developed the FITC-labeled pentameric nanobodies (Nb3-VT1B) as the detection antibody. The binding affinities of Nb1-Nb2-rFc (1.746 × 10-10) and Nb3-VT1B (1.279 × 10-11) were significantly higher than those of unmodified nanobodies (Nb1-rFc, 4.063 × 10-9; Nb2-rFc, 2.136 × 10-8; Nb3, 3.357 × 10-9). The PNIA showed a linear range of 0.625-160 ng mL-1 with a correlation coefficient R2 of 0.9985, and a limit of detection of 0.52 ng mL-1, which was 24-fold lower than the immunoassay using monomeric nanobody. The PNIA was validated with the spiked human serum. The average recoveries ranged from 91.8% to 102% and the coefficients of variation ranged from 0.026% to 0.082%. SIGNIFICANCE AND NOVELTY: The advantages of nanobodies offer a promising alternative to conventional antibodies in disease diagnosis. The novel PNIA demonstrated superior sensitivity and high specificity for the detection of CEACAM-5 antigen. This bispecific or multivalent nanobody design will provide some new insights into the design of immunoassays for clinical diagnosis.

Amorphous hollow manganese silicate nanosphere oxidase mimic for ultrasensitive and high-reliable colorimetric detection of biothiols.

Metal-based nanozymes with exceptional physicochemical property and intrinsic enzymatic properties have been widely used in industrial, medical, and diagnostic fields. However, low substrate affinity results in unsatisfying catalytic kinetic and instability in complicated conditions, which significantly decreases their sensitivity and reliability. Herein, an amorphous hollow manganese silicate nanosphere (defined as AHMS) has been successfully synthesized via a facile one-step hydrothermal method and utilized in the archetype for colorimetric detection of biothiols with high sensitivity and high reliability. The experimental data demonstrates that ultrafast affinity of the substrate contributes to enhanced sensitivity with outstanding catalytic kinetic features (Km = 27.1 µM) and low limit of detection (LODGSH = 20 nM). The designed sensor demonstrates a reliable applicability for analysis of biological liquids (fetal calf serum and Staphylococcus aureus) and design of visual logic gates. Therefore, AHMS provides a promising strategy for ultrasensitive and high-reliable biosensing.

Neuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images.

Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.

Morroniside Inhibits Inflammatory Bone Loss through the TRAF6-Mediated NF-κB/MAPK Signalling Pathway.

Osteoporosis is a chronic inflammatory disease that severely affects quality of life. Cornus officinalis is a Chinese herbal medicine with various bioactive ingredients, among which morroniside is its signature ingredient. Although anti-bone resorption drugs are the main treatment for bone loss, promoting bone anabolism is more suitable for increasing bone mass. Therefore, identifying changes in bone formation induced by morroniside may be conducive to developing effective intervention methods. In this study, morroniside was found to promote the osteogenic differentiation of bone marrow stem cells (BMSCs) and inhibit inflammation-induced bone loss in an in vivo mouse model of inflammatory bone loss. Morroniside enhanced bone density and bone microstructure, and inhibited the expression of IL6, IL1ß, and ALP in serum (p < 0.05). Furthermore, in in vitro experiments, BMSCs exposed to 0-256 µM morroniside did not show cytotoxicity. Morroniside inhibited the expression of IL6 and IL1ß and promoted the expression of the osteogenic transcription factors Runx2 and OCN. Furthermore, morroniside promoted osteocalcin and Runx2 expression and inhibited TRAF6-mediated NF-κB and MAPK signaling, as well as osteoblast growth and NF-κB nuclear transposition. Thus, morroniside promoted osteogenic differentiation of BMSCs, slowed the occurrence of the inflammatory response, and inhibited bone loss in mice with inflammatory bone loss.

Comorbidities of chronic prurigo: A systematic review and meta-analysis.

BACKGROUND: Chronic prurigo (CPG) is an inflammatory skin disease. Comorbidities including dermatological, cardiovascular, and psychiatric diseases have been reported in patients with CPG, however, the evidence has not been systematically evaluated. We aim to summarize the comorbidities, discuss underlying pathogenesis, and highlight the evaluation of CPG patients. METHODS: We performed a systematic search using PubMed, Embase, and Web of Science databases for all articles reporting possible associated diseases with CPG. Pooled random-effects odds ratios (OR) with 95% CI were calculated. RESULTS: A total of 17 studies were included in this systematic review. Statistically significant association(P<0.05) with CPG has been demonstrated with atopic diseases: atopic dermatitis (pooled OR, 10.91; 95% CI, 3.65-32.67), allergic rhinitis (2.66;1.12-6.27), asthma (3.23;1.55-6.74); infectious diseases: hepatitis B (pooled OR, 2.15; 95% CI, 1.11-4.14); endocrine diseases: diabetes (pooled OR, 4.93; 95% CI, 1.13-21.56), type 1 diabetes 2.46;2.16-2.81), type 2 diabetes (1.89;1.34-2.68), hyperlipoproteinemia (2.90; 1.61-5.22); cardiovascular diseases: heart failure (pooled OR, 4.13; 95% CI, 1.15-14.91), hypertension (3.17;1.56-6.45); respiratory system diseases: chronic obstructive pulmonary disease (pooled OR, 3.19; 95% CI, 1.42-7.16); urinary system diseases: chronic kidney disease (pooled OR, 4.16; 95% CI, 1.79-9.66); digestive system disease: inflammatory bowel disease (pooled OR, 2.06; 95% CI, 1.26-3.36); and others: osteoporosis (pooled OR, 3.08; 95% CI, 1.70-5.59), thyroid disease (1.70;1.17-2.47). CONCLUSION: CPG is associated with various systemic disorders. Recognition of comorbidities is critical to the appropriate management of affected patients.

The function of MSP-activated γδT cells in hepatocellular carcinoma.

Immunotherapeutic strategies targeting γδT cells are now recognized as a promising treatment method for hepatocellular carcinoma (HCC). To date, no specific antigen or antigenic epitope recognized by γδT cells has been identified, limiting their application in the field of HCC treatment. Previously, we used an established screening strategy to identify a novel HCC protein antigen recognized by γδT cells called MSP. In this study, we explored the function of MSP activated-γδT cells in HCC. Results demonstrated that the proportions of γδT cells in the peripheral blood of HCC patients and the level of IFN-γ in the serum were higher than in healthy controls. We also determined that γδT cells can bind MSP protein. MSP-activated γδT cells were shown to contain a specific CDR3δ2 sequence that supports the recognition of MSP by γδT cells. We determined that MSP is highly expressed in HCC, MSP-activated γδT cells in the peripheral blood of HCC patients express co-stimulatory molecules, and MSP-activated γδT cells directly killed HCC cells. In conclusion, we demonstrated that the novel protein ligand MSP activated γδT cells, leading to the killing of HCC cells through direct and indirect mechanisms. These findings could provide a potential new target for the clinical diagnosis and treatment of HCC and a foundation for clinical treatment strategies in HCC.

A peptidic network antibody inhibits both angiogenesis and inflammatory response.

Corneal neovascularization (CNV) is a global threat to human health. Traditional anti-angiogenesis agent may have therapy effect, while the inflammation in disease area remains unsolved. Herein, we reported two binding-induced fibrillogenesis (BIF) peptides as peptidic network antibodies for high-efficient and long-lasting anti-angiogenesis with reduced inflammatory response. BIF peptides could self-assemble into nanoparticles and further perform BIF behavior through binding Ca2+. In vitro, the migration of integrin αvß3 highly expressed endothelial cells was inhibited by BIF peptides. In vivo, one BIF peptide (0.012 mg/Kg) exhibited higher anti-angiogenesis effect than monoclonal antibody bevacizumab (0.96 mg/Kg) in a CNV rabbit model on day 14, despite that the dose of BIF was only 1.3% of bevacizumab. Meanwhile, the inflammatory response, such as PI3 kinase/Akt pathway in CNV was successfully inhibited as well. The peptidic network antibody could block integrin αvß3 via a long-term retention mode, which led to long-term therapeutic effect. The study provides BIF peptides as promising therapeutic agents for both anti-angiogenesis and reduced inflammatory response.

SOiCISCF: Combining SOiCI and iCISCF for Variational Treatment of Spin-Orbit Coupling.

It has recently been shown that the SOiCI approach [Zhang, N.; J. Phys.: Condens. Matter 2022, 34, 224007], in conjunction with the spin-separated exact two-component relativistic Hamiltonian, can provide very accurate fine structures of systems containing heavy elements by treating electron correlation and spin-orbit coupling (SOC) on an equal footing. Nonetheless, orbital relaxations/polarizations induced by SOC are not yet fully accounted for due to the use of scalar relativistic orbitals. This issue can be resolved by further optimizing the still real-valued orbitals self-consistently in the presence of SOC, as done in the spin-orbit coupled CASSCF approach [Ganyushin, D.; et al. J. Chem. Phys. 2013, 138, 104113] but with the iCISCF algorithm [Guo, Y.; J. Chem. Theory Comput. 2021, 17, 7545-7561] for large active spaces. The resulting SOiCISCF employs both double group and time reversal symmetries for computational efficiency and the assignment of target states. The fine structures of p-block elements are taken as showcases to reveal the efficacy of SOiCISCF.