BiSpec Pairwise AI: guiding the selection of bispecific antibody target combinations with pairwise learning and GPT augmentation.

PURPOSE: Bispecific antibodies (BsAbs), capable of targeting two antigens simultaneously, represent a significant advancement by employing dual mechanisms of action for tumor suppression. However, how to pair targets to develop effective and safe bispecific drugs is a major challenge for pharmaceutical companies. METHODS: Using machine learning models, we refined the biological characteristics of currently approved or in clinical development BsAbs and analyzed hundreds of membrane proteins as bispecific targets to predict the likelihood of successful drug development for various target combinations. Moreover, to enhance the interpretability of prediction results in bispecific target combination, we combined machine learning models with Large Language Models (LLMs). Through a Retrieval-Augmented Generation (RAG) approach, we supplement each pair of bispecific targets' machine learning prediction with important features and rationales, generating interpretable analytical reports. RESULTS: In this study, the XGBoost model with pairwise learning was employed to predict the druggability of BsAbs. By analyzing extensive data on BsAbs and designing features from perspectives such as target activity, safety, cell type specificity, pathway mechanism, and gene embedding representation, our model is able to predict target combinations of BsAbs with high market potential. Specifically, we integrated XGBoost with the GPT model to discuss the efficacy of each bispecific target pair, thereby aiding the decision-making for drug developers. CONCLUSION: The novelty of this study lies in the integration of machine learning and GPT techniques to provide a novel framework for the design of BsAbs drugs. This holistic approach not only improves prediction accuracy, but also enhances the interpretability and innovativeness of drug design.

Evaluation of mental load using EEG and eye movement characteristics.

Mental load is a major cause of human-induced accidents. In this study, an explosive impact sensitivity experiment was used to induce mental load. A combination of subjective questionnaires and objective prospective time-distance tests were used to judge whether subjects experienced mental load. Four indicators, namely, ß, γ, mean pupil diameter, and fixation time were selected by statistical analysis and PCA for the construction of a mental load assessment model. The study found that the occipital lobe was the most sensitive to mental load, especially ß and γ bands. Lastly, it was found that subjects showed different degrees of mental load for the same mental load induction task. The results of the study are applicable to the evaluation and monitoring of the mental characteristics of workers and provide a scientific basis for adjusting the mental load of workers over time to reduce the rate of accidents and enhance production efficiency.

Mental load is the main cause of human-induced accidents. This study used an explosive impact sensitivity experiment to induce mental load in subjects. We found that the mean pupil diameter and fixation time, as well as the beta and gamma bands in the occipital lobe were most sensitive to mental load.

Caloric restriction, Sirtuins, and cardiovascular diseases.

ABSTRACT: Caloric restriction (CR) is a well-established dietary intervention known to extend healthy lifespan and exert positive effects on aging-related diseases, including cardiovascular conditions. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylases, have emerged as key regulators of cellular metabolism, stress responses, and the aging process, serving as energy status sensors in response to CR. However, the mechanism through which CR regulates Sirtuin function to ameliorate cardiovascular disease remains unclear. This review not only provided an overview of recent research investigating the interplay between Sirtuins and CR, specifically focusing on their potential implications for cardiovascular health, but also provided a comprehensive summary of the benefits of CR for the cardiovascular system mediated directly via Sirtuins. CR has also been shown to have considerable impact on specific metabolic organs, leading to the production of small molecules that enter systemic circulation and subsequently regulate Sirtuin activity within the cardiovascular system. The direct and indirect effects of CR offer a potential mechanism for Sirtuin modulation and subsequent cardiovascular protection. Understanding the interplay between CR and Sirtuins will provide new insights for the development of interventions to prevent and treat cardiovascular diseases.

Systematic Investigation of the Degradation Properties of Nitrile-Butadiene Rubber/Polyamide Elastomer/Single-Walled Carbon Nanotube Composites in Thermo-Oxidative and Hot Oil Environments.

The physical blending method was used in order to prepare nitrile-butadiene rubber/polyamide elastomer/single-walled carbon nanotube (NBR/PAE/SWCNT) composites with better thermal-oxidative aging resistance. The interactions between SWCNTs and NBR/PAE were characterized using the Moving Die Rheometer 2000 (MDR 2000), rheological behavior tests, the equilibrium swelling method, and mechanical property tests. The 100% constant tensile stress and hardness of NBR/PAE/SWCNT composites increased from 2.59 MPa to 4.14 MPa and from 62 Shore A to 69 Shore A, respectively, and the elongation decreased from 421% to 355% with increasing SWCNT content. NBR/PAE/SWCNT composites had improved thermal-oxidative aging resistance due to better interactions between SWCNTs and NBR/PAE. During the aging process, the tensile strength and elongation at break decreased with the increase in aging time compared to the unaged samples, and the constant tensile stress gradually increased. There was a more significant difference in the degradation of mechanical properties when aged in a variety of oils. The 100% constant tensile stress of NBR/PAE/SWCNT composites aged in IRM 903 gradually increased with aging time while it gradually decreased in biodiesel. The swelling index gradually increased with increasing SWCNT content. Interestingly, the swelling index of the composites in cyclohexanone decreased with the increase in SWCNT content. The reasons leading to different swelling behaviors when immersed in different kinds of liquids were investigated using the Hansen solubility parameter (HSP) method, which provides an excellent guide for the application of some oil-resistant products.

Regulation of the trade-off between cold stress and growth by glutathione S-transferase phi class 10 (BcGSTF10) in non-heading Chinese cabbage.

Cold stress is a serious threat to global crop production and food security, but plant cold resistance is accompanied by reductions in growth and yield. In this study, we determined that the novel gene BcGSTF10 in non-heading Chinese cabbage [NHCC; Brassica campestris (syn. Brassica rapa) ssp. chinensis] is implicated in resistance to cold stress. Biochemical and genetic analyses demonstrated that BcGSTF10 interacts with BcICE1 to induce C-REPEAT BINDING FACTOR (CBF) genes that enhance freezing tolerance in NHCC and in Arabidopsis. However, BcCBF2 represses BcGSTF10 and the latter promotes growth in NHCC and Arabidopsis. This dual function of BcGSTF10 indicates its pivotal role in balancing cold stress and growth, and this important understanding has the potential to inform the future development of strategies to breed crops that are both climate-resilient and high-yielding.

HOXC10 promotes esophageal squamous cell carcinoma progression by targeting FOXA3 and indicates poor survival outcome.

Background: Esophageal cancer is one of the most unknown and deadliest cancers in the world. Although recent studies have identified some mutations linked to the development of squamous cell carcinoma of the esophagus (ESCC), the specific role of HomeoboxC10 (HOXC10) in the pathogenesis still requires further investigation. Methods: Agilent mRNA single-channel gene expression was employed to identify genome-wide gene signatures in ESCC. These signatures were also verified using qRT-PCR, immunohistochemical staining as well as Western blot. The biological functions of HOXC10 were further investigated through cellular studies conducted on ESCC cells. Survival analysis was conducted utilizing the Kaplan-Meier method. The GEPIA database and the STRING website were utilized to predict the potential targets that bind to HOXC10. Co-immunoprecipitation assays were performed to investigate the binding interaction between HOXC10 and Forkhead Box A3 (FOXA3). Animal models were established to analyze the effects of HOXC10 silencing on tumorigenesis in vivo. Results: The expression levels of HOXC10 mRNA were found to be upregulated in ESCC. Survival analysis revealed a significant association between abnormally elevated levels of HOXC10 mRNA and an unfavorable prognosis in patients with ESCC. In vitro studies revealed that the knockdown of HOXC10 expression resulted in the inhibition of the proliferation, invasion, and migrating ability of ESCC cells through the upregulation of FOXA3. Furthermore, tumor-bearing mouse models studies demonstrated that HOXC10 through knockdown techniques significantly suppressed ESCC tumor growth. HOXC10 was found to enhance the activation of the MAPK signaling pathway by regulating FOXA3 in ESCC cells. Conclusion: These results support a key role for HOXC10 in the tumorigenesis of ESCC by upregulating FOXA3 via the MAPK pathway and highlight its potential as a promising diagnostic and prognostic marker for ESCC.

Thyroid artery embolization of large solitary symptomatic benign thyroid nodules through transradial approach.

This study investigated the efficacy and safety of transradial access (TRA) thyroid artery embolization (TAE) for patients with large solitary symptomatic benign thyroid nodules. Six patients with a total of six nodules (three men and three women; mean age, 36.3 years; age range, 23-45 years) underwent TRA TAE between October 2021 and June 2022 and were subsequently followed up three months later, and their cases were retrospectively reviewed. The associated complications were recorded during and after TRA TAE. The volume change and nodule-related symptom score on a 10-cm visual analogue scale (VAS) between baseline, 1- and 3-month follow-up was analyzed using Wilcoxon signed-rank test. The technical success rate of the TRA TAE was 100% without conversion to transfemoral access. The mean volume of the nodules decreased between baseline (84.1 mL; range, 46.1-170.5 mL), 1-month (38.8 mL; range, 17.6-91.5 mL; P=0.028) and 3-month (14.8 mL; range, 3.95-26.4 mL; P=0.068) at follow-up after TRA TAE. The mean volume reduction rate was 54.9% (range, 45.2-71.8%) at 1-month follow-up and 81.8% (range, 62.0-92.0%) at 3-month follow-up. The VAS score was reduced at 1-month (P=0.028) and at 3-month follow up (P=0.068). Radial artery spasm (n=1) was noted during TRA TAE, and neck pain (n=5) and voice change (n=1) occurred within 1 week after the procedure and resolved with conservative treatment. No major complications were reported. TRA TAE may be a promising alternative therapy for the management of large solitary thyroid nodules.

SIRT6 is an epigenetic repressor of thoracic aortic aneurysms via inhibiting inflammation and senescence.

Thoracic aortic aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments. The current understanding of the pathogenesis of TAA is still limited, especially for sporadic TAAs without known genetic mutation. Sirtuin 6 (SIRT6) expression was significantly decreased in the tunica media of sporadic human TAA tissues. Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture, reduced survival, and increased vascular inflammation and senescence after angiotensin II infusion. Transcriptome analysis identified interleukin (IL)-1ß as a pivotal target of SIRT6, and increased IL-1ß levels correlated with vascular inflammation and senescence in human and mouse TAA samples. Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation. Genetic knockout of Il1b or pharmacological inhibition of IL-1ß signaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation, senescence, TAA formation and survival in mice. The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence, providing insight into potential epigenetic strategies for TAA treatment.

Deciphering Nucleic Acid Binding Proteome of Mouse Immune Organs Reveals Hub Proteins for Aging.

Profiling the nucleic acid-binding proteins (NABPs) during aging process is critical to elucidate its roles in biological systems as well as transcriptional and translational regulation. Here, we developed a comprehensive strategy to survey the NABPs of mouse immune organs by using single cell preparation and selective capture technology-based proteomics. Our approach provided a global view of tissue NABPs from different organs under normal physiological conditions with extraction specificity of 70 to 90%. Through quantitative proteomics analysis of mouse spleen and thymus at 1, 4, 12, 24, 48, and 72 weeks, we investigated the molecular features of aging-related NABPs. A total of 2674 proteins were quantified in all six stages, demonstrating distinct and time-specific expression pattern of NABPs. Thymus and spleen exhibited unique aging signatures, and differential proteins and pathways were enriched across the mouse lifespan. Three core modules and 16 hub proteins associated with aging were revealed through weighted gene correlation network analysis. Significant candidates were screened for immunoassay verification, and six hub proteins were confirmed. The integrated strategy pertains the capability to decipher the dynamic functions of NABPs in aging physiology and benefit further mechanism research.

Dynamic Phosphoproteomics of BRS3 Activation Reveals the Hippo Signaling Pathway for Cell Migration.

Bombesin receptor subtype-3 (BRS3) is an orphan G-protein coupled receptor (GPCR) that is involved in a variety of pathological and physiological processes, while its biological functions and underlying regulatory mechanisms remain largely unknown. In this study, a quantitative phosphoproteomics approach was employed to comprehensively decipher the signal transductions that occurred upon intracellular BRS3 activation. The lung cancer cell line H1299-BRS3 was treated with MK-5046, an agonist of BRS3, for different durations. Harvested cellular proteins were digested and phosphopeptides were enriched by immobilized titanium (IV) ion affinity chromatography (Ti4+-IMAC) for label-free quantification (LFQ) analysis. A total of 11,938 phosphopeptides were identified, corresponding to 3,430 phosphoproteins and 10,820 phosphosites. Data analysis revealed that 27 phosphopeptides corresponding to six proteins were involved in the Hippo signaling pathway, which was significantly regulated by BRS3 activation. Verification experiments demonstrated that downregulation of the Hippo signaling pathway caused by BRS3 activation could induce the dephosphorylation and nucleus localization of the Yes-associated protein (YAP), and its association with cell migration was further confirmed by kinase inhibition. Our data collectively demonstrate that BRS3 activation contributes to cell migration through downregulation of the Hippo signaling pathway.

GBP5 Identifies Immuno-Hot Tumors and Predicts the Therapeutic Response to Immunotherapy in NSCLC.

Background: Immunotherapy drugs, immune checkpoint inhibitors (ICIs), have been approved for first- and second-line treatment of non-small cell lung cancer (NSCLC), but only a portion of patients respond to ICIs. It is crucial to screen the beneficiaries of immunotherapy through biomarkers accurately. Methods: Several datasets were used to explore the predictive value for immunotherapy and immune relevance of guanylate binding protein 5 (GBP5) in NSCLC, including the GSE126044 dataset, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset, the Kaplan-Meier plotter dataset, the HLuA150CS02 cohort, and the HLugS120CS01 cohort. Results: GBP5 was upregulated in tumor tissues but associated with a good prognosis in NSCLC. Moreover, our findings demonstrated that GBP5 was strongly correlated with the expression of many immune-related genes, TIIC levels, and PD-L1 expression based on RNA-seq data onto online databases and validation of the NSCLC tissue microarray using IHC staining. Moreover, pan-cancer analysis has shown that GBP5 was a factor in identifying immuno-hot tumors, except for a few tumor types. Conclusion: In summary, our current research suggests that GBP5 expression is a potential biomarker for predicting the outcome of NSCLC patients treated with ICIs. More research with large-scale samples is needed to determine their value as biomarkers of ICIs benefit.

A Rare Strain Actinomadura geliboluensis Was First Isolated from the Bronchoalveolar Lavage Fluid of a Patient with Pneumonia.

Background: Actinomadura geliboluensis was first isolated in 2012 in Gelibolu, Canakkale, Turkey, and has not been reported to be isolated from humans until now. We have isolated it from the bronchoalveolar lavage fluid (BLF) of a patient with pneumonia and found its drug resistance. It is the first time that Actinomadura geliboluensis has been isolated from humans since its discovery and naming. This case may provide new ideas and methods for the clinical diagnosis and treatment of pulmonary actinomycosis. Case Description: The patient was a 75-year-old male who was hospitalized in a township hospital and failed to improve after penicillin treatment. After admission to our hospital, the patient was treated with piperacillin/tazobactam according to clinical guidelines for 14 days. Actinomadura geliboluensis was isolated from the patient's BLF and was identified by 16S rRNA sequencing. This report shows the biological characteristics and in vitro drug susceptibility testing, as well as the genomics analysis based on next-generation sequencing (NGS). The results demonstrated that Actinomadura geliboluensis was easy to be mistakenly identified as Actinomyces dental caries by using the Merieux ANC identification card. Based on the MIC test, Actinomadura geliboluensis was susceptible to tetracyclines, quinolones and sulfonamides, but resistant to carbapenems, penicillins and cephalosporins. The K-B test results showed Actinomadura geliboluensis was highly sensitive to piperacillin/tazobactam. Genomic analysis based on NGS showed that the Actinomadura geliboluensis belongs to Planobispora rosea EF-Tu mutants conferring resistance to inhibitor GE2270A, AAC(3)-VIIa, vanRO, chrB, and mexY. Conclusion: Actinomycetes is generally sensitive to Penicillin but Actinomadura geliboluensis is not. In vitro drug susceptibility test is needed to support individualized drug use to avoid delay in the disease.

Genome-wide association study reveals genetic loci and candidate genes for meat quality traits in a four-way crossbred pig population.

Meat quality traits (MQTs) have gained more attention from breeders due to their increasing economic value in the commercial pig industry. In this genome-wide association study (GWAS), 223 four-way intercross pigs were genotyped using the specific-locus amplified fragment sequencing (SLAF-seq) and phenotyped for PH at 45 min post mortem (PH45), meat color score (MC), marbling score (MA), water loss rate (WL), drip loss (DL) in the longissimus muscle, and cooking loss (CL) in the psoas major muscle. A total of 227, 921 filtered single nucleotide polymorphisms (SNPs) evenly distributed across the entire genome were detected to perform GWAS. A total of 64 SNPs were identified for six meat quality traits using the mixed linear model (MLM), of which 24 SNPs were located in previously reported QTL regions. The phenotypic variation explained (PVE) by the significant SNPs was from 2.43% to 16.32%. The genomic heritability estimates based on SNP for six meat-quality traits were low to moderate (0.07-0.47) being the lowest for CL and the highest for DL. A total of 30 genes located within 10 kb upstream or downstream of these significant SNPs were found. Furthermore, several candidate genes for MQTs were detected, including pH45 (GRM8), MC (ANKRD6), MA (MACROD2 and ABCG1), WL (TMEM50A), CL (PIP4K2A) and DL (CDYL2, CHL1, ABCA4, ZAG and SLC1A2). This study provided substantial new evidence for several candidate genes to participate in different pork quality traits. The identification of these SNPs and candidate genes provided a basis for molecular marker-assisted breeding and improvement of pork quality traits.

Formin protein DIAPH1 positively regulates PD-L1 expression and predicts the therapeutic response to anti-PD-1/PD-L1 immunotherapy.

Formins are evolutionarily conserved genes and profoundly affect cancer progression. This study aims to explore the expressions, prognostic values, and immunological correlations of Formins in cancer. Specific Formins were dysregulated and immuno-biologically correlated in breast cancer (BRCA). Formins showed different expression patterns, namely some were enriched in immune cells while some were enriched in tumor cells. Among all Formins, DIAPH1 was enriched in tumor cells and associated with an inflamed tumor microenvironment (TME). DIAPH1 functioned as an oncogene in BRCA and mediated TGF-ß1-induced epithelial-mesenchymal transformation (EMT) and PD-L1 expression. Moreover, DIAPH1 was overexpressed in most cancers and functioned as a novel pan-cancer immuno-marker, which could predict the response to anti-PD-1/PD-L1 immunotherapy. Overall, DIAPH1 functions as an oncogene and is immunologically correlated, which could be utilized as an alternative biomarker for predicting the immunotherapeutic response.

Pinning synchronization of stochastic neutral memristive neural networks with reaction-diffusion terms.

This paper investigates the pinning synchronization of stochastic neutral memristive neural networks with reaction-diffusion terms. Firstly, two novel pinning controllers, which contain both current state and past state, are designed. Subsequently, in terms of Green's theorem, inequality technology, stochastic analysis theory and pinning control technology, two easy-to-test sufficient conditions based on algebraic inequalities are obtained to ensure the mean-square asymptotic synchronization of stochastic memristive neural networks with neutral delays and reaction-diffusion terms by providing a new Lyapunov-Krasovskii functional. In addition, some existing results can be regarded as special cases of our work. Finally, illustrative examples further verify the correctness and validity of the derived results.

Stability and pinning synchronization of delayed memristive neural networks with fractional-order and reaction-diffusion terms.

Global asymptotic stability and synchronization are explored in this paper for fractional delayed memristive neural networks with reaction-diffusion terms (FDRDMNNs) in sense of Riemann-Liouville. First, we introduce diffusion into the existing model of fractional delayed memristive neural networks. Next, in terms of Green's theorem and inequality technique, a less conservative criterion for the asymptotic stability of FDRDMNNs is given by endowing Lyapunov direct method. Then, the appropriate pinning feedback controllers and adaptive controllers are designed to achieve the synchronization of the FDRDMNNs, and two sufficient conditions for global asymptotic synchronization are acquired. In addition, the results based on algebraic inequalities enhance some existing ones. The numerical simulations finally verify the validity of the derived results.

Novel hKDR mouse model depicts the antiangiogenesis and apoptosis-promoting effects of neutralizing antibodies targeting vascular endothelial growth factor receptor 2.

Vascular endothelial growth factor receptor 2 (VEGFR2)/KDR plays a critical role in tumor growth, diffusion, and invasion. The amino acid sequence homology of KDR between mouse and human in the VEGF ligand-binding domain was low, thus the WT mice could not be used to evaluate Abs against human KDR, and the lack of a suitable mouse model hindered both basic research and drug developments. Using the CRISPR/Cas9 technique, we successfully inserted different fragments of the human KDR coding sequence into the chromosomal mouse Kdr exon 4 locus to obtain an hKDR humanized mouse that can be used to evaluate the marketed Ab ramucirumab. In addition, the humanized mAb VEGFR-HK19 was developed, and a series of comparative assays with ramucirumab as the benchmark revealed that VEGFR-HK19 has higher affinity and superior antiproliferation activity. Moreover, VEGFR-HK19 selectively inhibited tumor growth in the hKDR mouse model but not in WT mice. The most important binding epitopes of VEGFR2-HK19 are D257, L313, and T315, located in the VEGF binding region. Therefore, the VEGFR2-HK19 Ab inhibits tumor growth by blocking VEGF-induced angiogenesis, inflammation, and promoting apoptosis. To our best knowledge, this novel humanized KDR mouse fills the gaps both in an animal model and the suitable in vivo evaluation method for developing antiangiogenesis therapies in the future, and the newly established humanized Ab is expected to be a drug candidate possibly benefitting tumor patients.

Interval changes of histogram-derived diffusion indices predict treatment response to induction chemotherapy in head and neck cancer: a feasibility study.

Background: This retrospective study investigated whether the interval change of apparent diffusion coefficient (∆ADC) [baseline and after the first cycle of induction chemotherapy (ICT)] can be used as a valid predictive imaging biomarker of the treatment response to ICT in head and neck cancer (HNC). Methods: A total of 19 consecutive patients with HNC who underwent diffusion-weighted magnetic resonance imaging (DWI) at baseline and after the first cycle of ICT were included. Whole-tumor ADC histogram parameters (mean, median, kurtosis, skewness, entropy, minimal, maximum, 25th percentile, and 75th percentile) were obtained. The correlations of ∆ADC histogram parameters, volume, T-stage, N-stage, and age with the treatment response were examined using the Mann-Whitney U test. The predictive value of histogram parameters was examined using receiver operating characteristic (ROC) curves. Results: Responders showed significantly higher values of ∆ADC25 (0.19±0.23) and ∆ADCmin (1.78±2.98) than non-responders (-0.09±0.15 and -0.73±0.36; P=0.035 and 0.009, respectively). When ∆ADC25 and ∆ADCmin were used for predicting the treatment response, the area under the ROC curve was 0.850/0.933 with a sensitivity of 73.3%/80.0% and specificity of 100%/100% (P=0.036 and 0.009, respectively). Conclusions: ∆ADC25 and ∆ADCmin derived from whole-tumor histogram analysis are valuable imaging biomarkers for the early prediction of the ICT response in HNC.