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关键词： autoimmune diseases   lupus   mathematical modeling   quantitative systems pharmacology   type 1 interferon  

摘要： Type I interferon (IFN1) pathway-targeting therapies represent a highly promising class of remedies for the treatment of systemic lupus erythematosus. However, the overall clinical benefit of these compounds is afflicted by marked variability. In this study, we developed a quantitative systems pharmacology model of type I IFN-mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient-level data from Phase IIb anifrolumab clinical trial. Within-target and within-pathway validation was performed using study-level pharmacokinetics, IFN alpha, and/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (< 2.75) and high (>= 2.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100-150 mg every 4 weeks). In contrast, IFNGS response under 150 mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFN alpha biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFN alpha, and IFN alpha fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (Delta IFNGS similar to 25%), which was further enhanced in patients with high baseline IFNGS or IFN alpha (Delta IFNGS similar to 50%-60%).

关键词： antigen presentation/processing   bioinformatics   MHC   TCR  

摘要： The ability to predict which antigenic peptide(s) the alpha beta TCR of a given CD8(+) T-cell clone can recognise would represent a quantum leap in the understanding of T-cell repertoire selection and development of targeted cell-mediated immunotherapies. Current methods fail to make accurate predictions for antigenic peptides not present in the training dataset. Here, we propose a novel deep learning method called nuTCRacker that makes accurate predictions for a subset of unseen peptides, with an AUC > 0.7 for around a third of peptides evaluated using a large dataset compiled from curated public resources. An additional evaluation was undertaken using a small cellula-validated dataset of alpha beta TCR peptides associated with cancer. Our analysis suggests that it is possible to make useful predictions for an unseen peptide provided the training dataset contains: many samples with the same HLA class I molecule as that bound to the peptide;at least one peptide that is similar to the target peptide;and a small number of alpha beta TCRs that are similar to those bound to the unseen peptide of interest.

关键词： HLA-B*13:212   Nanopore sequencing   novel allele  

摘要： HLA-B*13:212 differs from HLA-B*13:01:01:01 by one nucleotide substitution at codon 128 in exon 3.

关键词： Postbiotics   Inflammatory bowel disease   Tryptophan metabolism   Gut microbiota  

摘要： Inactivated probiotics, due to their high safety, effectiveness, stability, and resilience, are increasingly used for treating various diseases. To assess the efficacy of inactivated Bifidobacterium bifidum M1-3 in alleviating dextran sulfate sodium salt (DSS)-induced colitis, we compared the effects of live probiotics and inactivated probiotics at different concentrations on colitis in male C57BL/6J mice. Additionally, we explored potential mechanisms by analyzing changes in gut microbiota composition, tryptophan metabolites, and the AhR/IL-22 signaling pathway. Our study demonstrated that administering high doses (2 x 109 CFU/mL) of heat-inactivated probiotics by gavage for 14 days effectively alleviated DSS-induced colitis in mice, with effects comparable to those of live probiotics. This effect was attributed to the modulation of gut microbiota, with an increase in beneficial bacteria like Muribaculaceae, Alistipes, and Ruminococcaceae, and a reduction in harmful microbes such as Escherichia/ Shigella spp. Additionally, the inactivated probiotics enhanced tryptophan metabolism, leading to elevated levels of metabolites including indole-3-lactic acid, indole-3-propionic acid, indole acrylic acid, and indole, which subsequently activated the AhR/IL-22 signaling pathway. Our results confirmed the effectiveness of heat-inactivated Bifidobacterium bifidum M1-3 in alleviating colitis, demonstrating a dose-dependent response. The soluble capsular polysaccharides in the bacterial lysate supernatant are the potentially effective components of Bifidobacterium bifidum M1-3. This finding provides a theoretical basis for developing novel probiotic products containing heat-inactivated Bifidobacterium bifidum M1-3.

关键词： Millimeter wave communication   Band-pass filters   Resonators   Resonant frequency   Coplanar waveguides   Costs   Passband   Permittivity   Bandwidth   Acoustics   Bandpass filter   coplanar waveguide   lithium niobate   millimeter wave   miniaturization  

摘要： A millimeter-wave (mmWave) bandpass filter (BPF) based on single-crystal lithium niobate (LN) with multiple transmission zeros (TZs) is proposed in this work, which consists of four coplanar waveguide (CPW) resonators embedded with T-shaped slots and two T-shaped stubs for miniaturization and high stopband suppression. By leveraging the LN's small loss tangent and large permittivity, the filter achieves exceptional performance in terms of selectivity, miniaturization, and cost efficiency. The LN thickness is optimized to balance the tradeoff between compact size and the cutoff frequency of the first high-order mode. Each T-shaped slot creates parallel inductance and capacitance, reducing the resonator size while generating a TZ in the upper stopband. Simultaneously, the dual-mode T-shaped stub can create two TZs in the lower stopband, further enhancing selectivity. The fabricated mmWave BPF has a measured center frequency of 30.26 GHz, a fractional bandwidth of 17%, a minimum insertion loss of 1.12 dB, and a compact size of 2 mm x 1.7 mm x 0.16 mm. These features demonstrate the LN-based mmWave BPF as a promising solution with high selectivity, compact size, and low cost for 5G/6G mmWave terminal applications.

关键词： SCG   Sympathetic neurons   Chronic sleep deprivation   Hyperalgesia   TNF-alpha  

摘要： The mechanisms underlying the association between sleep deprivation (SD) and hyperalgesia remain incompletely understood. In this study, the Modified Horizontal Platform Method was employed to induce chronic SD. Neuropathic pain was induced using chronic constriction injury of the sciatic nerve. Pain-like behaviors were assessed through measurements of mechanical allodynia and thermal hyperalgesia, while gait analysis was used to evaluate motor function. Immunofluorescence and western blot analyses were conducted to examine the expression of TNF-alpha, Iba-1, TH, neurons and c-Fos. Apoptosis was assessed using TUNEL staining. To explore anatomical connections, anterograde and retrograde tracer viruses were injected into the superior cervical ganglion (SCG) and the spinal cord, respectively. Local injection of 6-OHDA was used to ablate sympathetic neurons in the SCG, and R-7050 was administrated to block the TNF-alpha receptor. We found that chronic SD induced hyperalgesia in both normal and neuropathic pain model, accompanied by significant infiltration of microglia in the dorsal horn. TH expression and apoptotic cells were increased in the SCG following chronic SD. Viral tracer results demonstrated the existence of anatomical connections between the SCG and the spinal cord. Ablation of sympathetic innervation improved pain-like behaviors and reduced microglia, without affecting movement. Furthermore, chronic SD led to increased expression of TNF-alpha in sympathetic neurons, which was associated with heightened SCG activity. Blocking the TNF-alpha receptor ameliorated pain-like behaviors, decreased microglia, reduced apoptosis, lowered SCG activity. In conclusion, TNF-alpha enhanced the activity of sympathetic neurons in the SCG, promoting hyperalgesia related to chronic SD.

摘要： Production of recombinant human leukocyte antigen class I (HLA-I) proteins in vitro is fundamental for molecular immunology. However, HLA-I protein refolding has remained inefficient due to challenges in the assembling of the trimolecular complex. Here, we compare various in vitro refolding methods that address the challenges of intrachain disulfide bond formation and assembly of the complex between the light and heavy chains in the presence of the target peptide. We developed methods that uncouple the oxidation of disulfide bond formation of both subunits of HLA-I, followed by renaturation to promote complex formation. CuSO4-catalyzed air oxidation enhances correct disulfide bond formation when the protein is solubilized with N-lauryl-sarcosine (sarkosyl);however, careful removal of sarkosyl did not prevent heavy chain aggregation. We modified the classical method of HLA-I refolding by pre-oxidizing the (32m light chain before adding the HLAI heavy chain and peptide. This method yielded successful complex refolding for HLA-A*02:01/GILGFVFTL at 24.2 % efficiency, and HLA-C*12:03/KAYNVTQAF at 14.5 % efficiency. Our results suggest that pre-folded (32m improves refolding efficiency of HLA-I molecules. This work presents novel approaches to HLA-I refolding that may be applied to other difficult-to-fold protein complexes.

关键词： Celastrol   Melanoma   CD8+T cell   MHC-I   JAK/STAT1   SHP2  

摘要： Background: Celastrol (CEL) has demonstrated promising anti-cancer properties, yet its specific mechanisms against melanoma remain insufficient. This study investigated the CEL's anti-tumor effects and determined its potential mechanisms in the regulation of MHC-I expression in melanoma. In addition, we also tested its efficacy in sensitizing immune checkpoint inhibitors (ICIs) to melanoma. Methods: CEL's anti-tumor activity was evaluated in B16F10 melanoma-bearing C57BL/6 mice across five groups (control, CEL 0.5 mg/kg, CEL 1 mg/kg, CEL 2 mg/kg, and ICIs), the tumor volume, histopathology, and body weight were assessed. Mechanistic insights were obtained through network pharmacology and RNA sequencing in B16F10 cells. Differential gene and pathway analysis were validated using qRT-PCR, Western blotting, and flow cytometry. CD8+T cell activation and cytotoxicity were analyzed in co-culture with CEL-pretreated B16F10 cells using flow cytometry and ELISA. CEL's interaction with potential targets was determined by molecular docking, surface plasmon resonance (SPR), and siRNA. The synergistic effect of CEL combined with ICIs was confirmed in B16F10-bearing C57BL/6 mice, and tumor-infiltrating T cells were assessed by flow cytometry across four groups (control, CEL, ICIs, CEL+ICIs). Results: CEL exhibited a significant anti-tumor effect in B16F10 melanoma-bearing mice. Mechanistically, CELpretreated B16F10 cells notably enhanced CD8+T cell activation and promoted IFN gamma and TNF alpha secretion, leading to B16F10 cell death. CEL upregulated MHC-I expression through activation of the JAK/STAT1 pathway in B16F10 cells. The binding assay revealed that CEL interacted with SHP2, with an affinity of 37.93 mu M. When SHP2 was silenced in B16F10 cells by siRNA, CEL failed to induce MHC-I upregulation. Moreover, CEL combined with ICIs produced superior antitumor efficacy compared to ICIs alone, which was accompanied by increased CD8+T cell infiltration in melanoma. Conclusion:

关键词： Cytokines   Survivin   Cytorisk index   Breast cancer  

摘要： Introduction: Breast cancer is one of the most prevalent cancers afflicting women. Immuno-oncology is an upcoming field which has established the role of immunocompetent cells and cytokines in the pathogenesis and progression of multiple cancers including breast cancer. Methods: The study comprised of three groups- Group Icytologically confirmed breast cancer, group II- benign breast disease, group IIInormal healthy controls. Survivin, IL-4 and IL-6 levels were estimated and a novel indexcytorisk index calculated. The breast cancer patients were followed up and the histopathological markers of tumour aggression were correlated with the cytorisk index calculated at the time of diagnosis. Results: The median Cytorisk Index values were: control group - 90.86 (IQR: 33.29-167.37), benign group - 0.004 (IQR: 0.002-0.012), and malignant group - 31.91 (IQR: 9.61-73.19). Pearson's correlation analysis between the Cytorisk Index and lymphovascular invasion (LV1) and perineural invasion (PN1) status revealed a statistically significant positive correlation (p = 0.016) Conclusion: The significance of our findings lies in the Cytorisk Index's ability to serve as a noninvasive biomarker for distinguishing between benign breast tumors, malignant breast tumors, and healthy individuals during the initial stages of tumor detection. The positive correlation with the histopathological markers of disease aggression highlights the importance of this index as an important marker of breast cancer prognostication.